Moschella & Hurley's Dermatology (2 Volumes), 4th Edition [4 ed.] 9352703588, 9789352703586

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Moschella and Hurley’s Dermatology

Moschella and Hurley’s Dermatology Fourth Edition

Volume 1

Editor

Babar K Rao  MD FAAD

Director and Professor Center for Dermatology Department of Pathology Rutgers Robert Wood Johnson Medical School New Brunswick, NJ, USA Adjunct Clinical Associate Professor  Department of Dermatology Weill Cornell Medicine New York, NY, USA

JAYPEE BROTHERS MEDICAL PUBLISHERS The Health Sciences Publisher New Delhi | London

Jaypee Brothers Medical Publishers (P) Ltd Headquarters Jaypee Brothers Medical Publishers (P) Ltd. 4838/24, Ansari Road, Daryaganj New Delhi 110 002, India Phone: +91-11-43574357 Fax: +91-11-43574314 E-mail: [email protected] Overseas Office J.P. Medical Ltd. 83, Victoria Street, London SW1H 0HW (UK) Phone: +44-20 3170 8910 Fax: +44(0)20 3008 6180 E-mail: [email protected] Website: www.jaypeebrothers.com Website: www.jaypeedigital.com © 2020, Jaypee Brothers Medical Publishers The views and opinions expressed in this book are solely those of the original contributor(s)/author(s) and do not necessarily represent those of editor(s) of the book. All rights reserved. No part of this publication may be reproduced, stored or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission in writing of the publishers. All brand names and product names used in this book are trade names, service marks, trademarks or registered trademarks of their respective owners. The publisher is not associated with any product or vendor mentioned in this book. Medical knowledge and practice change constantly. This book is designed to provide accurate, authoritative information about the subject matter in question. However, readers are advised to check the most current information available on procedures included and check information from the manufacturer of each product to be administered, to verify the recommended dose, formula, method and duration of administration, adverse effects and contraindications. It is the responsibility of the practitioner to take all appropriate safety precautions. Neither the publisher nor the author(s)/editor(s) assume any liability for any injury and/or damage to persons or property arising from or related to use of material in this book. This book is sold on the understanding that the publisher is not engaged in providing professional medical services. If such advice or services are required, the services of a competent medical professional should be sought. Every effort has been made where necessary to contact holders of copyright to obtain permission to reproduce copyright material. If any have been inadvertently overlooked, the publisher will be pleased to make the necessary arrangements at the first opportunity. The CD/DVD-ROM (if any) provided in the sealed envelope with this book is complimentary and free of cost. Not meant for sale. Inquiries for bulk sales may be solicited at: [email protected] Moschella and Hurley’s Dermatology (Vol. 1) First Edition: 1975 Second Edition: 1984 Third Edition: 1992 Fourth Edition: 2020 ISBN: 978-93-5270-358-6

Dedicated to My family, especially Sumiyo, Sofia, and Shaan, for allowing me to spend precious family time working on this book.

Senior Editors and Sections Editors Babar K Rao MD FAAD Tara Bronsnick MD Jennifer Tan MD Attiya Haroon MD PhD Gina Francisco  MD Ann M John MD Jisun Cha MD Lebwohl M MD

John Young III MD Marwa Abdallah MD Mahmoud Abdallah MD Jose Dario Martinez MD Lotti Torello MD MD (Hon) Helen T Shin MD BS A Yasmine Kirkorian MD Valerie D Callender MD Kristen Lo Sicco MD

Shari R Lipner MD PhD Andrew Avarbock MD PhD George W Elgart MD Dirk M Elston MD FAAD FCAP Maxwell Fung MD Heather Wickless MD Bahar F Firoz MD Thanh Nga Tran MD PhD Doris Day MD

Contributors A Yasmine Kirkorian MD

Assistant Professor Department of Dermatology and Pediatrics George Washington University School of Medicine and Health Sciences, Washington, DC Children’s National Health System Washington, DC, USA

Aaron Wallace MD

Pritzker School of Medicine University of Chicago Medicine Chicago, IL, USA

Abigail Waldman MD

Director, Mohs Surgery Boston, VA Mohs and Dermatologic Surgery Center Department of Dermatology Brigham and Women’s Hospital Instructor, Department of Dermatology Harvard Medical School Harvard University Boston, MA, USA

Adam Friedman MD

Professor and Interim Chair Residency Program Director Department of Dermatology George Washington University School of Medicine and Health Sciences Washington, DC, USA

Adriana Lozano-Platonoff MD Senior Researcher Section of Wound and Ostomy Care Center Division of Dermatology Hospital General “Dr Manuel Gea González” Mexico City, Mexico

Alba Posligua MD

Research Assistant Department of Dermatology University at Buffalo Buffalo, NY, USA

Alexander Marzuka MD

Dermatologist Advanced Dermatology and Center for Skin Research Houston, TX, USA

Alison Treichel 

Medical Student Department of Dermatology University at Buffalo Buffalo, NY, USA

Allireza Alloo MD

Assistant Professor Department of Dermatology Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Hempstead, NY, USA

Allison Weiffenbach  Allyson Tank  Alok Vij MD

Associate Staff Department of Dermatology Cleveland Clinic Foundation Cleveland, OH Assistant Clinical Professor Department of Dermatology Cleveland Clinic Lerner College of Medicine of Case Western Reserve University Cleveland, OH, USA

Amalia Lupoli MD

MD FAMS FRCP

Dermatologist Dermatology Unit Department of Mental and Physical Health and Preventive Medicine University of Campania Luigi Vanvitelli Naples, Italy

Consultant Dermatologist Kanwar Skin Clinic New Delhi, India Former Senior Professor and Head Department of Dermatology  Venereology and Leprology Post Graduate Institute of Medical Education and Research Chandigarh, India 

Assistant Lecturer Department of Dermatology Cairo University Kasr Alainy Faculty of Medicine Cairo University, Egypt Kasr Alainy Teaching Hospital, Abou Elrish Pediatric Teaching Hospital Cairo, Egypt

Amrinder Jit Kanwar

Amira Elbendary  MBBCh MSc

Amy Pappert MD

Residency Program Director Associate Professor Department of Dermatology Center of Dermatology Rutgers Robert Wood Johnson Medical School Somerset, NJ, USA

Andressa Costa MD

Research Fellow Department of Pathology Wake Forest School of Medicine Winston-Salem, NC, USA  

Andrew Avarbock  MD PhD Assistant Professor Department of Dermatology Weill Cornell Medicine New York, NY, USA

Andrew J Peranteau MD

Resident Department of Dermatology New York Medical College New York, NY, USA

Andy Nguyen  Animesh A Sinha  MD PhD

Rita M. and Ralph T. Behling Professor and Chair Department of Dermatology University at Buffalo Buffalo, NY, USA

Ann M John MD

Chief Resident Department of Dermatology Rutgers Robert Wood Johnson Medical School Somerset, NJ, USA

Annie Wang MD

Dermatologist Department of Dermatology Kaiser Permanente Moanalua Medical Center Honolulu, Hawaii

Anthony Fernandez  MD PhD

Assistant Clinical Professor Department of Medicine Cleveland Clinic Lerner College of Medicine Director of Medical Dermatology WD Steck Chair of Clinical Dermatology Departments of Dermatology and Pathology Cleveland Clinic Cleveland, Ohio, USA

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Moschella and Hurley’s Dermatology Anthony M Rossi  MD FAAD

Assistant Attending Department of Dermatology Memorial Sloan Kettering Cancer Center Assistant Professor Department of Dermatology Weill Cornell Medicine New York, NY, USA

Azeen Sadeghian  MD FAAD

Adjunct Associate Professor Department of Dermatology Tulane University School of Medicine Tulane University, New Orleans, LA, USA

Babar K Rao  MD FAAD

Ariel E Eber 

Director and Professor Center for Dermatology Department of Pathology Rutgers Robert Wood Johnson Medical School New Brunswick, NJ, USA Adjunct Clinical Associate Professor Department of Dermatology Weill Cornell Medicine New York, NY, USA

Ashleigh Briody  DDS MS

Center for Dermatology Department of Pathology Associate Professor Robert Wood Johnson University Hospital New Brunswick, NJ, USA

Anuradha Bishnoi MD

Senior Resident Department of Dermatology Postgraduate Institute of Medical Education and Research Chandigarh, India Research Fellow Department of Dermatology University of Miami Miller School of Medicine Miami, FL, USA

Diplomate American Board of Oral and Maxillofacial Pathology Staff Oral Pathologist Central Ohio Skin and Cancer Westerville, OH, USA

Ashley Keyes MD

Attending Physician Assistant Professor Department of Clinical Dermatology Weill Cornell Medical College New York, NY, USA Lincoln Medical Center Bronx, NY, USA

Ashley Eryn Pezzi MD

Department of Dermatology Baylor College of Medicine Houston, TX, USA

Ashwin Ganti BA

Rush Medical College Rush University Medical Center Chicago, IL, USA

Attiya Haroon  MD PhD

Resident Physician Center for Dermatology Department of Pathology Robert Wood Johnson University Hospital New Brunswick, NJ, USA

Audrey Rutherford MD

Resident Department of Dermatology UT Southwestern Medical Center Dallas, TX, USA

Bahar F Firoz MD

Basia Michalski MD

Dermatology Resident Division of Dermatology Washington University in St. Louis/Barnes Jewish Hospital in St. Louis St. Louis, MO, USA

Benjamin Farahnik MD

Bradley Saylors  MD FAAD

Adjunct Instructor Department of Dermatology Tulane University School of Medicine New Orleans, LA, USA

Brandon E Cohen MD

Physician Resident Department of Dermatology University of Southern California Los Angeles, CA, USA

Brian Scott MD

Resident Department of Ear, Nose and Throat Oregon Health Science University Portland, Oregon, USA 

Brian W Morrison MD

Assistant Professor Department of Dermatology University of Miami Miller School of Medicine Miami, FL, USA

Brittany Stumpf MD

Assistant Professor Department of Dermatology Tulane University School of Medicine New Orleans, LA, USA

Bucay VW MD

Dermatology Resident Department of Dermatology University of California—Davis Sacramento, CA, USA

Clinical Assistant Professor Department of Physician Assistant Studies UT Health Science Center San Antonio, TX, USA

Benjamin Perry MD

Bulat Vedrana MD

Dermatologist Silver Falls Dermatology Salem, OR, USA

Bhutani T  MD MAS

Assistant Professor Department of Dermatology Co-Director, Psoriasis and Skin Treatment Center Co-Director, Dermatology Clinical Research Unit Department of Dermatology University of California San Francisco San Francisco, CA, USA

Bradley S Bloom MD

Laser and Skin Surgery Center of New York New York, NY Clinical Assistant Professor Ronald O Perelman Department of Dermatology NYU Langone New York, NY, USA

Dermatologist Department of Dermatology and Venereology University Hospital Center “Sestre Milosrdnice” Vinogradska Cesta, Zagreb, Croatia

Caitlin Gilman MD

Assistant Professor Academic General Pediatrics Children’s Hospital at Montefiore Bronx, NY, USA

Caleb Jeon MD

Resident Physician Department of Dermatology Harbor-UCLA Medical Center Torrance, CA, USA

Carl F Schanbacher MD

Department of Surgery Martha’s Vineyard Hospital Oak Bluffs, MA, USA

Contributors Carlos Linares MD

Cynthia L Chen MD

Christina M Ring MD

Dalee M Zhou  MD PhD Candidate

Research Assistant Department of Dermatology University at Buffalo Buffalo, NY, USA

Research Fellow Center for Dermatology Rutgers New Jersey Medical School Newark, NJ, USA

Christina N Kraus MD

Resident Physician Department of Dermatology University of California Irvine Irvine, CA, USA

Christina Wong MD

Associate Physician Department of Dermatology The Permanente Medical Group Diablo Service Area, NC, USA

Department of Dermatology Weill Cornell/Rockefeller/Sloan Kettering Tri-Institutional MD-PhD Program New York, NY, USA

Danielle Tartar  MD PhD

Assistant Professor Department of Dermatology University of California—Davis Sacramento, CA, USA

Davinder Parsad MD

Dermatologist Department of Dermatology Cleveland Clinic Foundation Cleveland, OH, USA

Professor Department of Dermatology Postgraduate Institute of Medical Education and Research Chandigarh, India

Christine Ahn MD

Dendy Engelman MD

Assistant Residency Director Department of Dermatology Wake Forest School of Medicine Winston Salem, NC, USA  

Collin Blattner DO

Dermatologist Silver Falls Dermatology Salem, OR, USA

Connie R Shi MD

Resident Department of Dermatology Harvard Medical School, Brigham and Women’s Hospital Boston, MA, USA

Cory Maughan MD

Dermatologist Silver Falls Dermatology Salem, OR, USA

Cristian Fischer MD

Department of Dermatology Memorial Sloan Kettering Cancer Center New York, NY, USA

Cristian Navarrete-Dechent MD

Instructor Melanoma and Skin Cancer Unit Department of Dermatology Facultad de Medicina Pontificia Universidad Catolica de Chile Santiago, Chile

Dermatologist Manhattan Dermatology and Cosmetic Surgery New York, NY Director of Dermatologic Surgery and Laser Medicine Department of Dermatology Metropolitan Hospital New York Medical College New York, NY, USA

Diana W Bartenstein MD

Department of Medicine Brigham and Women’s Hospital Harvard Combined Dermatology Residency Training Program, Brigham & Women’s Hospital Harvard Medical School Boston, MA, USA

DiAnne S Davis  MD MS

ASDS Cosmetic Fellow Gateway Aesthetic Institute and Laser Center Salt Lake City, UT, USA

Dillon Nussbaum  BSc (Bachelor of Science)

Medical Student George Washington University School of Medicine and Health Sciences and The George Washington University Medical Faculty Associates Washington, DC, USA,

Dionicio Angel Galarza MD

Internal Medicine & Rheumatology Chief Department of Rheumatology University Hospital "Jose E Gonzalez", Universidad Autonoma de Nuevo Leon Monterrey, Mexico

Dirk M Elston MD

Professor and Chairman Department of Dermatology and Dermatologic Surgery Medical University of South Carolina Charleston, SC, USA

Donald A Glass II  MD PhD

Assistant Professor Department of Dermatology UT Southwestern Medical Center Dallas, TX, USA

Doris Day MD

Clinical Associate Professor Department of Dermatology NYU Langone Health New York, NY, USA

Edit Olasz-Harken  MD PhD Associate Professor Department of Dermatology Medical College of Wisconsin Milwaukee, WI, USA

Elena B Hawryluk  MD PhD

Assistant Professor Department of Dermatology Massachusetts General Hospital, Boston Boston Children’s Hospital, Boston Harvard Medical School Boston, MA, USA

Emily M Altman MD

Associate Professor Department of Dermatology University of New Mexico School of Medicine Albuquerque, NM, USA

Emily M Berger MD

Pediatric Dermatologist Hackensack-Meridian Health Hackensack, NJ, USA

Emily Newsom MD

Dermatologist Ronald Reagan UCLA Medical Center Los Angeles, CA, USA

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Moschella and Hurley’s Dermatology Enos Tyler MD

Resident Department of Dermatology UT Southwestern Medical Center Dallas, TX, USA

Era Murzaku MD

Resident Department of Dermatology UT Southwestern Medical Center Dallas, TX, USA

Eric Millican MD

Assistant Professor Department of Dermatology University of Utah Salt Lake City, UT, USA

Eric Tkaczyk  MD PhD FAAD

Department of Veterans Affairs Director Vanderbilt Dermatology Translational Research Clinic Vanderbilt University Medical Center Vanderbilt University Nashville, TN, USA

Erica H Lee MD

Assistant Attending Division of Dermatology Memorial Sloan Kettering Cancer Center New York Assistant Professor Department of Dermatology Weill Cornell Medicine New York, NY, USA

Erin Boh  MD PhD

Chair and Professor Department of Dermatology Tulane University School of Medicine Tulane University New Orleans, LA, USA

Eun J Kwon MD

Dermatopathologist Dermpath Diagnostics New York Port Chester, NY, USA

Faezeh T Liasi MD

Dermatology Fellow University of Washington School of Medicine Harbor-UCLA Hospital Torrance, CA, USA

Fermin Jurado Santa Cruz MD

Professor and Chairman Department of Collagen Vascular Diseases Centro Dermatologico "Dr. Ladislao de la Pascua", UNAM Mexico City, Mexico

Frank C Victor MD

Gonzalo Marrugo MD

Clinical Instructor Rutgers Robert Wood Johnson Medical School New Brunswick, NJ, USA

Professor Department of Dermatology University of Cartagena Cartagena, Bolivar, Colombia

Gabrielle R Vinding  MD PhD

Goren Andy MD

Garrett Vick  BS MD

Grisha Mateev  MD PhD

Dermatologist Department of Dermatology Bispebjerg Hospital University of Copenhagen Copenhagen, Denmark

Resident Physician Tulane University School of Medicine Tulane University Medical Center New Orleans, LA, USA

George I Varghese MD

Assistant Professor Department of Dermatology Weill Cornell Medicine New York, NY, USA

George W Elgart MD

Professor and Vice Chair for Education Dr. Phillip Frost Department of Dermatology University of Miami Miller School of Medicine, Miami Consultant, Jackson Memorial Hospital Miami, Florida, USA

Gina Francisco MD

Resident Center for Dermatology Department of Pathology Rutgers Robert Wood Johnson Medical School New Brunswick, NJ, USA

Giovanni Pellacani MD

Dean, Faculty of Medicine and Surgery Chairman, Department of Dermatology University of Modena and Reggio Emilia Policlinico di Modena, Modena, Italy

Giuseppe Argenziano  MD PhD

Full Professor Dermatology Unit Department of Mental and Physical Health and Preventive Medicine University of Campania Luigi Vanvitelli Naples, Italy

Goff HW

MD MPH Philip J Eichhorn Professorship in Clinical Dermatology

Associate Professor Department of Dermatology UT Southwestern Medical Center Dallas, TX, USA

Dermatology and Venereology Division Guglielmo Marconi University Via Plinio, Roma, Italy Applied Biology, Inc. Irvine, CA, USA Associate Professor Department of Dermatology and Venereology Medical University–Sofia Sofia, Bulgaria

Guillermo Antonio GuerreroGonzalez MD

Dermatologist and Dermatologic Surgeon University of Nuevo León Monterrey, Mexico

Guleva Dimitrina MD

Dermatologist Department of Dermatology Medical University–Sofia Sofia, Bulgaria

Hannah Song MD

Dermatology Resident Department of Dermatology Harvard Combined Dermatology Residency Program Boston, MA, USA

Heather Holahan MD

Clinical Assistant Professor University of North Carolina Department of Dermatology Chapel Hill, NC, USA

Helen T Shin  MD BS

Clinical Associate Professor Department of Dermatology and Pediatrics New York University Langone School of Medicine, New York Clinical Associate Professor Department of Pediatrics Hackensack University School of Medicine at Seton Hall University The Joseph M. Sanzari Children’s Hospital Hackensack Meridian Health Network Hackensack, NJ, USA

Jacob Berman MD

Dermatologist New Hyde Park, NY, USA

Contributors Jacqueline Marrugo MD

Professor Department of Dermatology University of Cartagena Cartagena, Bolivar, Colombia

Janet Y Li 

Dermatologist Center for Dermatology Plano, TX, USA

Jaspriya Sandhu  MBBS MD DNB

Assistant Professor Department of Dermatology Dayanand Medical College and Hospital Ludhiana, Punjab, India

Jeffrey D Bernhard MD

Professor Emeritus University of Massachusetts Medical School Department of Dermatology Shrewsbury, MA, USA

Jennifer Abrahams  MD DTM&H

Assistant Professor Director of Tropical and Infectious Disease Dermatology Director of Teledermatology Department of Dermatology University of Nebraska Medical Center Omaha, Nebraska, USA

Jennifer Huang MD

Associate Professor Department of Dermatology Harvard Medical School Boston Children’s Hospital Boston, MA, USA

Jeremy Brauer MD

Clinical Associate Professor Ronald O Perelman Department of Dermatology NYU Langone New York, NY, USA

Jessica Lin MD

Resident St. Mary’s Medical Center Long Beach, CA, USA

Jesus Alberto Cardenas MD

Dermatology Resident Department of Dermatology University Hospital "Jose E Gonzalez" Universidad Autonoma de Nuevo Leon Monterrey, Mexico

Jihee Kim MD

Assistant Clinical Professor Department of Dermatology Yonsei University College of Medicine Cutaneous Biology Research Institute, Severance Hospital Seoul, Republic of Korea

Jisun Cha MD

Associate Professor Department of Dermatology Thomas Jefferson University Philadelphia, PA, USA

Jo Cooke-Barber  MD FAAD

Tulane University School of Medicine Department of Dermatology New Orleans, LA, USA

John Hassani DO

Research Fellow Department of Dermatology University at Buffalo Buffalo, NY, USA

John Strasswimmer  MD PhD

Clinical Professor of Dermatology and Research Professor of Biochemistry Florida Atlantic University Country Boca Raton, FL, USA

John Young III MD

Silver Falls Dermatology Salem, OR, USA

Jordan Brooks  MD FAAD Forefront Dermatology Marquette, Michigan, USA

Jose A Jaller MD

Dermatopharmacology Fellow Department of Dermatology Albert Einstein College of Medicine New York, NY, USA

Jose Contreras-Ruiz MD

Department of Dermatology Hospital General Dr Manuel Gea Gonzalez Mexico City, Mexico

Jose Dario Martinez MD

Internal Medicine and Dermatology Chief, Internal Medicine Consult University Hospital "Jose E Gonzalez", Universidad Autonoma de Nuevo Leon Monterrey, Mexico

Joseph Zikry MD

Resident Physician Department of Dermatology University of Southern California Los Angeles, CA, USA

Joshua Farhadian MD

Clinical Assistant Professor The Ronald O Perelman Department of Dermatology NYU Langone Medical Center New York, NY, USA Assistant Professor Adjunct Department of Dermatology Section of Dermatologic Surgery and Cutaneous Oncology Yale School of Medicine New Haven, CT, USA

Ju Hee Lee  MD PhD

Professor, Chairman Yonsei University College of Medicine Cutaneous Biology Research Institute Severance Hospital Seoul, Republic of Korea

Julia A Benedetti MD

Senior Staff Department of Dermatology Lahey Hospital and Medical Center Burlington, MA Clinical Instructor, Part Time Department of Dermatology Harvard Medical School, Boston Adjunct Clinical Instructor Tufts University School of Medicine Boston, MA, USA

Julia May MD

Dermatologist Providence Medical Institute Torrance, CA, USA

Juliana Berk-Krauss MD

Research Fellow Yale School of Medicine New Haven, CT, USA

Julie B Zang  MD PhD

Assistant Professor Department of Dermatology Weill Cornell Medicine New York, NY, USA

Julie Karen MD

Clinical Assistant Professor (NYU) The Ronald O Perelman Department of Dermatology (NYU) Co-Founder, Co-Director Complete Skin MD NYU Langone School of Medicine New York, NY, USA

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Moschella and Hurley’s Dermatology Kalyani Marathe  MD MPH

Assistant Professor Department of Dermatology and Pediatrics George Washington University School of Medicine and Health Sciences Children’s National Health System Washington, DC, USA

Kara Sternhell-Blackwell MD

Division of Dermatology Washington University in St. Louis/Barnes Jewish Hospital in St. Louis St. Louis, MO, USA

Karen Connolly MD

Fellow Mohs Micrographic and Dermatologic Surgery Memorial Sloan Kettering Cancer Center New York, NY, USA

Katerina Damevska  MD PhD Assistant Professor University Clinic of Dermatology Medical Faculty, Ss Cyril and Methodius University Skopje, Macedonia

Katlein França  MD PhD

Dr. Philip Frost Department of Dermatology and Cutaneous Surgery Assistant Professor Department of Psychiatry and Behavioral Sciences Institute for Bioethics and Health Policy, Miami Faculty University of Miami Miller School of Medicine Miami, FL, USA

Kazandjieva Jana MD

Dermatologist Department of Dermatology Medical University–Sofia Sofia, Bulgaria

Kenneth Tomecki MD

Khalil Khatri MD

Medical Director Skin and Laser Surgery Center of New England Nashua, NH, USA

Khan AJ  MD FAAD FAACS FASLS FASHRS

Diplomate, American Board of Internal Medicine Diplomate, American Board of Dermatology Fellow, American Academy of Cosmetic Surgery Fellow, American Society for Liposuction Surgery Fellow, American Society for Hair Restoration Surgery Professor, Dermatology and Dermatologic Surgery Allama Iqbal Medical College, University of Health Sciences and Jinnah Hospital Lahore, Pakistan

Kishwer Nehal MD

Director Mohs Micrographic and Dermatologic Surgery Attending Physician, Dermatology Service Memorial Sloan Kettering Cancer Center Professor Department of Dermatology Weill Cornell Medical College New York, NY, USA

Kolić Maja MD

Dermatovenereologist Department of Dermatology and Venereology Sestre Milosrdnice University Hospital Centre Vinogradska, Zagreb, Croatia

Koo J MD

Dermatologist Director, Psoriasis, Phototherapy and Skin Treatment Clinic Department of Dermatology University of California San Francisco San Francisco, CA, USA

Kossara Drenovska  MD PhD

Kristen Elkins MD

Department of Dermatology University of California Irvine Irvine, CA, USA

Kristen Lo Sicco MD

Assistant Professor Department of Dermatology Associate Director, Skin and Cancer Unit The Ronal O Perelman Department of Dermatology NYU Langone Health New York, NY, USA

Lance W Chapman  MD MBA

Procedural Fellow University of California San Francisco Department of Dermatology San Francisco, CA, USA

Larry Millikan  MD FAAD FACP

Professor, Chair Emeritus Department of Dermatology Tulane University School of Medicine Department of Dermatology New Orleans, LA, USA

Lauren Boshnick MD

Resident Department of Dermatology Florida State University College of Medicine Tallahassee, FL, USA

Lauren Boudreaux DO

Dermatologist Silver Falls Dermatology Salem, OR, USA

Leah G Jacobs MD

Department of Dermatology Tulane University New Orleans, LA, USA

Lebwohl M MD

Waldman Professor and Chairman Kimberly and Eric J Waldman Department of Dermatology at the Icahn School of Medicine at Mount Sinai New York, NY, USA

Lence Neloska  MD MSc

Professor Department of Dermatology Cleveland Clinic Foundation Cleveland, OH, USA

Senior Assistant Professor Department of Dermatology and Venereology Medical University–Sofia Sofia, Bulgaria

Dermatologist Department of Dermatology Gerontology Institute 13 November Skopje, Macedonia

Keyvan Nouri MD

Kovacevic Maja MD

Lilia Correa-Selm  MD FAAD

Professor Department of Dermatology University of Miami Miller School of Medicine Miami, FL, USA

Department for Dermatology and Venereology Clinical University Hospital Centre “Sestre Milosrdnice” Zagreb, Croatia

Director of Cutaneous Surgery Assistant Professor Florida State University Cleveland Clinic at Indian River Hospital Vero Beach, FL, USA

Contributors Linus Grabenhenrich  Dr. rer. med./Dr. med.

Study Coordinator/Assistant Professor Division of Allergy and Immunology Department of Dermatology Venereology and Allergy Charité, Universitätsmedizin Berlin Berlin, Germany

Lotti Torello  MD MD (Hon)

Professor and Chair Department of Dermatology University of Rome “G. Marconi” Rome, Italy

Magda Arredondo MD

Internal Medicine Resident Department of Internal Medicine University Hospital “Jose E Gonzalez” Universidad Autonoma de Nuevo Leon Monterrey, Mexico

Mahin Alamgir MD

Resident Center for Dermatology Department of Pathology Rutgers Robert Wood Johnson Medical School New Brunswick, NJ, USA

Mahmoud Abdallah  MD PhD Professor of Dermatology Department of Dermatology and Venereology Ain Shams University Cairo, Egypt

Maja Vurnek Zivkovic PhD

Assistant Professor Department of Psychology Centre for Croatian Studies of the University of Zagreb Croatia

Manas Deolankar  BS (MD Candidate)

Fellow Department of Dermatology Cooper Medical School of Rowan University Camden, NJ, USA

Marc Avram MD

Clinical Professor of Dermatology Department of Dermatology Weill Cornell Medical College New York, NY, USA

Marco Manfredini MD

Dermatologist Department of Dermatology University of Modena and Reggio Emilia Policlinico di Modena Modena, Italy

Maressa C Criscito MD

Resident The Ronald O Perelman Department of Dermatology New York University Langone Health New York, NY, USA

Margit Juhasz  MD MSc

Resident Physician Department of Dermatology University of California Irvine Irvine, CA, USA

Margitta Worm MD

Director, Allergy and Immunology Department of Dermatology Venereology and Allergy Charité–Universitätsmedizin Berlin Berlin, Germany

Marija Buljan  MD PhD

Resident Department of Dermatology Yale University New Haven, CT, USA

Megan P Couvillion  MD MS FAAD

Associate Dermatologist Department of Dermatology Suzanne Bruce and Associates The Center for Skin Research Houston, TX, USA

Melissa Danesh MD

Clinical Fellow in Dermatology Massachusettes General Hospital Department of Dermatology Boston, MA, USA

Melissa M Mauskar MD

Assistant Professor Departments of Dermatology and Obstetrics and Gynecology UT Southwestern Medical Center Dallas, TX, USA

Michael A Marchetti MD

Attending Physician Department of Dermatology Memorial Sloan Kettering Cancer Center New York, NY, USA

Marilyn G Liang MD

Fellowship-Trained Mohs Surgeon and Board-Certified Dermatologist Advanced Dermatology Pearland, Sugar Land, and Katy, TX, USA Clinical Assistant Professor Department of Dermatology The University of Texas McGovern Medical School at Houston Houston, TX, USA

Associate Professor Department of Dermatology Boston Children’s Hospital Harvard Medical School Boston, MA, USA

Marina Perper 

BSc

Assistant Attending Department of Dermatology Memorial Sloan Kettering Cancer Center New York, NY, USA

Manuel Valdebran MD

Martin Shahid  MD BSc (Hon)

Fellow Department of Dermatology Beckman Laser institute University of California Irvine Irvine, CA, USA

Mary Laird MD

Assistant Professor Department of Dermatovenereology Sestre Milosrdnice University Hospital Centre Zagreb, Croatia

Student Department of Dermatology and Cutaneous Surgery University of Miami Miller School of Medicine Miami, FL, USA

Manu Jain MD

Marwa Abdallah  MD PhD

Professor of Dermatology Department of Dermatology and Venereology Ain Shams University Cairo, Egypt

Resident and PhD Candidate Department of Dermatology and Venereology Medical University–Sofia Sofia, Bulgaria

Michael Pelster MD

Michele Van Hal MD

Department of Dermatology University of California Irvine, CA, USA

Mirna Situm  MD PhD

Professor and Head Department of Dermatovenereology Sestre Milosrdnice University Hospital Centre Zagreb, Croatia

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Moschella and Hurley’s Dermatology Miroslava Kadurina MD

Professor of Dermatology University of Rome “G. Marconi” Rome, Italy

Miryam Eguia MD

Assistant Professor Internal Medicine and Rheumatology Department of Rheumatology University Hospital "Jose E Gonzalez", Universidad Autonoma de Nuevo Leon Monterrey, Mexico

Mohsin Malik MD

Private Practice Dermatology Physicians of Connecticut New London, CT, USA

Murad Alam MD

Vice Chair Department of Dermatology Chief of Cutaneous and Aesthetic Surgery Department of Dermatology Professor, Dermatology, Otolaryngology— Head and Neck Surgery and Surgery (Organ Transplantation) Northwestern University Feinberg School of Medicine Chicago, IL, USA

Mussarrat Hussain  MD MS Fellow Manhattan Dermatology and Cosmetic Surgery, New York Department of Dermatology Metropolitan Hospital New York Medical College New York, NY, USA

N Raboobee  MBChB (Natal) FFDerm (SA) Dermatologist Vitiligo Society of South Africa Westville Hospital Durban, Kwa Zulu Natal, South Africa

Nada Elbuluk  MD MSc

Clinical Assistant Professor Director, Skin of Color Center and Pigmentary Disorders Clinic Director, Dermatology Diversity and Inclusion Program University of Southern California Department of Dermatology Keck School of Medicine Los Angeles, CA, USA

Nakamura M  MD MS

Resident Department of Dermatology University of Michigan Ann Arbor, MI, USA

Natasha Mesinkovska  MD PhD Director, Clinical Research and Assistant Professor Department of Dermatology University of California Irvine Irvine, CA, USA

Neeta Malviya MD

Dermatology Resident Department of Dermatology Zucker School of Medicine at Hofstra/Northwell Hempstead, NY, USA

Neha Rajpal  BA in Human Science Medical Student Georgetown University School of Medicine Children’s National Health System Washington, DC, USA

Nicholas Fiumara MD

Clinical Professor of Dermatology Department of Dermatology Tufts University School of Medicine Medford, MA, USA

Nicole E Rogers  MD FAAD

Assistant Clinical Professor Private Practice Tulane Department of Dermatology Tulane University School of Medicine New Orleans, LA, USA

Nicole Reusser Bender MD Resident Department of Dermatology Medical College of Wisconsin Milwaukee, WI, USA

Nikhil Dhingra MD

Clinical Instructor Department of Dermatology Spring Street Dermatology and Icahn School of Medicine at Mount Sinai New York, NY USA

Noelani González MD

Clinical Instructor Department of Dermatology Mount Sinai Hospital New York, NY, USA

Ocampo-Candiani J  MD PhD

Chairman Department of Dermatology Full Time Professor Universidad Autonoma de Nuevo León University Hospital and School of Medicine Monterrey, NL, Mexico

Omar Noor  MD FAAD

Dermatologist Rao Dermatology New York, NY, USA

Omar Sangueza MD

Physician, Professor Pathology, Professor Dermatology Department of Dermatology and Pathology Wake Forest School of Medicine Winston Salem, NC, USA

Paola Chamorro MD

Resident Center for Dermatology Department of Pathology Rutgers Robert Wood Johnson Medical School Somerset, NJ, USA

Patricia K Farris MD

Clinical Associate Professor Department of Dermatology Tulane University New Orleans, LA, USA

Paula Torres-Camacho MD

Dermatologist (Medical and Surgical) Education and Research Coordinator Department of Dermatology General Hospital "Dr Eduardo Liceaga" Mexico City, Mexico

Pooja Virmani  MBBS MD

Resident Physician Center for Dermatology Department of Pathology Rutgers Robert Wood Johnson Medical School Somerset, NJ, USA

Rachel A Fayne BA

Medical Student, Clinical Research Fellow Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery University of Miami Miller School of Medicine Miami, FL, USA

Rachel Redenius MD

Nashville Skin: Comprehensive Dermatology Center Nashville, TN, USA

Radhika Shah  PharmD MD

Resident Center for Dermatology Department of Pathology Rutgers Robert Wood Johnson Medical School Somerset, NJ, USA

Contributors Radhika Srivastava MD

Fellow Center for Dermatology Department of Pathology Rutgers Robert Wood Johnson Medical School Somerset, NJ, USA

Raheel Zubair  MD MHS

Research Fellow Department of Dermatology Henry Ford Hospital Detroit, MI, USA

Ramya Vangipuram MD

UT Health Science Center at Houston/ McGovern Medical School Department of Dermatology Houston, TX, USA

Rashmi Sarkar  MBBS MD MNAMS Professor Department of Dermatology Maulana Azad Medical College and Associated Hospitals New Delhi, India

Rita N Sokkar

Department of Dermatology University of California Irvine, CA, USA

Robert A Schwartz

MD MPH DSc (Hon) FRCP Edin FAADV (Hon) FAAD FACP

Professor and Head Department of Dermatology Professor, Medicine, Pediatrics and Pathology Rutgers New Jersey Medical School Newark, NJ, USA

Robert Duffy MD

Resident Cooper Medical School of Rowan University Cooper University Hospital Camden, NJ, USA

Robin Burger MD

Dermatopathologist  Department of Dermatology Robert Wood Johnson University Hospital New Brunswick, NJ, USA

Rohini Shantharam MD Dermatologist Derma di Colore New York, NY, USA

Rosa Mateus MD

Dermatologist SIME Cumbaya Universidad San Francisco de Quito Quito, Ecuador

Rosalynn RZ Conic  MD PhD Resident Department of Surgery University of Maryland Baltimore, Maryland, USA

Roxanna Arakozie DO

Resident Physician Department of Dermatology University of North Texas Health Science Center Texas College of Osteopathic Medicine Bay Area Corpus Christi Medical Center Corpus Christi, TX, USA

Ryan Karmouta  MD MBA

Sarah T Arron  MD PhD

Associate Professor Department of Dermatology Associate Director, Dermatologic Surgery and Laser Center, Dermatology University of California San Francisco San Francisco, CA, USA 

Sarina B Elmariah  MD PhD

Assistant Professor Harvard Medical School, Boston, MA Assistant Physician Department of Dermatology Massachusetts General Hospital Cutaneous Biology Research Center at Massachusetts General Hospital Boston, MA, USA

Sekhon S MD

Resident Physician Howard University Washington, DC, USA

Resident Department of Dermatology UCLA Division of Dermatology Los Angeles, CA, USA

Kristina Semkova MD

Sabine Dölle  Dr. rer. med./Dr.med

Shahyan Rehman  BA BS

Study Coordinator/Assistant Professor Division of Allergy and Immunology Department of Dermatology, Venereology and Allergy Charité, Universitätsmedizin Berlin Berlin, Germany

Sairah Khokher  MD FAAD Dermatologist Rao Dermatology Atlantic Highlands, NJ, USA

Sandipan Dhar  MD DNB FRCP (Edin) Professor and Head Department of Pediatric Dermatology Institute of Child Health Kolkata, West Bengal, India

Sanja Manchevska  MD PhD

Associate Professor Department of Physiology Medical Faculty, Ss Cyril and Methodius University Skopje, Macedonia

Sara Hogan  MD MHS

Cosmetic and Laser Surgery Fellow Skin Care Physicians Chestnut Hill, MA, USA

Department of Dermatology University of Rome “G. Marconi” Rome, Italy

Medical Student Rutgers Robert Wood Johnson Medical School New Brunswick, NJ, USA

Shannon Watkins MD

Clinical Assistant Professor Department of Dermatology Weill Cornell Medical College Cornell University, New York Robert Wood Johnson University Hospital New Brunswick, NJ New York Presbyterian Hospital New York, NY, USA

Shari R Lipner  MD PhD

Associate Professor Department of Clinical Dermatology Weill Cornell Medicine New York Presbyterian New York, NY, USA

Shesly Jean-Louis MD

Clinical Professor  Department of Dermatology and Sexually Transmitted Disease State Hospital of University of Haiti Port-au-Prince, Ave.Mgr Guilloux et St-Honoré, Haiti

xvii

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Moschella and Hurley’s Dermatology Singh R MD

Department of Dermatology at the Icahn School of Medicine at Mount Sinai New York, NY, USA

Šitum Mirna MD

Chair Head Department of Dermatovenereology “Sestre milosrdnice” University Hospital Centre Zagreb, Croatia

Snejina Vassileva  MD PhD

Professor Department of Dermatology and Venereology Medical University–Sofia Sofia, Bulgaria

Soham Chaudhari MD

Resident Physician Department of Dermatology University of North Texas Health Science Center Texas College of Osteopathic Medicine Bay Area Corpus Christi Medical Center Corpus Christi, TX, USA

Sophia Delano  MPP MD

Instructor Department of Dermatology Harvard Medical School Attending Physician Dermatology Program Boston Children’s Hospital Boston, MA, USA

Sophie Vadeboncoeur  MD FRCPC FAAD

Associate Professor Department of Dermatology Université de Montréal/Hôpital Maisonneuve-Rosemont Montréal, QC, Canada

Stefano Caccavale MD

Research Fellow Dermatology Unit, Department of Mental and Physical Health and Preventive Medicine University of Campania Luigi Vanvitelli Naples, Italy

Stephanie Savory MD

Assistant Professor Department of Dermatology UT Southwestern Medical Center Dallas, TX, USA

Stephen K Tyring  MD PhD Clinical Professor Department of Dermatology Medical Director Center for Clinical Studies UT Health Science Center Houston, TX, USA

Steven Eilers MD

Mohs Fellow Hackensack University Medical Center Skin Laser and Surgery Specialists of NY and NJ Hackensack, NJ, USA

Susan Burgin MD

Assistant Professor Director of Medical Education Department of Dermatology Beth Israel Deaconess Medical Center Director of Resident Education Harvard Combined Dermatology Residency Program Boston, MA, USA

Tamara Lazic Strugar MD

Associate Clinical Professor Department of Dermatology Icahn School of Medicine at Mount Sinai New York, NY, USA

Tara Bronsnick MD

Center for Dermatology Department of Pathology Rutgers Robert Wood Johnson Medical School Somerset, NJ, USA

Teresa Russo MD

Associate Professor Dermatology Unit, Department of Mental and Physical Health and Preventive Medicine University of Campania Luigi Vanvitelli Naples, Italy

Thanh Nga Tran  MD PhD

Dermatologist Department of Dermatology Massachusetts General Hospital Boston, MA, USA

Thomas W Chu MD

Research Fellow Department of Dermatology University at Buffalo Buffalo, NY, USA

Tiffany Hinojosa MD

Research Assistant Center for Clinical Studies Houston, TX, USA

Tinatin Kiguradze MD

Medical Student College of Medicine University of Central Florida Orlando, USA

Torello Lotti  MD MD (Hon)

Professor and Chair Department of Dermatology University of Rome “G. Marconi” Rome, Italy

Tracey Nicole Liebman  MD FAAD Assistant Professor The Ronald O Perelman Department of Dermatology New York University School of Medicine New York, NY, USA

Valeria Mateeva  MD PhD

Senior Assistant Professor Department of Dermatology and Venereology Medical University–Sofia Sofia, Bulgaria

Valerie D Callender MD

Professor Department of Dermatology Callender Dermatology and Cosmetic Center Glenn Dale, MD Howard University College of Medicine Washington, DC, USA

Vijay Vanchinathan  MD FAAD

Dermatologist Department of Dermatology Washington Permanente Medical Group Tacoma, Washington, USA

Vikash S Oza MD

Assistant Professor Department of Dermatology and Pediatrics The Ronald O Perelman Department of Dermatology New York University School of Medicine New York, NY, USA

Contributors Vincenzo Piccolo MD

Dermatologist Department of Dermatology Dermatology Unit, Department of Mental and Physical Health and Preventive Medicine University of Campania Luigi Vanvitelli Naples, Italy

Vineet Mishra MD

Mohs Surgeon/Dermatologist Division of Mohs Surgery, Dermatology and Vascular Surgery Scripps Clinic Department of Dermatology Adjunct Clinic Associate Professor of Dermatology University of California San Diego San Diego, CA, USA

Vinod E Nambudiri  MD MBA

Assistant Professor Department of Dermatology Harvard Medical School, Brigham and Women’s Hospital Boston, MA, USA

Virginia A Tracey  MD MPH FAAD Associate Dermatologist Theta Dermatology Guilderland, NY, USA

Wei Huo  MD PhD

Professor of Dermatology Department of Dermatology No.1 Hospital of China Medical University Shenyang, China

William Lear  MD FAAD FACMS FRCPC Director, Dermatological Surgery and Program Director, Mohs Fellowship Silver Falls Dermatology Salem Oregon, USA

Wilson Liao MD Professor of Dermatology Director Psoriasis and Skin Treatment Center Department of Dermatology University of California San Francisco San Francisco, CA, USA

William G Stebbins MD Assistant Professor Department of Dermatology Vanderbilt University Medical Center Nashville, TN, USA

Xing-Hua Gao  MD PhD Professor of Dermatology Department of Dermatology No.1 Hospital of China Medical University Shenyang, China

Yang Yang  MD Postdoctor

Participated in Drafting the Part of Mechanism Department of Dermatology China Medical University No.1 Hospital of China Medical University Shenyang, China

Yen-Lin Chen MD

Department Radiation Oncology Massachusetts General Hospital, Boston Boston Children’s Hospital, Boston Harvard Medical School Boston, MA, USA

Yun Tong MD

Resident Physician Department of Dermatology University of California San Diego La Jolla, California, USA

Yuxiao Hong  MD PhD

Professor of Dermatology Department of Dermatology No.1 Hospital of China Medical University Shenyang, China

Zhu H MD

Dermatology Resident Division of Dermatology Department of Medicine Albert Einstein College of Medicine Montefiore Medical Center Bronx, New York, USA

xix

Preface We are excited to introduce the fourth edition of Moschella and Hurley’s Dermatology. The goal of this book is to provide a comprehensive summary of dermatological conditions, established diagnostic techniques, surgical, laser, and other procedures. Experts from around the globe contributed so that readers can benefit from their knowledge and experience. This textbook is an excellent resource for practicing dermatologists, resident physicians, and students. While keeping it up-to-date and easy-to-read, the authors were conscientious of not making it too digital. This text carries the traditional book format and contents. Beyond covering routine skin conditions, the book contains a special focus on dermatologic surgery and cosmetic procedures. It also includes a summary of noninvasive diagnostic tools in dermatology, discusses simple and practical approaches to clinical pattern analysis, and is the first text to include a discussion on the role of a dermatologist in biological, chemical, and nuclear disasters. In addition, this book may be the first dermatology textbook to have a chapter focusing on care for the lesbian, gay, bisexual, transgender (LGBT) community.

Babar K Rao

Acknowledgments I am thankful to all contributing authors for putting forth their best work for our readers. Without Tara Bronsnick, MD spending countless hours of her time to organize content and chapters, it would not have been possible to produce this book. Jennifer Tan, MD, Maxwell Fung, MD, Attiya Haroon, MD PhD, Gina Francisco MD and Catherine Reilly, who helped edit and function as liaisons between our authors, were instrumental in producing this book. I would also like to acknowledge the previous authors of this textbook and extremely thankful to Shri Jitendar P Vij (Group Chairman), Mr Ankit Vij (Managing Director), Ms Chetna Malhotra Vohra (Associate Director–Content Strategy) of M/s Jaypee Brothers Medical Publishers (P) Ltd, New Delhi, India in putting this tremendous work together. I had like to thank my mentors: Mehboob Ahmed, MD; Prof. Wilson Jones, MD; Prof. Malcolm Greaves, MD; Robert Freeman, MD; Jag Bhawan, MD; Evangelos Poulos, MD; Alfred Kopf, MD; Richard Granstein, MD, and countless others. “All I know, I know it from others. The little I knew, I shared with all.”

– Babar K Rao

Contents Volume 1 SECTION 1: BASIC SCIENCES 1. Structure and Function of Skin Development, Morphology, and Physiology

3

Animesh A Sinha, John Hassani, Alison Treichel, Thomas W Chu

2. Immunology

37

Animesh A Sinha, Carlos Linares, Alba Posligua, Tinatin Kiguradze

SECTION 2: PRINCIPLES OF CLINICAL DIAGNOSIS 3. Clinical Reaction Patterns

57

Frank C Victor, Susan Burgin

4. Principles of Dermoscopy

60

Stefano Caccavale, Amalia Lupoli, Vincenzo Piccolo, Teresa Russo, Giuseppe Argenziano

5 . Principles of Non-invasive Diagnostic Techniques in Dermatology

75

Cristian Navarrete-Dechent, Cristian Fischer, Eric Tkaczyk, Manu Jain

SECTION 3: DERMATOPATHOLOGY 6. Laboratory Techniques for Dermatopathology

97

Rita N Sokkar, Manuel Valdebran, Michele Van Hal, Jisun Cha

7. Fundamentals of Dermatopathology

112

Robert Duffy, Robin Burger, Amira Elbendary, Manuel Valdebran, Jisun Cha

8. Dermatopathology: An Approach to Skin Inflammation

125

Attiya Haroon, Babar K Rao

SECTION 4: DISORDERS OF IMMUNITY, HYPERSENSITIVITY AND INFLAMMATION 9. Anaphylaxis and Angioedema

141

Margitta Worm, Linus Grabenhenrich, Sabine Dölle, Paola Chamorro

10. Urticaria

152

Anuradha Bishnoi, Davinder Parsad

11. Transplant Dermatology

165

Nicole Reusser Bender, Edit Olasz-Harken

12. Graft-versus-host Disease

177

Ann M John, Babar K Rao

13. Immunodeficiency Syndromes (except HIV) Danielle Tartar

184

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14. Granulomatous Diseases

200

Julia A Benedetti

15. Low-dose Cytokine Therapy in Dermatology

213

Torello Lotti

SECTION 5: DRUG REACTIONS 16. Drug Eruptions

221

Megan P Couvillion, Virginia A Tracey, Bradley Saylors, Larry Millikan, Erin Boh

17. Erythema Multiforme, Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

232

Christina M Ring, Robert A Schwartz

18. Erythroderma

247

Sandipan Dhar, Amrinder Jit Kanwar

19. Figurate Erythemas

256

Andrew J Peranteau, Ashley Eryn Pezzi, Tiffany Hinojosa, Stephen K Tyring

SECTION 6: VESICULOBULLOUS DISEASES 20. Autoimmune Vesiculobullous Disorders

267

Julie B Zang

21. Nonautoimmune Bullous Diseases

287

Heather Holahan, Babar K Rao

SECTION 7: ECZEMATOUS DERMATITIS 22. Atopic Dermatitis

297

Diana W Bartenstein, Elena B Hawryluk

23. Allergic and Irritant Contact Dermatitis

312

Mohsin Malik, Amy Pappert, Babar K Rao

24. Other Eczemas

323

Rashmi Sarkar, Jaspriya Sandhu

SECTION 8: PAPULOSQUAMOUS DISORDERS 25. Psoriasis

335

Caleb Jeon, Nakamura M, Singh R, Wilson Liao, Bhutani T, Koo J, Lebwohl M

26. Papulosquamous Eruptions and Exfoliative Dermatitis

350

Sekhon S, Zhu H, Benjamin Farahnik, Bhutani T, Koo J, Lebwohl M

SECTION 9: OTHER DERMATOSES 27. Eosinophilic Dermatoses

367

Collin Blattner, William Lear, John Young III

28. Neutrophilic Dermatoses Collin Blattner, William Lear, Benjamin Perry, John Young III

376

Contents

29. Pregnancy-related Dermatoses

396

Collin Blattner, Melissa Danesh, William Lear, John Young III

30. Dermatoses due to Physical Factors and Occupation

405

Dillon Nussbaum, Adam Friedman

SECTION 10: PHOTOSENSITIVITY 31. Skin Types and the Physiology of Tanning and Sunburn

419

Basia Michalski, Edit Olasz-Harken

32. Photodermatoses

429

Marwa Abdallah, Mahmoud Abdallah

SECTION 11: CONNECTIVE TISSUE DISEASES 33. Lupus Erythematosus

451

Jose Dario Martinez, Dionicio Angel Galarza, Jesus Alberto Cardenas, Miryam Eguia

34. Dermatomyositis

465

Fermin Jurado Santa Cruz

35. Scleroderma

482

Sara Hogan, Anthony Fernandez

36. Other Rheumatologic Disorders with Cutaneous Manifestations

497

Jose Dario Martinez, Magda Arredondo, Jesus Alberto Cardenas

SECTION 12: VASCULITIS, VASCULOPATHY AND ULCERS 37. Approach to Purpura and Microvascular Occlusive Syndromes

513

Connie R Shi, Vinod E Nambudiri

38. Vasculitis

528

Rohini Shantharam, Jacob Berman, Allireza Alloo

39. Other Vascular Disorders

540

Ryan Karmouta, Vinod E Nambudiri

40. Vascular Malformations

550

Sophie Vadeboncoeur, Marilyn G Liang

41. Cutaneous Ulcers and Wound Care

569

Jose Contreras-Ruiz, Adriana Lozano-Platonoff, Paula Torres-Camacho

SECTION 13: DISORDERS OF THE DERMIS AND SUBCUTANEOUS TISSUE 42. Disorders of Collagen, Elastin and Ground Substance

587

Emily M Altman

43. Diseases of Subcutaneous Tissue Sandipan Dhar, Ann M John, Amrinder Jit Kanwar

620

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SECTION 14: PIGMENTATION DISORDERS 44. Introduction to the Biology of the Pigmentary System

635

Šitum Mirna, Bulat Vedrana, Goren Andy, Kazandjieva Jana, Guleva Dimitrina, Kovacevic Maja, Lotti Torello

45. Disturbances of Melanin Pigmentation

648

Miroslava Kadurina, Kristina Semkova, Šitum Mirna, Kovacevic Maja, Kolić Maja, Guleva Dimitrina, Lotti Torello

SECTION 15: PEDIATRIC DERMATOLOGY 46. Transient Benign Conditions of the Neonate and Infant

677

Caitlin Gilman, Vikash S Oza

47. Diaper Dermatitis

687

Helen T Shin

48. Vascular Tumors

690

A Yasmine Kirkorian

49. Genodermatoses

701

Neha Rajpal, Kalyani Marathe

50. Other Inflammatory Dermatoses in Children

725

Emily M Berger

SECTION 16: DISEASES OF SEBACEOUS, APOCRINE AND ECCRINE GLAND 51. Acne and Acneiform Dermatoses

731

Maressa C Criscito, Jisun Cha

52. Folliculitis and the Follicular Occlusion Tetrad

746

Nikhil Dhingra, Tamara Lazic Strugar

53. Rosacea and Perioral Dermatitis

756

Noelani González, Tamara Lazic Strugar

54. Diseases of the Eccrine Glands

763

Steven Eilers, Radhika Shah, Eun J Kwon

55. Diseases of the Apocrine Sweat Glands

782

Vijay Vanchinathan, Eun J Kwon

SECTION 17: HAIR DISORDERS 56. Cicatricial Alopecia

791

Valerie D Callender, Nicole E Rogers, DiAnne S Davis

57. Non-scarring Alopecias

809

Rosalynn RZ Conic, Jessica Lin, Natasha Mesinkovska

58. Hypertrichosis Kristen Elkins, Margit Juhasz, Joseph Zikry, Natasha Mesinkovska

821

Contents

59. Hirsutism

833

Faezeh T Liasi, Lance W Chapman, Natasha Mesinkovska

60. Hair Shaft Abnormalities

842

Brandon E Cohen, Nada Elbuluk

SECTION 18: DISORDERS OF THE NAILS 61. Disorders of the Nails

851

Shari R Lipner, Mary Laird, Kristen Lo Sicco

SECTION 19: DISORDERS OF THE ORAL CAVITY 62. Disorders of the Oral Cavity

879

Katerina Damevska, Snejina Vassileva, Grisha Mateev, Kossara Drenovska, Lence Neloska, Valeria Mateeva, Martin Shahid, Torello Lotti

SECTION 20: NON-INFECTIOUS DISEASES OF THE MALE AND FEMALE GENITALIA 63. Non-infectious Male Genital Dermatology

919

Alok Vij

64. Non-venereal Diseases of the Female Genitalia

930

Melissa M Mauskar, Christina N Kraus

Volume 2 SECTION 21: PSYCHOCUTANEOUS DISORDERS AND NEUROGENIC SKIN DISEASE 65. Psychodermatology

945

Katerina Damevska, Mirna Situm, Katlein França, Sanja Manchevska, Maja Vurnek Zivkovic, Marija Buljan, Torello Lotti

66. Pruritus: Pathophysiology and Clinical Aspects

957

Shahyan Rehman, Jeffrey D Bernhard, Sarina B Elmariah

67. Flushing

986

Azeen Sadeghian, Jordan Brooks, Brittany Stumpf, Erin Boh

SECTION 22: DISORDERS OF NUTRITION AND METABOLISM 68. Nutrition and Diet in Dermatology

999

Tara Bronsnick, Era Murzaku, Babar K Rao

69. Cutaneous Mucinoses and Amyloidosis

1007

Mahin Alamgir

70. Disorders of Metabolism Mahin Alamgir

1019

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SECTION 23: THE SKIN IN SYSTEMIC DISEASES 71. Cutaneous Manifestations of Systemic Diseases

1033

Mahin Alamgir

SECTION 24: BACTERIAL AND RICKETTSIAL INFECTIONS 72. Fundamental Cutaneous Microbiology

1077

Roxanna Arakozie, Soham Chaudhari, Collin Blattner, John Young III

73. Bacterial Infections of the Skin

1088

Gina Francisco, Rosa Mateus

74. Mycobacterial Infections

1118

Christina Wong, Kenneth Tomecki

75. Rickettsial Diseases and Other Arthropod-borne Infections

1130

Gina Francisco, Jacqueline Marrugo, Gonzalo Marrugo

SECTION 25: VIRAL INFECTIONS 76. Viral Diseases

1143

Cynthia L Chen

77. Herpes Simplex Virus

1146

Paola Chamorro, Andrew Avarbock

78. Varicella Zoster Virus

1155

Anuradha Bishnoi, Davinder Parsad

79. Poxviruses and Kawasaki Disease

1165

Ashley Keyes

80. Human Papillomavirus Infection

1173

Xing-Hua Gao, Yang Yang, Yuxiao Hong, Wei Huo

81. Viral Exanthems

1188

George I Varghese

82. Human Immunodeficiency Virus

1199

Pooja Virmani, Michael A Marchetti

SECTION 26: SUPERFICIAL AND DEEP MYCOSES 83. Superficial and Subcutaneous Mycoses

1215

Jennifer Abrahams, George W Elgart

84. Candidiasis

1233

Jennifer Abrahams, George W Elgart

85. Deep Mycoses Jennifer Abrahams, George W Elgart

1244

Contents

SECTION 27: SEXUALLY TRANSMITTED DISEASES 86. Non-treponemal Sexually Transmitted Diseases

1263

Shesly Jean-Louis, Brian W Morrison, Jose A Jaller

87. Treponematoses

1277

Shesly Jean-Louis, Brian W Morrison, Ariel E Eber, Marina Perper, Nicholas Fiumara

SECTION 28: PARASITES, ARTHROPODS, HAZARDOUS ANIMALS, AND TROPICAL DERMATOLOGY 88. Parasites, Arthropods, and Hazardous Animals of Dermatologic Significance

1291

Amira Elbendary, Manuel Valdebran, Lauren Boudreaux, Collin Blattner, Dirk M Elston

SECTION 29: TUMORS OF THE SKIN 89. Benign Epithelial Lesions

1311

Giovanni Pellacani, Marco Manfredini

90. Cysts

1319

Raheel Zubair, Omar Noor

91. Non-melanoma Epithelial Skin Cancers

1325

Giovanni Pellacani, Marco Manfredini

92. Adnexal Neoplasms

1335

Christine Ahn, Andressa Costa, Omar Sangueza

93. Benign Melanocytic Nevi and Neoplasms

1355

Neeta Malviya, Brian Scott, Alexander Marzuka, Stephanie Savory

94. Melanoma: Biological Knowledge and Prognostic Factors

1370

Marco Manfredini, Giovanni Pellacani

95. Vascular Neoplasms

1384

Christine Ahn, Andressa Costa, Omar Sangueza

96. Fibrous and Fibrohistiocytic Proliferations

1400

Audrey Rutherford, Donald A Glass II

97. Mastocytosis

1416

Andrew J Peranteau, Yun Tong, Ramya Vangipuram, Stephen K Tyring

98. Muscle, Adipose, and Cartilaginous Neoplasms

1427

Sophia Delano

99. Neural and Neuroendocrine Tumors

1437

Lauren Boshnick, Sairah Khokher, Ashleigh Briody

100. Histiocytoses

1450

Hannah Song, Jennifer Huang

101. Xanthomas Juliana Berk-Krauss, Tracey Nicole Liebman

1463

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Moschella and Hurley’s Dermatology

SECTION 30: TUMORS OF THE LYMPHORETICULAR SYSTEM 102. Cutaneous T-cell Lymphomas

1477

Goff HW

103. Cutaneous B-cell Lymphoma

1501

Enos Tyler, Goff HW

SECTION 31: DERMATOLOGIC SURGERY 104. Dermatologic Surgery

1515

105. Surgical Instruments

1534

Eric Millican, Rachel Redenius, William G Stebbins Collin Blattner, Cory Maughan, Benjamin Perry, William Lear

106. Wound Closure

Dalee M Zhou, Anthony M Rossi, Erica H Lee

107. Electrosurgery

Lilia Correa-Selm, Bahar F Firoz

108. Anatomy of the Head and Neck

Joshua Farhadian, Bradley S Bloom, Jeremy Brauer

109. Nerve Blocks

Abigail Waldman, Michael Pelster, Murad Alam

110. Local Anesthetics

Dalee M Zhou, Anthony M Rossi, Erica H Lee

111. Surgery Section

Marina Perper, Rachel A Fayne, Ariel E Eber, Keyvan Nouri

112. Wound Healing and Surgical Dressings

Emily Newsom, Karen Connolly, Kishwer Nehal

113. Surgery of the Nail

Ann M John, Bahar F Firoz

114. Lip Reconstruction

Janet Y Li, Jo Cooke-Barber, Vineet Mishra

115. Surgical Complications

1553 1569 1578 1596 1602 1610 1627 1638 1651 1667

Garrett Vick, Vineet Mishra

SECTION 32: PHYSICAL MODALITIES OF THERAPY 116. Phototherapy

1687

N Raboobee

117. Photodynamic Therapy

1702

Ashwin Ganti, Gabrielle R Vinding, Annie Wang, John Strasswimmer, Thanh Nga Tran

118. Laser Treatment Jihee Kim, Thanh Nga Tran, Ju Hee Lee

1709

Contents

119. Cryosurgery

1725

Julia May, Allyson Tank, Manas Deolankar, Carl F Schanbacher

120. Radiotherapy

1731

Aaron Wallace, Manas Deolankar, Julia May, Yen-Lin Chen, John Strasswimmer, Thanh Nga Tran

SECTION 33: COSMETIC SURGERY 121. Introduction to Skin Aging

1747

Doris Day

122. Injectable Fillers

1757

Guillermo Antonio Guerrero-Gonzalez, Ocampo-Candiani J

123. Neurotoxins in Aesthetic Medicine

1768

Patricia K Farris, Leah G Jacobs

124. Current Concepts and Techniques in Liposuction Surgery

1779

Khan AJ

125. Hair Transplantation

1791

Shannon Watkins, Marc Avram

126. Chemical Peeling

1803

Bucay VW

127. Lasers

1823

Mussarrat Hussain, Dendy Engelman, Khalil Khatri

128. Sclerotherapy for Telangiectasia and Endovenous Ablation

1841

Joshua Farhadian, Julie Karen

SECTION 34: DERMATOLOGIC CARE OF SEXUAL AND GENDER MINORITY PATIENTS 129. Dermatologic Care of Sexual and Gender Minority Patients

1853

Andy Nguyen, Sarah T Arron, Kara Sternhell-Blackwell

SECTION 35: DERMATOLOGIC CARE IN MASSIVE INFECTIOUS, CHEMICAL, AND NUCLEAR DISASTERS 130. Dermatologic Care in Massive Infectious, Chemical, and Nuclear Disasters

1867

Radhika Srivastava, Babar K Rao, Allison Weiffenbach

Index

1881

xxxi

Section

Basic Sciences

1

Chapter

1

Structure and Function of Skin Development, Morphology, and Physiology Animesh A Sinha, John Hassani, Alison Treichel, Thomas W Chu

INTRODUCTION The skin is a multicomponent organ system, with functions including protection, insulation, hormone production, and thermoregulation. There are several key cellular and non-cellular elements to this organ, which facilitate these functions. This chapter will describe the basic elements of the skin, which is a foundation for understanding dermatology, disease pathology, and management. The skin is composed of two distinct compartments: the epidermis and dermis. The epidermis is the thinnest component, varying in thickness from 0.04  mm on the eyelids to 1.6 mm on the palms, with an average of 0.1 mm. The epidermis is a stratified squamous, cornified epithelium populated by four types of cells: keratinocytes, melanocytes, Langerhans cells (LCs), and Merkel cells, in descending numerical order (Figs. 1.1A to D). The dermis consists mostly of collagen, elastic fibers, ground substance, nerves, blood vessels, lymph vessels, muscle, and folliculo-sebaceous-apocrine and eccrine units. The dermis is 15–40 times thicker than the epidermis. The cells of the dermis include fibroblasts, mast cells, histiocytes, LCs,

A

B

C

D

lymphocytes, and very rarely, eosinophils. Plasma cells are not seen in normal dermis except at mucocutaneous junctions. Below the dermis is the subcutaneous fat, to which several structures in the dermis interact with. The gross anatomy of the skin is diversified regionally and those variations are reflections of different functions. The dermis of the back is thick and consists of broad bundles of collagen, allowing it to withstand stress. In contrast, the dermis of the eyelid is thin. The middle of the face contains numerous large sebaceous glands associated with small hair follicles with prominent follicular ostia.1 Pigmented zones, such as those of the areola, contain increased amounts of melanin within the epidermis. Erectile tissues, such as the nipples, clitoris, and penis, are characterized by highly vascularized smooth muscle. Palmar and plantar skin is characterized by a thick cornified layer and granular zone, a prominent pattern of epidermal rete ridges and dermal papillae, numerous eccrine units, and nerve endings.1,2 There are no folliculosebaceous-aprocrine units. The pattern on the palms allows for gripping and grasping, and the fingertips have enhanced sensitivity (Fig. 1.2).

Figs. 1.1A to D: Cells of the epidermis: Keratinocytes (A), Melanocytes (B), Langerhans cells (C), Merkel cells (D).

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Section 1: Basic Sciences

Fig. 1.2: Acral skin. Notice the increased thickness of the (A) Stratum corneum. The epidermis (B) and dermis (C) are depicted as well. Courtesy: Dr Babar Rao, MD.

Regional variations in cutaneous topography and structure are, for the most part, adaptations for particular functions. During the fourth and fifth month of fetal life, ridges develop and become increasingly predominant during childhood.3 These markings remain stable throughout life. The developmental processes that determine the orientation of the surface ridges include (1) the configuration of contiguous dermal papillae and epidermal rete ridges; (2) the arrangement of underlying dermal collagen bundles; (3) the effects of the pull of skeletal muscles; (4) vascular and nerve patterns; and (5) growth stress.1,3 Variations in cell distribution and stresses on the deve­ loping skin account for the unique pattern of each individual, while cellular attachment sites establish pattern permanence.4 The pattern is established earlier in fetal life, at approximately the 10th week of development.3 Etchings that cover the entire surface of the palms and soles, excluding flexion creases, are collectively termed dermatoglyphic patterns. Swirled patterns characterize the palms and soles. The patterns found on fingertips are highly individualistic, even in identical twins. Clinically relevant topographic findings include a single palmar crease in Down syndrome, Trisomy 12, Trisomy 18, and Cri du Chat syndrome.5,6

EMBRYOLOGY All constituents of human skin are derived from either ectoderm or mesoderm. The epidermis, folliculo-sebaceousapocrine units, and nails are all derived from ectoderm.

Melanocytes, nerves, and specialized sensory receptors develop from the neuroectoderm. LCs, macrophages, muscle, lymph vessels, fibroblasts, blood vessels, and adipocytes originate from the mesoderm. By 3 weeks of development, the epidermis consists of a single layer of flattened epithelial cells.7,8 By 4 weeks, the epithelial cells stratify into a basal germinative layer of cuboidal cells and an outer layer of slightly flatter cells, termed periderm, surrounded by the amniotic fluid.7,8 Periderm functions as a protective, yet permeable, barrier until the developing epidermis beneath it cornifies. Near the end of the first trimester, intermediate cells develop in between the periderm and basal cell layer.9 Unlike cells of the periderm, these intermediate cells contain clumps of cytoplasmic tonofilaments that are connected with desmosomes that contacts at intercellular junctions. After the fifth month of development, keratohyaline granules become increasingly prominent in the upper part of the intermediate zone, basal germinative cells proliferate more rapidly, and epidermal cells near the surface lose their nuclei and begin to cornify. At 6 months of development, the periderm sloughs off and cornification becomes more pronounced in a craniocaudal direction and will make up part of the vernix caseosa (an outer coating that is shed by newborns shortly after birth).10 Approximately 80% of the vernix is water, which is located within corneocytes. Along with the shed periderm, the vernix is also composed of sebum and shed lanugo.10 Commencing at about 15 weeks of development, synthesis and secretion of sebum contribute increasingly to the lipid-rich vernix caseosa that coats the fetus, particularly in the third trimester. Nearing full term, the cornified layer increases in thickness to become a functional barrier and is coated with the vernix, which can be absent in preterm infants.10 A basal lamina develops at the dermoepidermal junction (DEJ) during the first trimester.11 At around 12 weeks, the DEJ is mature and marked by undulations as a consequence of proliferations of basal cells at regular intervals that represent of folliculo-sebaceous-apocrine and eccrine units.11 By the end of the first trimester, the appearance of the DEJ is similar to that of mature skin.11 Starting in the sixth month of fetal life, connective tissue joins the epidermal undersurface to become dermal papilla.12 By 8 weeks, cranial and trunk neural crest cells migrate to the epidermis, develop into melanoblasts, which turn into melanocytes.13 Melanocytes begin to synthesize melanosomes to transfer to keratinocytes between the fourth and sixth month of development.13

Chapter 1: Structure and Function of Skin Development, Morphology, and Physiology The microphthalmia-associated transcription factor (MITF) plays a key role in triggering the expression of melanogenic genes.13 From precursors in the neural crest, melanocytes migrate to the epidermis, various epithelia of mucous membranes, hair follicles, dermis, leptomeninges, inner ear, and heart.13 Melanocytes from the retina do not derive from the neural crest but originate from the optic cup of the primitive forebrain.13 Primitive melanocytes in the skin are seen during the eighth week of fetal life, and they begin to develop and transfer melanosomes to keratinocytes between the fourth and eighth month of development.13 In embryos, LCs are derived from hematopoietic stem cells of the fetal yolk sac first starting at week 9, and then by fetal liver monocytes at week 4–5.14 Unlike the classic antigen presenting cell, the dendritic cell, LCs are not supplied by the bone marrow in adult life. Instead, LCs are able to maintain themselves throughout adult life without help from bone marrow stem cells.14 In the sixth or seventh week of development, LCs are less dendritic and show different phenotypic markers than they do in late fetal or postnatal skin.15 LCs that are mature phenotypically make their appearance in the intermediate zone of fetal epidermis at 12–14 weeks.16 Merkel cells make their appearance in fetal skin by the 16th week of gestation17 and first appear in the epithelium of the fingertips, nail beds, and in the epithelium of follicular infundibula.18 The origin of Merkel cells has been debated for decades as neural versus epidermal origin. Once thought to be neural crest derivatives, recent studies have suggested an epidermal origin.19,20 These studies showed that deletion of the neural crest lineage in mice had no effect on the Merkel cell population, while deletion of ATOH1 transcription factor led to loss of Merkel-cell– neurite complexes in the skin, necessary for the maturation of Merkel cells from epidermal precursors; indicating a possible epidermal origin.19,20 The transcription factor ATOH1 is necessary for the maturation of Merkel cells from epidermal precursors; ATOH1 knock-out mice experienced a lack of Merkel cell development.19 Apocrine glands develop by week 24, with epithelial cell growth down into the reticular dermis and subcuta­ neous fat. The duct is coiled at its base and becomes straight as it enters the hair follicle above the entrance of a sebaceous duct.21,22 Apocrine glands fully develop in all hair follicles, but after the fifth month, most begin to regress and persist in only the axillae, areolae, periumbilical, and anogenital skin.21,22 Although the apocrine secretory segment secretes a milky fluid beginning at 7 months, apocrine glands are dormant postnatally until they resume secretory function around puberty.21,22

Eccrine units arise independently of folliculo-sebaceous-apocrine units and descend to meet the junction between the dermis and the subcutaneous fat. Eccrine units develop first on acral skin at 12 weeks at the base of epidermal rete ridges.23,24 These proliferations of basal cells are independent of folliculo-sebaceous-apocrine units and are not associated with mesenchymal papilla. The outer layer of these columns is continuous with the germinative basal cells of the epidermis. The inner cores connect with the cells in the intermediate zone of the epidermis, known as acrosyringia, and become canalized by confluence of cytoplasmic vacuoles in adjacent cells within the core of cellular cords. When epithelial downgrowths reach the deep reticular dermis or subcutaneous fat, their lowest portions become coiled. By the sixth month of intrauterine life, secretion of sweat commences and epithelial cells farthest from lumina differentiate into myoepithelial cells.23,24 From the base upward, a mature eccrine unit consists of a coiled secretory gland, a coiled intradermal duct, a straight intradermal duct, and a spiraled intraepidermal duct. The EDA gene and Wnt signaling pathway plays a role in eccrine sweat glands development.25,26 For eccrine glands, the Wnt signaling pathway initially in the dermis induces eccrine gland development.25,26 This is followed by the EDA signaling pathway continuing sweat duct formation. The Shh pathway is then needed for the secretory coil formation.25 The SHH signaling pathway may also serve to a roll in gland development.26 The sebaceous gland is a lipid-producing gland that develops in the fourth month of fetal life from an epithelial bud that arises from a hair follicle at a point that marks the junction of a future infundibulum and isthmus. The signals for sebocyte development are poorly understood, but evidence shows that hedgehog genes, Wnt, c-Myc, and other molecular pathways are involved.27 The nail unit development is related to the limb development, and pathways that affect dorsoventral polarity (LMX1B, Wnt7a, engrailed-1) will prevent the normal display of nails on the dorsal distal fingertip and lead to abnormal nail development.28 The Wnt signaling pathway is implicated in induction, development, and regeneration of the nail unit.29–31 Mouse models show that Notch1 signaling,32 MSx2, and Foxn1 [downstream of bone morphogenetic protein (BMP) signaling pathway play a role in nail development.33 The nail unit begins its development during the first trimester as a smooth, shiny, quadrangular area demarcated proximally and laterally by a continuous shallow groove. The epithelium in this region consists of three

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Section 1: Basic Sciences layers: surface, intermediate, and germinative. At 9 weeks, a column of germinative and intermediate cells, grows proximally and slants downward obliquely for a short distance into the dermis.34,35 Later, the distal boundary of the matrix will be delineated by the lunula, a whitish area in the shape of a half moon. The proximal nail fold forms dorsally in the angle between the matrix epithelium and the surface epidermis. At 13 weeks, the epithelium of the nail is stratified into the basal zone, spinous zone, granular zone, and the cornified layer. This region now termed the epithelium of the nail bed will lose its granular zone by the 20th week.34,35 At 14 weeks, the proximal part of the nail bed comes to be mounted by a hard covering of cornified cells that derive from the matrix and mature to form a nail plate.34,35 The nail plate cornifies well before any other cutaneous epithelium. By 16 weeks, the nail plate has advanced to cover the proximal half of the nail bed, and by the 20th week, covers it completely, at which time the fetal nail resembles that of the adult.34,35 It is still unclear whether the nail plate is derived from the nail matrix, the ventral part of the proximal nail fold, or the nail bed.36 Initially, embryonic dermis consists of numerous stellate mesenchymal cells suspended in acid mucosubstances.37 Dermal Wnt signaling/β-catenin lead to fibroblast development.38 Fibroblasts produce delicate collagen bundles by the 12th week of fetal development and more mature bundles of collagen by the 16th week.37 The papillary and reticular compartments of the dermis become recognizable by about the fourth month of intrauterine life.37 As fibrillar elements of the fetal dermis increase steadily and cellular components decline to the same degree, the dermis acquires features typical of mature connective tissue. By 24 weeks, fibroblast-derived elastic fibers begin to appear, interspersed among collagen bundles within the dermis.37 Dermal networks of blood and lymph vessels originate from mesenchymal cells late in the first trimester, but characteristic arborizing arterial and venous plexuses are not developed fully until the third trimester.39 Mast cells make their appearance in the dermis during the second trimester and are derived from stem cells located in the bone marrow. Cutaneous nerves take origin from ectoderm of the neural crest and are detectable in the embryonal dermis by the fifth week and goes on to form somatic sensory nerves, specialized sensory end organs such as Pacinian corpuscles, Meissner corpuscles, and mucocutaneous end organs, and autonomic motor nerves. The subcutaneous fat is derived embryologically from mesenchyme that

surrounds newly formed blood vessels, adipocytes form late in the second trimester.40 Primitive mesenchymal cells give rise to adipocytes and fibroblasts.

Embryogenesis of Hair Hair follicle formation involves a complex sequence of signals and interactions between the dermal mesenchyme and the overlying epithelium that first began from 8th to 12th week of gestation.41 Hair follicle formation typically begins on the face—particularly the eyebrows along with upper and lower lip—and then progressively spreads ventrally and caudally over the body.41 The development and differentiation of hair follicles during embryogenesis is classically divided into eight stages, characterized by distinct morphologies.42 Stage 1 began with an initial signal from the embryonic mesoderm that initiates the formation of regularly spaced thickening of the primitive epithelium called the placodes.43 From the placodes, an epithelial signal further induced the underlying dermal fibroblast cells to aggregate to form mesenchymal condensates.44 In stage 2, the dermal condensates signal the overlying ectodermal placode to continue to proliferate and penetrate down to the dermis. The epithelial placode continues to grow downward and at an angle into the dermis, whereby an early peg marks stage 3. By 12th–14th week of gestation, the dermal papilla is formed when the epithelial cells of the hair pegs invaginate and envelope the dermal condensate. The establishment of the dermal papilla—specialized dermal fibroblast cells derived from the mesoderm—is vital to hair follicle development. The dermal papilla cells prior to stage 3 were only loosely collected and are long, spindle shaped cells. The formation of a bulbous hair peg occurs during stage 4. In stage 5 during 13th–16th week of development, two distinct asymmetric bulges of cells are formed on the downside of superficial portion of the angled hair follicle—the upper bulge is destined to become the sebaceous gland while the lower bulge will contain presumptive follicular stem cells. The bulges will anchor the future arrector pili muscle to the hair follicle. In the second trimester, the hair follicle begins to differentiate into seven concentric layers of cells as seen in cross-section of the mature hair follicle. At the end of stage 4 or beginning of stage 5, a core of epithelial cells near the bulb begins to separate from the peripheral epithelial cells which later become the outer root sheath (ORS), which is continuous with epithelium of the skin. The epithelial core cells differentiate into the inner root sheath (IRS) made up of Henle, Huxley, and cuticle layers,

Chapter 1: Structure and Function of Skin Development, Morphology, and Physiology and central core of matrical cells that later give rise to the hair fiber cuticle, cortex, and the medulla (in terminal hair). At stage 6, the hair fiber is noticeably developed with the lengthening of the hair fiber and its IRS. The peripheral epithelial cells move aside to allow the cone of the central core of cells to move upwards away from the bulb. By the time the fetus enters 19th–21st week of gestation, the hair follicle development also reaches stage 7 when the hair canals form. By stage 8, the formation of hair follicles is complete and the initial hair fibers erupt from the skin. The initial lanugo hair of the first anagen hair growth phase starts from 24 to 28 weeks of development.45

Molecular Mediators of Hair Follicle Embryogenesis Identification of the molecular pathways controlling differentiation and proliferation in mammalian hair follicles provides the crucial link to understanding the regulation of normal hair growth, the basis of hereditary hair loss diseases, and the origin of follicle-based tumors. Current understanding in hair biology took a quantum leap with the discovery that mammalian counterparts (homologs) of genes important for normal Drosophila (fruit fly) development also affect hair follicle development. Decapentaplegic (Dpp), bone morphogenetic protein (BMP), Homeobox (hox), hedgehog (Shh), patched (ptc), wingless (wg)/wnt, disheveled (dsh), engrailed (en), Notch 1, and armadillo/B-catenin genes were first described in Drosophila but are all critical for hair follicle and vertebrate development in general.46 The names initially assigned to the genes describe the peculiar appearance of the corresponding fly carrying mutant genes. Regulatory molecules crucial for follicle formation have been identified, though mechanisms of their interactions are not fully understood. Also unproven is the source of the initial signal for folliculogenesis, though current evidence suggests it comes from the embryonic mesoderm. One of the earliest molecular pathways activated during hair follicle development involves the β-catenin pathway, which is a downstream mediator of Wnt signaling. Products of the Wnt gene family are secreted glycoproteins that regulate cell proliferation, migration, and specification of cell fate in the embryo and adult. Wnt proteins are classified according to their ability to promote stabilization of β-catenin in the cytoplasm. Normally β-catenin is rapidly degraded in the cytoplasm, but Wnt acts to inhibit such degradation.43 The β-catenin accumulates in the cytoplasm and translocate to the nucleus to activate gene transcription. Wnt gene coded proteins are the first precursors currently known to be

involved in hair follicle development, though there may be an earlier gene coded, signaling mechanism that activates hair follicle development and promotes Wnt gene signaling. Normally, the β-catenin pathway is inactive in the adult epidermis. Expression of stabilized β-catenin in the epidermis of transgenic mice resulted in hair follicle morphogenesis, demonstrating its importance in hair follicle development. The hair follicles formed were not only complete with sebaceous glands and dermal papilla but also ultimately led to hair follicle tumors. Conversely, when β-catenin expression was ablated in the epidermis, hair follicle morphogenesis was blocked. This remarkable finding through animal research could eventually have therapeutic implications. In addition to its role in hair follicle induction, Wnt signaling seems to participate in the induction of hair shaft differentiation. The pathway is specifically activated in precortex cells at the base of the hair shaft, and binding sites for the transcription factor Lef1—which mediates transcriptional responses to Wnt signaling—are found in the promoter regions of many hair keratin genes. Members of the BMP signaling have been implicated in the regulation of both proliferation and differentiation in the hair follicle. BMP2 is expressed in the embryonic ectoderm but then localizes to the early hair follicle placode and underlying mesenchyme. BMP4 is expressed in the early dermal condensate. BMPs are a key component of the signaling network controlling hair development and are required to induce the genetic program regulating hair shaft differentiation in the anagen hair follicle. The regulation of hair follicle development by the TNF family member ectodysplasin, and its receptor, EDAR, has also been studied extensively. Mutations in the X-linked EDA gene cause Anhidrotic Ectodermal Dysplasia (EDA), a syndrome associated with decreased numbers of hair follicles, and defects of the teeth and sweat glands. The EDAR gene is required for expression of BMP4, as well as Sonic hedgehog (SHH), indicating that EDAR acts very early in follicular morphogenesis, and is required both for promoting the hair follicle placode and for lateral inhibition of placode fate in surrounding cells. Inhibitors of BMP action, such as Noggin, are also important for normal hair follicle development. Mice lacking Noggin have fewer hair follicles than normal and retarded follicular development. Hair follicle development and hair formation involve the coordinated differentiation of several different cell types in which the Notch pathway appears to have a role. NOTCH-1 is expressed in ectodermal-derived cells of the follicle, in the inner cells of the embryonic placode and

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Section 1: Basic Sciences the follicle bulb, and in the suprabasal cells of the mature ORS. Delta-1, one of the three ligands, is only expressed during embryonic follicle development and is exclusive to the mesenchymal cells of the prepapilla located beneath the follicle placode. Delta-1 appears to promote and accelerate placode formation, while suppressing placode formation in surrounding cells. Other ligands, Serrate 1 and Serrate 2, are expressed in matrix cells destined to form the IRS and hair shaft. SHH signaling plays a critical role in hair follicle development, but how it controls these processes remains unclear. Skin from mice lacking SHH have extremely effete hair follicles with poorly developed dermal papillae, suggesting that SHH controls follicular proliferation, and follicle size.

Mediation of Hair Follicle Distribution Primitive hair germs, which are observed as a focal crowding of basal-cell nuclei in the fetal epidermis, first appear in the regions of the upper lip, eyebrows, and chin. All further primary follicle germs begin to develop over the surface of the body during the fourth month of gestation. As the fetus grows, new primary germs form among the existing ones, and secondary germs develop in such an orientation to the primary germs so that new follicles are formed in groups of two, three, or four (called follicular units). This results in hairs being arranged in patterns, keeping relatively constant distances from their neighbors, and having a uniform regional slant. The mechanism that regulates the distribution of hair follicles and their clustering is very poorly understood. However, it is presumed that the characteristic distribution of hair follicles over the body is determined in part by homeobox gene. Although it has been established that several homeobox genes are expressed during murine skin development, there is no definitive information about developmental expression of these genes in human skin. In adult mice, homeobox gene expression reappears in hair follicles and serves to maintain normal hair shaft production. Engrailed, a type of homeobox gene, is responsible for dorsal-ventral patterning, and mice lacking engrailed develop hair follicles on their footpads.

Mediation of Hair Follicle Melanocyte Infiltration Transgenic and mutant mice have been used to study the genetic control of the development of melanocytes, and

their progenitors, neural crest cells and melanoblasts. This had led to the identification of several factors that are important in melanoblast development. These include SOX10, the transcription factor PAX3, the basic helix–loop– helix leucine zipper MITF, endothelin receptor B, its ligand endothelin 3, and the receptor tyrosine kinase, KIT, and its ligand mast cell growth factor (MGF). Experiments in mice show that KIT and MGF are necessary for the survival, proliferation, and initial migration of melanoblasts from the neural crest. In addition, they are necessary in the later movement of melanocytes from the dermis to the epidermis. The failure of melanocytes to migrate to these locations explains the association of congenital piebaldism (congenital depigmented patches of the skin) and poliosis (congenital white hair) with mutations in the KIT gene. Similarly, Waardenburg syndrome (congenital disease characterized by deafness in association with pigmentary anomalies and defects of neural crest-derived tissues) can be caused by mutations in PAX3, MITF, endothelin-B receptor, endothelin-3, or SOXlO.

EPIDERMIS The epidermis is the outer layer of skin comprised chiefly of keratinocytes. The layers of the epidermis progressing from deep to superficial are the stratum basale, stratum spinosum, stratum granulosum, stratum lucidum (only in thicker skin), and lastly the stratum corneum (Fig. 1.3). The basal cell layer possesses hemidesmosomes, which anchor the

Fig. 1.3: Histology of normal skin, depicting (A) Stratum corneum; (B) Stratum granulosum; (C) Stratum spinosum; (D) Stratum basale; (E) Papillary dermis; and (F) Reticular dermis. Courtesy: Dr Babar Rao, MD.

Chapter 1: Structure and Function of Skin Development, Morphology, and Physiology basal keratinocytes to the basal lamina at the DEJ. One of the principal functions of the epidermis is to provide a protective barrier, which is achieved by the outermost stratum corneum or cornified layer. (1) synthesis of distinctive proteins (e.g., keratin, filaggrin, and involucrin) and lamellar granules, (2) alterations of nuclei, cytoplasmic organelles, plasma membranes, and desmosomes, (3) formation of a cornified cell envelop via transglutamination, and (4) merging of corneocytes into a multicellular barrier. Epidermal keratinocytes undergo characteristic changes as they ascend from the basal to the cornified layer with each layer representing successive stages of maturation ultimately leading to apoptosis (Fig. 1.4). The

Fig. 1.4: Cell layers of the epidermis.

Fig. 1.5: Cell layers of the epidermis extending down to the dermis.

basal row of cells consists of columnar or cuboidal cells that contain larger oval nuclei and more basophilic cytoplasm, and as cornification proceeds, basal keratinocytes gradually become transformed gradually into horizontally aligned, flat, anuclear, cornified cells with an eosinophilic cytoplasm (Fig. 1.5).47 During cell progression from the basal layer to the stratum corneum, tonofilaments of keratinocytes aggregate into bundles, eventually forming a fibrous protein termed α-keratin embedded in a sulfur-rich amorphous matrix.48 These intermediate filaments form the cytoskeleton of the cornified layer, providing strength, elasticity, and flexibility. Proteases are responsible for degrading

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Section 1: Basic Sciences linkages (desmosomes) between cells, which aids in the desquamation process. Cholesteryl sulfate has been implicated as an intercellular cement substance, the hydrolysis of which to free cholesterol coincides with desquamation of corneocytes.49 Also found in the intercellular matrix are lipids excreted from lamellar granules which contribute to the impermeability of the cornified layer. Biochemically, the stratum corneum consists of protein rich, lipid-poor cornified cells within a matrix replete with hydrophobic neutral lipids.50 A structure called the cornified cellular envelope, or marginal band, plays a pivotal role in the barrier function of the skin. This chemically resistant, highly insoluble proteinaceous structure parallels the skin surface and gradually thickens during the ascent, as a result of cross-linking catalyzed by epidermal transglutaminases.51 This calcium-dependent enzyme, positioned on the cytoplasmic side of the plasma membrane, forms cross-links with various proteins coded for in the “epidermal differentiation complex” such as keratolinin and involucrin (Latin for “envelope”).52 Ester linkages with neutral lipids containing ceramides, free fatty acids, cholesterol, and cholesteryl sulfate are chemically bound to the proteinaceous envelope. Numerous disulfide bonds provide the chemical basis for insolubility and stability. Specialized contact zones termed desmosomes link adjacent cells and provide a site for the intracytoplasmic tonofilament to anchor. Desmosomes house two groups of proteins: (1) those that occur extracellularly (termed desmogleins) and (2) those that are found within the cytoplasmic attachment plaques (termed desmoplakins). These attachments break and reform continuously as keratinocytes ascend and mature. The unique properties of permeability of the cornified layer underlie its crucial role throughout life in the maintenance of fluid and electrolyte balance of the body.51 In addition, the extent to which molecules diffuse through this layer accounts for the efficacy of topically applied medications and for the ability of allergenic substances to enter the epidermis, promote sensitization, and elicit reactions of contact dermatitis. The mean turnover of renewal time of epidermis has been estimated to be around 28 days.53 Under normal circumstances, shedding of corneocytes is in equilibrium with the generation of keratinocytes. In psoriasis, keratinocytes proliferate more rapidly and are replaced every 3–5 days.54 Stratification of the epidermal cells is dependent on intactness of the basal lamina. This phenomenon is

recognizable during re-epithelialization of healing wounds. Epithelial cells from folliculo-sebaceous units and eccrine ducts, as well as from nearby epidermal basal keratinocytes, migrate toward the wound to cover denuded dermis with a single row of cells.55 When the defect has been covered and epithelial cells are firmly adherent to basal lamina, the new basal cells generate a completely new epidermis.

SPECIAL CELLS OF THE EPIDERMIS Melanocytes Melanocytes are dendritic cells that produce pigment that gets distributed to keratinocytes. Melanocytes have many mitochondria, rough endoplasmic reticulum, Golgi apparatus, and cytoplasmic filaments.56 However, they do not contain tonofibrils or desmosomes, the identifying markers of keratinocytes.56 Melanocytes are not fully functional at birth; skin color darkens during the first few months of life, especially in darker skinned individuals. Exceptions to this include the skin of the areola and genitalia. Melanocytes are clear cells in the epidermal basal layer making up one in ten cells of this region.13 Melanocytes possess dendrites that allow each melanocyte to associate with 30–40 keratinocytes making up an epidermal melanin unit.13 Melanosomes are within the melanocytes and are the site of melanogenesis. They progress through stages: during Stage I, melanosomes are spherical, membrane bound vesicles with longitudinally oriented concentric lamellae with a distinctive periodicity of 9  nm. Stage I melanosomes do not contain melanin. Stage II melanosomes are oval and house numerous lamellae, some of which are cross-linked. Melanin deposition first begins during this stage. In Stage III melanosomes, electrondense melanin partially obscures the network of internal lamellae. Stage IV melanosomes are fully developed and electron opaque due to their dense deposits of melanin.56 Between their electron dense melanized cores and their outer-membranes, mature melanosomes house distinct vesicles, 40  nm in diameter, termed vesiculoglobular bodies. Additionally, melanosomes contain enzymes such as tyrosinase, acid phosphatase, and ATPase. During progression from Stage I to Stage IV, tyrosinase decreases and acid phosphatase increases57 (Flowchart 1.1). Once melanosomes are formed and transported to the tips of dendrites, they are transferred from melanocytes to keratinocytes by apocopation: keratinocytes snip off

Chapter 1: Structure and Function of Skin Development, Morphology, and Physiology Flowchart 1.1: Melanin synthesis in melanocytes during melanogenesis. Enzymatic production of eumelanin and pheomelanin from tyorsine.

(TYR: tyrosinase, TRP: tyrosinase-related protein, DHI: 5,6-dihydroxyindole, DHICA: 5,6-dihydroxyindole-2-carboxylic acid) Source: Cichorek, Mirosława, Małgorzata Wachulska, Aneta Stasiewicz, and Agata Tymińska. “Skin Melanocytes: Biology and Development.” Advances in Dermatology and Allergology Pdia 2013;30(1):30-41.

phagocytose the tips of melanosome-laden tips o melanocyte dendrites.58–60 In the process, follicular and epidermal keratinocytes phagocytize the melanosome-laden tips of melanocytic dendrites.58–60 In the epidermis, melanosomes become concentrated in an umbrella-like array above the nucleus of keratinocyte on the side toward the skin surface. Following transfer to keratinocytes, fully melanized melanosomes are conveyed upward as basal keratinocytes mature and eventually are degraded by lysosomal enzymes and shed as cornified cells are desquamated. The principal function of melanin is to protect the skin from harmful effects of sunlight by scattering and absorbing UV light. Melanin also may act as a neutralizer of free radical oxygen derivatives created by various inflammatory processes.61 Melanin is classified into two major classes, eumelanins and pheomelanins. Eumelanins contain ellipsoidal melanosomes and are found in brown/black skin and hair. Pheomelanins contain spherical melanosomes and are found in lighter colored yellow to reddish brown hair.13 Tyrosinase first hydroxylates tyrosine into L-3,4dihydroxyphenylalanine (L-DOPA), which is then oxidized into DOPAquinone.13 If cysteine is present, cysteinyl DOPA forms and is subsequently oxidized and undergoes

polymerization into pheomelanin.13 If cysteine is lacking, spontaneous cyclization of DOPAquinone occurs, creating DOPAchrome.13 From here, either dihydroxyindole (DHI) melanin or 5,6-dihydroxyindole-2-carboxylic acid (DHICA)-melanin is formed through a series of reactions, both of which are eumelanins.13 It is the amount of melanin in keratinocytes that determines the degree of pigmentation of skin and hair.62,63 The absolute number of melanocytes is the same in all races and both sexes, which is maintained around 1,200 melanocytes/mm2 of skin.13 Differences in colorization result from differences in number, size, degree of melanin distribution, and rate of degradation of melanosomes within keratinocytes.63 Each person has both eumelanin and pheomelanin; the ratios of which determine the color of skin and hair.62 Eumelanin content contributes to color variation amongst different races, while pheomelanin amount is similar amongst races.13 Melanosomes within the keratinocytes of Darker-skinned individuals are numerous, large, heavily melanized, distributed as solitary unit, and degraded slowly.63 In addition, darker-skinned individuals contain larger and more highly dendritic melanocytes. In contrast, melanosomes within keratinocytes of whites are fewer, smaller, less heavily melanized, and distributed as aggregates within phagosomes where they are degraded more rapidly.63 Skin that has been extensively and repeatedly exposed to sunlight is marked by a greater density of melanocytes than skin that has been spared such exposure. When white skin or fair skin is exposed to UV light, however, melanocytes increase in number and size and become more dendritic. Furthermore, after radiation by UV light, the processes of synthesis of melanosomes, melanization of melanosomes, transport of melanosomes to dendrites, and transfer of melanosomes then become larger and more heavily melanized and are distributed as solitary units in keratinocytes where their rate of degradation decreases.63 UV radiation causes secretion of several factors from keratinocytes such as adrenocorticotropin (ACTH), α-melanocyte-stimulating hormone (MSH), Endothelin-1 (ET-1), proinflammatory cytokines, BMP-4, and bFGF amongst others.64–66 These series of events results in darker skin or tanning. In addition to UV light, endogenous production of hormones such as MSH, ACTH, lipotropins, estrogen, progesterone, thyroxine, and androgens all possess melanocyte-stimulating capability.67 Aging is accompanied by a decline in the numbers and activity of follicular melanocytes, a phenomenon that results in progressive graying of hair. Starting around the third decade

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Section 1: Basic Sciences of life, 10–20% of melanocytes of the epithelium are lost every decade.68

Langerhans Cells Langerhans cells, described first by Paul Langerhans in 1868 while he was a medical student in Berlin, are dendritic cells that primarily populate the epidermis. These cells can be found in the epidermis, dermis, thymus, tonsils, lymph nodes, and epithelia of the oral and genital mucous membranes. In the epidermis, they are primarily found in the squamous and granular layers. The cell cycle length is 16 days.69 Approximately 1–6% of the cells in the epidermis are LCs.69,70 Although few in number, with their dendrites, LCs are able to contact 25% of the skin’s surface area.69 The LC granules are uniquely shaped like a tennis racquet. These granules arise from infoldings of the plasma membrane of a LC and function as phagosomes that digest extracellular material via hydrolytic enzymes. Functioning as antigen presenting cells, this material can be endocytosed and then be displayed on the cell surface to trigger an immune response from T lymphocytes.71 Langerhans cells, like macrophages, display major histocompatibility complex (MHC) class II or HLA-DR antigens and membrane receptors for both C3b component of complement and the Fc portion of IgG.72 Other cell markers include CD1a, CD11c, and Langerin (CD207).72,73 LCs are instrumental in the production of allergic contact sensitivity and initiating protective immune responses against a foreign antigen. They also play a role in peripheral tolerance toward self-antigens and harmless foreign antigens.74–76 Their presence also encourages a tonic level of T-cell responsiveness.77 Their primary role is to capture antigens, process them, and display them on MHC complexes. When activated, LCs decrease E-cadherin expression to release themselves from keratinocytes, allowing for migration to lymph nodes.78,79 They also upregulate the chemokine receptor CCR7 and MHC class II.78 The mature LC functions to promote sensitization of antigen specific naïve T cells or induce tolerization.

Merkel Cells Merkel cells are oval shaped cells that function as slowly adapting, low threshold type 1 mechanoreceptors found at the DEJ. They detect mechanical deformities of the epidermis via cytoplasmic processes and desmosomal attachments to neighboring basal keratinocytes. In

addition, they transduce mechanical forces into neural action potentials by synaptic mechanisms that involve release of neurotransmitters.80 Free sensory nerve endings from myelinated neurons extending processes beyond the dermis associate with Merkel cells, making up Merkel-cell–neurite complexes.81,82 Higher concentrations of Merkel cells are noted in regions of high sensitivity such as fingertips. They function in two-point discrimination, and sensing different textures or shapes. They can also be found in the lips, oral cavity, palms, soles, and the outer root sheath (ORS) of hair follicles.81,82

Dermoepidermal Junction The DEJ, also known as the basement membrane zone, is a highly specialized interface between the epidermis and the papillary dermis. The DEJ is composed of basal keratino­ cytes, melanocytes, and Merkel cells. Basal keratinocytes are the most important structural and functional connection to the dermis. Four major functions have been suggested for the DEJ including attachment, support, regulation, or permeability across the dermoepidermal interface, and a role in embryonic differentiation. Hemidesmosomes are electron dense attachment plaques that parallel the internal leaflet of the plasma membrane of the basal keratinocyte. Cytoplasmic tonofilaments in the basal keratinocytes attach to hemidesmosomes and consist of cytokeratin 5 and 14.48 On the basal cell surface, anchoring filaments connect the hemidesmosome to the lamina densa (basal lamina), which predominantly consists of type 4 collagen synthesized by keratinocytes and fibroblasts.83 This accounts for its electron-dense appearance on electron microscopy (EM) imaging. The lamina densa is about 40-nm thick and type 7 collagen forms loops around type 1 and 3 collagen using the type 4 collagen of the lamina densa as an anchor.84 Type 7 collagen is a major structural component of anchoring fibrils, and its carboxy-terminal domain interacts closely with type 4 collagen in the basal lamina.82 Subepidermal blisters as seen in bullous pemphigoid are the result of pathological alterations of various attachment structures.85 The lamina lucida or electron lucid region is the intermembranous space between the lamina densa and keratinocyte’s basal surface, and about 30 nm in thickness. Immediately beneath the basal lamina, is a fibrous zone called the sublamina densa. It is composed of anchoring fibrils, type 3 collagen fibers, and bundles of microfilaments. Anchoring fibrils are the strongest component of

Chapter 1: Structure and Function of Skin Development, Morphology, and Physiology the DEJ for securing the epidermis to the dermis; hemidesmosomes are second to anchoring fibrils in strength of attachment. Dermal microfibril bundles consisting of oxytalan fibers extend downward from their insertion in the basal lamina to the deep portion of the papillary dermis. These fibers are the weakest of the anchoring structures. The lamina lucida represents the weakest link in the DEJ. Nonetheless, the lamina lucida contains several functionally important biochemical components including laminin, fibronectin, the antigen of bullous pemphigoid, and type 5 collagen.86 There is charge-selective permeability across the dermis and epidermis that is created by anionic sites located in both epidermal and dermal edges of the basal lamina.87 Heparan sulfate proteoglycan, a major component of these anionic sites, restricts penetration by other anionic macromolecules.87–89 The DEJ is not a static region and under normal circumstances undergoes modifications throughout life. In pathological conditions such as Stevens–Johnson syndrome and toxic epidermal necrolysis (TEN), the connections of the DEJ are weakened, resulting in the epidermis sloughing off.91 Removal of this protective barrier accounts for the high mortality rates seen in these conditions, with the mortality rate of TEN approaching 35%.90

DERMIS The dermis is divided into two well-circumscribed compartments: (1) a thin zone immediately beneath the epidermis (the papillary dermis) and around adnexa (the periadnexal dermis) and (2) a thick zone of reticular dermis that extends from the base of the papillary dermis to the surface of the subcutaneous fat (the combination of papillary and periadnexal dermis is historically called the adventitial dermis). The papillary dermis is characterized by thin, haphazardly arranged collagen bundles, delicate branching elastic fibers, numerous fibroblasts, abundant ground substance, and a highly developed microcirculation (Fig. 1.6). The reticular dermis is composed predominantly of thick bundles of collagen with interspersed, coarse elastic fibers. Commonly adipocytes of the subcutaneous fat are found within the dermis, particularly around eccrine units. On the face and neck, striated muscle is also seen in the reticular dermis. Proportionally, there are fewer fibroblasts and blood vessels and less ground substance in the thick reticular dermis than in the thin papillary dermis. Bundles of

Fig. 1.6: Punch biopsy showing the thick dermal component of the skin. Courtesy: Dr Babar Rao, MD.

collagen in the papillary dermis are thinner than those in the reticular dermis.37

NEUROVASCULATURE The nerves of the skin are part of the peripheral nervous system and possess somatic sensory and autonomic motor components. They are derived mostly from the neural crest which gives rise to the dorsal root and sympathetic ganglia and to their nerve processes, Schwann cells, endoneurial sheath cells, and the laminar cells of specialized sensory end organs.91 The somatic sensory system mediates the sensations of pain, itch, temperature, light touch, pressure, vibration, proprioception, and discriminative sensations of touch. The autonomic motor nerves control cutaneous vascular tone, pilomotor responses, and activation of sweat glands. Cutaneous sensory receptors can be classified into two groups: specialized “end-organ” receptors, which are composed of terminal nerve endings surrounded by morphologically distinctive lamellar condensations of connective tissue, and Schwann cells. These structures are known as Pacinian corpuscles, Meissner corpuscles, and mucocutaneous end organs.91 The other group of unspecialized receptors includes free dermal nerve endings, including Merkel cells nerve endings.92 Pacinian corpuscles are located in the deeper layers of the skin in weight bearing regions and in subcutaneous fat. They can be found in palms, soles, ligaments, joint capsules, serous membranes, lips, penis, clitoris, and areola.93 Each corpuscle measures about 0.8 × 1.5 mm and is supplied by a myelinated axon arranged in concentric layered

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Section 1: Basic Sciences connective tissue that envelops the sensory terminal.91,94 The cells composing the concentric lamellae are modified Schwann cells, which give this structure an onionlike appearance.94 In the central core of each corpuscle, a bulbous terminal nerve ending, now devoid of its myelin sheath, is in direct contact with the innermost laminar cells.92,93,95 The Pacinian corpuscles are rapidly adapting mechanoreceptors that functions to detect deep pressure, touch, and rapid vibration (200–300 Hz).96 Meissner corpuscles are located at the tips of dermal papillae on volar skin located on the fingertips, soles of feet, eyelids, lips, and genital region.94 Each corpuscle measures about 50 × 150 µm and consists of layers of flattened laminar cells, which are modified Schwann cells. When viewed by electron microscopy, laminar cells possess a basal lamina and at the periphery of the corpuscle are separated by collagen fibers, elastic fibers, and fibrillary intercellular material.94 They are ovoid in shape and contain non-myelinated nerve branches derived from large myelinated sensory nerves.93,94 Mucocutaneous end organs are located in papillary dermis of modified hairless skin of the glans penis, prepuce, clitoris, labia minora, perianal area, eyelids, and lips.97 Silver staining reveals 2–6 myelinated nerves forming loops of nerve around the mucocutaneous end organ.97 These structures measure 50 µm in diameter and contain loops of loosely wound, branching axons that form irregular oval masses.97 Its ultrastructure can be described as lobular units that contain axon terminals surrounded by concentric lamellar processes originating from laminar (Schwann) cells. The interlamellar substance at the periphery contains collagen, elastic fibers, and cross-branded structures of coarse periodicity.98 These structures function as touch receptors. Unspecialized nerve endings are either hair-follicle associated or not. Hair-follicle associated nerve endings are myelinated sensory nerves, which branch extensively. One myelinated axon may supply many hair follicles, and each follicle may in turn be supplied by several different axons from distinct nerve cells.99 These sensory endings are most numerous just below the level of a sebaceous duct. Some axons connect synaptically with Merkel cells situated within the epithelium of the follicular infundibula.99 Other myelinated nerves that originate in the perifollicular network project upward alongside follicles to synapse with Merkel cells within the basal zone of the interfollicular epidermis.99 Non-hair follicle associated nerve endings are unmyelinated axons arranged in a branching, horizontally

oriented overlapping network within the papillary dermis. Many of these unmyelinated axons terminate near the DEJ where they make contact with the basal lamina of the epidermis. Free nerve endings are particularly abundant in the glans penis, where they are found in almost every dermal papilla, as well as scattered throughout the deeper dermis.92 Cutaneous receptors have a high degree of “selective sensitivity,” or a much-reduced threshold to a specific form of stimulation in contrast to their threshold for others.100,101 Afferent nerves of the skin were shown to have distinct functions in tactile perception, evidenced by differences in response patterns of cutaneous mechanoreceptor’s afferent neurons to various stimulations.100,101 Action potentials from nerve endings in the skin are carried to the sensory ganglion of cranial and spinal nerves via A-Beta fibers, A-Gamma fibers, A-delta fibers, and unmyelinated C fibers.102 A-Beta fibers are approximately 10–14 µm diameter heavily myelinated fibers with rapid conduction that discriminate sensations of touch, vibration, and proprioception.99 A-Gamma fibers are narrower, myelinated fibers, which carry information about light touch and pressure sensations.99 A-Delta fibers are even narrower and function to detect pain, temperature, and physiologic itch.99 Unmyelinated C fibers are the most narrow (20 different cell populations (Fig. 1.8). The pilosebaceous unit is comprised of the hair follicle, sebaceous gland, and the arrector pili muscle (Fig. 1.9). A significant anatomical division can be made between the upper permanent structure and the lower transient cycling component of the hair

follicle, which includes the hair bulb. The morphological dividing line between these two components lies below the bulge region, the putative site of epithelial stem cells and precursor populations of melanocytes, mast cells, and LCs. Hair growth results from the proliferative matrix of keratinocytes that reside in the bulb, where they sit on the dermal papilla, a condensate of specialized mesenchymal cells with important inductive properties. Hair cycling is traditionally divided into a growth phase (anagen I–VI), a regression phase (catagen), and a resting phase (telogen). The shedding of the hair fiber has recently been identified as an active process of its own (exogen). The events of hair follicle morphogenesis and cycling are controlled by a complex network of sequential activation and inactivation of autocrine, paracrine, and endocrine signaling pathways. The hair follicle is surrounded by a dense meshwork of blood vessels and nerve endings. Multiple specialized cell populations can be found that are associated with the different compartments of the hair follicle, including melanocytes, neuroendocrine cells, and immune cells. The definition of “normal hair growth” varies with gender, ethnicity, culture, fashion, age, and very often with the particular opinion of the individual concerned.232 For scalp hair coverage to be “normal,” there must be a certain density of terminal hair fibers/follicles over the frontal, temporal, auricular, midscalp, vertex, and occipital scalp; though there may be considerable degrees of tolerance in these parameters for any given population.233

Fig.1.8: Layers of the hair follicle.

Fig. 1.9: The pilosebaceous unit.

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Section 1: Basic Sciences

Hair Growth Cycle Potentially significant changes to normal hair cycling underlie nearly all of hair disorders.233 There are three main hair follicle growth cycling phases: anagen (I–VI), when follicles are actively growing hair fiber; hair follicle regression during catagen; and a telogen quiescent resting phase (Fig. 1.10).45,234 How long each phase takes partly depends on the type of hair follicle involved and its geographic location. On the scalp, about 85% of scalp hair follicles are in anagen and 15% are normally in telogen.45 Anagen in nonalopecia-affected scalp hair follicles may last 2–6 years in duration with about 3 months for telogen and 3–4 weeks for catagen.45 This hair cycle “clock” can become unbalanced in individuals affected by alopecia. Specific changes in expression of hormones, cytokines, and their respective receptors, as well as transcription factors, enzymes, antagonist binding proteins, and epigenetic events can modify the time duration of anagen and telogen.234–236 Unlike other mammals that have synchronized shedding that is also seasonal, a human’s hair cycle regulation is not synchronized. The molecular mechanisms that drive hair follicle cycling remain poorly understood, although molecular regulators have been identified through mutant mouse with defects in hair follicle cycling and by characterizing gene expression profiles of distinct murine hair cycle stages.231 The staging guide for mice is highly relevant for human hair biology, as the same basic follicle transformations occur in mice and men. However, significant differences exists: anagen in the human scalp lasts several years, where in mice it lasts 2–3 weeks; markers for epithelial hair follicle (HF) stem cells are different; and mice have coordinated and synchronized hair cycles

Fig. 1.10: Hair growth cycle.

while humans do not.237 There are recent attempts of using human hair follicle or scalp skin xenografted onto mice.237 Although the human hair cycle in vitro was first described in 1959,238 much of current understanding of the hair follicle cycle has come from murine models.239,240 Hair follicles of mice and men contain similar principal cells types and undergo repetitive cycling.

Anagen Anagen is the phase of hair follicle growth that spans the end of telogen (quiescent phase) to the start of catagen (regression phase). Anagen involves the complete regeneration of the lower, cycling portion of the follicle that is the main factory for hair production. The duration of active hair fiber production during anagen varies per species, genetic background, region on body, environmental factors (season), nutritional status, age, and sex. Anagen duration, which is genetically predetermined, varies with the size of the hair follicle and part of the body where it is located. An anagen growth phase may last several years in the terminal hair follicle on the scalp or just a few weeks on the legs.45 Anagen is initiated by complex molecular signaling among the dermal papilla, resident stem cells in the bulge area, and secondary hair germ. During the anagen phase, there is active growth of hair and deposit of materials in the hair shaft by cells found in the hair follicle. There are certain metabolically active and dividing cells above and around the dermal papilla of the follicle— they grow upward during this phase to form the hair shaft. The anagen phase is characterized by the growth of the hair, but more importantly, it is characterized by a highly increased proliferative rate of all hair follicle cells in all epithelial compartments with the highest activity observed in

Chapter 1: Structure and Function of Skin Development, Morphology, and Physiology matrix cells. Within the anagen phase, six stages have been identified.239

Substages of Anagen During anagen stage I, the dermal papilla increases in size and the hair germ cells in the overlying epithelium undergo a burst of mitotic activity. In anagen II, the epithelial cells of the secondary hair germ grow down into the dermis as an epidermal finger and partially enclose the dermal papilla. As they reach their destined depth, the cells in the central cylinder reverse their growth direction and now progress distally (outward), forming the IRS and the hair shaft.241 In anagen III, the hair matrix is formed and is 4–5 cell layers thick. It encloses ≥60% of the dermal papilla, which becomes enlarged and oval shaped. The hair shaft and IRS are developed and easily identified.237 There is continued mitotic activity in the external sheath and particularly the “germ” region and proliferation of the hair follicular melanocytes. At this time, the follicle attains its maximum length, which is about three times the length that it has in the resting condition. The bulb is now completely formed and the papilla cavity is constricted at its base.242 The melanocytes become aligned along the papilla cavity and each develops melanin granules and numerous dendritic processes. Although hair follicle melanogenesis has begun during this stage, the hair shaft still lacks visible pigmentation, though the dermal papilla (DP) contains occasional melanin clumps.237 The internal sheath is now an elongated cone, which extends up to the capsule and club of the old hair.242 In anagen IV, the hair shaft is fully mature and visibly pigmented from active melanogenesis, with the hair tip reaching the level of the sebaceous gland duct. The medulla (in terminal HFs), cortex and cuticle are clearly discernible, though still enclosed by the IRS. The hair bulb now reaches down to the upper dermal adipose layer, and a distinct connective sheath trail is visible proximal to the bulb, which guides further HF downgrowth.237 By anagen V, the tip of the hair shaft has broken through the tip of IRS, through the junction of the capsule with the ORS, and has grown to about the level of the epidermis. The hair bulb extends further into the adipose layer and attains its final characteristic shape, and the connective sheath trail disappears at this stage.237,242 The hair shaft finally emerges beyond the surface of the skin in anagen VI, with its hair bulb situated deep in the upper subcutaneous layer. In this stage, the hair emerges from the cone of the ORS and continues its

way up. Up until recently, the consensus was that the clubbed hair is discharged through a passive mechanism whereby the new hair from below pushes and dislodges the original hair shaft,45 though there is evidence that the shedding is an active process (refer to the “Exogen” section). Most terminal hair follicles on the scalp are in anagen VI. In mice, anagen VI lasts for 8–9 days with growth rate of 1  mm/day. In humans, a follicle on the scalp may remain in this state for 2–6 years, growing at 0.35 mm a day.

Catagen Catagen is the period of involution that marks the brief transition in which the HF exits the active growth phase and enters the resting phase. Although in the murine model there are eight distinct stages of catagen development, it can essentially be divided into early(I–IV), mid- (V–VI), and late catagen (VII–VIII). The earliest sign of catagen is the cessation of mitotic activity with volume reduction of matrix and DP. Melanogenesis also ceases with some melanocytes undergoing apoptosis so that there is less pigment in the proximal hair shaft. The newly formed club hair is positioned a short distance above the contracted DP. During mid-catagen, the matrix and DP continue to contract, so that residual matrix becomes 1–2 cell layers thick and partially surround the condensed, almond-shaped DP. An epithelial strand (the remnant of the regressing hair matrix and proximal ORS) between the club hair and the DP can be identified. At this stage, the vitreous membrane of the connective sheath becomes thickened and stains for glycoprotein, biglycan.237 In late catagen, the matrix disappears and the DP condenses to the shape of a ball. The epithelial strand has shortened, and the club hair is distinctly visible. Apoptosis occurs in the epithelial strand and the sebaceous gland.237 When the part of the hair follicle in contact with the lower portion of the hair becomes attached to the hair shaft, the so-called club hair is formed.45 Catagen, as opposed to anagen, is the initiating phase of the “first” hair cycle in utero after hair follicle morphogenesis in the fetus.243

Telogen The hair follicle is completely regressed during telogen so that only remnants of the upper permanent (bulge) region is present while the lower non-permanet (bulb) region disappears. The follicle is about half of its

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Section 1: Basic Sciences previous size and sits high in the upper dermis instead of the subcutaneous layer. The DP is compact and wellrounded and is connected to the unpigmented club hair above through a short unpigmented epithelial strand left behind during catagen, the secondary hair germ.237 The epithelial cells of the lower telogen follicle do not show significant DNA or RNA synthesis, nor is there any synthesis of proteins characteristic of the anagen follicle, such as trichohyalin and the hair cortical keratins. The telogen hair shaft, the club hair, can be retained for months in this epithelial sac.45

Exogen The shedding of the club hair has traditionally been assumed to be passive, that the newly formed hair fiber forces out the club hair during anagen VI to facilitate hair shedding. Recent findings suggest that the hair shedding is instead an active, controlled process for which the term exogen was introduced.244,245 This includes observations of empty telogen follicles (missing a club fiber) in phototrichograms of human scalp or in breeds of domestic sheep, where empty telogen follicles have lost their club fibers, without any underlying physical force from the new anagen hair.246 When a shed hair shaft root is compared to a plucked telogen hair shaft root by light or electron microscopy, major morphological differences are apparent. The telogen root is made of packed nucleated cells which show intracytoplasmic fractures surrounding a cornified core making up the shaft. The exogen root, in contrast, is made of very few cells and these cells are separated at their outer edge by intercellular cleavage. The morphology of the hair root suggests that the exogen process involves a proteolytic event that occurs between the moving cells of the telogen shaft base.245 The nature of this shedding process remains to be identified. A possible role of desmoglein and proteolytic events was suggested.247 A gradual decrease in the adhesion of the club hair within its epithelial silo has also been observed prior to its programed release from the follicle.246

Kenogen A novel phenomenon has been described by the phototrichogram whereby follicles are observed to be empty after shedding of club hairs. Kenogen was the term used to describe the interval of the hair cycle in which the hair follicle remains empty after the telogen hair has been extruded and before a new anagen hair reappears.

During kenogen, the hair follicle is at rest physiologically, and this is observed in healthy subjects.

Changes in Hair Cycle in Hair Disorders In isolation, increased anagen duration does not alter scalp hair density; it only defines the maximal length to which hair can grow. A brief anagen phase may only become apparent if the duration is shortened to a few weeks in scalp hair follicles. However, anagen effluvium and alopecia areata can involve a dystrophic anagen state where the follicle is active, but unable to produce healthy fiber.251,252 In contrast, prolongation of the telogen phase in scalp hair follicles can be a significant factor in many forms of alopecia development. Hair fibers may continue to be shed over time during exogen.45,253 Normally, the shedding of old club hair fibers occurs when follicles are in an early anagen phase. A new, actively growing fiber is present to take the place of the shed fiber; consequently, there is no net loss of hair. However, in prolonged telogen, with the failure of follicles to enter a new anagen phase, new hair fiber is not produced to replace the old, shed fibers. A hair follicle with no hair fiber present is described in the previous section as being in a state of kenogen. Kenogen can be observed in a few hair follicles in healthy scalp skin, but the frequency and duration of kenogen is significantly greater in individuals with alopecias.248 Such a situation is classically observed in the early stages of AGA and in telogen effluvium.248–250

Hair Follicle Density Outside of experimental induction or injury-mediated hair follicle formation (neofolliculogenesis),254,255 the total number of hair follicles in an individual is determined at birth to be from 2 to 5 million, of which 100,000–150,000 are located on the scalp.46 Extensive research has examined hair follicle embryogenesis and its control, though our understanding of the biological mechanisms involved is still quite limited.43,45 However, it is clear that very specific signaling through multiple pathways is required for the correct development and geographical distribution of hair follicle formation in the skin.241 Though very rare and typically due to a genetic modification, perturbations in hair follicle embryogenesis result in hypotrichosis, a deficiency of hair growth from birth.233 Much more common is an initially normal density of hair follicle formation, which is later adversely impacted by an insult subsequently leading to hair loss and alopecia development.

Chapter 1: Structure and Function of Skin Development, Morphology, and Physiology

Hair Fiber Size Hair fibers are classed into three different groups, and size is the key feature that determines their categorization.45,256 Most hair follicles produce short, fine, non-pigmented vellus hairs. In contrast, eyebrow, eyelash, and scalp follicles produce much bigger, slowly cycling, usually pigmented, terminal hairs from birth. Follicles retain a degree of plasticity with respect to the type of hair produced, and they can transform from vellus into terminal hair production and vice versa. Hair follicles progressing through a transition in size are defined as producing intermediate hairs. Hair follicle size, and so the size of the hair fiber they produce, potentially has a big impact on hair coverage. A switch of the hair follicle from terminal to vellus (miniaturization) can be seen with the development of AGA or chronic alopecia areata, for example. Conversely, a vellus-to-terminal body hair follicle switch is seen with hirsutism and hypertrichoses.

Androgen Hormones It is generally accepted that androgen hormone action on hair follicles via androgen receptors provides the driver of AGA though there is some debate over the true significance of androgens in female pattern hair loss (FPHL). The effect of androgens on hair follicles in specific scalp regions is likely due to a variation in factors, such as androgen receptor density and distribution, localized and systemic production of androgens, the local conversion of androgens to DHT, the local production of androgen antagonists, and the degradation rate of DHT.257,258 In the presence of androgens, dermal papilla cells alter their production of hair growth regulatory factors.259,260 The dermal papilla miniaturization and compromised growth factor signaling yield finer, unpigmented vellus-like hair.

Hair Follicles and Immune Privilege In the same way, as for other organs like the testis and the anterior eye chamber, hair follicles exhibit immune privilege (IP), a region of tissue where normal immune cell activity is modulated.233,261,262 IP sites are characterized by little or no expression of MHC class I (MHC-I), an increase in cytokines with immunoregulatory potential, and expression of cell surface immunosuppressive factors.262 Studies from several laboratories suggest IP is present in at least anagen-stage hair follicles, though catagen- and telogen-stage follicles may not be protected.263,264 Loss of

IP function in tissues has been demonstrated in several autoimmune conditions including multiple sclerosis, autoimmune uveitis, and autoimmune hepatitis.265 In theory, if hair follicles have defective IP function, immune surveillance cells may infiltrate and recognize hair follicle specific self-antigens.264 Activated immune cells express various inflammatory cytokines and proapoptotic factors that could interfere with hair fiber growth and, in turn, this may cause alopecia. Currently, changes to hair follicle IP function underpin several hypotheses of both nonscarring and scarring inflammatory alopecias.

CONCLUSION Recent discoveries in genetics and molecular biology have revolutionized our knowledge in hair cycling and hair growth. Experimentally generated murine mutations have provided valuable insights into the functional significance of selected gene products in hair follicle morphogenesis and cycling. The identification of animal models of human diseases has helped to evaluate the relevance of candidate gene approaches.

REFERENCES 1. Igarashi T, Nishino K, Nayar SK. The appearance of human skin. New York: Columbia University; 2005. 2. Verbov J. Clinical significance and genetics of epidermal ridges—a review of dermatoglyphics. J Invest Dermatol 1970;54:261–71. 3. Babler WJ. Embryologic development of epidermal ridges and their configurations. Birth Defects Orig Artic Ser 1991;27:95–112. 4. Wertheim K, Maceo A. The critical stage of friction ridge and pattern formation. J Forensic Identif 2002;52:35–85. 5. Cerruti Mainardi P. Cri du Chat syndrome. Orphanet J Rare Dis 2006;1:33. 6. Masjkey D, Bhattacharya S, Dhungel S, et al. Utility of phenotypic dermal indices in the detection of Down syndrome patients. Nepal Med Coll J 2007;9:217–21. 7. Holbrook KA, Odland GF. The fine structure of developing human epidermis: light, scanning, and transmission electron microscopy of the periderm. J Invest Dermatol 1975;65:16–38. 8. Smith LT, Holbrook KA, Madri JA. Collagen types I, III, and V in human embryonic and fetal skin. Am J Anat 1986;175:507–21. 9. Hashimoto K, Gross BG, DiBella RJ, et al. The ultrastructure of the skin of human embryos. IV. The epidermis. J Invest Dermatol 1966;47:317–35. 10. Singh G, Archana G. Unraveling the mystery of vernix caseosa. Indian J Dermatol 2008;53:54–60.

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71. Hanau D, Fabre M, Schmitt DA, et al. Human epidermal Langerhans cells internalize by receptor-mediated endocytosis T6 (CD1 “NA1/34”) surface antigen. Birbeck granules are involved in the intracellular traffic of the T6 antigen. J Invest Dermatol 1987;89:172–7. 72. Burke K, Gigli I. Receptors for complement of Langerhans cells. J Invest Dermatol 1980;75:46–51. 73. Clausen BE, Stoitzner P. Functional specialization of skin dendritic cell subsets in regulating T cell responses. Front Immunol 2015;6:534. 74. Waithman J, Allan RS, Kosaka H, et al. Skin-derived dendritic cells can mediate deletional tolerance of class I-restricted self-reactive T cells. J Immunol 2007;179:4535–41. 75. Steinman RM, Hawiger D, Nussenzweig MC. Tolerogenic dendritic cells. Annu Rev Immunol 2003;21:685–711. 76. Probst HC, Lagnel J, Kollias G, et al. Inducible transgenic mice reveal resting dendritic cells as potent inducers of CD8+ T cell tolerance. Immunity 2003;18:713–20. 77. Hochweller K, Wabnitz GH, Samstag Y, et al. Dendritic cells control T cell tonic signaling required for responsiveness to foreign antigen. Proc Natl Acad Sci USA 2010; 107:5931–6. 78. Weinlich G, Heine M, Stossel H, et al. Entry into afferent lymphatics and maturation in situ of migrating murine cutaneous dendritic cells. J Invest Dermatol 1998;110:441–8. 79. Tang A, Amagai M, Granger LG, et al. Adhesion of epidermal Langerhans cells to keratinocytes mediated by E-cadherin. Nature 1993;361:82–5. 80. Moll I, Roessler M, Brandner JM, et al. Human Merkel cells—aspects of cell biology, distribution and functions. Eur J Cell Biol 2005;84:259–71. 81. Young B, O’Dowd G., Woodford P. Nervous tissue. Wheater’s functional histology: a text and colour atlas. Elsevier Churchill Lygst; 2014. p. 122–42. 82. Young B, O’Dowd G., Woodford P. Skin. Wheater’s functional histology: a text and colour atlas. Philidelphia: Elsevier Churchill Lvgst; 2014. p. 159–79. 83. Lin MS, Mascaro Jr JM, Liu Z, et al. The desmosome and hemidesmosome in cutaneous autoimmunity. Clin Exp Immunol 1997;107 Suppl 1:9–15. 84. Gayraud B, Hopfner B, Jassim A, et al. Characterization of a 50-kDa component of epithelial basement membranes using GDA-J/F3 monoclonal antibody. J Biol Chem 1997;272:9531–8. 85. Westgate GE, Weaver AC, Couchman JR. Bullous pemphigoid antigen localization suggests an intracellular association with hemidesmosomes. J Invest Dermatol 1985;84:218–24. 86. Aumailley M, Krieg T. Laminins: a family of diverse multifunctional molecules of basement membranes. J Invest Dermatol 1996;106:209–14. 87. Kazama T, Yaoita E, Ito M, et al. Charge-selective permeability of dermo-epidermal junction: tracer studies with cationic and anionic ferritins. J Invest Dermatol 1988;91:560–5. 88. Kazama T, Oguro K, Sato Y. Effect of enzyme digestion on anionic sites and charge-selective

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Section 1: Basic Sciences 167. Olczyk P, Mencner L, Komosinska-Vassev K. The role of the extracellular matrix components in cutaneous wound healing. Biomed Res Int 2014;2014:747584. 168. Jakubovic HR, Salama SS, Rosenthal D. Multiple cutaneous focal mucinoses with hypothyroidism. Ann Intern Med 1982;96:56–8. 169. Neufeld E MJ. The mucopolysaccharidoses. The metabolic and molecular basis of inherited disease. New York: McGraw-Hill; 2000. 170. Clark RA. Fibronectin in the skin. J Invest Dermatol 1983;81:475–9. 171. Mosher DF, Furcht LT. Fibronectin: review of its structure and possible functions. J Invest Dermatol 1981;77: 175–80. 172. George EL, Georges-Labouesse EN, Patel-King RS, et al. Defects in mesoderm, neural tube and vascular development in mouse embryos lacking fibronectin. Development 1993;119:1079–91. 173. To WS, Midwood KS. Plasma and cellular fibronectin: distinct and independent functions during tissue repair. Fibrogenesis Tissue Repair 2011;4:21. 174. Takashima A, Grinnell F. Human keratinocyte adhesion and phagocytosis promoted by fibronectin. J Invest Dermatol 1984;83:352–8. 175. Yamada KM, Akiyama SK, Hasegawa T, et al. Recent advances in research on fibronectin and other cell attachment proteins. J Cell Biochem 1985;28:79–97. 176. Ushiki T. Collagen fibers, reticular fibers and elastic fibers. A comprehensive understanding from a morphological viewpoint. Arch Histol Cytol 2002;65:109–26. 177. Proctor RA. Fibronectin: a brief overview of its structure, function, and physiology. Rev Infect Dis 1987;9 Suppl 4:S317–21. 178. Hynes RO. Fibronectins. Sci Am 1986;254:42–51. 179. Grinnell F. Fibronectin and wound healing. J Cell Biochem 1984;26:107–16. 180. McCarthy JB, Basara ML, Palm SL, et al. The role of cell adhesion proteins—laminin and fibronectin—in the movement of malignant and metastatic cells. Cancer Metastasis Rev 1985;4:125–52. 181. Akiyama SK, Yamada KM. Fibronectin in disease. Monogr Pathol 1983;24:55–96. 182. Clark RA. Basics of cutaneous wound repair. J Dermatol Surg Oncol 1993;19:693–706. 183. Ruoslahti E. Fibronectin and its integrin receptors in cancer. Adv Cancer Res 1999;76:1–20. 184. Ryan TJ, Curri SB. The structure of fat. Clin Dermatol 1989;7:37–47. 185. Barnhill R. Panniculitis. In: Magro C, Crowson A, Piepkorn M, editors. Dermatopathology. New York: McGraw Hill Medical; 2010. 186. Reed RJ, Clark W, Mihm MC. Disorders of the panniculus adiposus. Hum Pathol 1973;4:219–29. 187. Elliott RIK. Pathological reactions in subcutaneous tissue: function and structure of the subcutaneous tissue. Cambridge: Cambridge University Press; 1964. p. 175–88.

188. Ryan TJ, Curri SB. Blood vessels and lymphatics. Clin Dermatol 1989;7:25–36. 189. Bjorntorp P. Hormonal control of regional fat distribution. Hum Reprod 1997;12 Suppl 1:21–5. 190. Wu J, Cohen P, Spiegelman BM. Adaptive thermogenesis in adipocytes: is beige the new brown. Genes Dev 2013;27:234–50. 191. Trayhurn P, Ashwell M. Control of white and brown adipose tissues by the autonomic nervous system. Proc Nutr Soc 1987;46:135–42. 192. Driskell RR, Jahoda CA, Chuong CM, et al. Defining dermal adipose tissue. Exp Dermatol 2014;23:629–31. 193. Alexander CM, Kasza I, Yen CL, et al. Dermal white adipose tissue: a new component of the thermogenic response. J Lipid Res 2015;56:2061–9. 194. Zouboulis CC, Baron JM, Böhm M, et al. Frontiers in sebaceous gland biology and pathology. Exp Dermatol 2008;17:542–51. 195. Downing DT, Strauss JS. Synthesis and composition of surface lipis of human skin. J Invest Dermatol 1974;62:228–44. 196. Sheu HM, Chao SC, Wong TW, et al. Human skin surface lipid film: an ultrastructural study and interaction with corneocytes and intercellular lipid lamellae of the stratum corneum. Br J Dermatol 1999;140:385–91. 197. Ottaviani M, Camera E, Picardo M. Lipid mediators in acne. Mediators Inflamm 2010;2010. 198. Downing DT, Greene RS. Double bond positions in the unsaturated fatty acids of vernix caseosa. J Invest Dermatol 1968;50:380–6. 199. Marples RR, Downing DT, Kligman AM. Control of free fatty acids in human surface lipids by Corynebacterium acnes. J Invest Dermatol 1971;56:127–31. 200. Stewart ME, McDonnell MW, Downing DT. Possible genetic control of the proportions of branched-chain fatty acids in human sebaceous wax esters. J Invest Dermatol 1986;86:706–8. 201. Stewart ME, Downing DT. Proportions of various straight and branched chain fatty acid chain types in the sebaceous wax esters of young children. J Invest Dermatol 1985;84. 202. Nicholaides N, Ansari MN. The dienoic fatty acids of human skin surface lipid. Lipids 1969;4:79–81. 203. Pochi PE, Strauss JS. Endocrinologic control of the development and activity of the human sebaceous gland. J Invest Dermatol 1974;62:191–201. 204. Strauss JS, Pochi PE. Effect of cyclic progestin-estrogen therapy on sebum and acne in women. JAMA 1964;190:815–9. 205. Pochi PE, Strauss JS. Sebaceous gland inhibition from combined glucocorticoid-estrogen treatment. Arch Dermatol 1976;112:1108–9. 206. Aakvaag A. Vogt JH, Fylling P. Plasma and urinary androgens in hirsute women during adrenal and ovarian suppression. Acta Derm Endocrinol 1970;64(1):103–10. 207. Shuster S, Thody AJ. The control and measurement of sebum secretion. J Invest Dermatol 1974;62:172–90. 208. Klingman AM, Shelley WB. An investigation of the biology of the human sebaceous gland. J Invest Dermatol 1958;30(3):99–125. 209. Agache P, Blanc D, Barrand C, et al. Sebum levels during the first year of life. Br J Dermatol 1980;103:643–9.

Chapter 1: Structure and Function of Skin Development, Morphology, and Physiology 210. Pochi PE, Strauss JS. Studies on the sebaceous glands in acne and endocrine disorders. Bull N Y Acad Med 1977;53: 359–67. 211. Sansone-Bazzano G, Cummings B, Seeler AK, et al. Differences in the lipid constituents of sebum from prepubertal and pubertal subjects. Br J Dermatol 1980;103:131–7. 212. Stewart ME, Steele WA, Downing DT. Changes in the relative amounts of endogenous and exogenous fatty acids in sebaceous lipids during early adolescence. J Invest Dermatol 1989;92:371–8. 213. Pochi PE, Strauss JS, Downing DT. Age-related changes in sebaceous gland activity. J Invest Dermatol 1979;73:108–11. 214. Zouboulis CC, Boschnakow A. Chronological ageing and photoageing of the human sebaceous gland. Clin Exp Dermatol 2001;26:600–7. 215. Plewig G, Kligman AM. Proliferative activity of the sebaceous glands of the aged. J Invest Dermatol 1978;70:314–7. 216. Zouboulis CC, Seltmann H, Neitzel H, et al. Establishment and characterization of an immortalized human sebaceous gland cell line (SZ95). J Invest Dermatol 1999;113:1011–20. 217. Aly R, Maibach HI, Rahman R, Shinefield HR, Mandel AD. Correlation of human in vivo and in vitro cutaneous antimicrobial factors. J Infect Dis 1975;131:579–83. 218. Nakatsuji T, Kao MC, Zhang L, et al. Sebum free fatty acids enhance the innate immune defense of human sebocytes by upregulating beta-defensin-2 expression. J Invest Dermatol 2010;130:985–94. 219. Lindsay SL, Holmes S, Corbett AD, et al. Innervation and receptor profiles of the human apocrine (epitrichial) sweat gland: routes for intervention in bromhidrosis. Br J Dermatol 2008;159:653–60. 220. Watabe A, Sugawara T, Kikuchi K, et al. Sweat constitutes several natural moisturizing factors, lactate, urea, sodium, and potassium. J Dermatol Sci 2013;72:177–82. 221. Niyonsaba F, Suzuki A, Ushio H, et al. The human antimicrobial peptide dermcidin activates normal human keratinocytes. Br J Dermatol 2009;160:243–9. 222. Dai X, Okazaki H, Hanakawa Y, et al. Eccrine sweat contains IL-1α, IL-1β and IL-31 and activates epidermal keratinocytes as a danger signal. PLoS One 2013;8:e67666. 223. Sato K, Leidal R, Sato F. Morphology and development of an apoeccrine sweat gland in human axillae. Am J Physiol 1987;252:R166–80. 224. Fleckman P, Allan C. Surgical anatomy of the nail unit. Dermatol Surg 2001;27:257–60. 225. Lee KJ, Kim WS, Lee JH, et al. CD10, a marker for specialized mesenchymal cells (onychofibroblasts) in the nail unit. J Dermatol Sci 2006;42:65–7. 226. Sellheyer K, Nelson P. The concept of the onychodermis (specialized nail mesenchyme): an embryological assessment and a comparative analysis with the hair follicle. J Cutan Pathol 2013;40:463–71. 227. Lee DY, Yang JM, Mun GH. Onychofibroblasts induce hard keratin in skin keratinocytes in vitro. Br J Dermatol 2009;161:960–2. 228. Perrin C. The nail dermis: from microanatomy to constitutive modelling. Histopathology 2015;66:864–72.

229. Baden HP. The physical properties of nail. J Invest Dermatol 1970;55:115–22. 230. Ito T, Ito N, Saathoff M, et al. Immunology of the human nail apparatus: the nail matrix is a site of relative immune privilege. J Invest Dermatol 2005;125:1139–48. 231. Schneider MR, Schmidt-Ullrich R, Paus R. The hair follicle as a dynamic miniorgan. Curr Biol 2009;19:R132–42. 232. Breitkopf T, Leung G, Yu M, et al. The basic science of hair biology: what are the causal mechanisms for the disordered hair follicle? Dermatol Clin 2013;31:1–19. 233. Chu TW, Santos L, McElwee KJ. Biology of the hair follicle and mechanisms of nonscarring and scarring alopecia. Semin Cutan Med Surg 2015;34:50–6. 234. Yu M, Finner A, Shapiro J, et al. Hair follicles and their role in skin health. Exp Rev Dermatol 2006;1:855–71. 235. Stenn KS, Paus R. What controls hair follicle cycling? Exp Dermatol 1999;8:229–33; discussion 33–6. 236. Geyfman M, Andersen B. Clock genes, hair growth and aging. Aging (Albany NY) 2010;2:122–8. 237. Oh JW, Kloepper J, Langan EA, et al. A guide to studying human hair follicle cycling in vivo. J Invest Dermatol 2016;136:34–44. 238. Kligman AM. The human hair cycle. J Invest Dermatol 1959;33:307–16. 239. Chase HB, Rauch R, Smith VW. Critical stages of hair development and pigmentation in the mouse. Physiol Zool 1951;24:1–8. 240. Muller-Rover S, Handjiski B, van der Veen C, et al. A comprehensive guide for the accurate classification of murine hair follicles in distinct hair cycle stages. J Invest Dermatol 2001;117:3–15. 241. Stenn KS, Paus R. Controls of hair follicle cycling. Physiol Rev 2001;81:449–94. 242. Chase HB. Growth of the hair. Physiol Rev 1954;34:113–26. 243. Montagna W, Ellis RA. The biology of hair growth. New York: Academic Press; 1958. 244. Stenn K. Exogen is an active, separately controlled phase of the hair growth cycle. J Am Acad Dermatol 2005;52:374–5. 245. Milner Y, Sudnik J, Filippi M, et al. Exogen, shedding phase of the hair growth cycle: characterization of a mouse model. J Invest Dermatol 2002;119:639–44. 246. Higgins CA, Richardson GD, Westgate GE, et al. Exogen involves gradual release of the hair club fibre in the vibrissa follicle model. Exp Dermatol 2009;18:793–5. 247. Koch PJ, Mahoney MG, Cotsarelis G, et al. Desmoglein 3 anchors telogen hair in the follicle. J Cell Sci 1998;111 (Pt 17):2529–37. 248. Guarrera M, Rebora A. Kenogen in female androgenetic alopecia. A longitudinal study. Dermatology 2005;210: 18–20. 249. Rebora A, Guarrera M. Kenogen. A new phase of the hair cycle? Dermatology 2002;205:108–10. 250. Rebora A, Guarrera M. Teloptosis and kenogen: two new concepts in human trichology. Arch Dermatol 2004;140:619–20. 251. Messenger AG, Slater DN, Bleehen SS. Alopecia areata: alterations in the hair growth cycle and correlation with the follicular pathology. Br J Dermatol 1986;114:337–47.

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Section 1: Basic Sciences 252. Trueb RM. Chemotherapy-induced alopecia. Semin Cutan Med Surg 2009;28:11–4. 253. Hanakawa Y, Li H, Lin C, et al. Desmogleins 1 and 3 in the companion layer anchor mouse anagen hair to the follicle. J Invest Dermatol 2004;123:817–22. 254. McElwee KJ, Kissling S, Wenzel E, et al. Cultured peribulbar dermal sheath cells can induce hair follicle development and contribute to the dermal sheath and dermal papilla. J Invest Dermatol 2003;121:1267–75. 255. Muller SA. Hair neogenesis. J Invest Dermatol 1971;56:1–9. 256. Rook A. Endocrine Influences on Hair Growth. Br Med J 1965;1:609–14. 257. Kaufman KD. Androgens and alopecia. Mol Cell Endocrinol 2002;198:89–95. 258. Sawaya ME, Price VH. Different levels of 5α-reductase type I and II, aromatase, and androgen receptor in hair follicles of women and men with androgenetic alopecia. J Invest Dermatol 1997;109:296–300. 259. Randall VA. Androgens and human hair growth. Clin Endocrinol (Oxf ) 1994;40:439–57.

260. Itami S, Inui S. Role of androgen in mesenchymal epithelial interactions in human hair follicle. J Investig Dermatol Symp Proc 2005;10:209–11. 261. Tobin DJ, Gunin A, Magerl M, et al. Plasticity and cytokinetic dynamics of the hair follicle mesenchyme during the hair growth cycle: implications for growth control and hair follicle transformations. J Investig Dermatol Symp Proc 2003;8:80–6. 262. Ito T, Meyer KC, Ito N, et al. Immune privilege and the skin. Curr Dir Autoimmun 2008;10:27–52. 263. Lu W, Shapiro J, Yu M, et al. Alopecia areata: pathogenesis and potential for therapy. Expert Rev Mol Med 2006; 8:1–19. 264. Wang E, McElwee KJ. Etiopathogenesis of alopecia areata: Why do our patients get it? Dermatol Ther 2011;24: 337–47. 265. Ito T, Ito N, Bettermann A, et al. Collapse and restoration of MHC-I-dependent immune privilege: exploiting the human hair follicle as a model. Am J Pathol 2004;164: 623–34.

Chapter

2

Immunology Animesh A Sinha, Carlos Linares, Alba Posligua, Tinatin Kiguradze

INTRODUCTION The immune system is a dynamic complex network of cells and humoral factors that protects, maintains life, and helps to mend damaged tissues. It is in charge of fighting infectious agents, destroying tumors, eliciting allergic reactions, participating in coagulation and wound-healing processes. The immune system is formed by a complex interplay between the innate and the adaptive immune systems, tailoring the response to the specific clinical presentation1 (Fig. 2.1). The skin is continuously exposed to trauma, chemicals, protein antigens, ultraviolet light, heat, cold, radiation, and infectious agents. It acts as a physical and physiological barrier between the outside environment and the host.1

INNATE IMMUNE SYSTEM Keratinocytes The skin, particularly the epidermis, is the first line of defense of the immune system against pathogens and allergens present in the environment. The keratinocytes of the skin contain keratin and filaggrin that physically guard against the entrance of foreign agents into the system. Should these agents invade the host, the immune response is elicited through the formation of antimicrobial peptides (i.e. β-defensins) that help to eliminate pathogens by expressing Toll-like receptors (TLRs). TLRs serve as initiators of a response from the immune system.2

Fig. 2.1: Innate and adaptive immune systems. Source: https://www.ncbi.nlm.nih.gov/pubmed/14708024; Dranoff G. Cytokines in cancer pathogenesis and cancer therapy. Nat Rev Cancer. 2004;4(1):11-22.

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Section 1: Basic Sciences The keratinocytes-immune system interaction is ligated to the development of chronic inflammatory diseases such as atopic dermatitis and psoriasis. Distorted epidermal differentiation, downregulation of filaggrin production, and T helper (Th) type 1 (Th1) and Th17 CD4+ T-cell polarization results in psoriasiform inflammation.3

Granulocytes Eosinophils Eosinophils are leukocytes with cytoplasmic granules, containing an abundance of basic proteins. Eosinophils thereby exhibit a strong affinity for acid dyes (e.g. eosin). By Wright-stained blood smear, mature eosinophils measure 10–15 µL , the nucleus is usually bilobed, and the cytoplasm contains characteristic orange-to-crimson red circular-toelliptical membrane-bound granules (Fig. 2.2).4,5 These granules contain arginine-rich proteins: major basic protein, eosinophil cationic protein, eosinophil protein X/eosinophil derived neurotoxin, and eosinophil peroxidase. Once activated, these proteins have cytotoxic capacity in response to parasites, tumoral cells, and a variety of inflammatory reactions.6 The process of migration and chemotaxis of the eosinophils from the blood vessels to the tissue begins with the expression of the very late activation antigen-4

Fig. 2.2: Eosinophils. Under a magnification of 100, this photomicrograph of a human peripheral blood smear revealed the presence of activated eosinophils from a patient with idiopathic HES, showing cytoplasmic clearing, nuclear dysplasia, and the presence of immature forms. Photo ID: 18166. (HES: hypereosinophilic syndrome) Courtesy: CDC/National Institute of Allergy and Infectious Diseases (NIAID).

(VLA4) by the eosinophil in the bloodstream. VLA4 binds to the vascular cell adhesion molecule 1 of the vessel’s endothelium and later travels to the affected skin in response to chemoattractants, such as eotaxin-3 and regulated on activation, normal T cell expressed and secreted.4 Activated eosinophils demonstrate increased generation of reactive oxidative products, increased oxygen utilization, increased glucose consumption, decreased self-surface charge, and reduced cell density. Cytokines play an important role in the activation of eosinophils. Interleukin (IL)-3, IL-5, and granulocyte macrophage colony-stimulating factor (GM-CSF) enhance eosinophil survival and function.7 The chief functions of eosinophils include killing of parasites and dampening of hypersensitivity reactions, which if go uncontrolled may damage tissue, producing fibrosis, and hypercoagulability. They may also have a phagocytic and expulsion role in gut parasitic infestations.7 In the skin, eosinophils have been associated with the presence of atopic dermatitis, allergic drug eruption, urticaria, allergic contact dermatitis, arthropod bites, parasitic infestations, autoimmune bullous diseases such as bullous pemphigoid and dermatitis herpetiformis, urticarial vasculitis, eosinophilic cellulitis, granuloma faciale, and eosinophilic fasciitis.8

Basophils Basophils are leukocytes that measure 10–15 µL on Wrightstained blood smears have centrally situated bilobed or trilobed nuclei and contain numerous, large, rounded, purplish granules. These granules contain mainly histamine and sulfated glycosaminoglycans. The sulfated glycosaminoglycans are responsible metachromatic staining of the granules with basic dyes such as toluidine blue.5 Basophils comprise 95% of T cells in normal skin are CD45RO memory T cells. Contact dermatitis is a T-cell mediated inflammatory condition. The most common cutaneous T-cell lymphoma is MF, characterized by the cutaneous infiltration of CD3+/CD4+ cells and epidermotropism. Cutaneous CD30+ anaplastic large cell lymphoma is characterized by IL-10 production, with spontaneous remission of the disease and reactivation.67 Different subsets of T cell are involved in the development of autoimmune and inflammatory conditions. For example, in discussing Th17 and IL-22 secretion dysregulation, the keratinocyte IL-22 receptor plays an important role in the development of psoriasis and atopic dermatitis.68 Different subsets of T cell are involved in the origin and progression of skin disease. Psoriasis is a condition in which Th17, Th22, and Tc22 cells synergistically play an important role in the development of the disease. The IL-22 receptor is expressed on keratinocytes, a process which is driven by TNF-α. IL-22 effects on epithelial cells include epidermal hyperplasia with hypergranulosis and parakeratosis, as seen in psoriasis. This mechanism explains the therapeutic response to TNF-α inhibitors in these patients. Atopic dermatitis is a condition which classically was described as a Th2-mediated condition. This highly pruritic, eczematous, and recurrent chronic inflammatory disease has an acute phase in which Th2 cells are activated with an elevation of IgE, accompanied by eosinophilia. In addition, it is suspected that IL-22 produced by Th22/Tc22 subsets plays an important role in atopic dermatitis, but further investigation is needed. Its production and regulation can be associated with the staphylococcal enterotoxin B; a positive correlation between bacterial skin colonization and AD severity has been found. Narrow-band UV B therapy induces epidermal hyperplasia with the reduction of IL-22 expression. Systemic sclerosis is an autoimmune disease with a broad clinical spectrum, in which inflammation and

Chapter 2: Immunology autoantibodies are the key mediators in the fibrosis of the skin and internal organs. Keratins 6 and 16 are two molecules involved in the healing of the epidermis. In scleroderma, they are highly expressed and are induced by IL-22. Furthermore, a concomitant production of fibroblast growth factor and fibrosis-associated chemokine CCL7 is implicated in the fibrotic changes of the skin. SCC is the second most common skin cancer. A hallmark feature is the proliferation of keratinocytes in the epidermis. IL-22 has been found to accelerate the proliferation of this disease.69 Alopecia areata is an autoimmune disorder in which the immune cell target is the hair follicle. As a T-cell predominant disease, it tends to coexist in patients with atopic eczema and psoriasis.70

B-Cells Introduction B-lymphocytes arise from multipotent hematopoietic cells and mature in the bone marrow. They are a major com­ ponent of the adaptive immune system. B lymphocytes are a population of cells that express clonally diverse cell sur­ face Ig receptors that recognize specific antigenic epitopes. B cells differentiate into plasma cells and antibodysecreting memory B cells. As such, B-lymphocytes play a major role in the adaptive humoral immune response.71 In addition to secreting antibodies (Fig. 2.8), B cells influence immune response by presenting antigens, providing costimulatory signals to T cells, regulating lymphoid tissue structure and neogenesis, and secreting cytokines.

Due to the variety of their function, B cells are considered to be therapeutic targets in a variety of immune-mediated diseases, including autoimmune conditions, and B-cell leukemia and lymphoma.71 B cells are characterized by the presence of BCRs on their cell surface, which allow the cells to bind antigens.72–74

B-Cell Development B-cell development is closely regulated. In the bone marrow, the pluripotent HSC differentiates first into a multipotent progenitor cell and then into a common progenitor cell. The fate of the stem cell is determined by its interaction with stromal cells in the bone marrow. The B-cell lineage cell starts as the pro-B-cell, which is characterized by the expression of CD22 in the cytoplasm. Furthermore, at this level of the pro-cell, Ig rearrangement occurs, potentiated by the RAG1 and RAG2 recombinase activating gene-encoding enzymes. Pro-B-cells do not express either pre-BCR or Ig on their surface; they give rise to pre-B-cells, which do express the pre-BCR on the cell surface as a result of complete rearrangement of the heavy µ, coupled with the surrogate light chain. Additionally, pre-B-cells also express CD19 on the surface.71 Immature B cells first express the BCR, which are complete IgM molecules on the cell surface. They undergo negative selection, and those with potential self-antigen reactivity are subject to clonal deletion, anergy, or receptor editing. Immature B cells that survive this process begin to express IgD, leave the bone marrow, and arise in the periphery as transitional B cells. Transitional B cells are immature splenic B cells that are subject to selection prior to developing into mature naïve B cells.71

B-Cell Subsets

Fig. 2.8: Plasma cells producing antibodies and attaching to foreign substances to fight infection and disease. AV number: 9504-4432. Courtesy: National Cancer Institute.

Mature B cells are classified into B-1 cells and B-2 cells. B-2 cells include FO B cells and marginal zone (MZ) B cells. FO B cells typically express the IgMlowIgDhiCD5− CD23+ phenotype, and comprise the majority of the B-cell population in the spleen, tonsil, and lymph nodes. FO B cells recirculate and form the primary follicles of B-cell zones in the white pulp of the spleen. FO B cells become activated through the interaction with APCs as well as T cells, and as such, they play an important role in mediating the majority of helper T-cell-dependent humoral response. B-cell activation happens via two mechanisms. Some B cells differentiate into short-lived plasma cells via clonal expansion, and begin producing IgM promptly.

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Section 1: Basic Sciences IgM plays a major role in the first-line humoral response. Other B cells migrate into the primary follicle, where they differentiate into centroblasts and initiate the germinal center (GC) reaction. During this process, somatic hypermutation takes place in centroblasts. High-affinity antibody producing cells are positively selected. They then expand and differentiate into centrocytes. Centrocytes interact with T cells and FO DCs, and undergo isotype switching, consequently acquiring different Ig isotypes. The centrocytes ultimately differentiate into memory B cells or plasmablasts. Memory B cells express CD27. They leave the GC to reenter the circulation. A small population of memory B cells enter the bone marrow where they survive for decades as long-lived plasma cells.71 The other subset of B-2 cells is the MZ B cell, located in the marginal sinus (MZ) of the spleen, expressing the IgMhiIgDlowCD1c+CD21hiCD23−CD27+ phenotype in humans. MZ B-2 cells originate from T2 B cells; however, the precise mechanism by which this differentiation occurs (FO vs MZ) is not yet fully understood. While it’s been determined that MZ B cells in mice are vital in the general humoral defense against blood-borne antigens, the role and ontogeny of human MZ B cells remain controversial. Evidence suggests that MZ B cells recirculate and are present in human peripheral blood, unlike murine MZ B cells that are limited to the spleen.75,76 It is likely that a significant proportion of IgM+CD27+ MZ B cells undergo somatic mutations in humans.75,76 The B-1 B cell is the third type of mature B cell that expresses a distinct cell-surface phenotype, at least in mice. B-1 B cells are predominantly located in the pleural and peritoneal cavities, with a much smaller population of B-1 cells residing in the spleen. While the B-1 B population is distinct in mice, the existence of human B-1 B cells has been controversial with recent studies reporting the presence of CD20+CD27+CD43+CD70− phenotype human B-1 cell.77

B-Cell Activation B cells respond to a vast variety of chemical and envi­ ronmental cues and can bind different antigens, including native proteins, glycoproteins, and polysac­charides. Upon recognition of an antigen, the B-cell becomes activated through one of two activation mech­anisms: T-dependent activation and T-independent activation. In T-dependent activation, the B cell is activated concomitantly by the antigen and T-cell interaction through CD40/CD40L.78 In T-independent response, T-independent antigens can activate B cells without T-cell assistance.71

B-cell fate is determined through BCR signaling.79 The BCR is comprised of transmembrane Ig that is noncovalently associated with a CD79a (Igα) and CD79b (Igβ) heterodimer, which serves as a signal transducing subunit.80,81 The cytoplasmic domains of CD79a and CD79b contain immunoreceptor tyrosine-based activation motifs (ITAMs). Upon BCR ligation, ITAMs within CD79a/CD79 are phosphorylated by the Src-family protein tyrosine kinases (PTKs), Lyn, Fyn, and Blk.82 Phosphorylated ITAMs then recruit other PTKs, including Syk, Brk, and other signaling molecules which mediate downstream signaling and further determine the fate of the cell during development, activation, and proliferation. BANK1 is one of the signaling proteins that serves as an adaptor protein expressed in B cells. Blk polymorphisms have been associated with several connective tissue disorders including SLE.83 Similarly, BANK1 polymorphisms are associated with SLE and systemic sclerosis.84,85 B-cell responses are further fine-tuned by other surface molecules. These molecules are roughly categorized into positive regulators and negative regulators. Positive regulators include CD19, CD40, and CD45. CD19 is expressed on the surface of B cells and FO DCs. This positive regulator works with CD21 to generate transmembrane signals in response to inflammation within microenvironments. CD40 is critical for GC formation and it serves as a survival factor for GC B cells allowing them to escape negative selection. CD40 also promotes B-cell activation, differentiation maturation, and Ig production.66,86 B-cell response is also regulated by TLRs expressed on B cells, with some present on the plasma membrane (i.e., TLR2, TLR4) and others contained within the endosomal compartment (i.e. TLR7, TLR9). TLR alone or with other stimuli can activate B cells. Although human naïve B cells do not express substantial levels of TLR, human memory B cells constitutively express TLR2, TLR6, TLR7, TLR9, and TLR10.87 B-cell response is also regulated by cytokines, such as IL-4, IL-5, INF-ϒ, and TGF-β, which differentially induce a class switch.87 B-cell-activating factor (BAFF) is a member of the TNF family of cytokines that plays a major role in B-cell survival and differentiation. BAFF binds three receptors, B-cell maturation antigen, transmembrane activator and calcium-modulator and cyclophilin ligand interactor, and BAFF-R. The BAFF signal induces immature B-cell survival and mature B-cell proliferation. Overexpression of BAFF in mice has been associated with development of lupuslike disease.87

Chapter 2: Immunology The negative regulators of B cells include CD22, CD72, and Fcϒr receptor IIB. CD22 has ITIM (immunoreceptor tyrosine-based inhibitory motifs) in the cytoplasmic domain that recruits SHP-1 phosphatase. CD19 (a positive regulator) and CD22 (a negative regulator) reciprocally control their functions, and their balance appears to play a major role in susceptibility to autoimmunity.87 CD72 negatively modulates signal transduction through the ITIM motif and as the B-cell ligand for Semaphorin 4D (CD100). Fcϒr receptor IIB binds the Fc portion of IgG, which is another important negative regulator of ITIM-containing B cells.87

Antibodies The B-cell plays a central role in humoral immunity due to its capacity to differentiate into antibody-secreting cells. Antibodies are the secreted form of the BCR. They are tetrameric molecules comprised of one pair of identical light chains and one pair of identical heavy chains. The two types of light chains are termed kappa (κ) and lambda (λ). Although no functional differences between these two types of light chains have been elucidated, kappa chains are more common among humans (60%) and mice (95%). Antibody molecules are composed of three elements roughly presenting a Y shape. Two arms of the Y-shaped antibody are identical and are termed Fab fragments. They contain a variable region of the light and the heavy chains, consisting of VL and CL domains and VH and CH domains, respectively. Antigen-binding sites are formed by the paired VL and VH domains. The tail of the Y is referred to as the Fc fragment, which consists of constant regions, the CH2 and CH3 domains. IgM and IgE contain an additional C domain. The constant regions of the heavy chains determine the Ig class or isotype. The antibody molecules are divided into five isotypes: IgG, IgM, IgA, IgE, and IgD. The functions of antibodies vary greatly with the Ig isotype, and include complement activation and binding to Fc receptors.71 IgG is the most abundant Ig isotype that accounts for approximately 75% of the serum Ig pool. In humans, there are four distinct IgG subclasses: IgG1, IgG2, IgG3, and IgG4. Each subclass is produced in response to a different antigen. IgG1, the most abundant IgG, is usually produced as the response to protein antigens; IgG2 is produced in response to polysaccharide antigens; IgG3—in response to respiratory viruses. IgG4 is the least abundant subclass (5.45) Reed and Spitz nevus sometimes observed in: Clark nevus with globular pattern Congenital melanocytic nevus

Table 4.7: Definition of dermoscopic criteria for the classic and revised seven-point checklist. Under the classic seven-point algorithm, excision is recommended if the total score is ≥3. Under the revised seven-point algorithm, excision is recommended if the total score is ≥1 (adapted from Ref. 14). Classic algorithm Dermoscopic pattern score Atypical network +2 Combination of at least two types of pigment network (in terms of color and thickness of the lines) asymmetrically distributed within the lesion +2 Blue-white veil Irregular, structureless area of confluent blue pigmentation with an overlying white “ground-glass” film The pigmentation cannot occupy the entire lesion and usually corresponds to a clinically elevated part of the lesion Atypical vascular pattern +2 Linear-irregular vessels, dotted vessels, and/or milky-red areas not clearly seen within regression structures Irregular dots⁄globules +1 More than three round to oval structures, brown or black in color, asymmetrically distributed within the lesion Irregular streaks +1 More than three brown to black, bulbous or finger-like projections asymmetrically distributed at the edge of the lesion and not clearly arising from network structures Irregular blotches +1 Black, brown, and or gray structureless areas asymmetrically distributed within the lesion Regression structures +1 White scar-like depigmentation and/or blue pepper-like granules usually corresponding to a clinically flat part of the lesion

Revised algorithm score +1

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Chapter 4: Principles of Dermoscopy Table 4.8: Menzies scoring method for the diagnosis of melanoma. For melanoma to be diagnosed, a lesion must have neither of both negative features and one or more of the nine positive features (adapted from Ref. 14). Negative criteria (cannot be present) Definition Symmetry of pattern Symmetry of pattern is required across all axes through the lesion’s center of gravity (center of the lesion). Symmetry of pattern does not require shape symmetry Single color The colors scored are black, gray, blue, dark brown, tan, and red. White is not scored as a color Positive criteria (at least one must be present) Definition Blue-white veil An irregular, structureless area of confluent blue pigmentation with an overlying white “groundglass” haze. The pigmentation cannot occupy the entire lesion and cannot be associated with red-blue lacunes Multiple brown dots Focal areas of multiple brown (usually dark brown) dots (not globules) Pseudopods Bulbous and often kinked projections that are found at the edge of a lesion directly connected to either the tumor body or pigmented network. They can never be seen distributed regularly or symmetrically around the lesion Radial streaming Finger-like extensions at the edge of a lesion that are never distributed regularly or symmetrically around the lesion Scar-like depigmentation Areas of white, distinct, irregular extensions (true scarring), which should not be confused with hypo- or depigmentation due to simple loss of melanin Peripheral black dots/ Black dots/globules found at or near the edge of the lesion globules Multiple (5–6) colors The colors scored are black, gray, blue, dark brown, tan, and red. White is not scored as a color

melanoma diagnosis). A lesion is assessed as suspicious when lacking both negative features (symmetric pigmentation and a single color) and exhibiting at least one of the positive features (blue-white veil, multiple brown dots, pseudopods, radial streaming, scar-like depigmentation, peripheral black dots/globules, multiple colors, multiple blue-gray dots, broad pigment network). When used by experts, the Menzies method is associated with a sensitivity of 92% and a specificity of 71% (Table 4.8).20 The abovementioned algorithms were established and tested about 20 years ago. In our era, the goal of clinicians is to detect melanoma in the possible earliest stage, even before acquiring dermoscopic criteria specific enough to allow its recognition on the basis of the previous algorithms. Following this modern trend, a revised sevenpoint checklist has been introduced, lowering the threshold for excision to the presence of only one of the seven melanoma criteria. This revised method better reflects also the practice of many clinicians, who usually do not use a scoring system but keep in mind a list of features that warrant excision. Using a lower threshold improves the diagnostic sensitivity with a reasonable cost in specificity (Table 4.7).21

THE PRACTICAL USEFULNESS OF DERMOSCOPY IN GENERAL DERMATOLOGY New indications for dermoscopy are suggested every day, and new terms, such as trichoscopy, entomodermoscopy, inflammoscopy, and onychoscopy, have been coined to address its implication to specific areas of dermatology. This is because dermoscopy not only facilitates the diagnosis of pigmented and non-pigmented skin tumors but also improves recognition of a growing number of nonpigmented skin conditions.22 In particular, its use has been extended to a variety of infectious cutaneous disorders (Figs. 4.6A to C), in order to assist the clinical diagnosis and reduce the need of semiinvasive or invasive procedures such as skin scrapings and/ or biopsy.23 Several reviews have reported the usefulness of dermoscopy in the diagnosis of many inflammatory cutaneous diseases (psoriasis, lichen planus, pityriasis lichenoides, pityriasis rosea, pityriasis rubra pilaris, porokeratosis, mycosis fungoides, prurigo nodularis, rosacea, lichen sclerosus, Darier disease, and pigmented purpuric dermatoses) (Figs. 4.7A to F).22,23

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Figs. 4.6A to C: (A) “Jet with contrail” appearance is pathognomonic of scabies and indicates the burrows inhabited by Sarcoptes scabiei that is seen by dermoscopy as hang-glider like triangle corresponding to the mite’s head at the end of the burrow; (B) Dermoscopy of phthiriasis revealing the typical broad body of the crab and the large middle and hind legs; (C) Dermoscopy in the upper part of the picture shows hair casts which can be easily confused with head lice. In contrast, dermoscopy in the lower part of the picture refers to the nits typical of pediculosis capitis.

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Figs. 4.7A and B: (A) Psoriasis lesions typically show dotted vessels on a light or dull red background. White scales are observed in the hyperkeratotic plaques; (B) Eczema typically shows yellow sero-crusts and dotted vessels.

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Figs. 4.7C to F: (C) Lichen planus lesions are characterized by typical Wickham striae; (D) Purpuric dermatitis shows purple–red dots/globules and often an orange–brown background; (E) Discoid lupus erythematosus dermoscopically shows follicular keratotic plugs and arborizing vessels emerging from yellow dots; (F) Porokeratosis lesions show the cornoid lamella as a well-defined white peripheral hyperkeratotic structure. The center of the lesions is usually whitish or brownish.

Dermoscopy may also be useful in the assessment of scalp and hair disorders (trichoscopy, for the differential diagnosis of common inflammatory cicatricial alopecias: discoid lupus erythematosus, lichen planopilaris, and folliculitis decalvans).24 The dermoscope confirms itself as the most useful and diagnostic non-invasive imaging technique and represents an important and relatively simple aid in daily clinical practice.

REFERENCES 1. Lacarrubba F. The role of imaging in dermatology. G Ital Dermatol Venereol 2015;150:505–6. 2. Lallas A, Zalaudek I, Argenziano G, et al. Dermoscopy in general dermatology. Dermatol Clin 2013;31:679–94.

3. Babino G, Lallas A, Longo C, et al. Dermoscopy of melanoma and non-melanoma skin cancer. G Ital Dermatol Venereol 2015;150:507–19. 4. Soyer HP, Argenziano G, Chimenti S, et al. Dermoscopy of pigmented skin lesions. Eur J Dermatol 2001;11:270–6. 5. Argenziano G, Soyer HP. Dermoscopy of pigmented skin lesions—a valuable tool for early diagnosis of melanoma. Lancet Oncol 2001;2:443–9. 6. Bombonato C, Argenziano G, Lallas A, et al. Orange color: a dermoscopic clue for the diagnosis of granulomatous skin diseases. J Am Acad Dermatol 2015;72(1 Suppl): S60–63. 7. Tiodorovic-Zivkovic D, Zalaudek I, Lallas A, et al. The importance of gray color as a dermoscopic clue in facial pigmented lesion evaluation: a case report. Dermatol Pract Concept 2013;3:37–9. 8. Longo C, Scope A, Lallas A, et al. Blue lesions. Dermatol Clin 2013;31:637–47.

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Section 2: Principles of Clinical Diagnosis 9. Blum A, Clemens J, Argenziano G. Three-colour test in dermoscopy: a re-evaluation. Br J Dermatol 2004;150:1040. 10. Argenziano G, Zalaudek I, Corona R, et al. Vascular structures in skin tumors: a dermoscopy study. Arch Dermatol 2004;140:1485–9. 11. Lallas A, Giacomel J, Argenziano G, et al. Dermoscopy in general dermatology: practical tips for the clinician. Br J Dermatol 2014;170:514–26. 12. Soyer HP, Argenziano G, Zalaudek I, et al. Three-point checklist of dermoscopy. A new screening method for early detection of melanoma. Dermatology 2004;208:27–31. 13. Zalaudek I, Argenziano G, Soyer HP, et al. DERMOSCOPY WORKING GROUP. Three-point checklist of dermoscopy: an open internet study. Br J Dermatol 2006;154:431–7. 14. Argenziano G, Soyer HP, Chimenti S, et al. Dermoscopy of pigmented skin lesions: results of a consensus meeting via the Internet. J Am Acad Dermatol 2003;48:679–93. 15. Pehamberger H, Steiner A, Wolff K. In vivo epiluminescence microscopy of pigmented skin lesions. I. Pattern analysis of pigmented skin lesions. J Am Acad Dermatol 1987;17:571–83. 16. Soyer HP, Argenziano G, Chimenti S, et al. Dermoscopy of pigmented lesions. An atlas based on the Consensus Net Meeting on Dermoscopy 2000. EDRA Medical Publishing & New Media: Milan, 2001.

17. Stolz W, Braun-Falco O, Bilek P, et al. Color atlas of dermatoscopy. 2nd ed. Cambridge, MA: Blackwell, 2002. 18. Nachbar F, Stolz W, Merkle T, et al. The ABCD rule of dermatoscopy. High prospective value in the diagnosis of doubtful melanocytic skin lesions. J Am Acad Dermatol 1994;30:551–9. 19. Argenziano G, Fabbrocini G, Carli P, et al. Epiluminescence microscopy for the diagnosis of doubtful melanocytic skin lesions. Comparison of the ABCD rule of dermatoscopy and a new 7-point checklist based on pattern analysis. Arch Dermatol 1998;134:1563–70. 20. Menzies SW, Ingvar C, McCarthy WH. A sensitivity and specificity analysis of the surface microscopy features of invasive melanoma. Melanoma Res 1996;6:55–62. 21. Argenziano G, Catricalà C, Ardigo M, et al. Sevenpoint checklist of dermoscopy revisited. Br J Dermatol 2011;164:785–90. 22. Errichetti E, Stinco G. The practical usefulness of dermoscopy in general dermatology. G Ital Dermatol Venereol 2015;150:533–46. 23. Lacarrubba F, Verzì AE, Dinotta F, et al. Dermatoscopy in inflammatory and infectious skin disorders. G Ital Dermatol Venereol 2015;150:521–31. 24. Miteva M, Tosti A. Hair and scalp dermatoscopy. J Am Acad Dermatol 2012;67:1040–8.

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Principles of Non-invasive Diagnostic Techniques in Dermatology Cristian Navarrete-Dechent, Cristian Fischer, Eric Tkaczyk, Manu Jain

INTRODUCTION Traditionally, the diagnosis of skin lesions relies on visual inspection and dermoscopy, often followed by a biopsy of the suspicious lesion for histopathological confirmation. Although biopsy and histopathological examination is the gold standard for definitive diagnosis, it is an invasive procedure associated with complications such as bleeding, pain, infection, and scarring.1 These are especially problematic in the setting of multiple skin cancers, and for lesions located in cosmetically sensitive regions such as the face. Additionally, histopathology requires time-consuming tissue processing that often delays diagnosis and management of the lesions. Furthermore, on histopathology, only a small fraction of the tissue is analyzed that may lead to false-negative results, especially when the disease is focal in nature or when small partial biopsies are performed. To overcome the existing diagnostic challenges, several non-invasive imaging technologies have emerged in recent years. These techniques can be broadly classified as non-optical (non-light-based) and optical (light-based) techniques (Table 5.1).2 Non-optical techniques include ultrasound (US: high-frequency ultrasound, US-elastography) and magnetic resonance imaging, among others; whereas optical techniques include reflectance confocal microscopy (RCM), optical coherence tomography (OCT), multi/hyperspectral imaging, Raman microscopy/spectroscopy, photoacoustic tomography, and multiphoton microscopy. The primary objective of these non-invasive technologies is to evaluate skin lesions in vivo in real time to reduce unnecessary biopsies and associated complications. Not surprisingly, the most common application of these non-invasive techniques is for the diagnosis and management of skin cancers.2 For this purpose, non-invasive techniques are primarily used as an adjunct tool to clinical evaluation and dermoscopy to confirm the diagnosis of a suspicious lesion to optimize the number needed to excise and consequently improve specificity but also sensitivity.

There are several advantages of non-invasive techniques over a biopsy. The biggest advantage is that since these techniques are performed in vivo, a bedside diagnosis can be made for appropriate and timely management of the lesion, which can spare biopsies for benign lesions, provide minimally invasive treatment options (topical application, photodynamic therapy, laser ablation, etc) for superficial and early skin cancers, and aid in the selection of biopsy techniques for malignant lesions (shave biopsy vs excisional biopsy). Another advantage is the ability to image skin tissue in its physiological state, enabling visualization of various dynamic phenomena such as blood flow, that may aid in cancer diagnosis. Furthermore, these techniques can be used to non-invasively monitor benign lesions and monitor post-treatment clearance and/or recurrence of cancer over a period of time. These technologies are not used only in oncologic dermatology; they also have applicability in cosmetic and inflammatory disease. Furthermore, most of these non-invasive technologies are also being used for a rapid evaluation of ex vivo tissue for intraoperative margin assessment of tumors during Mohs surgery. Despite a surge in non-invasive diagnostic tools, most of them are currently in a research phase with only a few already integrated into the routine diagnostic workflow.2 In this chapter, we will focus mainly on non-invasive optical imaging technologies that are currently being used in the clinic or have the potential to be integrated into clinics for in vivo use, including techniques such as RCM, OCT, and Raman spectroscopy. For each technology, we will discuss its basic principles and instrumentation, current applications, and limitations. We will also compare these technologies and their specific role in the diagnosis of skin lesions. As each technique has its own pros and cons, we will end this chapter with a brief discussion of some new multimodal approaches that could ultimately provide clinicians with their “dream-machine.”

Pigmented lesion experts, Dermspectra, Canfield, FotoFinder, Molemax, Molesafe, MoleMap, MelanoScan, Dermoscan, Visiomed; $10k–$250k

All dermatologists willing to invest in necessary training, six category 1 CPT reimbursement codes; Vivascope (Caliber ID and Mavig, formerly Lucid), Stratum (Optiscan); $100k

Total body digital photography (TBDP), regional imaging

Confocal microscopy (LSCM, CSLM, RCM) Identify diverse lesions for which biopsy can be avoided; preoperative mapping of malignancies including lentigo maligna for reduced surgical defects; melanoma vs benign nevi (sens 97%, spec 83%†) diagnosis of equivocal lesions vs

Monitoring melanocytic neoplasms in high risk pigmented lesion clinics, NMSC, and inflammatory diseases

Microscopic structures as in H&E but only in horizontal (en face) sections; 25 min for 6 × 6 mm image stack (including prep time described in CPT 96932)

Generally same features as clinical exam; 10 min for total body

Highest accuracy; only imaging technology with Medicare reimbursement; video-rate single-lesion, histology-grade (10 mm), e.g., 4 mm resolution at 5 mm depth

Limitations of currently available devices Little dermatologic clinical data

Technological developments and anticipations Much R&D needed; early data suggests sensitive detection of melanoma metastases in circulation and lymph nodes; high resolution microvasculature assessment; pilosebaceous unit imaging

AK: actinic keratosis; BCC: basal cell carcinoma; CARS: coherent anti-stokes Raman scattering; CSLM: confocal scanning laser microscopy; CPT: current procedure terminology; DEJ: dermoepidermal junction; FF-OCT: full-field optical coherence tomography; FTIR: Fourier transform infrared spectroscopy; GD-OCT: Gabor domain optical coherence tomography; H&E: hematoxilin and eosin; HAK: hyperkeratotic actinic keratosis; LASCA: laser speckle contrast analysis; LSCM: laser scanning confocal microscopy; MESI: multiexposure speckle imaging; MSOT: multispectral opto-acoustic tomography; NMF: natural moisturizing factor; OCT: optical coherence tomography. R&D: research and development; RCM: reflectance confocal microscopy; SCC: squamous cell carcinoma; Sens: sensitivity; SHG: second harmonic generation; SK: seborrhoeic keratosis; Spec: specificity. * Langley RG. Dermatology 2007;215(4):365–72 (125 patients single center). † Tkaczyk ER. Acta dermato-venereologica 2017; 97(218): 5–13. ‡ Guitera P. J Invest Dermatol. 2012;132(10):2386–94 (663 patients multicenter). § Monheit G. Arch Dermatol. 2011;147(2):188–94 (1,251 patients multicenter). || Tomatis S. Phys Med Biol. 2005;21;50(8):1675–87 (1,278 patients single center). ¶ Ulrich M. Br J Dermatol. 2015;173(2):428–35 (250 patients multicenter). ** Weibel L. et al. Arthritis Rheum. 2007;56(10):3489-95 (111 lesions). †† Zhao J. et al. Analyst 2016;7;141(3):1034–43 (127 lesions tested). ‡‡ Dimitrow E, et al. J Invest Dermatol. 2009;129(7):1752–8 (53 lesions). §§ Stoffels I, et al., Sci Transl Med. 2015;9;7(317):317ra199 (41 sentinel lymph nodes from 20 patients).

Fundamental technique and synonyms or variations Photoacoustic imaging (optoacoustic tomography, photoacoustic microscopy)

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Chapter 5: Principles of Non-invasive Diagnostic Techniques in Dermatology

REFLECTANCE CONFOCAL MICROSCOPY Of all the abovementioned non-invasive optical technologies, RCM has thus far shown the most promising results in the diagnosis and management of skin lesions.1 RCM has recently been granted category 1 current procedural terminology (CPT) reimbursement codes by the Centers for Medicare and Medicaid Services, and is now being integrated into the routine dermatology clinics; however, RCM is not a new technology.1 The history of RCM dates back to the 1950s when Marvin Minsky developed a confocal microscope to image a thick piece of brain tissue and obtained cellular resolution without performing traditional pathology.3 In 1995, Rajadhyaksha et al. demonstrated RCM imaging in human skin in vivo for the first time.4 In contrast to the conventional vertical sections in histopathology, the tissue is viewed in an en face plane on RCM.1

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Figs. 5.1A to E: Schematic diagram demonstrating the principles of reflectance confocal microscopy. (A) Represents the light source, an 830 nm diode laser; (B) The objective lens enables focusing at different depths; (C) The pinhole rejects “out-of-focus” light; (D) Only the infocus light enters the detector; (E) A confocal image generated in an en-face plane showing normal skin in vivo at cellular resolution.

Principles of RCM Most commercial RCM devices use a diode laser with a near-infrared wavelength (830  nm) as a monochromatic light source which penetrates the skin. It couples point illumination to a pinhole in the optical conjugate plane in front of the detector. This scheme eliminates out-of-focus signals, while allowing selective transmission of only the backscattered light from the illuminated point, thus the name “confocal” (Figs. 5.1A to E). By scanning the illumination point and collecting light from all the scanned points on a detector (which form pixels), an image of a thin “optical section” within the skin is produced noninvasively.5 This is in contrast to the conventional light microscopy where the entire tissue is flooded with a light source and all the backscattered light is allowed to enter the detector. RCM imaging with the Vivascope 1500 (Caliber ID, Rochester, NY, USA) provides optical sectioning of 2–5 µm and lateral resolution of 0.5–1.0 µm. It enables visualization of skin cells layer-by-layer starting from the superficial epidermis to papillary dermis, typically up to a depth of 200–250  µm (the imaging depth varies with the body site).6,7 Unlike histopathology where staining with hematoxylin and eosin dye is used to provide contrast for tissue visualization, RCM relies solely on one mechanism of contrast: reflection (i.e., back-scattering). Thus, images appear in the grayscale ranging from very bright structures to dark structures. This is due to sizes and mismatch in refractive

indices of interfaces within and between cells of the skin— hence the name RCM. Due to large mismatch in refractive index from bulk tissue, melanin, keratin, and collagen provide strong scattering contrast and serve as the sources of highest reflectance from the skin.4,8 Thus, cells containing melanin such as melanocytes (banal and malignant), melanized keratinocytes, and melanophages appear bright. Likewise, the cytoplasm of cells rich in keratin such as those found in the stratum corneum appear bright, as do non-cellular material like keratin cysts. Furthermore, keratohyalin granules present in the keratinocyte of stratum granulosum also appear bright. Another possible source of high reflectivity is the Birbeck granules in Langerhans cells. On the other hand, intranuclear content lacks the refractive index mismatches to cause reflectance, and so appear dark on confocal. This is also true for mucin secretions.

Instrumentation, Image Acquisition, and Interpretation Currently, there are two commercially available in vivo RCM devices for clinical use: an arm-mounted RCM (AMRCM) device (Vivascope 1500) and a hand-held RCM (HH-RCM) device (Vivascope 3000). The AM-RCM device enables visualization of large areas of the lesion by acquiring mosaics of images (displaying maximum area up to 8  mm × 8  mm at a time) at various depths in the skin.

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Section 2: Principles of Clinical Diagnosis Mosaics are obtained by stitching individual, 500  μm × 500 μm images together in “X–Y” (horizontal en face plane) to display a wide field of view. Additionally, single frame images (0.5 mm × 0.5 mm), stacks, and even videos can be acquired in the areas of interest. This device is attached to the skin by way of a disposable window and is well-suited for imaging flat and gently undulating body surfaces: trunk and extremities. HH-RCM, on the other hand, is a more flexible device used for imaging lesions located on curved and relatively more undulating body surfaces such as the nose, earlobes, eyelid, and genitalia. The HH-RCM acquires only single images, stacks, and videos (individual image frame measures 0.75 mm × 0.75 mm); mosaicking capability is currently not available on hand-held commercial devices. The decision to use either device relies on the characteristics and location of the lesion. The RCM images are interpreted in a manner that mimics evaluation of histopathology slides. Mosaics are evaluated first to get an overall architectural detail and identify areas of concern, akin to the evaluation of histology sections on scanning magnification (2×). Furthermore, the areas of interests are evaluated by zooming in on the mosaic for cellular details, similar to evaluating slides at high magnifications (~20–30×).

Normal Aspect of the Skin on Reflectance Confocal Microscopy To understand the pathologic processes, the first step is to familiarize oneself with the normal aspect of the skin on RCM. One should expect to see a variation in the appearance and thickness of the skin layers and density of the adnexal structures according to the anatomical site, age, and skin phototype. For example, the acral skin (skin of palms of the hands and soles of the feet) has the thickest stratum corneum compared to other body sites which hamper the evaluation of deeper layers such as the dermoepidermal junction (DEJ) and the dermis.4,6,9,10 Stratum corneum: The stratum corneum is the topmost layer of the skin and is located around 0–15 µm from the skin surface. This layer is the first bright layer encountered on RCM during imaging. The brightness arises from its high keratin content and from back-scattered light from the skin surface. Stratum corneum is composed of anucleated corneocytes that are large (20–45 µm), polygonalshaped, bright cells (Fig. 5.2A).4–6 Visible at this layer are the dark (due to lack of reflectance/contrast from air to air), linear non-reflective furrows of the dermatoglyphics that separate and delineate the bright islands of corneocytes. At this level, one can also visualize the superficial

part of the hair follicles (hair shafts and follicular orifice) and the eccrine ducts (acrosyringum and eccrine ostia). A hair shaft looks like tubular elongated non-cellular bright structures crossing the surface of the stratum corneum. At times, they are seen arising from the large dark holes of the follicular orifice. On the other hand, the acrosyringium is seen as the bright spiraling/coiling structures through the stratum corneum.11 Stratum granulosum: Moving down from the stratum corneum, the stratum granulosum is the first detectable nucleated layer of the skin. This layer is located around 15–25 µm from the skin surface and is composed of polygonal-shaped keratinocytes measuring up to 25–35  µm in diameter. The keratinocytes at this layer appear welldefined with a dark central nucleus and a surrounding rim of bright granular cytoplasm (organelles and keratohyalin granules impart bright granular appearance). These welldemarcated keratinocytes form a grid-like pattern resembling a honeycomb—hence the name honeycomb pattern. This pattern is seen both at the stratum granulosum and the stratum spinosum layer (Fig. 5.2B).4,6 Similar to the stratum corneum (as detailed above), dermatoglyphics, hair shafts, follicular orifice, acrosyringeal part, and eccrine ostia of the eccrine duct can also be visualized at this layer.11 Stratum spinosum: As we move further down from the stratum granulosum to stratum spinosum, the thickness (5–10 cells layer thick) of this layer increases while the size of the nucleated keratinocytes decreases to 15–25  µm in diameter. The previously described “honeycomb pattern” is the predominant feature of this layer. The intraepidermal portion of the acrosyringium and its orifice is often identified as bright, round swirling structures with a central dark hole spiraling through the epidermis. Additionally, dark round holes of the follicular orifice (with or without hair shaft) are also identified (Fig. 5.2C).4,6,11 Stratum basale: Stratum basale is the deepest layer of the epidermis and marks the transition between the stratum spinosum and the DEJ. It is usually located around 100–110  µm depth from the skin surface. The basal layer is composed of mainly basal keratinocytes and melanocytes. Both of these cells appear as small (measuring up to 7–12  µm in diameter) bright round to oval monomorphic cells. In healthy skin, it is not possible to distinguish between melanocytes and basal keratinocytes.4,6 The basal layer appears very bright and prominent in the skin phototypes (II–V) because of the high content of melanin present as a bright disk of the melanin caps on top of the basal cell nuclei. These bright disks group together at the basal layer, giving it an appearance of a cobblestone pattern

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Figs. 5.2A to F: Appearance of normal skin layers on reflectance confocal microscopy images. En-face reflectance confocal microscopy images acquired from the volar aspect of the forearm in a young healthy male with skin phototype II/III. (A) Stratum corneum shows as a highly reflective bright layer composed of anucleated large corneocytes (red arrows). Skin folds or dermatoglyphics (asterisk) appear as dark (non-reflective) linear furrows separating the bright corneal islands. A hair shaft appears as an anucleated elongated tubular structure with some bright keratin, visualized traversing the epidermis (yellow arrow); (B) Stratum granulosum shows a regular honeycomb pattern comprised of individual keratinocytes (red arrow) with a dark nucleus and a rim of bright granular cytoplasm. Skin folds (asterisk) and a hair shaft (yellow arrow) can still be seen at this level; (C) Stratum spinosum shows a regular honeycomb pattern, similar to stratum granulosum, but is composed of smaller-sized keratinocytes (red arrows). Skin folds (asterisk) are barely visible at this level; (D) Stratum basale shows a combination of a honeycomb (yellow asterisks) and a cobblestone pattern (red arrows). The latter is composed of a cluster of small bright (hypereflective) pigmented keratinocytes; (E) DEJ shows a ringed pattern (red arrows; “edged papillae”) composed of small uniform bright cells (basal melanocytes and pigmented keratinocytes) lining the dark round structures of dermal papillae (white asterisk). Thin vessels (yellow arrows) are seen within the dermal papillae (white asterisk); (F) Papillary dermis shows bright elongated fibrillar collagen fibres (red arrows). A–F = 500 µm × 500 µm. (DEJ: dermoepidermal junction)

(Fig.  5.2D). In contrast to the dark skin phototype (II–V), the basal layer in skin phototype I shows low refractivity and is often challenging to identify. Dermoepidermal junction (DEJ): DEJ is probably one of the most important layers of the skin as most pathological processes originate at this layer. Thus, it is important to identify this layer on RCM. The DEJ is an undulating layer on histopathology. On RCM, the DEJ is recognized by the presence of round to oval bright rings rimmed by basal cells that surround the central dark round area of dermal papillae. This pattern of dermal papilla lined by bright basal keratinocytes has been termed edged papillae

(Fig. 5.2E). With increasing depth of imaging, these bright rings increase in size until the neighboring rings touch each other, indicating the tip of the rete-ridges and the end of DEJ.4–6 Dermal papillae typically contain blood vessels and collagen fibers that are minimally refractive. However, vessels are best appreciated during real-time imaging. Similar to the basal layer, the DEJ appears very prominent and bright in skin phototypes (II–V), while difficult to identify in lighter skin phototype (I). It can also be challenging to identify the DEJ in anatomical sites with flattened reteridges such as the face or severly sun-damaged skin. At the deeper levels of DEJ, the acrosyringium has subtle bright

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Applications Thus far, RCM has been extensively used in the field of dermato-oncology. Here, RCM is being implemented as an adjunct to clinical and dermoscopic examination for the diagnosis of equivocal lesions. RCM is proven to be valuable for the diagnosis of both pigmented and nonpigmented skin lesions.15–17 Specifically, it has remarkably improved the diagnosis of non-pigmented and featureless lesions over dermoscopy.18 Aside from diagnosing equivocal lesions, RCM also plays an important role in image-guided laser ablation, radiation therapy, topical (Imiquimod), and photodynamic therapy of superficial and early nodular types of basal cell carcinomas (BCCs).19 It is also being used for delineating surgical margins of the large facial lesions of lentigo maligna (LM)20,21 as well as guiding biopsy acquisition in an ill-defined lesion such that of an extramammary Paget disease.22 Recently, the use of RCM has expanded beyond the realm of dermato-oncology to encompass the diagnosis of inflammatory, infectious, and vascular lesions. Inflammatory lesions include

dermatitis (Fig. 5.3), pemphigus,23 pemphigoids,24 and Stevens-Johnson syndrome.25 Infectious diseases include herpes simplex, zoster,23 molluscum contagiosum,26 onychomycosis,27 tinea,28 scabies,29,30 Demodex spp. (Fig. 5.4), and Dermanyssus gallinae.31 Vascular lesions include hemangiomas and vascular tumors.13 Due to the limited scope of this book chapter, our focus will be to describe the features

Fig. 5.3: View of allergic contact dermatitis by reflectance confocal microscopy. Images from a 37-year-old female who presented with an erythematous lesion on her right forearm within 5 days of poison ivy exposure. Clinical image (inset) shows an unspecific erythematous lesion. On RCM, microvesicles (white arrows) are distinctly seen in the stratum spinosum (white asterisks), confirming the diagnosis of an allergic contact dermatitis. RCM submosaic = 1.5 mm × 1 mm. (RCM: reflectance confocal microscopy)

Fig. 5.4: Reflectance confocal microscopy images of a Demodex mite. RCM image acquired at the epidermal level from a cheek of a 60-yearold male shows a cross-sectional view of a Demodex spp. mite (red circle) within a follicular infundibulum (red arrow). RCM image = 1 mm × 1 mm. (RCM: reflectance confocal microscopy)

Chapter 5: Principles of Non-invasive Diagnostic Techniques in Dermatology of commonly encountered benign and malignant cutaneous neoplasms and the role of RCM in their diagnosis.

Nonmelanocytic Neoplasms Several studies reported RCM imaging to achieve a sensitivity of 92%–100% and specificity 85%–97% for non-melanoma skin cancer (NMSCs).15,17,32 It is especially valuable for the non-pigmented non-melanocytic lesions that are featureless on dermoscopy.1 Basal cell carcinoma: Amongst all NMSCs, BCC has shown the highest diagnostic sensitivity of 100% and specificity of 95.7% by RCM,15,33 including clinically subtle and difficult to diagnose BCC lesions.34 The diagnostic criteria for BCC were first described by Gonzalez et al. in 2002. This included features such as elongated monomorphic nuclei, polarization of epidermis nuclei along the same axis (streaming), a prominent inflammatory infiltrate, increased dermal vasculature, and pleomorphism of the overlying epidermis.35 Later, various additional RCM features of BCC were reported including tumor islands with palisading and clefting and cord-like structures. These latter features were found to be highly specific for the diagnosis of BCC.36 Pigmented BCCs are relatively easy to diagnose because of their high melanin content present in the intratumoral melanocytes and the surrounding melanophages (Fig. 5.5). On the contrary, non-pigmented BCC lacks melanin pigment making them diagnostically challenging. Clues to differentiate various subtypes of BCC (superficial, nodular, and infiltrative) have been described.36 Nodular BCC (nBCC) shows tumor nests with peripheral palisading, “cleft-like space,” branch-like structures, fibrotic septa, and dilated blood vessels. Superficial BCC (sBCC) is characterized by solar elastosis and cord-like structures connected with the basal layer and an absence of “cleft-like space.” Infiltrative BCC (iBCC) is difficult to diagnose on RCM, but it can often be suspected in the presence of dark silhouettes with abundant surrounding bright collagen fibers and absence of the characteristic features of sBCC and nBCC.37 The ability to identify various subtypes of BCC in vivo may impact their management, including the use of non-surgical modalities (e.g. imiquimod) for sBCCs and surgical modalities for nBCC or iBCC.38 RCM not only aids in the diagnosis of BCC; it is also used to delineate the tumor margins and monitor the efficacy of a non-invasive treatment.37,39–41 Actinic keratosis and squamous cell carcinoma: Actinic keratosis (AK) and squamous cell carcinoma (SCC) represent different stages in the keratinocytic dysplasia-carcinoma spectrum. The key features of the

Fig. 5.5: Diagnosis of a basal cell carcinoma on reflectance confocal microscopy. Images from an 85-year-old female who presented for the evaluation of a new lesion on her left forearm. Dermoscopy (inset) showed blue-gray globule (white arrows) and telangiectatic vessels (yellow arrows), highly suspicious for a basal cell carcinoma. On RCM (images acquired at the DEJ level), the ovoid nests corresponded to the tumor islands (white arrows) with “peripheral palisading” and “clefting” (red arrowheads). Surrounding the tumor islands were dilated canalicular vessels (yellow arrows) and bright fibrous stroma (red asterisks). Based on the dermoscopic and RCM features a diagnosis of BCC was made. The lesion was treated topically with imiquimod. The patient is now recurrence-free after 1-year of follow-up. RCM submosaic = 2 mm × 1.5 mm. (BCC: basal cell carcinoma; DEJ: dermoepidermal junction; RCM: reflectance confocal microscopy)

lesions include an “atypical honeycomb pattern,” roundnucleated cells at the stratum granulosum (dyskeratosis), and multiple round blood vessels traversing through the dermal papillae that run perpendicular to the skin surface (“button-hole” vessels; Figs. 5.6A and B). Parakeratosis (white oval nuclei surrounding the dark cytoplasm in the stratum corneum) and scale (refractile amorphous material) may also be seen in both the lesions.42 Bowen disease and SCC may additionally show “targetoid cells,” representing apoptotic keratinocytes.43 Due to the overlapping features between AK and SCC on RCM, it is not always possible to differentiate between these two entities. However, as a general rule, keratinocyte atypia is milder and focal in AK but more extensive and diffuse in SCC. Seborrheic keratosis and solar lentigo: Seborrheic keratosis (SK) and solar lentigo (SL) belong to the same spectrum of benign neoplasms with overlapping clinical, dermoscopic, histopathologic, and RCM features. These lesions can often easily be diagnosed clinically or dermoscopically and do not require RCM evaluation; however, they may at times mimic LM, especially when located on sun-exposed sites such as the

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Figs. 5.6A and B: Diagnosis of a squamous cell carcinoma on reflectance confocal microscopy. (A) Images from a 58-year-old female who presented with a new erythematous plaque. Dermoscopy (inset) showed diffuse dotted vessels and scale and included a differential diagnosis of Bowen disease vs amelanotic melanoma. RCM (images acquired at the epidermal/DEJ level) showed a disarranged epidermal pattern with atypical keratinocytes (white asterisks) and multiple round blood vessels visible, also called “button-holes” vessels high-up in the epidermis (traversing from the dermis to the epidermis) (white arrows). Based on the dermoscopic and RCM features, a diagnosis of SCC was made; (B) A biopsy was performed that confirmed the diagnosis of a squamous cell carcinoma in situ on H&E. A = 2 mm × 1.5 mm (RCM submosaic); B = 20× magnification (H&E image). (DEJ: dermoepidermal junction; H&E: hematoxilin and eosin; RCM: reflectance confocal microscopy; SCC: squamous cell carcinoma)

face. RCM is very valuable in differentiating SL/SK from LM in the pigmented facial macules.44 To rule out LM, the first step is to exclude any large nucleated (round or dendritic) bright cells (pagetoid cells)—a hallmark of LM—in the epidermis. In contrast to LM, the epidermis in SL/SK has a regular honeycomb and/or cobblestone pattern devoid of any pagetosis. At the DEJ, both SL and SK show bright elongated cords (polycyclic DEJ pattern) lined by a layer of monomorphic cell with no cytological atypia (Fig. 5.7). In particular, SK has a papillated surface (also called cerebriform surface) with surface holes and fissures (crypts), and horn/pseudohorn cyst that are characterized with bright round structures within the epidermis or dermis.44,45 In pigmented SK, isolated epidermal dendritic cells (activated banal melanocytes) and plump-bright melanophages can also be seen in the dermis. Additionally, dilated round and linear blood vessels in the papillary dermis are common (47%).45

Melanoma and Melanocytic Lesions RCM is an excellent non-invasive imaging modality to evaluate clinical and dermoscopic suspicious melanocytic lesions. This is due to the strong contrast provided by melanin. RCM has shown a high sensitivity of 93% and a high specificity of 76% for diagnosing melanoma.46 Although the sensitivity is similar to that of dermoscopy (88% vs 91%), RCM has improved the specificity of melanoma detection by a factor of two (32% vs 68%).47 It has been

Fig. 5.7: Diagnosis of a solar lentigo on reflectance confocal microscopy. Images from a 79-year-old male who presented with a pigmented retroauricular macule. On RCM (images acquired at the DEJ level), a polycyclic papillary contour (red arrows) with elongated bulbous projections (yellow arrows) were identified. No pagetoid or atypical cells were identified. A diagnosis of solar lentigo was made and the patient spared a biopsy. 0.75 x 0.75 mm. (DEJ: dermoepidermal junction; RCM: reflectance confocal microscopy)

particularly useful for the detection of hypomelanotic and amelanotic melanomas that are difficult to diagnose on

Chapter 5: Principles of Non-invasive Diagnostic Techniques in Dermatology dermoscopy.47–50 Likewise, RCM has shown a high sensitivity of 85%–93% and specificity of 76%–82% for diagnosing LM subtype.51 While evaluating RCM features of melanocytic lesions, both the architectural and cytological details (similar to histopathological evaluation) should be evaluated. Also, it is very important to correlate the clinical and dermoscopic finding with RCM to arrive at a final diagnosis. Due to the limited scope of this book chapter, we will only describe RCM features of some common acquired nevi and melanoma using the 2007 consensus terminology7 as well as recently described terminology.52 a. Nevi: In order to exclude a diagnosis of melanoma, it is imperative to learn to recognize the benign patterns of the common acquired nevi at various skin layers. The DEJ is the most important layer to evaluate in melanocytic lesions, followed by the epidermis. At the DEJ, various welldefined benign patterns can be recognized including the “ringed,” the “meshwork,” and the “clods” pattern or a combination of any of these patterns called the “mixed” pattern.52 No atypical cells are identified at the DEJ. Junctional nevi usually show a “ringed” or a “meshwork” pattern” (Fig. 5.8). The “ringed pattern” is often appreciated when there is a predominance of the “edged papillae” in a lesion (Fig. 5.8) and correlates well with the junctional nevi with lentiginous proliferation or small melanocytic nests on

Fig. 5.8: Diagnosis of a compound nevus on reflectance confocal microscopy. Images from a 30-year-old female who presented with a new pigmented macule on her left forearm. Dermoscopy (inset) showed benign features of regular peripheral network (white arrows) and central globules (red arrows). On RCM (images acquired at the DEJ level), the central globules corresponded to regular dense nests (red arrows) and the peripheral network corresponded to “edged-papillae” forming a “ring pattern” (white arrows). This was compatible with the diagnosis of a benign compound nevus. A= 3 mm × 2 mm (RCM submosaic). (DEJ: dermoepidermal junction; RCM: reflectance confocal microscopy)

histopathology. The “meshwork” pattern is seen as an interconnected, thickened, elongated structure widening the interpapillary spaces. This pattern correlates well with junctional nevi with a predominant nested pattern on histopathology.52 “Clod pattern” is defined by a predominance of dense compact nests/clusters of melanocytes within the superficial dermis.52 This pattern is usually seen in intradermal nevi, where clusters of bright monomorphic cells fill and expand the dermal papillae and correlate well with the large dermal nests or aggregates of nevocytes on histopathology. The “mixed pattern” is usually seen in compound nevi. In most of the common acquired nevi, the suprabasal layer typically shows either a honeycomb or a cobblestone pattern or both. Usually no pagetosis, described as large bright nucleated round or dendritic cells (a hallmark of melanoma), are seen. The exception to this rule can be seen in recurrent53 or traumatized nevi, Spitz nevi,54 and dysplastic nevi with severe atypia.55 Melanoma: Similar to the evaluation of the nevi, the diagnosis of melanoma begins with the evaluation of the DEJ. However, one should be aware that the RCM features of melanoma may vary according to its subtype and dermal melanomas will generally be missed completely on RCM due to the lack of any component within the depths accessible to RCM imaging. Herein, we describe the features of the two most common subtypes of melanomas— superficial spreading melanoma (SSM) and LM melanoma. SSM often shows an “aspecific” pattern or a disarrangement at the DEJ with “non-edged” papillae (defined as dermal papillae without a well-outlined contour) and the presence of a varied number of large “markedly atypical cells” (Figs. 5.9A and B).56,57 After evaluating the DEJ, it is important to evaluate the epidermal layer to identify any “pagetoid cells”—another hallmark of melanoma. Pagetoid cells are defined as large (at least twice the size of a neighboring keratinocyte), round, dendritic, or spindle-shaped atypical cells with bright (refractive) cytoplasm and hyporeflective nucleus (Figs. 5.9A and B).7 The widespread pagetoid infiltration and their periphery location (focal and central pagetosis can often be seen in dysplastic nevi, traumatized nevi, or Spitz nevi) in the lesion is diagnostic for melanoma. Finally, dermis should also be evaluated for the presence of any atypical cells that may be single cells, in a “sheetlike” distribution, or as irregular non-homogenous nests (also called “sparse nests”), signifying dermal invasion. Infrequently, “cerebriform nests” may also be seen in the dermis of SSM with a nodular component.57 Enlarged vessels and melanophages can also be identified in the dermis. The LM type melanoma usually appears on sundamaged, chronically exposed skin. RCM shows atypical

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Figs. 5.9A and B: Diagnosis of a superficial spreading melanoma on reflectance confocal microscopy. (A) Images from a 59-year-old female who presented for the evaluation of a highly suspicious pigmented lesion on her right arm. Dermoscopy (inset) showed an atypical network with streaks, regression, and shiny white structures—features highly suspicious for a melanoma. On RCM (images acquired at the suprabasal/ DEJ level), numerous atypical, pleomorphic nucleated (round and dendritic; white and red arrows, respectively) pagetoid cells were identified arranged singly and in clusters in the suprabasal layer. Non-edged papilla at the DEJ (asterisks), and bright dots in the epidermal layer (yellow arrowheads) were also seen; (B) A biopsy was performed that confirmed the diagnosis of an invasive superficial spreading melanoma with a 0.65 mm Breslow thickness. A = 3 mm × 2.5 mm (RCM submosaic); B = 20× magnification (H&E image). (DEJ: dermoepidermal junction; H&E: hematoxilin and eosin; RCM: reflectance confocal microscopy)

dendritic cells infiltrating the hair follicle. Guitera et al. defined various major criteria (non-edged papilla, round pagetoid cells >20  µm in diameter) and minor criteria (atypical cells at DEJ in five images of 0.5 × 0.5 mm,2 follicular localization of pagetoid cells, and/or atypical junctional cells; nucleated cells within the papilla) for diagnosing LM.51 However, in clinical practice, the most relevant features for LM are the presence of an abundant round and large pagetoid cells in the suprabasal layer distribution with folliculotropism (Fig. 5.10).20,51

Limitations and Future Development The main limitation of RCM technology is the shallow depth of imaging that precludes the evaluation of lesions located in the deep dermis.1 Another limitation is the lack of specificity to differentiate various cell types such as Langerhans cells from dendritic pagetoid cells of melanoma58 and differentiating various BCC mimickers such as hair follicles and epidermal proliferations59 from BCC tumor nodules. Moreover, RCM requires a trained, dedicated person to capture the images, and access to a physician trained in interpreting the images (either on staff or remote access). Once slow image acquisition was a limiting factor for the clinical workflow has now been overcome by a faster new generation of AM-RCM, reducing the original speed of image acquisition from 20-25 minutes to 5-10 minutes. Reading the en-face RCM images in grayscale requires

Fig. 5.10: Diagnosis of a lentigo maligna on reflectance confocal microscopy. Images from an 80-year-old female who presented with a new pigmented lesion on her left cheek. Dermoscopy (inset) showed asymmetric pigmentation of follicular openings. On RCM, sheets of atypical large nucleated dendritic cells (red arrows) were seen surrounding the hair follicles (asterisks). RCM submosaic = 2  mm × 1.5 mm. (RCM: reflectance confocal microscopy)

specialized training;1 however, access to remote image interpretation by a trained physician is provided by way of a HIPAA-compliant, secure private network with Digital Images and Communication in Medicine (DICOM) compatibility. Certain limitations are device specific. For example, the HH-RCM device not only has a small field-of-view of

Chapter 5: Principles of Non-invasive Diagnostic Techniques in Dermatology imaging but also lacks dermoscopic guidance, at times leading to false-negative results.1 To improve the diagnostic ability of HH-RCM, a video-mosaicking approach60 and integration of a white field camera in HH-RCM61 are under development; however, application of these technologies into commercial devices is yet to be accomplished. The former will enable large field-of-view, while the latter will provide dermoscopic guidance during imaging.60,61

OPTICAL COHERENCE TOMOGRAPHY Principle and Instrumentation OCT is the second most common non-invasive optical imaging technique (after RCM) that is used in clinics. It is based on low-coherence interferometry to detect the intensity of backscattered infrared light (910 nm–1,305 nm wavelengths) from biological tissues at differing optical path lengths.62 OCT produce a real-time, in vivo , crosssectional (vertical) images, similar to an ultrasound image but with much higher resolution (micron scale). The conventional frequency domain (FD)-OCT has a lateral resolution of approximately 7.5  µm and provides an optical sectioning (or axial resolution) of 5–10 µm.63 Additionally, FD-OCT generates large field of view images measuring 6.0 × 6.0  mm–10  mm.62 Unlike RCM, where the depth of imaging is up to 250 µm, OCT can image up to 1 mm–2 mm (>1,000 µm) deep in the skin. However, this depth of imaging is achieved at the cost of a much lower resolution, without visualization of cellular details.64 The newer highdefinition OCT (HD-OCT; swept-source and time domain) has a better lateral resolution of 3 µm but a shallower depth of imaging of 0.57 mm and a smaller field of view of 1.5 × 1.8 mm62 (Vivosight, Michelson Diagnostics, Kent, United Kingdom); however, these specs vary with the commercial device used.

inflammatory lesions, as well as to identify various infectious skin diseases. Besides diagnosis, OCT is also valuable for non-invasively monitoring the tumor clearance and therapy efficacy.63 Additionally, the newer generation Dynamic OCT (D-OCT) enables in vivo characterization of blood vessels (including the deeper vascular network of the dermis) to assess the metastatic potential of a tumor. Normal skin: Under OCT, normal skin shows a layered structure with varying signal intensities. The stratum corneum appears as two thin bright lines, followed by a layer of the less-signal-intense epidermis. The DEJ is observed as an undulated dark line with an underlying signalintense dermis. Blood vessels and hair follicles can also be identified in the dermis (Fig. 5.11).63 Basal cell carcinoma: According to the largest conducted study, addition of OCT with dermoscopy showed significant improvement in the specificity (from 54.3 to 75.3%) of diagnosing BCC, without much impact on sensitivity (90%–95%).65 BCC is characterized by (1) alteration in the undulating appearance of the DEJ by hyporeflective tumor nodules, (2) change of surface contour in the hypoflective tumor area, and (3) prominent dilated vessels in the superficial dermis below the hyporeflective nodules (Fig. 5.12). Furthermore, it can reliably differentiate between sBCC and nBCC.66 In sBCC, the tumor nodules are adherent to the epidermis and separated from bright collagen by “clefting” at its inferior border, while this “clefting” completely encompasses the nodule of nBCC nodule and separates it from the collagen.65–69 Actinic keratosis and squamous cell carcinoma: Distinguishing AK from SCC has clinical and therapeutic

Applications Recently, some of the OCT devices have acquired a license for clinical use in Europe and an FDA approval in the USA. OCT is mostly used for the diagnosis and management of BCC. While RCM can differentiate benign from malignant lesions (related to cellular resolution), OCT can provide depth, location, and thickness of the lesion (related to the increased depth of imaging). It may also be used for differentiating AK from SCC, but this role is still preliminary. Furthermore, OCT is not a suitable technique for diagnosing melanocytic lesions.63 It has also been explored for the diagnosis of nail lesions and to determine the nature of

Fig. 5.11: Appearance of normal on optical coherence tomography. OCT image of healthy skin of the forearm shows a layered (vertical) structure with a bright entrance signal in the stratum corneum (“E” stands for the epidermis), “DEJ” for dermoepidermal junction, and dermis (D). Blood vessels (V) and hair follicles (HF) are also identified. OCT image= 6 × 2 mm. (DEJ: dermoepidermal junction; OCT: optical coherence tomography) Courtesy: Prof. Dr. Julia Welzel, General Hospital Augsburg, Department of Dermatology and Allergology, Augsburg, Germany. Reprinted with permission from Sattler E, Kastle R, Welzel J. “Optical coherence tomography in dermatology.” J Biomed Opt. 2013;18(6):061224. OCT image = 6 × 2 mm.

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Fig. 5.12: Optical coherence tomography image of a basal cell carcinoma. OCT image of a basal cell carcinoma showing tumor island (white arrow) with clefting. OCT image= 6 × 2 mm. (OCT: optical coherence tomography) Courtesy: Prof. Dr. Julia Welzel, General Hospital Augsburg, Department of Dermatology and Allergology, Augsburg, Germany. Reprinted with permission from Sattler E, Kastle R, Welzel J. “Optical coherence tomography in dermatology.” J Biomed Opt. 2013;18(6):061224.

implications. AK appears as a hyperechogenic areas that correspond to hyperkeratotic scales and thickening of the epidermis. The DEJ has an ill-defined border but appears well-demarcated from the dermis. SCC tends to display larger and wider areas of DEJ disruption (absence of an outlined DEJ) than AK. However, it has also overlapping features with AK such as hyperkeratosis and epidermal thickening.62,70 In contrast to AK/SCC, invasive SCC shows a marked disruption of the DEJ. With HD-OCT, one can sometimes visualize the invasion of adnexal structures.71 Melanoma and melanocytic lesions: Pigmented lesions show irregular scattering on OCT due to melanin. Features of early melanoma are difficult to diagnose with OCT; however, loss of DEJ can be seen in an invasive melanoma.63

Raman spectroscopy is based on the Raman scattering effect discovered by the Nobel Prize laureate Sir CV Raman in 1928.72,73 The Raman scattering effect describes an inelastic exchange of energy between light and matter.72,73 Raman spectroscopy uses a laser light source (785-nm wavelength) to change the vibrational state of molecular bonds. Photons either get scattered or absorbed upon encountering a molecule. The scattered photons have the same energy and wavelength as the incident photon (“elastic scattering”). Only a minor fraction of photons (10−10) show a slightly different energy (“inelastic scattering”), causing a shift in the light that is reflected back to a sensor. This minor energy difference between the incident and inelastic photon is called the “Raman Effect” (or Raman shift). This energy difference corresponds to the unique vibrational levels of the scattering molecule.72,74 Due to an inverse relation of photon energy with wavelength, the Raman Effect shows a slight color difference for the scattered photon. This color shift may be evaluable with a highly sensitive spectrometer, hence the name “Raman spectroscopy.” The plotting of transitions as a spectrum provides a “molecular fingerprint” that is used to identify cancerous lesions.72,75 A commercial clinical laser Raman spectroscopy device has been developed to evaluate skin in vivo in human subjects. It is a hand-held device that uses 785-nm lasers as a light source (Aura systems, Verisante, Canada). Raw signals from a 3.5-mm diameter area of skin are collected. The attached spectrometer performs the spectral analysis in less than 1 s.

Limitations

Applications

Most OCT devices generate low-resolution images and cannot image at the cellular level. With the advent of new HD-OCT devices, this limitation has been addressed to some extent. OCT is also not suitable for the diagnosis of melanoma, as previously mentioned.

In contrast to RCM and OCT, current Raman spectroscopy devices cannot produce an image for interpretation by a clinician. Instead, bulk spectra across the different wavelengths are analyzed by a computer and results are displayed as a percentage predicted probability for malignancy for a given lesion using an automated internal algorithm based on training sets.72 The largest clinical study of Raman spectroscopy for in vivo diagnosis of 512 different skin lesions both malignant and benign (melanomas, basal cell carcinomas, SCCs, actinic keratoses, atypical nevi, melanocytic nevi, blue nevi, and seborrheic keratoses) was published in 2012. In this study, a sensitivity of 90% and a specificity of 64% was achieved in differentiating benign from malignant lesions using a computer-generated automated algorithm, but testing was only performed within

RAMAN SPECTROSCOPY Raman spectroscopy has acquired a license in Europe for in vivo evaluation of lesions that are clinically suspicious for skin cancers (SCC and/or basal cell carcinoma); however, it is not approved for clinical use in the USA. Unlike RCM and OCT that provides morphological information, Raman has the capability of detecting molecular and/or biochemical changes, also called “molecular footprints,” associated with various diseases.

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Limitations

the same set of lesions that was used for training, so it is not clear how accurate the device would be if it were used prospectively, or in a different clinical setting.75 Aside from dermato-oncology applications, Raman spec­ troscopy has also been demonstrated to be useful in inflammatory conditions such as vitiligo, psoriasis, melasma, and bullous diseases.73 The most widely accepted role of Raman spectroscopy has been in atopic dermatitis to monitor specific signatures of natural moisturizing factor (NMF) levels to predict FLG mutation status, thereby overcoming the need for the more invasive or technically demanding genotyping.2 It is also being used in cosmetic industry for determining skin hydration, antioxidant levels, and distribution of cosmetics.

Raman spectroscopy is still in its experimental phase. Prospective studies are needed to establish its diagnostic potential.

FUTURE ADVANCEMENTS IN THE NONINVASIVE IMAGING TECHNIQUES In recent years, non-invasive imaging in the dermatological field has brought about a major paradigm shift in the diagnosis and management of skin lesions, especially skin cancers. However, as discussed in this chapter, all mentioned technologies have their own pros and cons and there is not yet

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Figs. 5.13A to E: RCM-OCT image of a basal cell carcinoma. (A) Clinical image showing an erythematous macule on the back; (A) Dermoscopy image showing shiny white lines and serpentine vessels; (B) Cross-sectional and (C) enface OCT images showing multiple hypoechoic areas (arrows), suggestive of BCC; (D) Reflectance confocal microscopy showing cord-like structures with peripheral palisading (arrows) within a fibrotic stroma, suggestive of BCC; (E) Histology image of the lesion (confirming the diagnosis of superficial BCC), showing multiple small tumor nests originating from the epidermis (H&E, 4× magnification) (OCT: optical coherence tomography; RCM: reflectance confocal microscopy; BCC: basal cell carcinoma; H&E: hematoxilin and eosin). Courtesy: Nicusor Iftimia, Physical Sciences, Inc., Andover, Massachusetts, United States. Reprinted with permission from Iftimia N, Yelamos O, Chen CJ, Maguluri G, Cordova MA, Sahu A et al. “Handheld optical coherence tomography-reflectance confocal microscopy probe for detection of basal cell carcinoma and delineation of margins.” J Biomed Opt. 2017;22:76006.

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Section 2: Principles of Clinical Diagnosis a perfect device that can be used in the clinic.2 To overcome these limitations, non-invasive imaging is now advancing toward a new era of imaging called the “multi-modal approach,” whereby a combination of devices could lead to better diagnosis by a synergistic association. Such devices include, but are not limited to, a combination of RCM–OCT device,64 RCM with two-photon microscopy76 or spectral imaging device, and Confocal Raman spectroscopy.77 Most of these devices are in early-stage research explorations.78 The RCM–OCT prototype (Figs. 5.13A to E) is now being tested in the clinical setting for the evaluation of deeper margins of BCC in anticipation of guiding management.64,78

Conflict of Interest None.

Funding Source Dr. Tkaczyk is grateful for support from NIH K12 CA 090625. This research is funded in part by a grant from the National Cancer Institute / National Institutes of Health (P30-CA008748) made to the Memorial Sloan Kettering Cancer Center. And upload when it is ready the appropriate copy of this chapter accordingly to PMC with your appropriate embargo, if you are able.

ACKNOWLEDGMENT Dr. Tkaczyk was supported for this work by Career Development Award Number IK2 CX001785 from the United Sates Department of Veterans Affairs Clinical Science R&D (CSRD) Service.

REFERENCES 1. Rajadhyaksha M, Marghoob A, Rossi A, et al. Reflectance confocal microscopy of skin in vivo: from bench to bedside. Lasers Surg Med 2017;49:7–19. 2. Tkaczyk E. Innovations and developments in dermatologic non-invasive optical imaging and potential clinical applications. Acta Derm Venereol 2017;97(218):5–13. 3. Minsky M. Memoir on inventing the confocal scanning microscope. Scanning 1988;10:128–38. 4. Rajadhyaksha M, Grossman M, Esterowitz D, et al. In vivo confocal scanning laser microscopy of human skin: melanin provides strong contrast. J Invest Dermatol 1995;104:946–52. 5. Gonzalez S. Confocal reflectance microscopy in dermatology: promise and reality of non-invasive diagnosis and monitoring. Actas Dermosifiliogr 2009;100 Suppl 2: 59–69. 6. Rajadhyaksha M, Gonzalez S, Zavislan JM, et al. In vivo confocal scanning laser microscopy of human skin II:

advances in instrumentation and comparison with histology. J Invest Dermatol 1999;113:293–303. 7. Scope A, Benvenuto-Andrade C, Agero AL, et al. In vivo reflectance confocal microscopy imaging of melanocytic skin lesions: consensus terminology glossary and illustrative images. J Am Acad Dermatol 2007;57:644–58. 8. Calzavara-Pinton P, Longo C, Venturini M, et al. Reflectance confocal microscopy for in vivo skin imaging. Photochem Photobiol 2008;84:1421–30. 9. Robertson K, Rees JL. Variation in epidermal morphology in human skin at different body sites as measured by reflectance confocal microscopy. Acta Derm Venereol 2010;90:368–73. 10. Huzaira M, Rius F, Rajadhyaksha M, et al. Topographic variations in normal skin, as viewed by in vivo reflectance confocal microscopy. J Invest Dermatol 2001;116:846–52. 11. Gonzalez S. Reflectance confocal microscopy of cutaneous tumors. 2nd ed. In: Gonzalez S, editor. Boca Raton, FL: CRC Press; 2018. p. 535. 12. Busam KJ, Charles C, Lee G, et al. Morphologic features of melanocytes, pigmented keratinocytes, and melanophages by in vivo confocal scanning laser microscopy. Mod Pathol 2001;14:862–8. 13. Navarrete-Dechent C, Schwartz R, Gonzalez S, et al. Reflectance confocal microscopy in the evaluation of targetoid haemosiderotic haemangioma apropos two cases. Australas J Dermatol 2017;59(2):135–7. https://www. ncbi.nlm.nih.gov/pubmed/28498483. 14. Guitera P, Li LX, Scolyer RA, et al. Morphologic features of melanophages under in vivo reflectance confocal microscopy. Arch Dermatol 2010;146:492–8. 15. Nori S, Rius-Diaz F, Cuevas J, et al. Sensitivity and specificity of reflectance-mode confocal microscopy for in vivo diagnosis of basal cell carcinoma: a multicenter study. J Am Acad Dermatol 2004;51:923–30. 16. Gerger A, Koller S, Weger W, et al. Sensitivity and specificity of confocal laser-scanning microscopy for in vivo diagnosis of malignant skin tumors. Cancer 2006;107:193–200. 17. Pellacani G, Guitera P, Longo C, et al. The impact of in vivo reflectance confocal microscopy for the diagnostic accuracy of melanoma and equivocal melanocytic lesions. J Investig Dermatol 2007;127:2759–65. 18. Langley RG, Walsh N, Sutherland AE, et al. The diagnostic accuracy of in vivo confocal scanning laser microscopy compared to dermoscopy of benign and malignant melanocytic lesions: a prospective study. Dermatology 2007;215:365–72. 19. Sierra H, Yelamos O, Cordova M, et al. Reflectance confocal microscopy-guided laser ablation of basal cell carcinomas: initial clinical experience. J Biomed Opt 2017;22:1–13. 20. Menge TD, Hibler BP, Cordova MA, et al. Concordance of handheld reflectance confocal microscopy (RCM) with histopathology in the diagnosis of lentigo maligna (LM): a prospective study. J Am Acad Dermatol 2016;74:1114–20. 21. Chen CS, Elias M, Busam K, et al. Multimodal in vivo optical imaging, including confocal microscopy, facilitates presurgical margin mapping for clinically complex lentigo maligna melanoma. Br J Dermatol 2005;153:1031–6. 22. Yelamos O, Hibler BP, Cordova M, et al. Handheld reflectance confocal microscopy for the detection of recurrent

Chapter 5: Principles of Non-invasive Diagnostic Techniques in Dermatology

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extramammary paget disease. JAMA Dermatol 2017; 153(7):689–93. Lacarrubba F, Verzi AE, Pippione M, et al. Reflectance confocal microscopy in the diagnosis of vesicobullous disorders: case series with pathologic and cytologic correlation and literature review. Skin Res Technol 2016;22:479–86. Samhaber KT, Buhl T, Brauns B, et al. Morphologic criteria of vesiculobullous skin disorders by in vivo reflectance confocal microscopy. J Dtsch Dermatol Ges 2016;14:797–805. Samhaber KT, Bertsch HP, Schon MP, et al. In vivo reflectance confocal microscopy of erythema multiforme and Stevens–Johnson syndrome: a histopathological correlation based on a case series. J Dtsch Dermatol Ges 2017;15:573–6. Lacarrubba F, Verzi AE, Ardigo M, et al. Handheld reflectance confocal microscopy for the diagnosis of molluscum contagiosum: histopathology and dermoscopy correlation. Australas J Dermatol 2017;58:e123–5. Pharaon M, Gari-Toussaint M, Khemis A, et al. Diagnosis and treatment monitoring of toenail onychomycosis by reflectance confocal microscopy: prospective cohort study in 58 patients. J Am Acad Dermatol 2014;71:56–61. Navarrete-Dechent C, Bajaj S, Marghoob AA, et al. Rapid diagnosis of tinea incognito using handheld reflectance confocal microscopy: a paradigm shift in dermatology? Mycoses 2015;58:383–6. Cinotti E, Labeille B, Cambazard F, et al. Videodermoscopy compared to reflectance confocal microscopy for the diagnosis of scabies. J Eur Acad Dermatol Venereol 2016;30: 1573–7. Uysal PI, Gurel MS, Erdemir AV. Crusted scabies diagnosed by reflectance confocal microscopy. Indian J Dermatol Venereol Leprol 2015;81:620–2. Cinotti E, Labeille B, Bernigaud C, et al. Dermoscopy and confocal microscopy for in vivo detection and characterization of Dermanyssus gallinae mite. J Am Acad Dermatol 2015;73:e15–6. Guitera P, Menzies SW, Longo C, et al. In vivo confocal microscopy for diagnosis of melanoma and basal cell carcinoma using a two-step method: analysis of 710 consecutive clinically equivocal cases. J Invest Dermatol 2012;132:2386–94. Ulrich M, Stockfleth E, Roewert-Huber J, et al. Noninvasive diagnostic tools for nonmelanoma skin cancer. Br J Dermatol 2007;157 Suppl 2:56–8. Ruini C, Hartmann D, Saral S, et al. The invisible basal cell carcinoma: how reflectance confocal microscopy improves the diagnostic accuracy of clinically unclear facial macules and papules. Lasers Med Sci 2016;31:1727–32. Gonzalez S, Tannous Z. Real-time, in vivo confocal reflectance microscopy of basal cell carcinoma. J Am Acad Dermatol 2002;47:869–74. Peppelman M, Wolberink EA, Blokx WA, et al. In vivo diagnosis of basal cell carcinoma subtype by reflectance confocal microscopy. Dermatology 2013;227:255–62. Longo C, Lallas A, Kyrgidis A, et al. Classifying distinct basal cell carcinoma subtype by means of dermatoscopy and reflectance confocal microscopy. J Am Acad Dermatol 2014;71:716–24.e1.

38. Kadouch DJ, Elshot YS, Zupan-Kajcovski B, et al. One-stopshop with confocal microscopy imaging vs. standard care for surgical treatment of basal cell carcinoma: an open-label, noninferiority, randomized controlled multicentre trial. Br J Dermatol 2017;177:735–41. 39. Webber SA, Wurm EM, Douglas NC, et al. Effectiveness and limitations of reflectance confocal microscopy in detecting persistence of basal cell carcinomas: a preliminary study. Australas J Dermatol 2011;52:179–85. 40. Venturini M, Sala R, Gonzalez S, et al. Reflectance confocal microscopy allows in vivo real-time noninvasive assessment of the outcome of methyl aminolaevulinate photodynamic therapy of basal cell carcinoma. Brit J Dermatol 2013;168:99–105. 41. Pan ZY, Lin JR, Cheng TT, et al. In vivo reflectance confocal microscopy of Basal cell carcinoma: feasibility of preoperative mapping of cancer margins. Dermatol Surg 2012;38:1945–50. 42. Rishpon A, Kim N, Scope A, et al. Reflectance confocal microscopy criteria for squamous cell carcinomas and actinic keratoses. Arch Dermatol 2009;145:766–72. 43. Ulrich M, Kanitakis J, Gonzalez S, et al. Evaluation of Bowen disease by in vivo reflectance confocal microscopy. Br J Dermatol 2012;166:451–3. 44. de Carvalho N, Farnetani F, Ciardo S, et al. Reflectance confocal microscopy correlates of dermoscopic patterns of facial lesions help to discriminate lentigo maligna from pigmented nonmelanocytic macules. Br J Dermatol 2015;173: 128–33. 45. Ahlgrimm-Siess V, Cao T, Oliviero M, et al. Seborrheic keratosis: reflectance confocal microscopy features and correlation with dermoscopy. J Am Acad Dermatol 2013;69: 120–6. 46. Stevenson AD, Mickan S, Mallett S, et al. Systematic review of diagnostic accuracy of reflectance confocal microscopy for melanoma diagnosis in patients with clinically equivocal skin lesions. Dermatol Pract Concept 2013;3:19–27. 47. Guitera P, Pellacani G, Longo C, et al. In vivo reflectance confocal microscopy enhances secondary evaluation of melanocytic lesions. J Invest Dermatol 2009;129:131–8. 48. Gill M, Gonzalez S. Enlightening the pink: use of confocal microscopy in pink lesions. Dermatol Clin 2016;34:443–58. 49. Guitera P, Menzies SW, Argenziano G, et al. Dermoscopy and in vivo confocal microscopy are complementary techniques for diagnosis of difficult amelanotic and light-coloured skin lesions. Br J Dermatol 2016;175:1311–9. 50. Busam KJ, Hester K, Charles C, et al. Detection of clinically amelanotic malignant melanoma and assessment of its margins by in vivo confocal scanning laser microscopy. Arch Dermatol 2001;137:923–9. 51. Guitera P, Pellacani G, Crotty KA, et al. The impact of in vivo reflectance confocal microscopy on the diagnostic accuracy of lentigo maligna and equivocal pigmented and nonpigmented macules of the face. J Invest Dermatol 2010;130:2080–91. 52. Pellacani G, Scope A, Farnetani F, et al. Towards an in vivo morphologic classification of melanocytic nevi. J Eur Acad Dermatol Venereol 2014;28:864–72.

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Section 2: Principles of Clinical Diagnosis 53. Yelamos O, Jain M, Busam KJ, et al. Recurrent nevus as a pitfall of melanoma diagnosis under reflectance confocal microscopy. Australas J Dermatol 2017;59(3):227–9. 54. Pellacani G, Longo C, Ferrara G, et al. Spitz nevi: in vivo confocal microscopic features, dermatoscopic aspects, histopathologic correlates, and diagnostic significance. J Am Acad Dermatol 2009;60:236–47. 55. Larre Borges A, Zalaudek I, Longo C, et al. Melanocytic nevi with special features: clinical-dermoscopic and reflectance confocal microscopic-findings. J Eur Acad Dermatol Venereol 2014;28:833–45. 56. Segura S, Puig S, Carrera C, et al. Development of a twostep method for the diagnosis of melanoma by reflectance confocal microscopy. J Am Acad Dermatol 2009;61:216–29. 57. Farnetani F, Scope A, Braun RP, et al. Skin cancer diagnosis with reflectance confocal microscopy: reproducibility of feature recognition and accuracy of diagnosis. JAMA Dermatol 2015;151:1075–80. 58. Hashemi P, Pulitzer MP, Scope A, et al. Langerhans cells and melanocytes share similar morphologic features under in vivo reflectance confocal microscopy: a challenge for melanoma diagnosis. J Am Acad Dermatol 2012;66: 452–62. 59. Rao BK, Mateus R, Wassef C, et al. In vivo confocal microscopy in clinical practice: comparison of bedside diagnostic accuracy of a trained physician and distant diagnosis of an expert reader. J Am Acad Dermatol 2013;69:e295–300. https://www.ncbi.nlm.nih.gov/pubmed/29998289. 60. Kose K, Cordova M, Duffy M, et al. Video-mosaicing of reflectance confocal images for examination of extended areas of skin in vivo. Br J Dermatol 2014;171:1239–41. 61. Dickensheets DL, Kreitinger S, Peterson G, et al. Widefield imaging combined with confocal microscopy using a miniature f/5 camera integrated within a high NA objective lens. Opt Lett 2017;42:1241–4. 62. Levine A, Wang K, Markowitz O. Optical coherence tomography in the diagnosis of skin cancer. Dermatol Clin 2017;35:465–88. 63. Sattler E, Kastle R, Welzel J. Optical coherence tomography in dermatology. J Biomed Opt 2013;18:061224. 64. Iftimia N, Yelamos O, Chen CJ, et al. Handheld optical coherence tomography-reflectance confocal microscopy probe for detection of basal cell carcinoma and delineation of margins. J Biomed Opt 2017;22:76006. https://www.ncbi. nlm.nih.gov/pubmed/?term=sahu+navarrete-dechent. 65. Ulrich M, von Braunmuehl T, Kurzen H, et al. The sensitivity and specificity of optical coherence tomography for the assisted diagnosis of nonpigmented basal cell carcinoma: an observational study. Br J Dermatol 2015;173:428–35.

66. Boone MA, Marneffe A, Suppa M, et al. High-definition optical coherence tomography algorithm for the discrimination of actinic keratosis from normal skin and from squamous cell carcinoma. J Eur Acad Dermatol Venereol 2015;29:1606–15. 67. Cheng HM, Lo S, Scolyer R, et al. Accuracy of optical coherence tomography for the diagnosis of superficial basal cell carcinoma: a prospective, consecutive, cohort study of 168 cases. Br J Dermatol 2016;175:1290–300. 68. Markowitz O, Utz S. Differentiating early stage cystic keratoacanthoma, nodular basal cell carcinoma, and excoriated acne vulgaris by clinical exam, dermoscopy, and optical coherence tomography: a report of 3 cases. J Clin Aesthet Dermatol 2015;8:48–50. 69. Markowitz O, Schwartz M, Feldman E, et al. Evaluation of optical coherence tomography as a means of identifying earlier stage basal cell carcinomas while reducing the use of diagnostic biopsy. J Clin Aesthet Dermatol 2015;8: 14–20. 70. Olsen J, Themstrup L, De Carvalho N, et al. Diagnostic accuracy of optical coherence tomography in actinic keratosis and basal cell carcinoma. Photodiagnosis Photodyn Ther 2016;16:44–9. 71. Warszawik-Hendzel O, Olszewska M, Maj M, et al. Noninvasive diagnostic techniques in the diagnosis of squamous cell carcinoma. J Dermatol Case Rep 2015;9: 89–97. 72. Zhao J, Zeng H, Kalia S, et al. Using Raman spectroscopy to detect and diagnose skin cancer in vivo. Dermatol Clin 2017;35:495–504. 73. Sharma A, Sharma S, Zarrow A, et al. Raman spectroscopy: incorporating the chemical dimension into dermatological diagnosis. Indian J Dermatol 2016;61:1–8. 74. Fink C, Haenssle HA. Non-invasive tools for the diagnosis of cutaneous melanoma. Skin Res Technol 2017;23: 261–71. 75. Lui H, Zhao J, McLean D, et al. Real-time Raman spectroscopy for in vivo skin cancer diagnosis. Cancer Res 2012;72:2491–500. 76. Wang H, Lee AM, Frehlick Z, et al. Perfectly registered multiphoton and reflectance confocal video rate imaging of in vivo human skin. J Biophoton 2013;6:305–9. 77. Caspers PJ, Lucassen GW, Puppels GJ. Combined in vivo confocal Raman spectroscopy and confocal microscopy of human skin. Biophys J 2003;85:572–80. 78. Iftimia N, Peterson G, Chang EW, et al. Combined reflectance confocal microscopy-optical coherence tomography for delineation of basal cell carcinoma margins: an ex vivo study. J Biomed Opt 2016;21:16006.

Section

Dermatopathology

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6

Laboratory Techniques for Dermatopathology Rita N Sokkar, Manuel Valdebran, Michele Van Hal, Jisun Cha

INTRODUCTION The field of dermatopathology aims to provide detailed analysis of the etiologies underlying various skin conditions. Both molecular and microscopic examinations can be employed to diagnose tissue samples. These laboratory tools range from simple histological staining, immunohistochemistry (IHC), and microscopy to more sophisticated procedures like polymerase chain reaction (PCR), in situ hybridization (ISH), and DNA microarray. This chapter discusses the procedures, applications, and limitations of the most common techniques used in dermatopathology.

POTASSIUM HYDROXIDE PROCEDURE Direct examination with potassium hydroxide is a procedure used to detect the presence of fungal elements on skin. Scales from the affected site are removed with a blade or with a glass slide. This material is collected onto a slide, and a drop of a 10–20% KOH solution is added. A coverslip is placed on top. Examination for hyphae can be performed using 40× magnification.1,2 Clinicians may take advantage of this fast and effective use of KOH direct preparation to identify Sarcoptes scabiei organisms, which are present in the stratum corneum of affected individuals. In atypical cases, it is preferable to use simple saline as it will allow the identification of Sarcoptes fecal material.3

TZANCK SMEAR The Tzanck technique has been used for decades for the investigation of cell structure and cell abnormalities. This technique utilizes Giemsa stain and is simple, rapid, inexpensive, and non-invasive. A Tzank smear has special utility for herpetic infections where the following features can be observed: abnormal keratinocytes with multinucleation and nuclear molding as well as the “ballooning” or

“pregnant cells” which appears as such secondary to the presence of large nuclei (60–80 µm).4

GRAM STAIN For over a century, the Gram stain has been used to provide rapid information on the etiology of infectious processes. This method differentiates bacteria according to the retention of a crystal violet-iodine complex in the cell wall. Gram-positive bacteria appear purple because of retained crystal violet color in the cell wall, whereas gramnegative bacteria appear pink due to the lack of retention of the staining complex. The pink color observed in gramnegative bacteria reflects the color of safranin, which is used as a counterstain.5 This method stains most bacteria, many fungi, and some parasites. It is useful to identify gram-positive cocci in chains suggesting Streptococcus pyogenes in necrotizing fasciitis or gram-negative diplococci in hemorrhagic lesions in patients with septicemia suggesting Neisseria meningitidis.3 Identification of bacterial classification is vital to start empiric antibiotic treatment in infected patients while awaiting more specific results.

WOOD LIGHT Wood light or “black light” is generated by filtering visi­ ble light through silicate and nickel oxide. A high intensity 100-watt mercury vapor bulb and power supply is recommended. Examination under Wood lamp should take place in a complete darkened room; several seconds are also required for the eye to accommodate to low light. Wood lamp is useful diagnostic tool for pigmentary disorders, cutaneous infections, and porphyrias.3 Wood light is useful in pigmented lesions to detect borders of lentigo maligna, where the pigment appears enhanced by the light and is easily recognizable. Dermal and epidermal components of melasma can be evaluated.

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Section 3: Dermatopathology Dermal pigment will not be enhanced by the light, whereas epidermal pigment will be enhanced. It is useful in nonpigmented lesions such as vitiligo, which appears milkwhite under the Wood light. Microsporum species in tinea capitis shows bluishgreen under Wood lamp. Actively infected areas of tinea versicolor will show a white, yellowish to orange fluorescence. Erythrasma shows a coral-pink fluorescence secondary to the porphyrins produced by Corynebacterium species. Pseudomonal infections can be identified by a yellowish green fluorescence produced by pyocyanin, which is a toxin. For cases of porphyria cutanea tarda, urine and feces will exhibit a pink-orange fluorescence under Wood light. Similar effects are found when examining the teeth in congenital erythropoietic porphyria and the blood in erythropoietic protoporphyria.

BIOPSY TECHNIQUES IN DERMATOLOGY Skin biopsies are commonly performed to provide a differential diagnosis or other important information regarding morphological changes in skin structures, tumor formation, and inflammation. A biopsy technique is selected according to its diagnostic utility for specific skin diseases. Some of these techniques are (1) tangential cut with scissors, curettage, shave biopsy, punch biopsy, and elliptical biopsy.

Fig. 6.1: Shave biopsy. The dermablade is curved and adjusted to the width of the lesion. It is gently brought forward to the edge of the lesion. Courtesy: Dr. Janellen Smith and the Department of Dermatology at the University of California, Irvine, CA, USA.

Shave Biopsy A shave biopsy utilizes a blade or a razor to shave off a portion of or an entire lesion. This technique is usually performed in superficial neoplasms such as seborrheic keratoses, actinic keratoses, squamous cell carcinoma (SCC), BCC, and melanocytic lesions (Fig. 6.1).

Tangential Cut with Scissors

Punch Biopsy

Sterile scissors are placed at a tangent to the lesion targeted for removal. Closure is usually not required as just a simple compression dressing can be used to stop the bleeding. This technique is used for the evaluation and/or removal of pedunculated or sessile lesions such as fibroepithelial polyps, or seborrheic keratosis.

Round blades are used to perform punch biopsies and range in size from 1 to 8 mm. Punch biopsy is the preferred method to evaluate inflammatory conditions as the specimen contains the epidermis, dermis, and subcutaneous tissue. After the punch tool has been inserted in the skin, practitioners should avoid crushing the specimen while using forceps to remove the cylindrical tissue because tissue maceration can result in an inability to perform proper histological examination. Punch biopsies of ≤2 mm can be left to heal by secondary intention. Large biopsies benefit from tissue approximation and closure with sutures.

Curettage Curettage is a procedure in which tissue is removed by using a curette. It is used for concurrent diagnostic and treatment purposes. Removal of superficial papulosquamous lesions can be performed with this technique. These include actinic keratoses, warts, seborrheic keratoses, molluscum contagiosum, and superficial basal cell carcinomas (BCCs). One of the disadvantages of this technique is that it yields only fragmented tissue for evaluation. Curettage is contraindicated when melanocytic proliferations are considered in the differential diagnosis as it could potentially spread neoplastic cells.

Elliptical Biopsy This technique is used to fully excise a tumor or to provide a large portion of a lesion for histopathological evaluation. Panniculitis, an inflammatory condition, or dermatofibrosarcoma protuberans, a tumor, are some of the examples in which this elliptical biopsy is useful6 (Figs. 6.2A to D).

Chapter 6: Laboratory Techniques for Dermatopathology

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B

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D

Figs. 6.2A to D: Excisional biopsy. (A) An ellipse is drawn on the skin to guide the excision; (B and C) A #15 blade is placed perpendicular to the skin, and brought forward using its belly; (D) Finally the defect is sutured. Courtesy: Dr. Christopher Zachary and the Department of Dermatology at the University of California, Irvine, CA, USA.

CHOOSING APPROPRIATE TECHNIQUE FOR DIAGNOSIS When selecting the area of interest for a biopsy, practitioners should consider the condition being assessed.7 In bullous diseases, a saucerized removal of intact bullae or at least the inclusion of the periphery of a bulla is vital for thorough examination by hematoxylin and eosin (H&E) stain. Direct immunofluorescence (DIF) will have the highest diagnostic potential if the samples are obtained from perilesional skin 72  h should be obtained. For DIF, the target lesion should ideally haven been present for 6 months. This is the same for DIF. In cases of alopecia, a punch biopsy of 4 mm is strongly recommended. For scarring alopecia and pattern alopecia or telogen effluvium clinicians should consider an active and well-established lesion that has been present for >6 months. For alopecia areata or syphilis, an active lesion of more recent onset has higher diagnostic utility. In melanocytic lesions, a punch biopsy may be done for small lesions especially if a dermal component is suspected. This technique allows for complete removal of the lesion and assessment of the entire epidermal and dermal structure. If the lesion is broad, a shave, which contains

non-involved skin, is preferred to enable evaluation of the lesion as a whole. If melanoma is suspected, complete excisional removal or saucerization is recommended. In cases of cutaneous T-cell lymphoma, a broad shave biopsy is preferred over punch biopsies in order to identify possible foci of atypical lymphocytes. For primary cutaneous B-cell lymphoma, an incisional biopsy is recommended in order to evaluate architectural changes.

HISTOCHEMICAL STAINING In order to facilitate visualization under light or electron microscopy, conventional histochemical dyes are used to stain cells and biomolecules; such as polysaccharides, proteins, and lipids. These histological stains are usually applied to formalin-fixed, paraffin-embedded (FFPE) specimens after they are sectioned and mounted on microscopic slides. By color-coding certain biological structures, microscopic examination of tissue samples is then able to detect structural anomalies that reflect underlying pathologies. Based on this premise, several histochemical stains (Table 6.1; modified from Dettmeyer 20118) are commonly used as a diagnostic tool to detect various infectious and inflammatory skin disorders. For example, Elastika (Verhoeff ) van Gieson can be used to evaluate cicatricial alopecia and scars, Fontana-Masson for vitiligo, periodic acid–Schiff for a tinea infection (Fig. 6.3A), or Alcian blue can stain mucin (Fig. 6.3B).

IMMUNOHISTOCHEMISTRY Immunohistochemistry relies on the concept of antibody–antigen binding to detect the presence of specific

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Section 3: Dermatopathology Table 6.1: Histochemical stains commonly used in dermatopathology. Stains Detected structures Alcian blue Acid mucopolysaccharides Brown-Brenn Gram Gram-positive bacteria Gram-negative bacteria Congo red Amyloid Colloidal iron

Crystal violet EvG

Fite acid-fast Fontana-Masson Giemsa

Gomori stain Grocott stain

H&E [Most commonly used] Luxol fast blue Mallory Trichrome

Masson Trichrome (MassonGoldner)

Methylene blue

Mucicarmine Naphthol AS-D chloroacetate esterase stain Oil Red O Orcein stain PAS Perl prussian blue

Acid mucopolysaccharides Nuclei Cytoplasm Acid mucopolysaccharides Amyloid Collagen Elastic fibers Cytoplasm, muscles, amyloid, and fibrin Mycobacterium leprae Melanin Nuclei Nucleoli Cytoplasm Erythrocytes Mast cell granules and acid mucopolysaccharides Eosinophil granules and Leishmania organisms Argyrophilic reticular fibers Fungal conidia and fungal fibers Donovan bodies, as in Calymmatobacterium granulomatis Frisch bacilli in rhinoscleroma Basophilic Nuclei Acidophilic cytoplasm, erythrocytes, collagen, muscles, and nerves Myelin and phospholipids Collagen and reticular connective tissue Nuclei Smooth musculature Striated musculature Mucus Parenchyma and fibrin Mesenchyme and collagen Muscles and nerve Nuclei Nuclei Plasma cells Erythrocytes Mucin Cryptococcus capsule Neutrophil myeloid cells Lipids Elastic fibers and HBsAG Glycogen, epithelial mucin, and fungi Trivalent iron (hemosiderin) deposits

Presented color Blue Blue Red Red with green birefringence in polarized light Blue Pink-red Pink Metachromatic purple Purple-red Red Black and brown Yellow Bright red Black Purple-red Blue Blue-gray to red-violet Pink-orange at neutral pH Green-blue at alkaline pH Purple Red-blue Silver Black

Blue Red

Light-blue Red Violet Orange-red Blue Red-orange Green Dark red Black Sharp blue Deep blue Greenish Red Wine Red Orange to bright red Purple-red (magenta) Blue (Contd…)

Chapter 6: Laboratory Techniques for Dermatopathology (Contd…) Stains PTAH Reticulin stain Silvering Sudan III Sudan IV Toluidine blue Von Kossa Warthin-Starry

Weigert elastin stain Weigert fibrin stain Ziehl-Neelsen

Detected structures Fibrin Muscle Fine (pre-) collagen reticulin fibers Reticular and nervous fibers Collagen fibers Lipids Lipids Acid mucopolysaccharides and metachromatic substances Calcium salts Calcified bone tissue Spirochetes, as in cat-scratch disease and bacillary angiomatosis bacilli Donovan bodies, as in C. granulomatis Elastic fibers Fibrin and bacteria Nuclei Acid-resistant rods, mycobacteria Mycobacterium leprae

Presented color Deep blue Blue to purple Silver Black Brown Yellow-red Orange red Purple Black Black

Violet-black Blue Red Bright red

(EvG: Elastika (Verhoeff) van Gieson; H&E: hematoxylin and eosin; HBsAG: hepatitis B surface antigen; PAS: periodic acid-Schiff; PTAH: phosphotungistic acid hematoxylin)

A

B

Figs. 6.3A and B: (A) Skin specimen highlighting fungal elements utilizing periodic acid-Schiff stain. Green staining was added to create a background for comparison. PAS x 2000X; (B) Mucin deposition around tumor islands is highlighted in blue utilizing alcian blue stain in this basal cell carcinoma case. Alcian Blue x 1000X.

biological markers. The antibodies, either monoclonal primary antibodies, which are specific to a single antigenic marker in the tissue samples or secondary antibodies that bind to the primary antibodies, are added to FFPE specimens after they are cut into 3–5 µm thick sections and mounted on microscopic slides.9 Chromogenic enzymes are then added as labels to the antibodies (Table 6.2;

modified from Dettmeyer 20118). The signal emitted by these enzymes requires amplification for detection by light microscopy; therefore, several modifications can be implemented (Fig. 6.4). First, the most basic implementation is the direct technique, in which a monoclonal primary antibody, linked to a chromogenic enzyme, binds a single antigenic marker in the tissue sample. This is in contrast to the

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Section 3: Dermatopathology Table 6.2: Chromogenic enzymes used as labels to antibodies in immunohistochemistry. Chromogenic enzyme Substrate Chromogen dye Presented color Horseradish peroxidase Hydrogen peroxide AEC Red-brown Chloronaphthol Blue DAB Brown (with nickel sulfate = black) Alkaline phosphatase Naphthol phosphate Fast red Red Fast blue Blue New fuchsine Red (AEC: amino-ethyl carbazole; DAB: diaminobenzidine)

Fig. 6.4: Immunohistochemical complex (IHC).

indirect technique, which requires a secondary antibody to link to a chromogenic enzyme and bind to the monoclonal primary antibody. A more elaborate technique is the avidin–biotin complex (ABC) protocol, where a biotinlabeled secondary antibody, linked to an avidin-conjugated chromogenic enzyme, binds a monoclonal primary antibody. In addition to using a two-antibody labeling method, there are other techniques where three antibodies are utilized in tagging certain biological markers.8 For example, the peroxidase–antiperoxidase complex protocol requires a secondary polyclonal antibody in order to link an antiperoxidase antibody to a monoclonal primary antibody that will then bind to a single antigenic marker.8 Finally, there is the alkaline phosphatase–antialkaline phosphatase technique in which the secondary polyclonal antibody links an antialkaline phosphatase antibody to the monoclonal primary antibody.8

Due to its ability to detect the presence of specific biological markers on leukocytes (Table 6.39), and on other tissues (Table 6.49), IHC is used to diagnose and evaluate several skin conditions. More specifically, an IHC stain like CD20 identifies B cells (Fig. 6.5B) while T cells stain with CD3 stain (Fig. 6.5A). MELAN-A (MART-1) can be used to highlight melanocytes in melanomas and, therefore, assess the size of melanocytic lesions10 (Fig. 6.6A). SOX-10, which is a nuclear melanocytic stain, can also be used to stain melanomas with the advantage of its lower expression in background cells, such as fibroblasts and histiocytes10,11 (Fig. 6.6B). In addition to diagnosing melanoma, IHC stains, such as BER EP-4, can be used, in the ABC protocol, to distinguish BCC from SCC by showing a positive diffused stain in a BCC sample compared to a light or no stain in an SCC sample.12 MOC31can accomplish the same task as BER EP-4 but with greater sensitivity.13

Chapter 6: Laboratory Techniques for Dermatopathology Table 6.3: Predominant cell reactivity against antigen cluster designation. Antigen cluster designation Antibody Similar clones Predominant reactivity CD1 Leu-6 OKT6, NA1/34 Langerhans’ cells, thymocytes CD2 Leu-5b OKT11 Pan T cells, E-rosette receptor CD3 Leu-4 OKT3 Pan T cells CD4 Leu-3a OKT4 Helper/inducer T cells, monocytes CD5 Leu-1 OKT1 Pan T cells, rare B cells CD6 – T12,TU33 Pan T cells, rare B cells CD7 Leu-9 3A1 T cells, NK cells CD8 Leu-2 OKT8 Cytotoxic/suppressor T cells CD9 – J2, BA2 T cells, B cells, myeloid CD10 – J5, BA3,vilA1 Pre-B cells, Pre-T cells, germinal center (common acute lymphocytic leukemia antigen) CD11b Leu-15 (CR3) OKM1, Mac-1 Suppressor T cells, NK cells, monocytes, granulocytes CD11c Leu-M5 Ki-M1 Monocytes, macrophages, histiocytic lymphomas, NK cells, hairy cell and acute myeloid leukemia CD14 Leu-M3 63D3 Monocytes, macrophages CD15 Leu-M1 My1, anti-X hapten Monocytes, granulocytes, Reed–Sternberg cells, epithelial cells CD16 Leu-11 VEP13, 3G8, L23 IgG, receptor on NK cells, neutrophils CD19 Leu-12 B4 B cells CD20 Leu-16 B1 B cells CD21 CR2 B2 Mature B cells CD22 Leu-14 TO15, SHCL1 B cells CD23 – TU1, blast2 B-cell subset CD24 – BA1 B cells, granulocytes, plasma cells CD25 Interleukin-2 TAC Activated T and B cells, HTLV-infected T-cell leukemia Receptor lines CD30 – Ki-1 Reed–Sternberg cells, activated T and B cells, pagetoid mycosis fungoides, lymphomatoid papulosis (type A) CD35 CR1 C3Br Monocytes, granulocytes, B cells, erythrocytes CD38 Leu-17 OKT10 Thymocytes, NK cells, activated T and B cells CD45R Leu-18 2H4, HB10, HB11, 3AC5 Suppressor T cells, NK cells, B cells CD45 HLe-1 LCA, T29/33, PD7/26 Leukocytes CD79A SP18, Pharmingen, – B cells, plasma cells Mississauga, Ontario – HLA-DR Ia B cells, monocytes, endothelial cells, Langerhans cells, cytotoxic T cells – – OKM1 Monocytes (NK: natural killer)

Although clearly a valuable asset in dermatopathology, IHC may show false-negative or false-positive results. For instance, tears, artifacts, and thick or folded tissue sections accumulate excessive dye, which can result in a false-positive.8 Besides false-positives and -negatives, IHC may have non-specific staining, due to tissue necrosis, or background staining, due to endogenous inhibition of the chromogenic enzyme,

non-specific binding of antibodies, and cross reactivity of polyclonal antibodies.8

IMMUNOFLUORESCENCE As a variation of IHC, immunofluorescence (IF) utilizes fluorescent dyes, instead of chromogenic enzymes, in order to tag certain biomarkers. In DIF, a monoclonal primary

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Section 3: Dermatopathology Table 6.4: Commonly used immunostains and their utilization in the dermatopathological practice. Stain Predominant reactivity/positivity Utilization (examples) α-Antitrypsin/α-antichymotrypsin Macrophages Fibrohistiocytic neoplasms and granulomas Ber Ep4 EpCAM antigen on epithelial cells and Basal cell carcinoma, Merkel cell sebaceous gland epithelium carcinoma, adnexal neoplasms, trichoepithelioma, sebaceous gland neoplasm CEA Adenocarcinomas Paget disease, sweat gland tumors Chromogranin Eccrine glands, neuroendocrine tumors Merkel cell carcinoma Cytokeratin Epithelial and adnexal tumors Squamous cell carcinoma, Merkel cell carcinoma Desmin Skeletal and smooth muscles Leiomyosarcomas EMA Sweat and sebaceous gland epithelium Paget disease, adnexal neoplasms, metastatic adenocarcinomas Ulex Europaeus lectin Endothelial cells Vascular and lymphatic tumors Factor VIII-related antigen Endothelial cells Vascular tumors Human melanoma black (HMB45) Melanoma cells, benign dysplastic cells, Melanoma Spitz nevi Ki67 Melanoma cells, melanocytic nevi Melanoma/desmoplastic melanoma LCA Benign or malignant leukocytes Lymphomas/leukemias MELAN A (MART-1) Melanocytes Primary malignant melanoma, cutaneous nevi, clear cell sarcoma, melanocytic neurofibroma, melanocytic Schwannoma MiTF Fibroblasts and melanocytes Melanoma, metastasized melanocytic tumors Myelin basic protein Schwann cells Neural tumors, granular cell tumor MOC31 EpCAM antigen on epithelial cells and Basal cell carcinoma, Merkel cell sebaceous gland epithelium carcinoma, adnexal neoplasms, trichoepithelioma, sebaceous gland neoplasm NSE Neural tissue, some melanocytes Merkel cell carcinoma S-100 protein Melanocytes, Schwann cells, Amelanotic melanoma, desmoplastic Langerhans cells, sweat glands, melanoma, neural tumors, histiocytosis X chondrocytes, fibroblasts, histiocytes S-100 A6 Pigmented spindle cells Benign melanocytic lesions, Spitz nevi Sry-related HMG-BOX gene 10 Melanocytes, Schwann cells Melanocytic tumors, desmoplastic (SOX-10) melanoma Synaptophysin Neuroendocrine tumors Merkel cell carcinoma Vimentin Fibroblasts, endothelial cells, Sarcomas, melanomas, lymphomas lymphocytes, histiocytes, melanocytes, Schwann cells (CEA: carcinoembryonic antigen; EMA: epithelial membrane antigen; LCA: leukocyte common antigen; MiTF: microphthalmia transcription factor; NSE: neuron-specific enolase)

antibody, linked to a fluorophore by fluorescein isothiocyanate antisera, binds a single antigenic marker in a freshfrozen tissue specimen that has been placed in a phosphate buffered saline and Michel solutions. The tissue specimen is then cut into 3–5 µm thick sections and examined with a fluorescence microscope. As in IHC, DIF can detect abnormal cutaneous deposits of serum immunoglobulins,

complement, and fibrinogen in inflammatory skin disorders.9 See Table 6.5 for further examples of clinical disorders diagnosed by DIF.9 While the direct technique is applied for fresh-frozen samples, indirect IF (IDIF) is used on venous blood serum samples that have been diluted with phosphate buffered saline solution and bovine serum albumin.9 This technique

Chapter 6: Laboratory Techniques for Dermatopathology

A

B

Figs. 6.5A and B: (A) CD3 lymphocyte stain; (B) CD20 stain, used to identify T and B cells respectively.

A

B

Figs. 6.6A and B: (A) Melan-A stain; (B) SOX-10 stain, each used as melanocytic markers.

is commonly used in diagnosing autoimmune blistering disorders, such as bullous pemphigoid, via detection of circulating autoantibodies to skin antigens.9 The use of IF, similar to IHC, is susceptible to false positives and negatives that may result from improper tissue preparation or artifacts.

ONE MICROMETER SECTIONS (MICROTOMY) To optimize sample examination with transmission electron microscopy (TEM), 1 µm thick tissue sections are first prepared. A finely diced or a 4 µm punch biopsy specimen that has been either fixed in buffered glutaraldehyde or postfixed in osmium tetroxide, dehydrated

and embedded in Epon or other plastic resin is cut into 1 µm thick sections and then stained with toluidine blue or Giemsa.9 This preparatory procedure can improve the evaluation and the diagnosis of skin pathologies. For example, obtaining well-prepared 1 µm thick sections, before TEM, allows for examining subtle and early microvascular alterations, such as in atopic and contact dermatitis, delayed hypersensitivity reactions, allograft rejection, and vasculitides.9

ELECTRON MICROSCOPY To achieve a detailed magnification of the biological ultrastructure, tissue samples may be examined by electron microscopy. There are two main types of electron

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Section 3: Dermatopathology Table 6.5: Direct immunofluorescence patterns and preferred biopsy site. Disorder Preferred biopsy site Results Lupus erythematosus Lesional (or normal for systemic disease) IgM, IgG, C3 in a granular pattern at the DEJ Pemphigus Perilesional Epidermal, intercellular staining with C3 and IgG Bullous pemphigoid Perilesional IgG, C3 in a linear pattern at DEJ Dermatitis herpetiformis Perilesional or normal IgA with or without C3 in a granular pattern at DEJ Linear IgA dermatosis Perilesional IgA with or without C3 in a linear pattern at DEJ Leukocytoclastic Lesional IgM, IgG, C3, fibrin in and around blood vessels of vasculitis early lesions (DEJ: dermoepidermal junction)

microscopy: TEM and scanning electron microscopy (SEM). TEM, in which 1 µm thick sections are prepared then sectioned into 9-nm-thick sections, mounted on copper grids and stained with uranyl acetate and lead citrate.9 TEM can provide ultrastructural examination and diagnostic information for certain skin disorders (Table 6.69); however, it is not preferred for lesions with advanced autolysis. SEM examines FFPE specimens that have been affixed to carbon plachets, deparaffinized, dehydrated, and coated with carbon.9 Unlike TEM, this technique does not require 1 µm thick sections to be prepared. A scanning electron microscope focuses an electron beam on the specimen. The rectangular section of the localized particular matter is bombarded with electrons that provide X-ray emissions which are then analyzed spectrometrically.9 Due to its ability to produce three-dimensional images, SEM is useful for investigating abnormal keratinization and trichogenesis, for detecting trace amounts of exogenous elements that are causative to some cases of granulomatous dermatitis or for simply detailing the morphology of skin wounds.9

GENE REARRANGEMENT STUDIES Gene rearrangement studies can be used for evaluating melanocytic lesions and monoclonal lymphocytic proliferations. DNA digestion with restriction enzymes, followed by separation with gel electrophoresis and Southern blot analysis, shows diverse smeared bands in a benign reactive infiltrate that contains a polyclonal population of B cells with different immunoglobulin gene rearrangement.9 In contrast, a malignant neoplastic infiltrate, which contains monoclonal populations of B cells with the same immunoglobulin gene rearrangement, will show only a single band.9 However, such analysis may result in false negatives or even false positives if the smeared bands are highly indistinctive.9

Table 6.6: Application of transmission electron microscopy in dermatology. Disorder Example Diagnostic use Bullous Epidermolysis bullosa Locate blister diseases site and assess anchoring fibrils Viral Human papillomavirus Identify viral diseases (HPV) particles Neoplasms Amelanotic melanoma Identify Histiocytosis-X, mycosis melanosomes fungoides Identify cell type Pigmentary Vitiligo Assess disorders melanocytes/ melanosomes Deposition Amyloidosis, Identify disorders mucopolysaccharidosis morphology of deposits

In Situ Hybridization In order to detect target DNA or mRNA in tissue samples, ISH is commonly utilized. ISH relies on DNA probes, which are more stable than RNA probes.8 The DNA probes can bind to the complement target sequences directly in the cells of FFPE samples or to the cytological tissue sections of metaphase spreads, of interphase nuclei sections, of extended chromatin fibers sections, or even to DNA microarrays.8,14 Upon hybridization, the probe-DNA/mRNA complex is detected by fluorescence microscopy, if the probe is marked by a fluorophore, or by light microscopy, if the probe is marked by a chromogenic enzyme (Fig. 6.7). Fluorescence ISH (FISH) employs several types of fluorescent-labeled DNA probes (Table 6.715). The fluorescent marker can be tagged to the probe directly or indirectly in a matter similar to IF. FISH can be used to detect viral DNA, such as herpesvirus or human papilloma virus

Chapter 6: Laboratory Techniques for Dermatopathology in epidermodysplasia verruciformis, Bowenoid papulosis, and digital SCC.14 Also, FISH can locate viral mRNA, such as Epstein-Barr virus in cutaneous T-cell lymphoma, abnormal gene rearrangements as in B-cell and T-cell lymphomas, oncogenes in malignant transformed cells, and chromosomal aberrations as in cutaneous neoplasms (e.g., melanoma and melanocytic sarcoma).15 Despite its valuable applications in diagnostics, FISH may be limited by the availability of DNA probes and by the use of fluorescence microscopy, which can hinder the visualization of detailed tissue morphology.15 Moreover, the ability of FISH to spot chromosomal anomalies requires prior knowledge of the specific chromosomal aberrations and unfortunately is susceptible to false positive and negative results.14 Chromogenic ISH (CISH) utilizes DNA probes that are marked directly or indirectly with chromogenic enzymes, such as peroxidase and alkaline phosphatase. CISH has similar applications to FISH in diagnostic ability and consequently in the field of dermatopathology.15 However, CISH uses light rather than fluorescence as the source for microscopy, which enables visualization of detailed tissue morphology. Therefore, correlation is improved between the tissue structure and the detected genomic aberrations.15 However, CISH has been shown to have a less intense detection signal than FISH.15 CISH may also be limited by the availability of DNA probes and the required prior knowledge of the targeted chromosomal aberrations.15

aspirated from one of the following: fresh frozen tissue, FFPE specimen, blood and other bodily fluids, mucosal scrapes, or fine needle extracts;15 then, the exponential amplification is carried by a three-step procedure. Step one is to denature the dsDNA at 92°C. Step two requires DNA primers, which are single-stranded oligonucleotides, to be annealed at 55°C to their complementary ends on either strand of the DNA substrate.15 Step three uses the enzyme Taq polymerase, which is a temperature-resistant DNA polymerase and is derived from the Thermus aquaticus bacterium, to elongate the annealed primers at 72°C. In addition to the Taq polymerase, step three uses preadded free nucleotides to synthesize the new DNA strands.15 Subsequently, the three steps are repeated to create a newly synthesized dsDNA pool (Fig. 6.8). Finally, the new dsDNA library is run on agarose gel, polyacrylamide gel, or capillary electrophoresis for analysis.14,15 As

POLYMERASE CHAIN REACTION Polymerase chain reaction can generate sufficient DNA pool to allow further genetic analysis. Initially, the targeted double-stranded DNA (dsDNA) substrate is

Fig. 6.7: The difference between direct ISH and indirect ISH.

Table 6.7: Probes utilized for in situ hybridization. Type of probe Probed structure Whole chromosome Entire chromosome Alphoid/centromeric repeat Centromere Locus-specific Specific locus/gene Two probes: dual-color, Two specific loci/genes dual-fusion Two probes: dual-color, break-apart

One specific locus/gene proximal to a certain gene and another specific locus/gene distal to the same gene

Emitted signal Single fluorescent dye Single fluorescent dye Single fluorescent dye 1. Normal sequence: two fluorescent dyes 2. Chromosomal translocation: fusion of two fluorescent dyes into a third color dye 1. Normal sequence: fusion of two fluorescent dyes into a third color dye 2. Chromosomal translocation/breakpoint: two fluorescent dyes

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Fig. 6.8: The 3 steps to synthesize the dsDNA pool.

an alternative to electrophoresis, the newly synthesized DNA can also be examined via restriction fragment polymorphism, single-strand conformation polymorphism, or heteroduplex analysis.14,15 Due to its ability to create a large DNA library of a miniature DNA sample, PCR can be used to identify genetic mutations, translocations, or amplifications that can be associated with genetic diseases or certain pathologies of genetic etiology.15 Thus, PCR can be helpful in detecting viral, bacterial, mycobacterial, parasitic, or fungal DNA in cutaneous infections.14 Moreover, PCR can play a role in assessing some cutaneous malignancies. For example, it can facilitate the recognition of viral DNA in virally induced cutaneous malignancies, or it can allow the evaluation of melanocytic and non-melanocytic skin tumors and lymphoid neoplasms, such as melanoma, BCC, SCC, and Kaposi sarcoma. In addition, PCR can assist in confirming B-cell and T-cell lymphomas by evaluating genetic rearrangement and clonality and allows the detection of micrometastases in sentinel lymph node biopsies.14,15 Despite these advantageous applications, PCR may impose a few disadvantages. For instance, its high sensitivity and the possibility of cross contamination can result in a false positive.14 False negatives may also occur secondary to the use of low quality DNA substrate.14

REVERSE TRANSCRIPTIONPOLYMERASE CHAIN REACTION Utilizing the same approach as PCR, reverse transcription-PCR (RT-PCR) permits the analysis of sampled single stranded RNA substrate that can also be taken from

FFPE specimen, blood and other bodily fluids, mucosal scrapes, or fine needle extracts.15 To amplify the starting genetic material, RT-PCR follows a four-step protocol. The first step is annealing single-stranded oligonucleotide reverse DNA primers to the complementary ends of the RNA substrate at 45°C.15 The second step is to utilize the enzyme reverse transcriptase, which is a retroviral RNA-directed DNA polymerase, in order to elongate the annealed reverse primers and create a cDNA strand.15 The newly synthesized cDNA strand follows step two and step three of the original PCR.15 The end result is a cDNA library that can be analyzed by electrophoresis or other methods identical to those employed to examine PCR products. Although RT-PCR is a modified PCR, it still shares the same applications in diagnostics and dermatopathology as the original PCR. RT-PCR has the same disadvantages as PCR with the added difficulty of obtaining pure RNA and contending with its inherent instability and quick degradation.15

REAL-TIME POLYMERASE CHAIN REACTION Besides the rapid amplification of the starting genetic material, real-time PCR enables efficient quantifications of the amplified products.15 Either the PCR or the RT-PCR protocol to create a newly synthesized genetic pool can be followed; however, to quantify the products, real-time PCR utilizes certain molecular labels. Such labels can be fluorescent intercalating dyes, such as SYBR green and ethidium bromide, that enter between nucleotide bases, or fluorescent sequence-specific probes, like molecular beacon, TaqMan, and fluorescence resonance energy transfer (FRET) that bind to specific sequences.15 Either of these labels can emit a degree of fluorescence, which is detected by a fluorescence microscope and reflects the quantity of the amplified product PCR product.15 The additional ability at quantification enables realtime PCR to be a vital diagnostic tool with application in assessing cutaneous infections and other skin conditions similar to those that can be evaluated by PCR and RT-PCR.15

LIGASE CHAIN REACTION Ligase chain reaction (LCR) is one of the latest modifications of PCR. Rather than simply replicating a dsDNA substrate, LCR is amplifies selected probes.15 Upon denaturing the dsDNA substrate, just as in PCR, a pair of single-stranded

Chapter 6: Laboratory Techniques for Dermatopathology DNA probes hybridizes to adjacent sequences of either strands of the target DNA at 55°C. A thermostable ligase joins the two probes.15 Following ligation, ssDNA primers anneal to the ligated probes. Using the ligated-probe as a template, Taq polymerase then elongates the annealed primers at 72°C.15 Once the amplified products are examined using regular PCR analytical methods, the replicated probes can be distinguished through IDIF. This modified PCR technique has found specific application in detecting point mutations, such as insertions, deletions, or single base-pair alterations in the target DNA because ligation is halted at these sites.15 However, just like PCR, LCR requires prior knowledge of the suspected mutations. LCR can be used in detecting viral, bacterial, mycobacterial, parasitic, and fungal DNA in cutaneous infections.15

MULTIPLEX-LIGATION-DEPENDENT PROBE AMPLIFICATION Following the same procedural steps as LCR, multiplex-ligation-dependent probe amplification (MLPA) can be used to detect and amplify multiple target sequences by simply using a small amount of DNA substrate. However, as a variation of LCR, MLPA uses MLPA probe composed of two half probes; each has a primer sequence and an oligonucleotide sequence complementary to adjacent sequences of either strands of the target DNA.15 Also in MLPA, the DNA primers used are typically labeled with a fluorophore following the FISH procedure.15 Therefore, upon examination and separation of the amplified products by gel electrophoresis, fluorescence spectroscopy can be used to quantify the target sequences. Since MLPA can replicate multiple target sequences at once, it can analyze skin conditions where there is accelerated DNA replication and proliferation such as in melanoma, B-cell lymphomas, and other lymphoproliferative disorders.15 In addition to the previously stated limitations of LCR and regular PCR, MLPA is also limited by the dependency on the specially designed probes.

SOUTHERN BLOT As a preliminary technique, Southern blotting can detect the presence of certain DNA sequences in samples prepared with bacterial restriction enzymes and run on gel matrix, which are then transferred to a nitrocellulose or nylon paper via capillary action.15 After radiolabeling and autoradiography (X-ray film), the target DNA sequences

can be easily spotted. Therefore, Southern blot can detect cutaneous T-cell lymphomas (CTCL), human T-cell lym­ photropic virus type 1 in cutaneous T-cell leukemia/ lymphoma, and Merkel cell polyomavirus in Merkel cell carcinoma.15 In addition to diagnosis, Southern blot may also help in predicting the prognosis for CTCL by detecting identical T-cell receptor gene rearrangements (TCR -GRs).15 Despite its various applications in the laboratory, Southern blot has some disadvantages: the need for copious amounts of initial DNA material; the preferential use of a fresh frozen tissue sample because of increased DNA degradation; and low sensitivity, which makes it best used at early stages of applicable conditions, such as CTCL.15

COMPARATIVE GENOMIC HYBRIDIZATION Detection of chromosomal aberrations and abnormal genomic sequences, especially in malignancies, can be achieved through comparative genomic hybridization (CGH). Two DNA samples are collected and are compared to each other, hence the descriptive name, comparative. The first sample is a neoplastic DNA sample labeled with green fluorochrome and is extracted from FFPE tumor cell culture.14 The second is of normal DNA, labeled with red fluorochrome and is also extracted from FFPE cell culture, to serve as a reference.14 During metaphase CGH, equal amounts of these two DNA samples hybridize to a normal metaphase chromosome that serves as a gene map.15 Fluorescence microscopy and quantitative image analysis can then detect the fluorescent signals emitted (Table 6.815). In array CGH, the equal amounts of neoplastic and normal DNA samples hybridize to probes that are extracted from oligonucleotides or cDNAs and are then positioned on a glass slide array.14,15 To capture the fluorescence emission in array CGH, the labeled DNA samples are examined with an array scanner (Table 6.815). Both metaphase and array CGH are vital tools for detection of any genetic gains or losses that are associated with chromosomal aberrations in solid tumors.15 CGH can also be used to spot chromosomal changes in some cases of genodermatosis and cutaneous lymphoma or to identify the genomic sequences that distinguish malignant melanoma from benign melanocytic nevus, epithelioid and spindle-cell “Spitz” nevus, and congenital nevus.14,15 However, both metaphase and array CGH cannot detect subtle intrachromosomal mutations, such as point mutations, or balanced translocations.14

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Section 3: Dermatopathology Table 6.8: Significance and presentation of detected emissions in comparative genomic hybridization. Type of CGH Examination tool Presentation of detected emission Significance of detected emission Metaphase Fluorescence • High green intensity signal • Gain mutation at a certain locus in the tumor microscope • High red intensity signal DNA • Yellow intensity signal • Loss mutation at a certain locus in the tumor DNA • No change in the copy number at a certain locus in the tumor DNA Array Array scanner • Green spots • Genomic gain in the tumor DNA • Red spots • Genomic loses in the tumor DNA • Yellow spots • No change of the genomic copy number in the tumor DNA (CGH: comparative genomic hybridization)

Besides its limited application at detecting genetic mutations, metaphase CGH also faces several technical disadvantages. For instance, metaphase CGH, in addition to its low resolution and sensitivity and its preferred requirement of fresh cell culture, only enables screening at one genetic locus at a time.15

DNA MICROARRAY In DNA microarray, there are primary DNA sequences extracted from simple oligonucleotides in order to probe the genes of interest, otherwise known as secondary DNA.14,15 The secondary DNA sequences get radiolabeled, then hybridized to the primary DNA, which is immobilized in a glass or nylon array.14,15 A phosphoimager or a laser scan detects the radiolabel signal and the hybridized sequences can be visualized as colored dots on the array.14 DNA microarray can detect different cytokines that are involved in inflammatory skin diseases, such as psoriasis and atopic dermatitis. It can also detect microbial infections that cause inflammatory skin disorders such as Staphylococcus aureus in impetigo.15 Moreover, DNA microarray can be used in the molecular evaluation of malignant cutaneous neoplasms, such as BCC, SCC, CTC, and melanoma.15 The only significant limitation associated with DNA microarrays is the complexity of the procedure.14

TISSUE MICROARRAYS Tissue microarray (TMA) may be a useful tool to study the molecular alterations associated with different stages of tumor progression.14 First, 0.6-mm tissue core biopsies, extracted from different specimens, are mounted on

paraffin blocks and then transferred onto a glass microscopic slide where subsequent molecular techniques, such as those previously described, may be performed for further examination.14 TMAs allow the analysis of various tissue samples in a timely and a cost-effective matter.14 Moreover, TMAs composed of different types of tumors help to identify new biomarkers. Despite its efficiency and obvious benefits, TMA is still difficult to prepare, and the small amount of core biopsies used may not be sufficient to generate results about the whole tissue from which they have been extracted.14

HYBRID CAPTURE ASSAY Hybrid capture assay is a technique that is often used to detect viral and bacterial DNA such as human papilloma virus, hepatitis B virus, and cytomegalovirus or DNA of bacteria, such as Chlamydia trachomatis and Neisseria gonorrhoeae.15 This procedure utilizes an RNA probe that is complementary to a target ssDNA, which has been extracted from mucosal swaps or skin biopsies.15 The RNA– DNA hybrid is added to a primary antibody immobilized to a microtiter plate.15 Then, a secondary antibody, linked to the enzyme alkaline phosphatase, specifically binds the primary antibody in a fashion similar to indirect IHC.15 Lastly, a chemiluminescent substance is added in order to be cleaved by the alkaline phosphatase and then emits light.15 The diagnostic ability of hybrid capture assay can be impaired due to the low sensitivity of the technique or to the possible cross-reactivity of the antibodies.15

G-BANDING G-banding scans metaphase chromosomes for abnormalities chromosomal size or number.15 Also, it can facilitate the

Chapter 6: Laboratory Techniques for Dermatopathology detection of chromosomal aberrations as in lymphoproliferative disorders, such as CTCL, and parapsoriasis.15 Just like CGH, G-banding is unable to detect subtle intrachromosomal mutations, such as point mutations, balanced translocations, inversions, or deletions.15 Also, because of its requirement for fresh cell culture sample, G-banding cannot be used to evaluate chromosomal aberrations associated with conditions like cutaneous lymphoma because cells in these fresh skin biopsies hardly proliferate or produce metaphase chromosomes in vitro.15

SPECTRAL KARYOTYPING Spectral karyotyping utilizes 24 distinct fluorescing DNA probes to bind the 22 autosomal chromosomes, X-chromosome, and Y-chromosome within metaphase spreads that are extracted from fresh-frozen tissue samples.15 By facilitating chromosomal visualization, spectral karyotyping detects chromosomal aberrations such as rearrangements or translocations in conditions such as in CTCL, HPV-associated SCC, mycosis fungoides, and Sezary syndrome.15 Because spectral karyotyping examines chromosomes in a fashion similar to G-banding, it faces similar limitations and disadvantages.

CONCLUSION Dermatopathology unites the fields of dermatology and pathology with these specialized laboratory techniques. Tools, such as H&E stain, highlight certain morphological features in skin biopsies. Anomalies are detected such as an atrophic epidermis with hyperkeratosis and dermal sclerosis as in lichen sclerosis; acanthosis with elongated rete ridges as in chronic psoriasis; or, inflammatory infiltrate as in eczema and seborrheic dermatitis. In contrast, techniques such as IHC and IF are used to detect inflammatory cytokines and immunoglobulins, as in lupus erythematous and bullous pemphigoid, or lymphocytic infiltrate, as in cutaneous lymphomas. Other diagnostic techniques that enable DNA analyses, such as via PCR, MLPA, DNA microarray, and hybrid capture assay, can screen for DNA aberrations in BCC, SCC, CTC, and melanoma or and/or microbial DNA as in cutaneous infectious diseases. Finally, CGH, G-banding, and spectral karyotyping can trace specific chromosomal anomalies to certain dermatologic malignancies. These laboratory

techniques provide a powerful asset for diagnostic ability in the field of dermatology as each may shed light on the likely causative agents for many of the skin diseases. Therefore, they should be used as able and indicated to assist in diagnoses, outlining prognoses, and directing treatment.

REFERENCES 1. Dasgupta T, Sahu J. Origins of the KOH technique. Clin Dermatol 2012 Mar–Apr;30(2):238–41. 2. Ponka D, Baddar F. Microscopic potassium hydroxide preparation. Can Fam Physician 2014 Jan;60(1):57. 3. Ruocco E, Baroni A, Donnarumma G, Ruocco V. Diagnostic procedures in dermatology. Clin Dermatol 2011 Sep–Oct;29(5):548–56. 4. Ruocco V, Ruocco E. Tzanck smear, an old test for the new millennium: when and how. Int J Dermatol 1999 Nov;38(11):830–4. 5. Coico R. Gram staining. Curr Protoc Microbiol 2005 Oct;Appendix 3:Appendix 3C. 6. Llamas-Velasco M, Paredes BE. Basic concepts in skin biopsy. Part I. Actas Dermosifiliogr 2012 Jan;103(1): 12–20. 7. Elston DM, Stratman EJ, Miller SJ. Skin biopsy: biopsy issues in specific diseases. J Am Acad Dermatol 2016 Jan;74(1):1–16. 8. Dettmeyer RB. Forensic histopathology: fundamentals & perspectives. Germany: Justus-Liebig-University Geiben; 2011. p. 17–19, 23–26, 31–33. 9. Moschella S, Hurley H. Dermatology. 3rd ed. Saunders. p. 141–7. 10. Emanuel P, Cheng H. Melanocytic lesions pathology; 2015 Feb. Retrieved July 2, 2015, from DermNet NZ web: http://www.dermnetnz.org/pathology/intro-melanocyticpath.html. 11. Ramos-Herberth FI, Karamchandani J, Kim J, Dadras SS. SOX10 immunostaining distinguishes desmoplastic melanoma from excision scar. J Cutan Pathol 2010 Sep;37(9):944–52. 12. Dasgeb B, Mohammadi TM, Mehregan DR. Use of Ber-EP4 and epithelial specific antigen to differentiate clinical simulators of basal cell carcinoma. Biomark Cancer 2013 Jun;5:7–11. 13. Pai RK, West RB. MOC-31 exhibits superior reactivity compared with Ber-EP4 in invasive lobular and ductal carcinoma of the Breast: a Tissue Microarray Study. Appl Immunohistochem Mol Morphol 2009 May;17(3): 202–6. 14. Dadzie OE, Neat M, Emley A, Bhawan J, Mahalingam M. Molecular diagnostics—an emerging frontier in dermatopathology. Am J Dermatopathol 2011 Feb;33(1):1–6. 15. Elaba Z, Murphy MJ, Mnayer L. Molecular diagnostics in dermatology and dermatopathology. Hartford, CT: Humana Press; 2011. p. 27–50.

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Chapter

Fundamentals of Dermatopathology

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Robert Duffy, Robin Burger, Amira Elbendary, Manuel Valdebran, Jisun Cha

INTRODUCTION This chapter provides an introduction to the fundamental basics of normal skin histology and descriptive terms for dermatopathologic phenomena. Histologically, the skin is composed of three separate and distinct layers: the epidermis, the dermis, and the subcutis. The epidermis is composed of keratinized stratified squamous epithelium and can then be further subdivided into five distinct strata. From bottom to top, the strata are the stratum basale, the stratum spinosum, the stratum granulosum, the stratum lucidum, and the stratum corneum (Fig. 7.1). The dermis lies directly under the epidermis’ basement membrane and can also be further subdivided into two layers (top to bottom): the papillary and the reticular layers. Finally, the subcutis is the deepest layer of the skin.

EPIDERMIS The stratum basale is attached to the basement membrane by hemidesmosomes and is the layer of proliferation. Keratinocytes and melanocytes are found in the stratum basale. Basal keratinocytes are columnar or cuboidal shaped and in constant mitosis. Melanocytes can be

visually differentiated from keratinocytes on Hematoxylin and eosin (H&E) by their lack of coherence with the surrounding basal cells, smaller and darker nuclei, and apparent gaps within them due to fixation.1 The stratum spinosum is characterized by keratinocytes in this layer that are slightly separated from each other but attached with desmosome proteins giving them a spinous appearance on high magnification. These cells contain rounded nuclei and are various shapes with sharp edges. Langerhans cells are also found in the stratum spinosum and are identifiable on H&E because their cytoplasm shrinks during fixation, giving the appearance of lacunae.1 In the stratum granulosum, keratinocytes begin to flatten and lose their nuclei. The stratum lucidum sits above the stratum granulosum and is clear and anucleate. It is a thin layer and only can be visualized on microscopy of the thick skin of the palms and soles.1 The stratum corneum is the most superficial layer of the epidermis. This layer is composed of dead keratinocytes called corneocytes. With microscopy, the upper layer appears flattened and anucleate and stains darkly because the cells are completely filled with keratin. Individual cells are difficult to distinguish due to lipids released by the stratum granulosum and the spaces that form between them.1

DERMIS

Fig. 7.1: The epidermis is composed of keratinized stratified squamous epithelium further subdivided into four distinct strata: stratum basale, stratum spinosum, stratum granulosum, and stratum corneum from bottom to top.

The dermis is located directly under the epidermis and provides much of the support for the skin. The papillary layer is the cellular layer directly under the basement membrane composed of thin and loosely organized collagen fibers. The reticular layer is composed of thicker collagen fibers that are arranged into bundles. Throughout the dermis, elastic fibers and sebaceous glands can be identified. Sebaceous glands are usually adjacent to hair follicles (Fig. 7.2). The lining of these glands is comprised of flattened, dark staining, regenerative cells. As they divide, some will differentiate and be pushed into the center of the gland where the cells are filled with lipids, thus the lack

Chapter 7: Fundamentals of Dermatopathology of staining. As these cells mature, they develop irregular nuclei due to the increase in intracellular pressure from the excess of lipids. When sebum is released, the cell membrane bursts and the contents spill out of the gland’s duct onto the skin surface via the hair follicle.1

SUBCUTIS Finally, the subcutis is the deepest layer of the skin. This layer is composed primarily of adipocytes organized into lobules through fibrous septations. Within the upper area of the subcutis and lower area of the dermis, apocrine and eccrine sweat glands can be found. They are composed of a lumen surrounded by two rows of cuboidal epithelium (Figs. 7.3 and 7.4). Eccrine glands can be distinguished from apocrine glands as they have a smaller lumen, contain myoepithelial cells, and are located throughout the body, whereas apocrine glands are restricted to the axillae and genitals.1

ANATOMIC VARIATION IN SKIN HISTOPATHOLOGY The appearance of skin differs on various regions of the body. Facial skin has a thin epidermis with abundant hair follicles and sebaceous glands in the dermis (Fig. 7.5). Common findings on facial skin include Demodex mites within hair follicles and solar elastosis, which appear as an accumulation of elastic tissue, seen as abundant basophilic strands, in the dermis.3 Eyelids appear histologically similar to the other areas of the face with the addition of skeletal muscle in the upper dermis and multiple vellus hairs corresponding to eyelashes.2 Skin of the trunk has a very thick dermis with scattered sebaceous units and fat extending to the adnexa (Fig. 7.6). Skin of the lower extremities has a thinner dermis relative

Fig. 7.2: Sebaceous glands are spherical glands composed of rounded cells filled with lipid filled vacuoles.

Fig. 7.4: Eccrine glands are composed of simple cuboidal epithelium that is smaller in size than the apocrine glands. The excretory duct is formed of two layers of stratified cuboidal epithelium.

Fig. 7.3: Apocrine glands are composed of simple cuboidal epithelium and dilated lumen. There are some blebs on the apical surface of secretory epithelium.

Fig. 7.5: Facial skin is characterized by a thin epidermis, numerous hair follicles, sebaceous glands, and solar elastosis, which gives rise to wavy blue deposits of elastin in the superficial dermis.

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Section 3: Dermatopathology to the trunk and may have dilated veins in the papillary dermis due to gravitational effects.2 Acral skin on the palms and soles contains a compact stratum corneum with a prominent stratum lucidum seen on H&E (Fig. 7.7). Pacinian (lamellar) and Meissner corpuscles may be seen in the dermis (Fig. 7.8). Pacinian corpuscles are a nerve ending responsible for sensation of vibration and pressure. They are located in the deep dermis or subcutis and are composed of concentric lamellae made up of epithelial cells on the outer surface and modified Schwann cells in the inner capsule. Meissner corpuscles are responsible for sensation of light touch and are in highest density in finger pads. They are located in the dermal papilla and are composed of unmyelinated nerve endings arranged in horizontal lamella and are surrounded by connective tissue.4 Areolar skin is characterized by acanthosis (thickening of the epidermis), smooth muscle in the mid-dermis, and apocrine glands in the reticular dermis (Fig. 7.9).2 Fig. 7.8: Meissner corpuscles located in the dermal papilla are composed of unmyelinated nerve endings arranged in horizontal lamella and are surrounded by connective tissue. Courtesy: Dermatopathology service at the University of California San Francisco with special thanks to Dr. Philip LeBoit, San Francisco, California, USA.

Fig. 7.6: Skin of back or trunk demonstrates increased dermal thickness.

Fig. 7.7: Acral skin reveals a compact stratum corneum with a prominent stratum lucidum.

Fig. 7.9: Areolar skin shows acanthosis, smooth muscle bundles in the mid-dermis, and apocrine glands in the reticular dermis. Courtesy: Dermatopathology service at the University of California San Francisco with special thanks to Dr. Philip LeBoit, San Francisco, California, USA.

Chapter 7: Fundamentals of Dermatopathology

ADNEXAL STRUCTURES Adnexal structures include hair, nails, hair follicles, sebaceous glands, eccrine, and apocrine glands. The follicular unit includes a hair follicle with adjacent arrector pili muscle and sebaceous gland. A hair follicle is formed by an epithelial and a mesenchymal component. The epithelial cells extend inferiorly and combine with mesenchymal cells to form the root sheath and papilla. The papilla is located at the base of the follicle and made up of connective tissue and mitotically active epithelial cells. Surrounding the papilla is the hair matrix.1 The hair shaft is made up of three layers (inner to outer); medulla, cortex, and cuticle. These layers are surrounded by the inner and outer root sheath, which is surrounded by a fibrous root sheath (Fig. 7.10). These distinct layers can be differentiated by light microscopy. The inner root sheath contains cuboidal eosinophilic cells with trichohyalin granules. The outer root sheath consists of large cells that undergo abrupt keratinization (keratinization without a granular layer) at the level of the midshaft and regular keratinization more distally. Additionally, hair anatomy is divided into distinct regions. The most inferior region is known as the “bulb” and is located from the base to the area where hair starts to cornify (Fig. 7.11). Superior to that region is the “stem,” which refers to the place at which hair starts to cornify to the arrector pili muscle. The “isthmus” is the region spanning the arrector pili muscle to the sebaceous gland. The “infundibulum” is from the insertion of the sebaceous gland to the top of the epidermis.5 Hair grows in phases that can be distinguished on H&E. The phases of hair growth are anagen (growing) phase, catagen (regression) phase, and telogen (resting)

Fig. 7.10: A hair follicle contains clear glycogenated cells in the outer root sheath and keratohyalin granules, germinative cells, and papillary mesenchymal body in the bulb.

phase. Histologically, a hair in anagen phase is fully developed compared to a hair in catagen phase, where the lower portion of the follicle is involuted and the basement membrane is markedly thickened. During telogen phase, the papilla condenses and the epithelium has abrupt keratinization without a granular layer (i.e. trichilemmal keratin), which appears “flame like” on H&E.2 Sebaceous glands are ductless glands that are adjacent to hair follicles and secrete sebum. Histologically, these glands contain a peripheral rim of smaller basaloid cells with lipid-laden cells in the center. Sweat glands consist of a secretory unit in the lower dermis or subcutis and a duct system. The distal duct leading to the epidermis is known as the “acrosyringium.” There are two categories of sweat glands; eccrine and apocrine. Eccrine glands are located all over the body while apocrine glands are found in restricted areas such as areola of the breast, axilla, perianal regions, eyelids, and ear canal.6 These glands function in thermoregulation. Apocrine glands may secrete pheromones.7 Eccrine glands are comprised of clear and blue cuboidal to columnar cells, which are surrounded by a myoepithelial layer. Apocrine glands consist of eosinophilic cuboidal to columnar cells with decapitation secretion.6,8 Nails are composed of a keratin plate that extends from the nail matrix, which is covered by a skin fold. Histologically, the nail matrix consists of stratified squamous epithelium

Fig. 7.11: This is a horizontal section of a hair follicle.

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Fig. 7.12: Histologic features of the proximal nail unit include: proximal nail fold (a), distal nail matrix with incidental subungual epidermoid inclusions (b), distal matrix (c), proximal matrix (d), ventral surface of proximal nail fold aka. eponychium (e), keratogenous zone (f ), nail plate (g). Courtesy: Beth S. Ruben , MD. San Francisco, California, USA.

Fig. 7.13: Histologic features of the distal nail matrix, nail bed, and hyponychium include: false cuticle (a), true cuticle (b), nail plate (c), distal nail matrix (d), nail bed (e1), nail bed in transverse section with melanoma in situ (e2), hyponychium reverts to acral skin (f ). Courtesy: Beth S. Ruben, MD. San Francisco, California, USA.

with the absence of a granular cell layer. The dermis beneath the proximal matrix is dense. It is possible to see glomus bodies in the dermis, which are specialized arteriovenous vessels involved in thermoregulation. The nail matrix gives rise to the nail plate. The nail plate consists of multiple layers of keratin cells made from anucleated cells called onychocytes. The nail in general undergoes “onycholemmal keratinazation” (keratin formation without a granular layer) (Figs. 7.12 and 7.13); however, the granular layer returns at the proximal nail fold, lateral nail fold, and hyponychium (skin under the distal nail bed).9

CELLS OF THE SKIN • Keratinocytes comprise the epidermis and were described earlier • Melanocytes are normally found in the epidermis and were described previously • Mast cells have a characteristic “fried-egg” appearance, meaning a round nucleus (yolk) in the middle of an irregular cellular border (egg white) (Fig. 7.14)10 • Lymphocytes (Fig. 7.15) are mononuclear and are notable for their high nuclear to cytoplasmic ratio10 • Plasma cells (Fig. 7.16) have an off-center nuclei and a peri-nuclear halo, which represents the Golgi apparatus staining. They may contain Russell and/or Dutcher

Fig. 7.14: Mast cells are round cells with basophilic or granular cytoplasm and centrally located nuclei. Courtesy: Dermatopathology service at the University of California San Francisco with special thanks to Dr. Philip LeBoit, San Francisco, California, USA.

bodies which are intracytomasic and nuclear eosinophilic inclusions, respectively10 • Neutrophils (Fig. 7.17) have multilobulated nuclei and a homogeneous eosinophilic cytoplasm • Eosinophils (Fig. 7.15) can be identified by their eosinophilic cytoplasm and bilobed nucleus

Chapter 7: Fundamentals of Dermatopathology

Fig. 7.15: Eosinophils have intensely eosinophilic granules. Lymphocytes (arrow head) are small white blood cells with a round nucleus and scant cytoplasm.

Fig. 7.17: Neutrophils have multilobulated nuclei.

Fig. 7.16: Plasma cells have characteristic eccentric nuclei with a clock face appearance.

• Histiocytes are mononuclear phagocytic cells. Langerhans cells are histiocytes specific to the epidermis and were described earlier. Macrophages are histiocytes of the dermis10

GLOSSARY OF TERMS • Acantholysis (Fig. 7.18) is the loss of connection between keratinocytes in the stratum spinosum • Acanthosis (Fig. 7.19) is diffuse hyperplasia of the stratum spinosum10 The percentage of overall size of the stratum basale and spinosum in comparison to the remaining epidermis is much greater than in a normal skin specimen

• Anaplasia is loss of differentiation within a cell group causing the characteristics of the particular cell type to become less apparent. It is usually a marker of malignant progression • Apoptosis is the process of programed cell death. The cytoplasm of an apoptotic cell is deeply eosinophilic and the nucleus can be either in the process of condensation (pyknosis), fragmentation (karyorrhexis), or dissolution (karyolysis). At the end of apoptosis, the cell is anucleate11 • Atrophy of dermis is the relative decrease in thickness of the dermal layer of skin. This can be because of a decrease in size of the dermal layer or an increase in size of the epidermis or hypodermis • Atrophy of epidermis is decreased thickness of the epidermis with particular effect on the stratum spinosum10 • Basaloid cells (Fig. 7.20) are cells that have the same morphology as the keratinocytes found within the stratum basale. • Dyskeratosis (Fig. 7.21) is the process by which keratinocytes prematurely keratinize becoming corneocytes prior to reaching the stratum granulosum. These cells stain bright pink on H&E stain • Follicular mucinosis is mucin around hair follicles between keratinocytes • Follicular plugging is the thickening of the stratum corneum within the hair follicle

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Fig. 7.18: Acantholysis is the loss of cohesion between keratinocytes in the epidermis. Rounded keratinocytes appear floating within clear spaces in the epidermis.

Fig. 7.20: Basaloid cells are characterized by a distinct dark blue hue due to a high nuclear-to-cytoplasmic ratio and crowding of cells. Note the peripheral palisading in this basal cell carcinoma.

Fig. 7.19: Acanthosis is epidermal thickening due to hyperplasia in the spinous layer.

Fig. 7.21: Dyskeratosis is premature keratinization occurring in individual cells at the level of the stratum spinosum. These cells become more eosinophilic and rounded. They tend to detach from the neighboring cells. Courtesy: Dermatopathology service at the University of California San Francisco with special thanks to Dr. Philip LeBoit, San Francisco, California, USA.

• Granulomas (Fig. 7.22) are aggregations of macrophages with or without other leukocytes. Multinucleated giant cells, which are formed through the fusion of the macrophages, may be present10 • Granulation tissue is characterized by neovascularization of capillaries, spindle-shaped fibroblasts, myofibroblasts, and inflammatory cells in a collagen stroma11 • Grenz zone (Fig. 7.23) is an area of the superficial papillary dermis that is spared from inflammation, which may be seen in several disease entities • Hemosiderin (Fig. 7.24) is an iron-containing brown pigment that stains with Prussian blue10

• Horn cysts (Fig. 7.25) are well-demarcated, rounded areas of keratin within aggregates of multiplying keratinocytes. These should not be confused with pseudohorn cysts, which are invaginations of the stratum corneum surface filled with keratin (Fig. 7.26)10 • Hyalinization is a degenerative process resulting in the appearance of an acellular, avascular, homogeneous area

Chapter 7: Fundamentals of Dermatopathology

Fig. 7.22: A granuloma is a collection of histiocytes, which often form multinucleated giant cells.

Fig. 7.24: Hemosiderin is an iron-containing brown pigment that can be seen in dermis. Courtesy: Dermatopathology service at the University of California San Francisco with special thanks to Dr. Philip LeBoit, San Francisco, California, USA.

Fig. 7.23: The grenz zone is an unaffected area in the papillary dermis. Note the inflammation beneath.

• Hypergranulosis (Fig. 7.27) is thickening of the stratum granulosum • Hyperkeratosis is a thickened stratum corneum • Hyperpigmentation can be seen on histology as an increase in pigment within the deep areas of the epidermis and dermis • Hyperplasia of epidermis is an overall increase in the thickness of the epidermis relative to the dermis and hypodermis. Epidermal hyperplasia is usually a combination of hyperkeratosis and acanthosis10 • Hypogranulosis is a diminished stratum granulosum • Hypopigmentation is characterized by a lack of melanin pigment within the stratum spinosum and stratum basale. This can be due to a lack of melanocytes or a lack of melanin production from the melanocytes • Interface dermatitis (Fig. 7.28) is lymphocytic inflammation at the dermoepidermal junction leading to degenerative and vacuolar changes

Fig. 7.25: Horn cysts are intraepidermal pseudocystic spaces filled with lamellar keratin. Courtesy: Dermatopathology service at the University of California San Francisco with special thanks to Dr. Philip LeBoit, San Francisco, California, USA.

• Interstitial dermatitis is inflammation of the dermis with a diffuse leukocytic infiltrate (Fig. 7.29) • Koilocytes (Fig. 7.30) are cells that have gone through morphologic changes secondary to a human

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Fig. 7.28: Hypergranulosis is characterized by increased thickness of the stratum granulosum.

Fig. 7.26: Pseudohorn cysts are invaginations of the stratum corneum surface filled with keratin.

Fig. 7.27: Interface dermatitis is characterized by a collection of lymphocytes at the dermoepidermal junction with associated vacuolar degeneration of keratinocytes. Courtesy: Dermatopathology service at the University of California San Francisco with special thanks to Dr. Philip LeBoit, San Francisco, California, USA.

Fig. 7.29: Koilocytes are cells with perinuclear clearing and wrinkled nuclei that contain Human papillomavirus (HPV) particles. Courtesy: Dermatopathology service at the University of California San Francisco with special thanks to Dr. Philip LeBoit, San Francisco, California, USA.

papillomavirus infection. These cells show an enlarged, hyperchromatic, and irregularly shaped nucleus with a perinuclear halo Lichenoid dermatitis is a band-like leukocytic infiltrate at the dermoepidermal junction • Melanin incontinence is melanin within the dermis (Fig. 7.31). This is generally secondary to epidermal

damage in the papillary dermis and due to melanin synthesis in the reticular dermis10 • Myxomatous change occurs with a significant amount of mucin which generally appears as an empty space due to the fixation process • Necrotic keratinocytes (Fig. 7.32) describes keratinocytes that are dead

Chapter 7: Fundamentals of Dermatopathology

Fig. 7.30: Interstitial dermatitis is characterized by inflammatory cells amidst collagen bundles. Courtesy: Dermatopathology service at the University of California San Francisco with special thanks to Dr. Philip LeBoit, San Francisco, California, USA. Fig. 7.32: Necrotic keratinocytes are depicted here.

Fig. 7.33: Pagetoid spread is characterized by atypical cells extending upward toward the surface of the epidermis.

Fig. 7.31: Melanin incontinence demonstrates melanin granules in the upper dermis.

• Orthokeratosis is a thickening of the stratum corneum • Pagetoid spread (Fig. 7.33) is the movement of melanocytes into superficial layers of the epidermis. Nests of cells or individual cells are present high within the stratum spinosum • Papillomatosis is an accentuation and enlargement of dermal papillae (Fig. 7.34)

• Parakeratosis (Fig. 7.35) describes retention of nuclei within cells of the stratum corneum. These nuclei have usually begun the process of pyknosis (nuclear condensation) and will be denser and smaller in size than those of the stratum basale10 • Perivascular dermatitis (Fig. 7.36) is inflammation characterized by lymphocytic inflammatory infiltrate around the dermal vasculature • Pseudoepitheliomatous hyperplasia (Fig. 7.37) is prominent acanthosis of the epidermis that extends downward toward the dermis10

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Fig. 7.34: Papillomatosis is characterized by finger-like exophytic projections formed by enlargement of the dermal papillae. Fig. 7.37: Pseudoepitheliomatous (pseudocarcinomatous) hyperplasia shows irregular epidermal hyperplasia. Note the acanthosis extends to the reticular dermis. Courtesy: Dermatopathology service at the University of California San Francisco with special thanks to Dr. Philip LeBoit, San Francisco, California, USA.

Fig. 7.35: Parakeratosis reveals retained nuclei in the stratum corneum.

Fig. 7.38: Psoriasiform hyperplasia is depicted here.

Fig. 7.36: Perivascular dermatitis reveals inflammatory infiltrate distributed around vessels. Courtesy: Dermatopathology service at the University of California San Francisco with special thanks to Dr. Philip LeBoit, San Francisco, California, USA.

• Pseudohorn cysts are invaginations of the stratum corneum surface filled with keratin • Psoriasiform hyperplasia is defined by acanthosis and regular, club-shaped rete ridges (Fig. 7.38)10 • Pustules are visualized on histopathology as a subcorneal neutrophilic infiltrate (Fig. 7.39) • Spindle cell neoplasms (Fig. 7.40) are characterized by slender, elongated cells • Spongiosis (Fig. 7.41) is edema within the epidermis. This fluid accumulation may change the morphologic features of the keratinocytes that are located in the affected area, giving them a more drawn out appearance. On histology, intercellular gaps and stretched cells will be apparent in the epidermal layer

Chapter 7: Fundamentals of Dermatopathology

Fig. 7.39: A pustule is a collection of neutrophils. In this figure, a collection of neutrophils is seen underneath epidermal erosion.

Fig. 7.41: Spongiosis is intercellular edema with prominent intercellular bridges.

Fig. 7.40: Spindle cell neoplasms are characterized by narrow, elongated cells.

Fig. 7.42: Squamous eddies are pink whirls of squamous cells.

• Squamous eddies (Fig. 7.42) are islands of keratin surrounded by layered keratinocytes. These are differentiated from keratin pearls by their gradual change from cellular to acellular components, while keratin pearls have an abrupt cellular to acellular margin10 • Squamatization is an increase in the staining capacity of the epithelium, giving it a deeper red color. It can be due to either necrotic keratinocytes or dyskeratosis

2. Alsaad K, Obaidat N, Ghazarian D. Skin adnexal neoplasms—part 1: an approach to tumours of the pilosebaceous unit. J Clin Pathol 2006;60(2):129–44. 3. Ferringer T, Ko C. The basics: diagnostic terms, skin anatomy and stains. In: Elston D, Ferringer T, editors. Dermatopathology. 2nd ed. Elsevier Philadelphia; 2014. p. 1–36. 4. Diegel K, Danilenko D, Wojcinski Z. Integument. In: Haschek W, editor. Haschek and Rousseaux’s handbook of toxicologic pathology. 3rd ed. Elsevier Inc; 2013. p. 2219–75. 5. Khavkin J, Ellis D. Aging skin: histology, physiology, and pathology. Facial Plast Surg Clin North Am 2011;19(2): 229–34. 6. Fernandez-Flores A, Saeb-Lima M, Martínez-Nova A. Histopathology of the nail unit. PubMed—NCBI [Internet].

REFERENCES 1. Ackerman AB, Böer A, Bennin B, et al. Histologic diagnosis of inflammatory skin diseases: an algorithmic method based on pattern analysis. 3rd ed. Ardor Scribendi New York; 2005.

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Section 3: Dermatopathology Ncbi.nlm.nih.gov. 2016 [cited 8 June 2016]. Available from: http://www.ncbi.nlm.nih.gov/pubmed/ 24969971. 7. McGrath J. The structure and function of skin. In: Calonje E, editor. McKee’s pathology of the skin. 4th ed. Elsevier Philadelphia; 2012. p. 1–31. 8. McGrath K. Apocrine sweat gland obstruction by antiperspirants allowing transdermal absorption of cutaneous generated hormones and pheromones as a link to the

observed incidence rates of breast and prostate cancer in the 20th century. Med Hypotheses 2009;72(6):665–74. 9. Mills S. Histology for pathologists. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins; 2012. 10. Rapini R. Practical dermatopathology. Elsevier Mosby Philadelphia; 2005. 11. Kumar V, Abbas AK, Aster JC. Robbins and Cotran pathologic basis of disease. Elsevier Saunders Philadelphia; 2015.

Chapter

8

Dermatopathology: An Approach to Skin Inflammation Attiya Haroon, Babar K Rao

INTRODUCTION Biopsy is the gold standard in diagnosing skin inflamma­ tion. Differentiating skin inflammation histologically can be difficult, as the findings encompass a long list of condi­ tions. The aim of this chapter is to elaborate on a simple and practical approach, known as the ASAP model, used to diagnose skin pathologies with the help of illustrations and histological images. This model is based upon on the common reaction patterns of inflammation. Diagnostic histological features along with the differentiating charac­ teristic findings in each category and subcategory are also a part of this chapter.

A

ASAP MODEL TO DIAGNOSE SKIN INFLAMMATION According to the ASAP model, skin inflammation is broadly classified into three main types (Figs. 8.1A and B) based on the cutaneous layer response to injury. 1. Epidermal 2. Dermal 3. Subcutaneous.

B Figs. 8.1A and B: (A) Classification of skin inflammation; and (B) Sites of blister formation (Image courtesy Elsevier 2005).

Epidermal Skin Inflammation A distinctive epidermal reaction pattern occurs in res­ ponse to different injuries/stimuli. These responses vary from changes in epidermal cellular kinetics, for instance, epidermal hyperplasia or atrophy, to changes like spongio­ sis, acantholysis (Fig. 8.2), or degeneration.1 Inflammatory cell infiltrate also helps to differentiate an acute epidermal response from a chronic one. Histologically, epidermal skin inflammations are subdivided into four categories based on the inflammatory reaction pattern (Figs. 8.1A and B) evident: 1. Subcorneal 2. Intraepidermal 3. Subepidermal 4. Interface dermatitis.

Fig. 8.2: Dyskeratosis and acantholysis.

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Subcorneal Inflammation Inflammatory response in this category is limited to the upper layer of the epidermis. Common causes of skin inflammation included in this category are conditions such as impetigo, candidiasis, superficial pemphigus, and pustular psoriasis. • Thin-walled subcorneal blisters, which easily burst to form a crust with neutrophils in the blister space, are diagnostic features of impetigo2 • Candidiasis is a common skin inflammation. In can­ didiasis, fungal spores and hyphae are seen on peri­ odic acid-Schiff (PAS) stain in the stratum corneum3 (Figs. 8.3A and B) • Pemphigus could be a severe and life-threatening con­ dition caused by autoantibodies. The reaction of the autoantibodies with host antigens causes acantholysis with subcorneal blister formation.4 Superficial pem­ phigus can either be drug-induced or paraneoplastic. Drugs, such as penicillamine, can trigger a pemphi­ gus-like reaction; however, antibodies are rarely found in these cases. Paraneoplastic superficial pemphigus is associated with an underlying malignancy and could present with severe mucosal reactions5

• Subcorneal neutrophilic abscess is a diagnostic feature of pustular psoriasis6 (Fig. 8.4).

Intraepidermal Inflammation Histologically, intraepidermal inflammation can be divided into four categories. These include: 1. Acantholytic 2. Spongiotic 3. Papulosquamous 4. Reticular degenerations which include: a. Herpetic b. Non-herpetic. Acantholytic inflammation: This group of inflamma­ tion is classified on the basis of acantholysis (the loss of intracellular connections).7 Skin conditions, for instance, Hailey-Hailey, Grover, Pemphigus vulgaris, and Darier, are included in this class. • Hailey-Hailey is a genetic disease which is clinically recognized as painful outbreaks of blisters in inter­ triginous regions. On histology, prominent supraba­ sal acantholysis is seen in all layers of the epidermis.8 Absence of dyskeratosis and the presence of dilapidated brick wall appearance of cells are diagnostic of Hailey–Hailey disease9 (Figs. 8.5A and B) • Acantholysis in pemphigus vulgaris is limited to the suprabasal layers of the epidermis, while the basal keratinocytes remain attached to basement mem­ brane, thus giving a characteristic tombstone appear­ ance10 (Fig. 8.6) • In contrast to the two aforementioned patterns, Darier disease is characterized histologically as suprabasal

A

B Figs. 8.3A and B: Candidiasis. (A) Fungal hyphae on hematoxylin and eosin (H&E); (B) Fungal hyphae on periodic acid Schiff (PAS) stain.

Fig. 8.4: Pustular psoriasis.

Chapter 8: Dermatopathology: An Approach to Skin Inflammation

A

A

B

B

Figs. 8.5A and B: Hailey–Hailey disease. (A) Low power magnification view showing marked acantholysis; (B) High power magnification showing dilapidated brick wall appearance.

Figs. 8.7A and B: Darier disease. (A) and (B) Histology of Darier disease with scattered apoptotic or dyskeratotic cells (corps round) within various levels of epidermis.

Fig. 8.6: Pemphigus vulgaris (PV).

acantholysis with scattered apoptotic or dyskeratotic cells within the various levels of the epidermis11 (Figs. 8.7A and B) • Transient acantholytic dermatosis, also referred to as Grover disease, clinically presents as a temporary papulovesicular rash of the upper trunk. Acantholysis in Grover disease occurs in a variety of different pat­ terns, and often deeper sections or multiple biopsies are required to appreciate the diagnostic acantholytic pattern. The most common pattern seen in Grover dis­ ease is a pemphigus-vulgaris-like pattern12 (Fig. 8.8). Darier-like, spongiotic, pemphigus-foliaceous-like, and Hailey–Hailey-like patterns are also seen in Grover dis­ ease. These patterns can occur either individually, or in combinations.13

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A Fig. 8.8: Grover disease.

Spongiotic inflammation:  Spongiosis is the diagnostic histological feature of this category. The term spongiosis is defined as intercellular edema, causing a separation of keratinocytes and a widening of the intercellular spaces.14 It usually occurs with exocytosis of lymphocytes. This class of inflammation includes common cutaneous con­ ditions such as contact dermatitis, atopic dermatitis, seb­ orrheic dermatitis, and photoallergic dermatitis. These conditions share common histological features. Therefore, a detailed history and clinicopathological correlation is essential in making the right diagnosis in these cases.15 Spongiotic dermatitis is further classified into acute, subacute, and chronic depending upon the age of the lesion and time of the biopsy performed. • Acute spongiotic dermatitis shows epidermal spongiosis and superficial dermal edema with perivascular lympho­ cytic inflammatory infiltrates.16 Exocytosis is also seen with no acanthosis or parakeratosis (Figs. 8.9A and B). Eosinophils may also be present in the epidermis or der­ mis in the case of allergic or contact acute dermatitis.17 • Subacute spongiotic dermatitis is characterized by mild-to-moderate exocytosis, spongiosis with some parakeratosis, and acanthosis18 • In the case of chronic spongiotic dermatitis, there is pronounced acanthosis, parakeratosis, and hyperker­ atosis. However, there is absent-to-mild epidermal or dermal spongiosis with minimal exocytosis of inflam­ matory cells.19 Fibrosis of the papillary dermis may also be present in chronic spongiotic dermatitis Papulosquamous inflammation:  Papulosquamous intra­ epidermal inflammation or the scaly skin diseases are characterized clinically as discrete or localized papules

B Figs. 8.9A and B: Acute dermatitis. (A) Marked spongiosis and blister formation; (B) Exocytosis and mild spongiosis.

or plaques, and histologically hyperkeratosis is present.20 Common conditions in this category are pityriasis rosea, psoriasis, porokeratosis, pityriasis rubra pilaris (Fig. 8.10), parapsoriasis, and pityriasis lichenoid. • Along with hyperkeratosis, elongated rete ridges and the loss of the granular layer with neutrophils in the stratum corneum (spongiform pustules of Kojog and Munro microabscesses) are diagnostic features of psoriasis21 (Fig. 8.11). Reticular degeneration: Reticular degeneration, or bal­ looning degeneration, is defined histologically as severe intracellular epidermal edema with secondary rupture of keratinocytes.22 Ruptured keratinocytic membranes remain attached to intact keratinocytes with desmosomal attachments, hence giving an irregular meshwork/ground glass appearance to the epidermis. This category is further classified into (1) herpetic and (2) non-herpetic types.

Chapter 8: Dermatopathology: An Approach to Skin Inflammation

Fig. 8.10: Pityriasis rubra pilaris (PRP).

Fig. 8.12: Herpes zoster (HZ).

A Fig. 8.11: Psoriasis.

1. Herpetic reticular degeneration includes infectious diseases like herpes zoster, herpes simplex, and vari­ cella. Giant multinucleated keratinocytes are present in herpes zoster23 (Fig. 8.12), while eosinophilic intra­ nuclear inclusion bodies of ballooned keratinocytes are seen in herpes simplex viral infection24 (Figs. 8.13A and B). 2. Non-herpetic reticular degeneration includes hand, foot, and mouth disease, orf, and Milker’s nodule. Absence of intranuclear inclusions with spongiosis and ballooning degeneration of keratinocytes are diagnostic histological features of hand, foot, and, mouth disease.25 In the case of milker’s nodule, intracy­ toplasmic eosinophilic inclusion bodies of epidermal keratinocytes are characteristic histological features.26

B Figs. 8.13A and B: Herpes simplex. (A) Spongiosis, vesicle formation and dense inflammation; (B) Multinucleated giant cells.

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Subepidermal Inflammation These lesions show subepidermal blister formation between the epidermis and dermis, along with various inflammatory cell infiltrates.27 On the basis of inflam­ matory cells involved in the pathogenesis of a particu­ lar lesion, subepidermal inflammation is classified into subcategories. • Subepidermal inflammatory skin lesions with eosino­ phils include bullous pemphigoid (Fig. 8.14) and her­ pes gestationis28 • Subepidermal inflammatory skin lesions with neutro­ phils include dermatitis herpetiformis (Fig. 8.15), lin­ ear IgA dermatoses, and drug reactions29 • Subepidermal inflammatory skin lesions with lym­ phocytes include epidermolysis bullosa and porphyria cutanea tarda.30

and some histiocytes along the dermoepidermal junc­ tion.32 Lichenoid inflammation is associated with the presence of apoptotic bodies, otherwise known as civ­ atte or colloid bodies, and vacuolar degeneration of basal keratinocytes.33 Cutaneous pathologies, which result in the lichenoid interface dermatitis pattern, are lichen planus, lichen-planus-like keratosis (Fig. 8.17), lichenoid drug eruption, and secondary syphilis. The prototype of this histological pattern is lichen planus. In addition to the defining feature of interface der­ matitis, Orthohyperkeratosis overlying an epidermis with a “saw tooth” pattern of acanthosis is a diagnostic feature of lichen planus.34 In idiopathic lichen planus, there is no deep infiltration of inflammatory cells. In chronic lesions, basal keratinocytes release mela­ nin into the dermis, which results in accumulation of

Interface Dermatitis Inflammation This pattern is defined by the presence of inflammatory cells (neutrophils, lymphocytes, lymphohistiocytic cells), which are seen obscuring the dermoepidermal junc­ tion.31 Based on the type of inflammatory cells involved at the DEJ or the intensity of interface inflammation, this class is subdivided into (1) lichenoid inflammation (Fig. 8.16) and (2) non-lichenoid inflammation (with or without eosinophils). Each class has distinctive morpho­ logical features. 1. Lichenoid interface dermatitis is also called cell-rich interface dermatitis. It is characterized by band-like, confluent, dense accumulation of inflammatory cells in the papillary dermis, which includes lymphocytes

Fig. 8.15: Dermatitis herpetiformis.

Fig. 8.14: Bullous pemphigoid.

Fig. 8.16: Lichenoid dermatitis.

Chapter 8: Dermatopathology: An Approach to Skin Inflammation

A Fig. 8.17: Lichen planus like keratosis (LPLK).

dermal melanophages.35 This presents as postinflam­ matory hyperpigmentation clinically. Parakeratosis is also seen in patients with itchy or chronically irritated lichen planus. 2. Non-lichenoid interface dermatitis shows vacuolar changes within basal keratinocytes with inflammatory cell infiltrates along the dermoepidermal junction.36 Fixed drug eruptions and phototoxic dermatitis are examples of non-lichenoid dermatitis with eosinophils. Non-lichenoid skin inflammation without eosinophils encompasses a long list such as erythema multiforme, lupus erythematosus, pityriasis lichenoides et varioli­ formis acuta (Figs. 8.18A and B).37

B Figs. 8.18A and B: Pityriasis lichenoid. (A) Hyperkertosis, parakeratosis, and a wedge shaped inflammation; (B) Epidermal necrosis and extravasation of red blood cells.

Dermal Skin Inflammation The dermis is the second layer of the skin, composed of the papillary and reticular dermis. Dermal response to injury is exhibited either by an increase or decrease in dermal com­ ponents or by degenerative alterations.38 Histologically, dermal inflammation is subdivided into six types. They are (1) superficial dermatitis, (2) superficial and deep derma­ titis, (3) granulomatous, (4) sclerosing/fibrosing, (5) depo­ sition, and (6) vascular (Fig. 8.19).

Superficial Dermatitis As the name implies, inflammatory response is limited to the superficial dermis only. This is further categorized into two variants based on the inflammatory reaction pattern (Fig. 8.19). These variants are (1) monomorphous superfi­ cial dermatitis and (2) polymorphous superficial dermatitis.

Fig. 8.19: Classification of dermal skin inflammation.

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Section 3: Dermatopathology 1. The monomorphous variant includes viral, morbili­ form drug, and dermal contact.39 2. Polymorphous superficial dermatitis includes drug reactions (with eosinophilic infiltrates), urticarial allergic eruptions (with perivascular neutrophils and edema) (Figs. 8.20A and B), dermal hypersensitivity reactions, and urticarial phase bullous pemphigoid.40

Superficial and Deep Dermatitis Inflammatory responses occur in both the superficial and the deep dermis (Figs. 8.21A and B). Based on inflamma­ tory reaction patterns, they are further classified into (1) monomorphous superficial and deep dermatitis and (2) polymorphous superficial and deep dermatitis. 1. The differential diagnosis of polymorphous superficial and deep dermatitis includes insect bites (Figs. 8.22A and B), scabies, Wells syndrome, cellulitis (Figs. 8.23A and B), and other infestations.

A

B Figs. 8.21A and B: Dermal hypersensitivity reaction. (A) and (B) Displaying dermal hyper sensitivity reaction.

A

2. Monomorphous superficial and deep dermatitises include lupus erythematous (Figs. 8.24A and B), polymorphous light eruption, Jessner lymphocytic infiltrate of skin, gyrate erythema, and lymphocytoma cutis.

Granulomatous

B Figs. 8.20A and B: Allergic eruption. (A) Perivascular inflammation; (B) Perivascular and interstitial mixed inflammatory infiltrates.

In this type of dermal inflammation, histiocytes are the predominant inflammatory infiltrate, at least in some foci. This class is further divided into three variants that are pal­ isading, sarcoidal, or necrotizing. • In the case of sarcoidal granulomatous dermatitis, numerous histiocytes are present in compact col­ lections with few lymphocytes (Figs. 8.25A to C).41 Sarcoidal granulomatous dermatitis includes a long list of cutaneous conditions

Chapter 8: Dermatopathology: An Approach to Skin Inflammation

A

A B Figs. 8.22A and B: Insect bite reaction. (A) and (B) Showing polymorphous superficial and deep dermatitis.

• Palisading granulomas are defined by the presence of mononuclear phagocytes with spindle-shaped nuclei that are palisaded parallel to each other and perpendicular to the edge of central necrotic zone.42 Histiocytes surround less cellular areas in cases of pali­ sading granulomatous dermatitis. Differential diagno­ sis of palisading granulomatous dermatitis includes granuloma annulare (Figs. 8.26A and B), necrobiosis lipoidica diabeticorum, rheumatoid nodules, and gout • Necrotizing granulomas are characterized by infiltrates of lymphocytes, which may also be seen surround­ ing the aggregates of histiocytes in case of tuberculoid granulomatous dermatitis. The list of necrotizing gran­ ulomatous dermatitis includes fungal and mycobacte­ rial infection, tuberculoid reactions (Figs. 8.27A to C), granulomatous rosacea, papillary necrosis tubercu­ loid, erythema induratum, and lichen scrof.

B Figs. 8.23A and B: Cellulitis. (A) Interstitial inflammation and dermal edema; (B) Interstitial inflammation with numerous neutrophils.

Sclerosing Dermal Inflammation This category is characterized by dermal sclerosis or dermal fibrosis with little inflammation. Morphea/scleroderma is

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Section 3: Dermatopathology the most common example of this pattern. However, in the early inflammatory phase of morphea, biopsy shows

superficial and deep perivascular and interstitial infil­ trates of lymphocytes and plasma cells. Few eosinophils and neutrophils are also seen in the basal layer. There is no recognizable dermal sclerosis at this stage. It is therefore important to know these early phase histological features and correlate history and clinical features with histological findings. Other differential diagnosis includes lichen sclerosus et atrophicus, necrobiosis lipoidica, dermatofibroma, cic­ atrix/keloid, and pseudopelade of Brocq.

Dermal Deposition

A

B

Figs. 8.24A and B: Lupus. (A) and (B) Characteristic histological features of lupus including perivascular and periadnexal lymphocytic infiltrates and degeneration of basal layer.

Mentioned here is a group of unrelated conditions, which are categorized by the abnormal deposition of the corre­ sponding endogenous substances in dermis. These sub­ stances are not a normal constitution of the skin. They are laid down in the dermis or sometimes in deeper subcuta­ neous tissue. Five major pathologies in this group involve multiple organs other than the skin: amyloid, colloid mil­ ium, porphyrias, lipoid proteinosis, and gout.

A

B

C

Figs. 8.25A to C: Sarcoid. (A to C) Sarcoidal granulomatous dermatitis with numerous histiocytes present in compact collections with few lymphocytes.

Chapter 8: Dermatopathology: An Approach to Skin Inflammation

A

B

Figs. 8.26A and B: Granuloma annulare. (A) Interstitial inflammation and mucinous degeneration; (B) Palisading histicocytes surrounding an altered central area of collagen degeneration.

A

B

C

Figs. 8.27A to C: Tuberculoid. (A to C) Tuberculoid necrotizing granulomas characterized by infiltrates of lymphocytes surrounding the aggregates of histiocytes.

• Amyloidosis is characterized histologically by abnor­ mal deposition of amyloid. Microscopically, amyloid appears as eosinophilic, homogenous hyaline mate­ rial. Cutaneous amyloidosis has two major types, which includes localized cutaneous amyloidosis and systemic amyloidosis with cutaneous involvement.43 These two classes of amyloidosis and their further subcategories show distinct patterns and location of amyloid deposi­ tion. In case of macular and lichen amyloidosis, eosin­ ophilic globules of amyloid are seen in the superficial dermis, and the overlying epidermis shows presence of basal keratinocytes with cytoplasmic vacuolization. Moreover, lichen amyloidosis has epidermal hyper­ keratosis and acanthosis which are not seen in macular amyloidosis. In contrast to the aforementioned types, nodular amyloidosis has dense infiltration of amyloid

in the dermis, subcutaneous tissue, and blood vessel wall along with plasma cell infiltrates in close proxim­ ity to amyloid deposits. Histopathologically, systemic amyloidosis with cutaneous involvement shows eosin­ ophilic deposits in the dermis, extending into the sub­ cutaneous tissue. In the subcutaneous tissue, amyloid may be seen surrounding the individual fat cells • Lichenoid proteinosis also known as hyalinosis cutis et mucosae is histologically characterized by a PASpositive, diastase-resistant hyaline material which is deposited diffusely throughout the dermis. At the onset of the disease, this hyaline material is seen deposited around small blood vessels and other adnexal struc­ tures.44 Later on in the course of the disease, these deposits surrounding the blood vessels have an onion skin appearance.

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Dermal Vascular Inflammation

neutrophils, histiocytes, and granuloma with giant cells (Figs. 8.29A to C).47 There is also perivascular and periadnexal chronic inflammatory cell infiltrates

Vasculitis is defined histologically as inflammation with subsequent destruction of blood vessels and surround­ ing tissue. This class is further subdivided into small, medium, and large vasculitis based on the size of the ves­ sel involved. • Leukocytoclastic vasculitis is the most common der­ mal vascular inflammation. Microscopic findings include disruption of the small vessels by inflamma­ tory cells (neutrophil, eosinophils, or lymphocytes) and the deposition of fibrin within the lumen and/or vessel wall. It is always important to rule out a systemic disease, an infection, or a medication in case of histo­ logically confirmed leukocytoclastic vasculitis of a skin lesion (Fig. 8.28).45,46

Subcutaneous Skin Inflammation

A

Subcutaneous fat is divided into lobules by connective tis­ sue septa. Arterioles supply the center of the lobule, while venules drain the septae. Based on this normal organiza­ tion, subcutaneous inflammations are divided into (1) septal and (2) lobular types.

Septal Septal subcutaneous skin inflammation includes primary and secondary types of inflammation. • Primary septal skin inflammation includes erythema nodosum. It is the most common type of septal pan­ niculitis. Histologically, erythema nodosum is char­ acterized by septal inflammation, hemorrhage, and marked septal fibrosis with infiltration of lymphocytes,

B

C

Fig. 8.28: Vasculitis.

Figs. 8.29A to C: Erythema nodosum. (A to C) Characteristic histology of erythema nodosum with septal inflammation, hemorrhage and marked septal fibrosis with infilteration of lymphocytes, neutrophils, histiocytes and granuloma with giant cells.

Chapter 8: Dermatopathology: An Approach to Skin Inflammation • Secondary septal inflammations include scleroderma and necrobiosis lipoidica. Scleroderma is character­ ized by marked thickening of the dermal collagen with loss of periadnexal fat and compression of adnexal structures. Epidermal atrophy with dystrophic cal­ cification of blood vessels is also seen. In necrobio­ sis lipoidica, plasma cells/lymphocytes are the main inflammatory cellular infiltrates.48

Lobular Lobular subcutaneous inflammation also includes pri­ mary and secondary types. The lobular variety of subcu­ taneous inflammation includes sarcoid, lupus profundus, post-traumatic fat necrosis, erythema nodosum leprosum, and pancreatic fat necrosis. • Lupus profundus demonstrates lobular panniculitis with lymphocytes, plasma cells, and histiocytes infil­ trates. Endothelial necrosis and lymphocytic vasculitis are also seen. Important differential diagnosis is T-cell

A

B Figs. 8.30A and B: Lupus profundus. (A) and (B) Lobular panniculitis with lymphocytes, plasma cells and histiocytes infiltration.

lymphoma with significant percentage of lymphoid atypia (Figs. 8.30A and B).49

Limitations of the ASAP Model The ASAP model is a simple way to narrow down the list of cutaneous pathologies; it does not include every single pattern seen in dermatopathology.

REFERENCES 1. Alsaad KO, Ghazarian D. My approach to superficial inflammatory dermatoses. J Clin Pathol 2005;58:1233–41. 2. Wick MR. Bullous, pseudobullous, & pustular dermatoses. Semin Diagn Pathol 2017;34:250–60. 3. Campois TG, Zucoloto AZ, de Almeida Araujo EJ, et al. Immunological and histopathological characterization of cutaneous candidiasis. J Med Microbiol 2015;64:810–7. 4. Aste N, Fumo G, Pinna AL, et al. IgA pemphigus of the sub­ corneal pustular dermatosis type associated with mono­ clonal IgA gammopathy. J Eur Acad Dermatol Venereol 2003;17:725–7. 5. Horn TD, Anhalt GJ. Histologic features of paraneoplastic pemphigus. Arch Dermatol 1992;128:1091–5. 6. Griffiths CE, Barker JN. Pathogenesis and clinical features of psoriasis. Lancet 2007;370:263–71. 7. Scheinfeld N, Mones J. Seasonal variation of transient acantholytic dyskeratosis (Grover’s disease). J Am Acad Dermatol 2006;55:263–8. (Grovers disease). 8. Yordanova I, Gospodinov DK. Familial benign chronic pemphigus (Hailey-Hailey disease). J IMAB 2007;13:60–2. 9. Vasudevan B, Verma R, Badwal S, Neema S, Mitra D, Sethumadhavan T. Hailey-Hailey disease with skin lesions at unusual sites and a good response to acitretin. Indian J Dermatol Venereol Leprol 2015;81:88–91. 10. Arya SR, Valand AG, Krishna K. A clinico-pathological study of 70 cases of pemphigus. Indian J Dermatol Venereol Leprol 1999;65:168. 11. Szigeti R, Kellermayer R. Autosomal-dominant calcium ATPase disorders. J Invest Dermatol 2006;126:2370–6. 12. Weaver J, Bergfeld WF. Grover disease (transient acantho­ lytic dermatosis). Arch Pathol Lab Med 2009;133:1490–4. 13. Davis MD, Dinneen AM, Landa N, et al. Grover’s dis­ ease: clinicopathologic review of 72 cases. Mayo Clin Proc 1999;74:229–34. 14. Patterson JW. Weedon’s skin pathology E-book. Elsevier Health Sciences UK/USA; 2014. 15. Gru AA, Salavaggione AL. Common spongiotic dermato­ ses. Semin Diagn Pathol 2017;34:226–36. 16. Ackerman AB. More about spongiosis. Am J Dermatopathol 1984;6:419–22. 17. Streit M. Contact dermatitis: clinics and pathology. Acta Odontol Scand 2001;59:309–14. 18. Busam KJ. Dermatopathology E-book: a volume in the series: foundations in diagnostic pathology (expert con­ sult-online). Elsevier Health Sciences UK/USA; 2014. 19. Wick MR. Psoriasiform dermatitides: a brief review. Semin Diagn Pathol 2017;34:220–5.

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Section 3: Dermatopathology 20. Fox BJ, Odom RB. Papulosquamous diseases: a review. J Am Acad Dermatol 1985;12:597–624. 21. De Rosa G, Mignogna C. The histopathology of psoriasis. Reumatismo 2007;59 Suppl 1:46–8. 22. Glusac EJ. Lever’s histopathology of the skin. Wolters Kluwer. USA; 1999. 23. Requena L, Requena C. Histopathology of the more common viral skin infections. Actas Dermosifiliogr 2010;101:201–16. (English Edition). 24. Leinweber B, Kerl H, Cerroni L. Histopathologic features of cutaneous herpes virus infections (herpes simplex, herpes varicella/zoster): a broad spectrum of presentations with common pseudolymphomatous aspects. Am J Surgical Pathol 2006;30:50–8. 25. Shieh WJ, Jung SM, Hsueh C, et al. Pathologic studies of fatal cases in outbreak of hand, foot, and mouth disease, Taiwan. Emerg Infect Dis 2001;7:146. 26. Al-Salam S, Nowotny N, Sohail MR, et al.. Ecthyma con­ tagiosum (orf )—report of a human case from the United Arab Emirates and review of the literature. J Cutan Pathol 2008;35:603–7. 27. Bachot N, Roujeau JC. Differential diagnosis of severe cuta­ neous drug eruptions. Am J Clin Dermatol 2003;4:561–72. 28. Walsh SR, Hogg D, Mydlarski PR. Bullous pemphigoid. Drugs2005;65:905–26. 29. Caproni M, Antiga E, Melani L, et al.. Guidelines for the diagnosis and treatment of dermatitis herpetiformis. J Eur Acad Dermatol Venereol 2009;23:633–8. 30. Fine JD, Bauer EA, Briggaman RA, et al. Revised clinical and laboratory criteria for subtypes of inherited epidermol­ ysis bullosa: a consensus report by the Subcommittee on Diagnosis and Classification of the National Epidermolysis Bullosa Registry. J Am Acad Dermatol 1991;24:119–35. 31. Crowson AN, Magro CM, Mihm Jr MC. Interface dermati­ tis. Arch Pathol Lab Med 2008;132:652–66. 32. Sontheimer RD. Lichenoid tissue reaction/interface der­ matitis: clinical and histological perspectives. J Invest Dermatol 2009;129:1088–99. 33. Sharquie KE, Al-Azzawy KK. Lichenoid dermatosis. A clinical and histopathological study. Saudi Med J 2002;23:1335–8. 34. Scully C, El-Kom M. Lichen planus: review and update on pathogenesis. J Oral Pathol Med 1985;14:431–58.

35. Vega ME, Waxtein L, Arenas R, et al.. Ashy dermatosis and lichen planus pigmentosus: a clinicopathologic study of 31 cases. Int J Dermatol 1992;31:90–4. 36. Roujeau JC. Clinical heterogeneity of drug hypersensitivity. Toxicology 2005;209:123–9. 37. Crowson AN, Magro C. The cutaneous pathology of lupus erythematosus: a review. J Cutan Pathol 2001;28:1–23. 38. Weyers W, Metze D. Histopathology of drug eruptions— general criteria, common patterns, and differential diag­ nosis. Dermatol Pract Concept 2011;1:33. 39. Creytens D. Inflammatory dermatopathology: a practical approach. In: Forum of pathology workshop: dermatopa­ thology. Forum of Pathology (FORPATH); 2011. 40. Kossard S, Hamann I, Wilkinson B. Defining urticarial der­ matitis: a subset of dermal hypersensitivity reaction pat­ tern. Arch Dermatol 2006;142:29–34. 41. LeBoit PE, Zackheim HS, White Jr CR. Granulomatous variants of cutaneous T-cell lymphoma: the histopathology of granulomatous mycosis fungoides and granulomatous slack skin. Am J Surg Pathol 1988;12:83–95. 42. Muhlbauer JE. Granuloma annulare. J Am Acad Dermatol 1980;3:217–230. 43. Brownstein MH, Helwig EB. The cutaneous amyloidoses: I. Localized forms. Arch Dermatol 1970;102:8–19. 44. Dyer JA. Chapter 137: Lipoid proteinosis and heritable disorders of connective tissue. Fitzpatrick’s dermatology in general medicine. 8th ed. McGraw-Hill Education; 2012. 45. Demirkesen C. Approach to cutaneous vasculitides with special emphasis on small vessel vasculitis: histopathol­ ogy and direct immunofluorescence. Curr Opin Rheumatol 2017;29:39–44. 46. Waller R, Ahmed A, Patel I, et al.. Update on the classifi­ cation of vasculitis. Best Pract Res Clin Rheumatol 2013; 27:3–17. 47. Requena L, Requena C. Erythema nodosum. Dermatol Online J 2002;8. 48. Muller SA, Winkelmann RK. Necrobiosis lipoidica diabet­ icorum: histopathologic study of 98 cases. Archi Dermatol 1966;94:1–10. 49. Massone C, Kodama K, Salmhofer W, et al. Lupus erythe­ matosus panniculitis (lupus profundus): clinical, histo­ pathological, and molecular analysis of nine cases. J Cutan Pathol 2005;32:396–404.

Section

4

Disorders of Immunity, Hypersensitivity and Inflammation

Chapter

Anaphylaxis and Angioedema

9

Margitta Worm, Linus Grabenhenrich, Sabine Dölle, Paola Chamorro

PART I: ANAPHYLAXIS Definition Anaphylaxis, as defined by an international group of experts, is a serious allergic reaction that is rapid in onset and can cause death.1 The diagnosis is based on defined clinical criteria (Box 9.1). At present, no uniform

worldwide definition of anaphylaxis exists. A mechanistic approach uses the term “anaphylaxis” for systemic generalized reactions of all degrees of severity. Pathophysiologically, anaphylactic reactions in humans are mast cell dependent and mostly triggered by type-E antibodies. Other immunologic mechanisms that do not involve IgE are less common (Fig. 9.1), including

Fig. 9.1: Pathogenesis of anaphylaxis: mechanisms and triggers, cells, mediators, and organ systems. Source: Modified according to Simons. J Allergy Clin Immunol 2009.

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Section 4: Disorders of Immunity, Hypersensitivity and Inflammation Box 9.1: Clinical criteria for diagnosing anaphylaxis. Anaphylaxis is highly likely when any one of the following three criteria is fulfilled: 1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both, e.g. generalized hives, pruritus or flushing, swollen lips-tongue-uvula and at least one of the following: i. Respiratory compromise (e.g. dyspnea, wheeze–bronchospasm, stridor, reduced PEF*, hypoxemia) ii. Reduced BP** or associated symptoms of end-organ dysfunction (e.g. hypotonia (collapse), syncope, incontinence) 2. Two or more of the following that occur rapidly after exposure to a likely allergen for that patient (minutes to several hours): i. Involvement of the skin-mucosal tissue (e.g. generalized hives, itch-flush, swollen lips–tongue–uvula) ii. Respiratory compromise (e.g. dyspnea, wheeze-bronchospasm, stridor, reduced PEF*, hypoxemia) iii. Reduced BP** or associated symptoms [e.g. hypotonia (collapse), syncope, incontinence] iv. Persistent gastrointestinal symptoms (e.g. crampy abdominal pain, vomiting) 3. Reduced BP** after exposure to known allergen for that patient (minutes to several hours): i. Infants and children: low systolic BP** (age specific) or >30% decrease in systolic BP** ii. Adults: systolic BP** of 30% decrease from that person’s baseline iii. Low systolic blood pressure for children is defined as 6 weeks. Those cases of CSU, where functional histamine releasing autoantibodies can be demonstrated in-vitro are said to be having chronic autoimmune urticaria (AIU). Even after an extensive evaluation, if the cause for CU cannot be demonstrated, those cases are actually the chronic idiopathic urticaria. But, since the facilities for demonstration of functional autoantibodies are not widely available and even autologous serum/plasma skin tests (ASST/APST) are not widely and routinely carried out, the term CSU is better chosen over the term CIU. More than one subtype of urticaria can coexist in a single subject and it is common to have delayed pressure urticaria in conjunction with CSU. Classification of urticaria, with or without angioedema, according to recent EAACI guidelines2 is stated in Table 10.1. • Diseases related to urticaria (where the clinical morphology can resemble urticaria, but the pathophysiology is different) –– Urticaria pigmentosa (maculopapular cutaneous mastocytosis) –– Urticarial vasculitis –– Familial cold urticaria (vasculitis) –– Nonhistaminergic angioedema (e.g., hereditary angioedema, which is bradykinin mediated). • Syndromes that are associated with urticaria/ angioedema –– Exercise induced urticaria/anaphylaxis –– Muckle–Wells syndrome (familial cold autoinflammatory syndrome) –– Schnitzler syndrome (associated with IgG monoclonal gammopathy)

Chapter 10: Urticaria Table 10.1: Classification of urticaria with or without angioedema according to recent EAACI guidelines. Type Subtype Character Urticaria Acute Lasts 6 weeks Chronic urticaria Chronic spontaneous urticaria Spontaneous weals and/or angioedema >6 weeks Chronic inducible urticaria Chronic inducible physical urticaria Urticaria factitia/dermographism Eliciting factor: mechanical sheering forces (weals arising within 1–5 min) Cold contact urticaria/cold urticaria Eliciting factor: cold objects, air, fluids, wind Heat contact urticaria/heat urticaria Eliciting factor: localized heat Solar urticaria Eliciting factor: UV and/or visible light Delayed pressure urticaria/pressure Eliciting factor: vertical pressure (weals urticaria arising with 3–12 h latency) Vibratory urticaria/angioedema Eliciting factor: vibratory forces Chronic inducible non-physical urticarial Aquagenic urticaria Eliciting factor: water Cholinergic urticaria Eliciting factor: increase in core body temperature, by exercise or spicy food Contact urticaria Eliciting factor: contact with urticariogenic substance

–– Gleich syndrome (episodic angioedema with eosinophilia) –– Wells syndrome (granulomatous dermatitis with eosinophilia).

EPIDEMIOLOGY Urticaria has a bimodal age distribution and is seen in patients aged from birth to 9 years and again at an age of 30–40 years.5 Lifetime prevalence of acute urticaria is 8%–20%.6 The lifetime prevalence of CU is approximately 1.8% in the adult population and 0.1%–0.3% in children7 with a period prevalence of 0.6%–0.8%.6,8,9 The duration for which CU lasts in adults has been reported as follows: 6–12 weeks in 52.8%, 3–6 months in 18.5%, 7–12 months in 9.4%, 1–5 years in 8.7%, and over 5 years in 11.3%.9 This approximate timeline helps to counsel the patients when they pose questions regarding the possible duration for which their disease is going to last. CU is twice as common in women than in men.10

ETIOPATHOGENESIS An identifiable cause is usually found in only 30% or fewer of CU patients (most of these patients belong to physical

urticaria subgroup).11 It is now increasingly accepted that many patients with CSU have an endogenous, rather than exogenous, cause of their illness (like production of functional histamine releasing autoantibodies). In addition to somehow acquiring this primary endogenous tendency to develop spontaneous urticaria, there is a wide range of secondary external aggravating factors that can bring out wheals in CSU, and influence the day-to-day variability of the illness. These secondary aggravating factors include localized heat, pressure, friction, some medicines (especially non-steroidal anti-inflammatory drugs), dietary pseudoallergens, alcohol, stress, and mild infections. In acute urticaria, an identifiable exogenous cause (infectious [acute respiratory tract infections], allergic, or pseudoallergic) may be found, but many cases remain unexplained despite evaluation and some of these cases evolve into chronic disease. Urticaria can be mast cell dependent or mast cell independent, though the mast-cell-mediated pathway is the predominant pathway.

Mast Cells Mast cells are the principal effector cells and histamine is the principal mediator in urticaria, resulting in itch, flare,

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Mediators Histamine

and wheal reaction. Cutaneous mast cell is the key effector cell of both acute and CU, and it is very likely that the ultimate mediator pathways are similar, even though the initiating cause may be different for acute and chronic disease. Cutaneous mast cells are the major effector cells in most forms of urticaria12 and angioedema, although other cells like basophils, neutrophils, and eosinophils may be involved. Mast cells are responsible for the initial response, and other cells mediate the late phase together. Mast cells degranulate, releasing preformed mediators including histamine and proteases (tryptase, chymase, and carboxypeptidase). Simultaneous synthesis of new cytokines, including prostaglandins (PGs), leukotrienes (LTs), and interleukins (ILs) like PGD2, LTC4, proteoglycans (heparin and chondroitin sulfate),12 IL-4, IL-8, and TNF-α also occurs.13–15 All of these mediators result in formation of urticarial wheals. Degranulation of mast cells requires dimerization of Fc epsilon receptors (high-affinity IgE [immunoglobulin E] receptors). This process can occur upon binding of a specific antigen on IgE bound to these receptors or may also occur through attachment of functional IgG autoantibodies directed against either IgE or Fc epsilon receptors, resulting in signal transduction and degranulation. Further, mast-cell-dependent urticaria may be immunemediated or non-immune-mediated. Immune-mediated mechanism can be:

It is the prime mediator. Binding of histamine to H1 receptors on small cutaneous blood vessels mediates vasopermeability and vasodilatation. It also mediates itch through stimulation of cutaneous nociceptors and the surrounding flare by antidromic stimulation of local C-fiber networks. The flare response is also mediated by substance P released from cutaneous nerve endings. Stimulation of H2 receptors on cutaneous blood vessels is responsible for vasodilatation and vasopermeability within the weal, but not itch or flare.

Leukotrienes The cysteinyl LTs may also contribute to vasopermeability and vasodilatation in urticaria but are secondary in importance to histamine. Synthesis of LTC4, D4, and E4 by mast cells at the time of degranulation, and subsequently by infiltrating basophils and eosinophils, may be a factor in the prolongation of urticaria in some types of urticaria; like aspirin-sensitive urticaria, autoimmune urticaria (AIU), and delayed pressure urticaria. Aspirin and other non-selective NSAIDs inhibit the enzyme cyclooxygenase and formation of PGE2 inside mast cells. Simultaneously, there is an enhanced production of LTC4, D4 and E4, as the enzyme lipooxygenase gets relatively more activated. Also, PGE2 has some inhibitory action on activation of mast cells. Therefore, aspirin and other NSAID mediated urticaria is characterized by an excess of LTs and decrease of PGE2, leading to formation of urticarial wheals that typically respond to leucotriene inhibitors.16 Flowchart 10.1 shows the effect of NSAIDs on the PG and LT imbalance. Various other mediators, like platelet-activating factor, proteases, heparin, TNF-α, and other ILs, are synthesized by mast cells and other infiltrating cells. These cytokines

Chapter 10: Urticaria Flowchart 10.1: Effect of NSAIDs on the PG and LT imbalance.

in 0.1%–0.7% of the cases.24,25 Other drugs implicated are penicillins, alcohol, oral contraceptives, and narcotics.

Genetics A strong association between CU and HLA DR4 has been reported in English26 and Turkish27 patients, especially those with evidence of histamine-releasing autoantibodies.

Autoimmunity cause further chemotaxis and also mediate some of the systemic effects, such as fatigue, malaise, and mild fever. Mast-cell-independent urticaria includes hereditary angioedema and angiotensin-converting enzyme (ACE) inhibitor induced urticaria and angioedema, which are bradykinin-dependent. Also, certain chemicals like benzoic acid and sorbic acid may have direct vasodilatory action on the vasculature resulting in localized wheals.

Basophils These cells are mainly responsible for the late phase response. They exhibit significantly reduced histamine release17 in response to antigen stimulation, and their counts are low in peripheral blood,18 suggesting that they are recruited to the skin. A recent contribution in understanding the hyporesponsiveness of basophils to anti-IgE stimulation in some CU patients is the finding of increased expression of Src-homology 2-containing inositol phosphatases (ships).19

Other Cells Neutrophils play a role in the late response. Neutrophils and Eosinophils (major basic protein) seem to play role in delayed pressure urticaria.

Role of Food In 2%–30% of urticaria cases, food allergy has been implicated as a cause.20,21 The most commonly implicated foods are nuts, dairy products, chocolate, and spices. Food additives like benzoic acid and azo dyes may play a role in exacerbation of CU by acting as pseudoallergens that can cause acute urticaria as well as exacerbation of CU.22,23

Role of Drugs Aspirin exacerbates CU in 6.7%–67% of the patients.10,20 ACE inhibitors cause urticaria in 0.3% and angioedema

In 1986, Grattan et al.28 reported that serum from some patients with urticaria could induce an immediate whealand-flare response upon reinjection into normal skin. The response was similar clinically to spontaneous urticaria wheals, in that it and would fade without residue within 24  h and could be also got inhibited by oral antihistamines. Most of the wheal-producing activity of the autologous serum skin test (ASST)-positive sera was confined to ultrafiltered fractions >100 kD, suggesting the cause to be an immunoglobulin or immune-complex. Initial studies of ASST-positive CU sera on basophils from atopic donors showed substantial histamine-releasing activities, suggestive of IgG anti-IgE autoantibodies. These sera also released histamine from a healthy basophil donor having very low levels of cell bound IgE. Further study showed that these sera actually contained functional autoantibodies against the α subunit of high-affinity IgE Fc epsilon receptor on basophils and mast cells.29 CU patients who have IgG autoantibodies directed against either the high-affinity IgE receptor (Fc epsilon receptor I) present on mast cells, or less commonly against IgE itself, are said to have autoimmune urticaria (AIU). Subsequent studies have demonstrated that these autoantibodies are present in 35%–55% of CU patients1,30–33 who were previously classified as CIU. Sabroe et al.34 and Zweiman et al.35 reported these figures to be 31% and 30%, respectively. ASST response has not been demonstrated in patients with physical urticaria (symptomatic dermographism, cholinergic urticaria) or healthy controls. Also, the ASST result is negative once the disease attains remission. Other than CU, IgG autoantibodies to high-affinity IgE Fc receptors have been demonstrated in the sera of patients with pemphigus vulgaris, dermatomyositis, SLE, and bullous pemphigoid. However, they are not functional and do not release histamine while performing in vitro functional assays.36 An association with other autoimmune diseases has been observed. Thyroid antibodies have been found in

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Section 4: Disorders of Immunity, Hypersensitivity and Inflammation 12%–33% of patients10,37 and clinical thyroid disease is reported in 2% of CU patients.38 Autoimmune conditions (thyroid disease, vitiligo, insulin-dependent diabetes mellitus, pernicious anemia) were seen more frequently in CU patients having functional autoantibodies than those without autoantibodies.34 Association with HLA DR4 has been shown.26 We noticed 28% patients having anti-thyroid antibodies and 20% patients having clinical thyroid disease in our patient subset with chronic refractory urticaria.39 The diagnosis of AIU can often be suspected from a history of symptomatic, severe, and continuous whealing, linked with systemic features of malaise. A past or family history of autoimmune disease, especially thyroiditis, can be indicative. Patients with CU, who are not positive for histamine releasing functional IgG autoantibodies (i.e. true CIU), may be a heterogeneous group having other nonantibody histamine releasing factor, or novel mast-cellspecific factor. Other theories proposed for pathogenesis of CU include complement activation,35,40–43 cellular defect theory,17,44–47 chronic infections stimulating T cells,48–54 and thyroid autoantibodies.55–59 Asero et al.60,61 demonstrated that in patients with CIU, plasma showed signs of thrombin generation and the autologous plasma skin tests (APSTs) score was positive in as many as 95% of cases. The extrinsic pathway of the clotting cascade62–64 is activated in CIU, and disease severity has been seen to be associated with activation of the coagulation cascade.

Fig. 10.2: Well-defined, erythematous-to-pink, edematous, pruritic swellings characterize urticarial wheals. They are accompanied by a surrounding flare.

CLINICAL FEATURES An urticarial wheal is characterized by three typical features: (1) a central swelling of variable size, almost invariably surrounded by a reflex erythema (Fig. 10.2), (2) associated itching, and (3) a transient nature, with skin returning to its normal appearance usually within 1–24  h. Angioedema is sometimes painful and resolution is slower than wheals (up to 72 h). Those with autoimmunity display significantly higher wheal scores off treatment, wheals at more sites, a higher itch score, and a higher association with systemic symptoms, such as gastrointestinal symptoms and flushing.34 Urticarial vasculitis is characterized by an eruption of erythematous wheals that clinically resemble urticaria (Fig. 10.3), but histologically show changes of leukocytoclastic vasculitis. It is often accompanied by a painful or burning sensation. Lesions are generalized wheals or erythematous plaques chiefly localized to abdomen, thighs and arms, occasionally demonstrating central clearing. Lesions last for >24  h in a fixed location (in contrast to

Fig. 10.3: Urticarial vasculitis. Courtesy: Babar K. Rao, Rao Dermatology, New York, New Jersey, USA.

urticaria, which resolves in minutes-to-hours or migrates continually). The lesions of urticarial vasculitis can have purpuric spots signifying the small vessel leucocytoclastic vasculitis, vessel damage and subsequent red-blood-cell extrvasation.

INVESTIGATIONS IN CHRONIC URTICARIA Routine Investigations They include routine hemogram (to ascertain absolute eosinophil count, in case of chronic parasitic infections)

Chapter 10: Urticaria and an erythrocyte sedimentation rate. Thyroid function tests can be done if AIU is suspected. The EAACI recommends against extensive laboratory evaluation of these patients.

Autologous Serum Skin Test and Autologous Plasma Skin Test Historically, in 1986, Grattan et al.28 were the first to use the ASST to differentiate AIU from CIU. They injected intradermal 0.1  mL of autologous serum and normal saline as a control in 12 patients with CIU. The positive results were arbitrarily defined as the formation of a wheal within 2 h of injection that was ≥5 mm larger than the wheal resulting from the saline control. A difference of 10  mm in the diameter of surrounding erythema was required as well. They observed positive responses in seven patients within 30  min, which attained zenith in 90–120 min, and remained positive for an average of 8 h. Subsequently, Sabroe et al.65 standardized the methodology and defined the parameters to provide an optimum sensitivity and specificity for detecting patients of CU with autoantibodies. There have been numerous modifications in the methodology and interpretation of the ASST since then in various studies. Methodology has been reviewed by the EAACI.66 ASST is currently the best in vivo clinical test for the detection of in vitro basophil histaminereleasing activity. It has a sensitivity of approximately 70% and a specificity of 80% when read as a pink seruminduced wheal, 1.5 mm or greater than an adjacent normal saline-control injection at 30 min.65,66 Various practical considerations may influence the outcome of ASST, including the use of antihistamines within 3 days of the test, injection over the sites of recent wheals, and health and safety issues in relation to preparation of the serum. A study done by Asero et al.60,61 showed that most patients with CU are positive for wheal-and-flare when injected intradermally with sodium citrate-treated autologous plasma. This suggests that CU is associated with the generation of thrombin, a serine protease, that is able to activate mast cells and also causes increase in permeability of the endothelium. These findings provided new insights into the pathogenesis of CU. In another study done by same author, it was observed that factors other than histamine are probably involved in the flare following APST in CU; such factors may play a pathogenic role, particularly in patients not responding to standard antihistamine therapy. There are conflicting reports regarding the comparative sensitivity and specificity of ASST and APST

in CU patients, although most studies have observed that both of these tests correlate well with clinical severity in CU patients.

IgE Levels In a study done by Augey et al.,67 IgE sensitization was demonstrated to be higher in CU patients than in the global adult population, suggesting that it is an important etiopathogenic factor in CU. They consider CU as an IgEmediated chronic inflammatory disorder. In subsequent studies,68 it was observed that total serum IgE levels are frequently elevated in patients with CU and these levels are associated with disease severity and duration. Zazzali et al.69 reported that allergic rhinitis was present in 48%, asthma in 21%, atopic dermatitis in 8%, and other allergies in 19% of CU patients. The beneficial effect of omalizumab further adds to the role of IgE in urticaria.

Histamine Release Assays In-vitro basophil histamine release assay is currently the gold standard for detecting functional autoantibodies in the sera of patients with CU. However, the assay is difficult to standardize, and is likely to remain confined to research centers at the present time. These assays still rely primarily on the use of selected healthy donor basophils, with or without the use of IL-3 as a priming agent.

Histopathology Skin biopsy shows edema in the papillary dermis in wheals, and in the deep dermis and subcutis in angioedema. The edema fluid originates from postcapillary venules rather than arterioles. Lumina of individual vessels may be dilated, and the integrity of their linings may show transient contraction and separation of the endothelial cells. Although small blood vessels are functionally impaired by these events, they are not permanently damaged, unlike the changes that are seen in small vessel vasculitis, including fibrinoid necrosis, endothelial damage and leucocytoclasia. Perivascular infiltrate is chiefly composed of monocytes and CD4+ T lymphocytes (both Th1 and Th2). Other cells seen are neutrophils, mast cells, basophils, and eosinophils. Few studies70,71 show an increased number of mast cells in CU, whereas other studies72 demonstrate that increased skin histamine in CIU is not caused by increased number of mast cells and rather reflect an increase in histamine content per mast cell, enhanced mast cell activation, permeability

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Section 4: Disorders of Immunity, Hypersensitivity and Inflammation and increased histamine releasability, or recruitment of basophils into the skin in patients with CIU. In a study comparing the cutaneous infiltrate in functional antibody-positive patients with antibody-negative patients, it was seen that neutrophil and eosinophil accumulation occurs early in the evolution of a wheal in all patients with CIU (12 h).73 Overall, the qualitative and quantitative features of inflammatory infiltrates do not help define a specific pathogenesis or etiology for an individual patient of CU.

TREATMENT Management of CU consists of two important approaches:74 1. Identification and elimination of the underlying cause and/or triggers. 2. Providing symptomatic relief by inhibiting the release and/or the effect of mast cell mediators, and possibly other inflammatory mediators. Treating the cause is the most desirable option, but it is unfortunately not applicable in the majority of patients, in whom urticaria is idiopathic and spontaneous. Symptomatic treatment is currently the most common form of management and should be offered in all cases, while simultaneously searching for the underlying cause. A stepladder approach is preferred in the treatment of urticaria. In line with recent EAACI guidelines,74 the recommended first-line treatment is the new generation, non-sedating H1-antihistamine agents. If standard licensed dosing is not effective, increasing the dosage up to four-fold is recommended.75 For patients who do not respond to a four-fold increase in dosage of non-sedating H1-antihistamines, another non-sedating antihistamine should be tried, followed by addition of LT receptor antagonists (monteleukast), H2 receptor antagonists (ranitidine), and doxepin.76,77 Leukotriene receptor antagonists may be effective in CU associated with aspirin and food additive hypersensitivity or with a positive ASST, but the effect is seen in combination with antihistamines, and they are not recommended alone. Furthermore, they have not been shown to be effective in mild or moderate CU without any possible secondary causes.78–80 Response is likely over the first 3 weeks of treatment, in absence of which, the medication should be discontinued. Although they add to the cost, LT receptor antagonists have an excellent safety profile. They have also been reported to be effective in some types of physical urticaria, such as primary cold urticaria, delayed

pressure urticaria, and dermographism (Fig. 10.4). Firstgeneration sedating antihistamines should no longer be used as initial therapy, except in those few countries where second-generation antihistamines are not available or where their use outweighs their risks. About half of CU patients tend to be more severely affected and have disabling disease, which is usually severe enough to impair the quality of life.81–86 They are less responsive, and sometimes resistant, to conventional urticaria treatment.83 They remain uncontrolled on multiple antihistamines and require immunosuppressive and immuno­ modulatory therapies like corticosteroids, omalizumab, methotrexate, cyclosporine, mycophenolate mofetil, plasmapheresis, azathioprine, cyclophosphamide, dapsone, colchicine, sulfasalazine, hydroxychloroquine, and IVIG.

Factors Associated with Difficult-to-treat and Longer Duration Urticaria87–91 • Failure of a single labeled dose of an H1 receptor blocker to control CU • Long duration (6 months or more) at time of presentation • Angioedema • Physical urticaria • Autoimmune diseases • Positive autologous serum or plasma intradermal skin test • Presence of serum IgG anti-IgE or IgG anti-Fc epsilon receptor I autoantibodies • Hypertension

Fig. 10.4: Dermographism upon scratching. Courtesy: Babar K. Rao, Rao Dermatology, New York, New Jersey, USA.

Chapter 10: Urticaria • Subclinical activation of the extrinsic coagulation pathway (prothrombin fragments detected) or evidence of fibrinolysis (d-dimer >500 ng/mL) • Basophil activation (CD203c+).

Treatment of Difficult-to-treat, Chronic, Persistent, and Refractory Urticaria The following agents are used for the treatment of difficultto-treat, chronic, persistent, and refractory urticaria.

Corticosteroids Oral corticosteroids are able to control severe, acute disease in most CU patients who do not respond to antihistamines. However, no controlled study has been carried out thus far to show their efficacy. In one recent, retrospective study,92 oral prednisone at a dose of 0.3–0.5 mg/kg for 3–5 days, followed by tapering, was able to induce remission of the disease (followed by control with antihistamines at licensed doses) in about 50% of cases. Effect starts within 1 day of treatment initiation. Typically short courses lasting for less than 10 days are recommended.

Biologics Omalizumab93–98 Omalizumab is FDA approved for use in CIU, not controlled by H1 receptor antagonists, for patients 12 years of age and older. The dosage is either 150 mg or 300 mg subcutaneously every 4 weeks. The rapid response within 1–2 weeks reflects: • Binding of omalizumab to free IgE antibodies, which occurs within a few hours of administration, that reduces the binding of IgE to the high-affinity receptor Fc epsilon RI on basophils and mast cells • Downregulation of the expression of Fc epsilon RI on whole blood basophils (within 2 weeks) and mast cells (within 8 weeks) and a subsequent activation of apoptosis. • An antieosinophil effect. The most effective dose is 300 mg every 4 weeks. Unlike asthma, the dosing in urticaria does not depend upon serum IgE levels or body weight. The disease usually relapses after the discontinuation of omalizumab, and responds to re-initiation of omalizumab. Nasopharyngitis and headache are the most commonly reported adverse events after omalizumab. The package inserts provide a black-box warning of anaphylaxis with omalizumab, though the risk is more in asthma.

Immunomodulatory Agents Dapsone99,100 An open, uncontrolled study in 11 patients showed the efficacy of dapsone at the dosage of 25–50 mg/day in CU/ angioedema. In another randomized open study, addition of dapsone to desloratadine did not reduce urticaria activity scores when compared with desloratadine alone (but was associated with a higher rate of complete remission). Dapsone is generally well tolerated, and requires careful follow-up of the patient, as it may rarely cause dose-related anemia, along with peripheral neuropathy, gastrointestinal complaints, hepatotoxicity, methemoglobinemia, blood dyscrasias, and drug reaction with eosinophilia and systemic symptoms syndrome. It is contraindicated in G6PD-deficient subjects because of the risk of severe hemolysis.

Sulfasalazine101 Up to 2  g/day are needed for effective treatment, and response occurs within 1 month of therapy. The main adverse effects include gastrointestinal, and headache, and less frequently, hematologic abnormalities, proteinuria, and hepatotoxicity.

Hydroxychloroquine102 A randomized, double-blind, placebo-controlled study showed a significant improvement in quality-of-life scores in patients with CU treated with hydroxychloroquine, although urticaria activity scores changed only marginally. Hydroxychloroquine bears the risk of retinopathy with prolonged use beyond 5 years. The dose should be 5 mg/kg body weight and a baseline retinal screening should be done preferably within 6 months and definitely within an year of initiation of hydroxychloroquine.

Role of Immunosuppressants Methotrexate At a weekly mean dosage of 15 mg, it seems effective and safe in most CU patients who are not responsive to conventional therapy. In a case report by Gach et al.,103 in two patients having severe urticaria refractory to standard therapies, control of the disease was achieved with methotrexate. In subsequent studies done by Perez et al.,104 Sagi et al.,105 it was concluded that methotrexate may be a useful treatment for steroid-dependent CU, with complete response achieved in about 80% of the patients.

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Cyclosporine It is the only immunosuppressive drug that inhibits histamine release from human basophils or skin mast cells. Studies done by Grattan et al.,106 Kessel et al.,107 Di Leo et al.108 show a beneficial role of cyclosporine, with complete clearing in about 60%–80% of patients. However, significant side effects, such as a reversible increase in creatinine levels, directly correlated with increased dosages. It is generally agreed upon that effective doses are in the range of 3–5 mg/ kg/day (preferably to be started at 3mg/kg, i.e. a lower dose), and that treatment should last for approximately 3–6 months. During the treatment period, blood pressure, kidney function, and liver function should be assessed regularly. Once the drug course has been completed, remission may last up to 9 months in about 50% of patients, while other patients show a decreased number of flare-ups and a restored response to antihistamine treatment. Long-term maintenance therapy with low-dose cyclosporine (1.5– 2.0 mg/kg/day) for 5–7 years has been suggested in unresponsive cases. Cyclosporine is approved by EAACI as a 3rd line treatment option for refractory urticaria. Other agents Tacrolimus has also been shown to be effective in a single study.109 Azathioprine,110 cyclophosphamide,111,112 mycophenolate mofetil,113,114 and mizoribine115 are other immunosuppressants that have been shown to be beneficial in the treatment of chronic refractory and steroid-dependent urticaria. The chimeric monoclonal antibody rituximab is specific for the protein CD20, which is primarily found on the surface of B cells. It destroys B cells and thus reduces the production of antibodies, including autoantibodies. Rituximab was shown to be effective in two CU patients resistant to H1-antihistamines.116,117 CU is frequently characterized by an increase of plasma markers of thrombin generation and fibrinolysis during severe exacerbations of the disease, possibly as a consequence of tissue factor expression by activated eosinophils. Whether the activation of coagulation/fibrinolysis plays a pivotal pathogenic role in the disease, or simply acts as an amplification system, remains to be defined. However, such activation parallels the activity of CU may provide the rationale for anticoagulation and antifibrinolytic therapy in patients with severe CU. In few previous studies, the efficacy of anticoagulant therapy in some patients with refractory CU was established using oral anticoagulants118,119 and heparin.120,121 Recent studies have reported the efficacy of serine protease inhibitors, nafamostat mesilate and camostat mesilate, in refractory CU.122 Such drugs inhibit different proteases, including tryptase, kallikrein,

complement, factor XII, and plasmin, and show an anticoagulant effect, similar to that of heparin. Efficacy of plasmapheresis123 and intravenous immunoglobulin124 and miltefosine125 has also been noted in severe AIU. However, immunosuppressive therapy is often associated with significant side effects. Phototherapy has been used successfully in uremic pruritus,126 cutaneous mastocytosis,127 indolent systemic mastocytosis,128 solar urticaria,129,130 and antihistamine resistant symptomatic dermographism.131 The authors have found phototherapy to be beneficial in their patients with steroid-dependent antihistamine-refractory CU.39 Both narrow-band ultra-violet B and psoralen and ultra-violet A were found to be beneficial in the management of such patients when administered over 3 months (thrice weekly) and restored response to antihistamines. To conclude, the etiological dilemma and commonplace antihistamine failure (around 50% in some studies) complicate CU management. With a lifetime prevalence of 0.6%–0.8%,6 and without an identifiable cause in 75%– 90%11 of cases, CSU often provokes unnecessary die­ tary modifications and laboratory testing. Unpredictable attacks, sleep disruption, and decreased work productivity decrease quality-of-life scores significantly.81–85 So, a safe and effective treatment option is the need of hour.

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urticaria—a clinical, immunological and histological evaluation. Br J Dermatol 1986;114:583–90. 29. Grattan CE, Hamon CG, Cowan MA, Leeming RJ. Preliminary identification of a low molecular weight serological mediator in chronic idiopathic urticaria. Br J Dermatol 1988;119:179–83. 30. Hide M, Francis DM, Grattan CE, et al. Autoantibodies against the high-affinity IgE receptor as a cause of histamine release in chronic urticaria. N Engl J Med 1993;328:1599–604. 31. Tong LJ, Balakrishnan G, Kochan JP, Kinet JP, Kaplan AP. Assessment of autoimmunity in patients with chronic urticaria. J Allergy Clin Immunol 1997;99:461–5. 32. Fiebiger E, Maurer D, Holub H, et al. Serum IgG autoantibodies directed against the alpha chain of Fc epsilon RI: a selective marker and pathogenetic factor for a distinct subset of chronic urticaria patients? J Clin Invest 1995;96:2606–12. 33. Konstantinou GN, Asero R, Ferrer M, et al. EAACI taskforce position paper: evidence for autoimmune urticaria and proposal for defining diagnostic criteria. Allergy 2013;68:27–36. 34. Sabroe RA, Greaves MW. Chronic idiopathic urticaria with functional autoantibodies: 12 years on. Br J Dermatol 2006;154:813–9. 35. Zweiman B, Valenzano M, Atkins PC, Tanus T, Getsy JA. Characteristics of histamine-releasing activity in the sera of patients with chronic idiopathic urticaria. J Allergy Clin Immunol 1996;98:89–98. 36. Fiebiger E, Hammerschmid F, Stingl G, Maurer D. Anti-FcepsilonRIalpha autoantibodies in autoimmunemediated disorders. Identification of a structure-function relationship. J Clin Invest 1998;101:243–51. 37. Verneuil L, Leconte C, Ballet JJ, et al. Association between chronic urticaria and thyroid autoimmunity: a prospective study involving 99 patients. Dermatology 2004;208:98–103. 38. Nettis E, Pannofino A, D’Aprile C, Ferrannini A, Tursi A. Clinical and aetiological aspects in urticaria and angiooedema. Br J Dermatol 2003;148:501–6. 39. Bishnoi A, Parsad D, Vinay K, Kumaran MS. Phototherapy using narrowband ultraviolet B and psoralen plus ultraviolet A is beneficial in steroid-dependent antihistamine-refractory chronic urticaria: a randomized, prospective observer-blinded comparative study. Br J Dermatol 2017;176(1):62–70. doi:10.1111/bjd.14778. 40. Kikuchi Y, Kaplan AP. A role for C5a in augmenting IgGdependent histamine release from basophils in chronic urticaria. J Allergy Clin Immunol 2002;109:114–8. 41. Fagiolo U, Kricek F, Ruf C, et al. Effects of complement inactivation and IgG depletion on skin reactivity to autologous serum in chronic idiopathic urticaria. J Allergy Clin Immunol 2000;106:567–72. 42. Ferrer M, Nakazawa K, Kaplan AP. Complement dependence of histamine release in chronic urticaria. J Allergy Clin Immunol 1999;104:169–72. 43. Huber-Lang M, Sarma JV, Zetoune FS, et al. Generation of C5a in the absence of C3: a new complement activation pathway. Nat Med 2006;12:682–7.

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reactions much more frequently than autologous serum. J Allergy Clin Immunol 2006;117:1113–7. 61. Asero R, Tedeschi A, Coppola R, et al. Activation of the tissue factor pathway of blood coagulation in patients with chronic urticaria. J Allergy Clin Immunol 2007;119:705–10. 62. Razin E, Marx G. Thrombin-induced degranulation of cultured bone marrow-derived mast cells. J Immunol 1984;133:3282–5. 63. Takahagi S, Mihara S, Iwamoto K, et al. Coagulation/ fibrinolysis and inflammation markers are associated with disease activity in patients with chronic urticaria. Allergy 2010;65:649–56. 64. Vliagoftis H. Thrombin induces mast cell adhesion to fibronectin: evidence for involvement of protease-activated receptor-1. J Immunol 2002;169:4551–8. 65. Sabroe RA, Grattan CE, Francis DM, et al. The autologous serum skin test: a screening test for autoantibodies in chronic idiopathic urticaria. Br J Dermatol 1999;140: 446–52. 66. Konstantinou GN, Asero R, Maurer M, et al. EAACI/GA(2) LEN task force consensus report: the autologous serum skin test in urticaria. Allergy 2009;64:1256–68. 67. Augey F, Gunera-Saad N, Bensaid B, et al. Chronic spontaneous urticaria is not an allergic disease. Eur J Dermatol 2011;21:349–53. 68. Huilan Z, Runxiang L, Bihua L, Qing G. Role of the subgroups of T, B, natural killer lymphocyte and serum levels of interleukin-15, interleukin-21 and immunoglobulin E in the pathogenesis of urticaria. J Dermatol 2010;37:441–7. 69. Zazzali JL, Broder MS, Chang E, Chiu MW, Hogan DJ. Cost, utilization, and patterns of medication use associated with chronic idiopathic urticaria. Ann Allergy Asthma Immunol 2012;108:98–102. 70. Elias J, Boss E, Kaplan AP. Studies of the cellular infiltrate of chronic idiopathic urticaria: prominence of T-lymphocytes, monocytes, and mast cells. J Allergy Clin Immunol 1986;78:914–8. 71. Nettis E, Dambra P, Loria MP, et al. Mast-cell phenotype in urticaria. Allergy 2001;56:915. 72. Smith CH, Kepley C, Schwartz LB, Lee TH. Mast cell number and phenotype in chronic idiopathic urticaria. J Allergy Clin Immunol 1995;96:360–4. 73. Sabroe RA, Poon E, Orchard GE, et al. Cutaneous inflammatory cell infiltrate in chronic idiopathic urticaria: comparison of patients with and without anti-FcepsilonRI or antiIgE autoantibodies. J Allergy Clin Immunol 1999;103: 484–93. 74. Zuberbier T, Asero R, Bindslev-Jensen C, et al. EAACI/ GA(2)LEN/EDF/WAO guideline: management of urticaria. Allergy 2009;64:1427–43. 75. Staevska M, Popov TA, Kralimarkova T, et al. The effectiveness of levocetirizine and desloratadine in up to 4 times conventional doses in difficult-to-treat urticaria. J Allergy Clin Immunol 2010;125:676–82. 76. Greene SL, Reed CE, Schroeter AL. Double-blind crossover study comparing doxepin with diphenhydramine for the treatment of chronic urticaria. J Am Acad Dermatol 1985;12:669–75.

Chapter 10: Urticaria 77. Goldsobel AB, Rohr AS, Siegel SC, et al. Efficacy of doxepin in the treatment of chronic idiopathic urticaria. J Allergy Clin Immunol 1986;78:867–73. 78. Bagenstose SE, Levin L, Bernstein JA. The addition of zafirlukast to cetirizine improves the treatment of chronic urticaria in patients with positive autologous serum skin test results. J Allergy Clin Immunol 2004;113:134–40. 79. de Silva NL, Damayanthi H, Rajapakse AC, Rodrigo C, Rajapakse S. Leukotriene receptor antagonists for chronic urticaria: a systematic review. Allergy Asthma Clin Immunol 2014;10:24. 80. Di Lorenzo G, D’Alcamo A, Rizzo M, et al. Leukotriene receptor antagonists in monotherapy or in combination with antihistamines in the treatment of chronic urticaria: a systematic review. J Asthma Allergy 2008;2:9–16. 81. O’Donnell BF, Lawlor F, Simpson J, Morgan M, Greaves MW. The impact of chronic urticaria on the quality of life. Br J Dermatol 1997;136:197–201. 82. Kulthanan K, Jiamton S, Thumpimukvatana N, Pinkaew S. Chronic idiopathic urticaria: prevalence and clinical course. J Dermatol 2007;34:294–301. 83. Hiragun M, Hiragun T, Mihara S, et al. Prognosis of chronic spontaneous urticaria in 117 patients not controlled by a standard dose of antihistamine. Allergy 2013;68:229–35. 84. Maurer M, Ortonne JP, Zuberbier T. Chronic urticaria: an internet survey of health behaviours, symptom patterns and treatment needs in European adult patients. Br J Dermatol 2009;160:633–41. 85. Delong LK, Culler SD, Saini SS, Beck LA, Chen SC. Annual direct and indirect health care costs of chronic idiopathic urticaria: a cost analysis of 50 nonimmunosuppressed patients. Arch Dermatol 2008;144:35–9. 86. Baiardini I, Pasquali M, Braido F, et al. A new tool to evaluate the impact of chronic urticaria on quality of life: chronic urticaria quality of life questionnaire (CU-QoL). Allergy 2005;60:1073–8. 87. Asero R. d-dimer: a biomarker for antihistamine-resistant chronic urticaria. J Allergy Clin Immunol 2013;132:983–6. 88. Magen E, Mishal J, Zeldin Y, Schlesinger M. Clinical and laboratory features of antihistamine-resistant chronic idiopathic urticaria. Allergy Asthma Proc 2011;32:460–6. 89. Nebiolo F, Bergia R, Bommarito L, et al. Effect of arterial hypertension on chronic urticaria duration. Ann Allergy Asthma Immunol 2009;103:407–10. 90. Rabelo-Filardi R, Daltro-Oliveira R, Campos RA. Parameters associated with chronic spontaneous urticaria duration and severity: a systematic review. Int Arch Allergy Immunol 2013;161:197–204. 91. Ye YM, Yang EM, Yoo HS, et al. Increased level of basophil CD203c expression predicts severe chronic urticaria. J Korean Med Sci 2014;29:43–7. 92. Asero R, Tedeschi A. Usefulness of a short course of oral prednisone in antihistamine-resistant chronic urticaria: a retrospective analysis. J Investig Allergol Clin Immunol 2010;20:386–90. 93. Vestergaard C, Deleuran M. Two cases of severe refractory chronic idiopathic urticaria treated with omalizumab. Acta Derm Venereol 2010;90:443–4.

94. Kaplan A, Ledford D, Ashby M, et al. Omalizumab in patients with symptomatic chronic idiopathic/spontaneous urticaria despite standard combination therapy. J Allergy Clin Immunol 2013;132:101–9. 95. Maurer M, Rosen K, Hsieh HJ. Omalizumab for chronic urticaria. N Engl J Med 2013;368:2530. 96. Metz M, Ohanyan T, Church MK, Maurer M. Omalizumab is an effective and rapidly acting therapy in difficult-to-treat chronic urticaria: a retrospective clinical analysis. J Dermatol Sci 2014;73:57–62. 97. Saini S, Rosen KE, Hsieh HJ, et al. A randomized, placebocontrolled, dose-ranging study of single-dose omalizumab in patients with H1-antihistamine-refractory chronic idiopathic urticaria. J Allergy Clin Immunol 2011;128:567–73 e1. 98. Sussman G, Hebert J, Barron C, et al. Real-life experiences with omalizumab for the treatment of chronic urticaria. Ann Allergy Asthma Immunol 2014;112:170–4. 99. Cassano N, D’Argento V, Filotico R, Vena GA. Low-dose dapsone in chronic idiopathic urticaria: preliminary results of an open study. Acta Derm Venereol 2005;85:254–5. 100. Engin B, Ozdemir M. Prospective randomized non-blinded clinical trial on the use of dapsone plus antihistamine vs. antihistamine in patients with chronic idiopathic urticaria. J Eur Acad Dermatol Venereol 2008;22:481–6. 101. McGirt LY, Vasagar K, Gober LM, Saini SS, Beck LA. Successful treatment of recalcitrant chronic idiopathic urticaria with sulfasalazine. Arch Dermatol 2006;142:1337–42. 102. Reeves GE, Boyle MJ, Bonfield J, Dobson P, Loewenthal M. Impact of hydroxychloroquine therapy on chronic urticaria: chronic autoimmune urticaria study and evaluation. Intern Med J 2004;34:182–6. 103. Gach JE, Sabroe RA, Greaves MW, Black AK. Methotrexateresponsive chronic idiopathic urticaria: a report of two cases. Br J Dermatol 2001;145:340–3. 104. Perez A, Woods A, Grattan CE. Methotrexate: a useful steroid-sparing agent in recalcitrant chronic urticaria. Br J Dermatol 2010;162:191–4. 105. Sagi L, Solomon M, Baum S, et al. Evidence for methotrexate as a useful treatment for steroid-dependent chronic urticaria. Acta Derm Venereol 2011;91:303–6. 106. Grattan CE, O’Donnell BF, Francis DM, et al. Randomized double-blind study of cyclosporin in chronic ‘idiopathic’ urticaria. Br J Dermatol 2000;143:365–72. 107. Kessel A, Toubi E. Cyclosporine-A in severe chronic urticaria: the option for long-term therapy. Allergy 2010;65: 1478–82. 108. Di Leo E, Nettis E, Aloia AM, et al. Cyclosporin-A efficacy in chronic idiopathic urticaria. Int J Immunopathol Pharmacol 2011;24:195–200. 109. Kessel A, Bamberger E, Toubi E. Tacrolimus in the treatment of severe chronic idiopathic urticaria: an open-label prospective study. J Am Acad Dermatol 2005;52:145–8. 110. Tedeschi A. Paradoxical exacerbation of chronic urticaria by H1-antihistamines and montelukast. Eur Ann Allergy Clin Immunol 2009;41:187–9. 111. Bernstein JA, Garramone SM, Lower EG. Successful treatment of autoimmune chronic idiopathic urticaria with

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Section 4: Disorders of Immunity, Hypersensitivity and Inflammation intravenous cyclophosphamide. Ann Allergy Asthma Immunol 2002;89:212–4. 112. Asero R. Oral cyclophosphamide in a case of cyclosporin and steroid-resistant chronic urticaria showing autoreactivity on autologous serum skin testing. Clin Exp Dermatol 2005;30:582–3. 113. Shahar E, Bergman R, Guttman-Yassky E, Pollack S. Treatment of severe chronic idiopathic urticaria with oral mycophenolate mofetil in patients not responding to antihistamines and/or corticosteroids. Int J Dermatol 2006;45:1224–7. 114. Zimmerman AB, Berger EM, Elmariah SB, Soter NA. The use of mycophenolate mofetil for the treatment of autoimmune and chronic idiopathic urticaria: experience in 19 patients. J Am Acad Dermatol 2012;66:767–70. 115. Hashimoto T, Kawakami T, Ishii N, et al. Mizoribine treatment for antihistamine-resistant chronic autoimmune urticaria. Dermatol Ther 2012;25:379–81. 116. Arkwright PD. Anti-CD20 or anti-IgE therapy for severe chronic autoimmune urticaria. J Allergy Clin Immunol 2009;123:510–1; author reply 1. 117. Chakravarty SD, Yee AF, Paget SA. Rituximab successfully treats refractory chronic autoimmune urticaria caused by IgE receptor autoantibodies. J Allergy Clin Immunol 2011;128:1354–5. 118. Parslew R, Pryce D, Ashworth J, Friedmann PS. Warfarin treatment of chronic idiopathic urticaria and angiooedema. Clin Exp Allergy 2000;30:1161–5. 119. Khalaf AT, Liu XM, Sheng WX, Tan JQ, Abdalla AN. Efficacy and safety of desloratadine combined with dipyridamole in the treatment of chronic urticaria. J Eur Acad Dermatol Venereol 2008;22:487–92. 120. Chua SL, Gibbs S. Chronic urticaria responding to subcutaneous heparin sodium. Br J Dermatol 2005;153:216–7. 121. Asero R, Tedeschi A, Cugno M. Heparin and tranexamic acid therapy may be effective in treatment-resistant chronic urticaria with elevated d-dimer: a pilot study. Int Arch Allergy Immunol 2010;152:384–9.

122. Takahagi S, Shindo H, Watanabe M, Kameyoshi Y, Hide M. Refractory chronic urticaria treated effectively with the protease inhibitors, nafamostat mesilate and camostat mesilate. Acta Derm Venereol 2010;90:425–6. 123. Grattan CE, Francis DM, Slater NG, Barlow RJ, Greaves MW. Plasmapheresis for severe, unremitting, chronic urticaria. Lancet 1992;339:1078–80. 124. O’Donnell BF, Barr RM, Black AK, et al. Intravenous immunoglobulin in autoimmune chronic urticaria. Br J Dermatol 1998;138:101–6. 125. Magerl M, Rother M, Bieber T, et al. Randomized, doubleblind, placebo-controlled study of safety and efficacy of miltefosine in antihistamine-resistant chronic spontaneous urticaria. J Eur Acad Dermatol Venereol 2013;27:e363–9. 126. Ada S, Seckin D, Budakoglu I, Ozdemir FN. Treatment of uremic pruritus with narrowband ultraviolet B phototherapy: an open pilot study. J Am Acad Dermatol 2005;53:149–51. 127. Prignano F, Troiano M, Lotti T. Cutaneous mastocytosis: successful treatment with narrowband ultraviolet B phototherapy. Clin Exp Dermatol 2010;35:914–5. 128. Brazzelli V, Grasso V, Manna G, et al. Indolent systemic mastocytosis treated with narrow-band UVB phototherapy: study of five cases. J Eur Acad Dermatol Venereol 2012;26:465–9. 129. Calzavara-Pinton P, Zane C, Rossi M, Sala R, Venturini M. Narrowband ultraviolet B phototherapy is a suitable treatment option for solar urticaria. J Am Acad Dermatol 2012;67:e5–9. 130. Dawe RS, Ferguson J. Prolonged benefit following ultraviolet A phototherapy for solar urticaria. Br J Dermatol 1997;137:144–8. 131. Borzova E, Rutherford A, Konstantinou GN, Leslie KS, Grattan CE. Narrowband ultraviolet B phototherapy is beneficial in antihistamine-resistant symptomatic dermographism: a pilot study. J Am Acad Dermatol 2008;59: 752–7.

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Transplant Dermatology Nicole Reusser Bender, Edit Olasz-Harken*

INTRODUCTION Organ transplantation has evolved rapidly in the last few decades, due predominantly to advances in antirejection and immunosuppressive medications. Transplantation has decreased mortality of patients with several cancers, hematologic disorders, and end-organ dysfunction; however, posttransplantation health maintenance is incredibly complex and leads to life-long immunosuppression and exposure to medication regimens with significant adverse effects. Nearly 30,000 transplants are performed in the United States every year. As a result of the growing organ transplant recipient (OTR) population, multidisciplinary transplant care teams have emerged. Dermatologists are important members of this team, as many complications after transplantation are cutaneous in nature. Infections, malignancies, and immunosuppressive medication side effects plague the average OTR, with some studies stating that >90% of patients report at least one dermatologic complaint. This chapter covers the major principles of transplant dermatology, including the effects of acute and chronic immunosuppression, common dermatologic side effects of these immunosuppressive medications, as well as the need for close surveillance and aggressive treatment of cutaneous malignancies.

NON-NEOPLASTIC LESIONS IN OTRs Effects of Immunosuppressive Medications Organ transplant recipients (OTRs) frequently develop complications from chronic immunosuppression, including the increased risk of infection and direct toxic effect of these medications. The cutaneous adverse effects of these drugs are generally both dose dependent and time dependent and can be mitigated by changing the dose or treatment regimen.1 Commonly used immunosuppressive agents and their cutaneous adverse effects are detailed below and in Table 11.1. *Senior author

Glucocorticoids Nearly all patients on systemic steroids for >1 month will develop an adverse effect. Immediately after transplantation, OTRs are generally given very high doses of glucocorticoids to avoid initial rejection. These high doses of steroids commonly result in acne or an acneiform folliculitis, which presents as an erythematous follicular papular and pustular eruption predominantly distributed on the face and chest.2 Rarely, these lesions may progress to a more severe nodulocystic form known as acne conglobata.1 Standard face wash and topical treatments for acne may be sufficient; however, some patients may require oral medications, such as doxycycline or spironolactone. Isotretinoin is rarely employed, as severity of acne generally decreases as the patient’s glucocorticoid regimen is tapered to lower maintenance doses.1 If inadequate response to traditional treatments is observed, Pityrosporum folliculitis, a cofactor for steroid acne, may be considered. This acneiform eruption is generally confined to the seborrheic areas of the face, chest, and back and associated with pruritus.3 A potassium hydroxide (KOH) preparation reveals budding yeast and short hyphal elements. Topical antifungal agents may be added to traditional acne therapies with good response.3 Redistribution of body fat may occur in patients on chronic corticosteroids and results in a characteristic cushingoid appearance, with facial and neck fullness (moon facies, buffalo hump), increased supraclavicular and suprasternal fat, and truncal obesity.1 These changes may coexist as part of Cushing syndrome, hallmarked by hypertension, fatigue, proximal muscle weakness, changes in mood, and menstrual cycle irregularities. These changes of fat distribution usually resolve with tapering or discontinuation of systemic steroids; however, in some patients, this appearance persists.1 Striae distensae, commonly known as stretch marks, occurs with higher frequency in children and women. These atrophic violaceous stripes located on the abdomen,

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Section 4: Disorders of Immunity, Hypersensitivity and Inflammation Table 11.1: Cutaneous manifestations of immunosuppressive medications. Medication Glucocorticoids Cyclosporine Tacrolimus mTOR inhibitors Azathioprine Mycophenolate salts

Side effects Acne, cushingoid appearance, striae, ecchymoses, Bateman purpura, atrophy, and fragility Pilosebaceous disease (hypertrichosis, sebaceous hyperplasia), gingival hyperplasia, increased risk of malignancy Alopecia, atopic dermatitis Aphthous stomatitis, acneiform eruptions, lymphedema, onychodystrophy, impaired wound healing Increased risk of cutaneous malignancies, hypersensitivity reaction Aphthous ulcers, herpetic viral infections

(mTOR: mammalian target of rapamycin)

thighs, and buttocks initially appear erythematous and indurated (striae rubra) before maturing and becoming atrophic and hypopigmented (striae alba). Treatment is difficult but may include pulsed dye laser and fractional ablative or non-ablative light-based therapies.1 Nearly all patients receiving prolonged glucocorticoid courses develop ecchymoses, Bateman purpura, and severe skin atrophy. Bateman purpura is described as irregularly shaped purpura on the extensor surfaces of the hands, forearms, and legs that occur after minor trauma or even spontaneously. These initial lesions may leave behind star-shaped pseudo-scars but frequently resolve without intervention.1 Minor trauma may also result in skin tears due to skin atrophy, demonstrated by increased fragility and reduction in skin thickness. Topical retinoic acid (0.01%–0.05%) has been used to improve skin atrophy.

Cyclosporine Cyclosporine (CSA) is a calcineurin inhibitor that acts selectively on T cells, depletes lymphocytes and macrophages, and prevents the activation of T cells, Natural killer (NK) cells, and antigen-presenting cells. CSA also inhibits kera­ tinocyte hyperproliferation and histamine released from mast cells and downregulates the expression of cellular adhesion molecules on dermal capillary endothelium.4 Cutaneous adverse effects of CSA involve the pilosebaceous unit, because CSA is lipophilic and potentially eliminated in part through the sebaceous gland.1 Reported CSA side effects in renal transplant recipients include hypertrichosis (60%), epidermal cyst (28%), keratosis pilaris (21%), acne (15%), folliculitis (12%), and sebaceous hyperplasia (10%).5 Hypertrichosis, characterized by thick pigmented hair on the trunk, back, shoulders, arms, neck, forehead,

helices and malar areas, is a well-known side effect of CSA. This can be of particular concern in women and children with dark-colored hair.5 Standard depilatory cream, shaving, or laser hair removal may mitigate cosmetic concerns. Ultimately, if the patient has resistant hypertrichosis and is unable to tolerate the cosmetic appearance, the immunosuppressive regimen may be modified. Other pilosebaceous lesions include acneiform eruptions or worsening of pre-existing acne vulgaris, sebaceous hyperplasia, epidermal cysts, and keratosis pilaris. Gingival hyperplasia has been reported in up to 30% of patients on CSA, with higher incidence noted in children and in the setting of chronic graft dysfunction.1,4,5 Gingival hyperplasia is caused by fibrous hyperplasia of the epithelial and connective tissue components and by altered extracellular metabolism. Onset is during the first 3–6 months of treatment and symptoms may worsen by the concomitant administration of calcium channel blockers or phenytoin.1,5 Optimal oral hygiene, plaque control, and removal of local irritants are beneficial. Topical and systemic azithromycin improves symptoms and physical findings. Severe cases may require gingivectomy.1 Infectious side effects from CSA are rare and usually mild.5 Other less common cutaneous adverse effects include alopecia areata and universalis, accelerated malepattern hair loss, hyperpigmentation, and bullous or vegetative lesions.1

Tacrolimus Tacrolimus (FK 506) is a calcineurin inhibitor that binds the FK-binding protein causing suppression of IL-2 production and IL-2 receptor expression, which subsequently selectively inhibits the activation of T cells (helper and regulatory), NK cells, and monocytes.5 Tacrolimus has fewer

Chapter 11: Transplant Dermatology side effects than CSA, with a notable absence of gingival hyperplasia and hypertrichosis.1 Tacrolimus instead is associated with rare cases of alopecia and hypotrichosis. Cases of severe atopic dermatitis in tacrolimus-treated OTRs have also been reported and may require transitioning to another immunosuppressive medication.1,5

mTOR Inhibitors These medications (sirolimus and everolimus) inhibit the mammalian target of rapamycin (mTOR), a regulatory protein kinase involved in lymphocyte proliferation. There are multiple relevant cutaneous and mucosal side effects.1,6,7 Aphthous stomatitis with oral ulcers can develop immediately after the first loading dose of sirolimus, suggesting a direct toxic effect.1,6 Mucosal ulcers are usually self-limited and confined to the soft oral mucosa (buccal and labial mucosa) and ventral surface of tongue, but they may last for several days and have a high risk of recurrence.1,6 Coadministration of an mTOR inhibitor with mycophenolate mofetil intensifies the severity and incidence of aphthous stomatitis in a dose-dependent manner.6 Anorexia and significant pain due to oral ulcers have been reported in patients with recurrent and severe disease, which may result in poor adherence to treatment. Treatment with topical corticosteroid decreases the duration and associated pain from oral ulcers if the dose of sirolimus cannot be reduced.6 Acneiform eruptions can be seen in nearly half of OTRs on an mTOR inhibitor and generally appear in the first few months of therapy initiation.6 Acneiform lesions typically occur on the face, trunk, and extremities, are more pronounced in seborrheic areas, and show a strong male predominance. Follicular acneiform and ulcerative maculopapular eruptions severe enough to justify discontinuation of mTOR therapy have been described.1 Chronic lymphedema, largely affecting the lower limbs, has been reported with high incidence in OTRs on sirolimus. Infrequently involvement of the upper extremities or even the face and oral cavity, resulting in angioedema may occur. This edema is generally resistant to diuretics, and cannot be explained by local, renal or cardiac causes for fluid accumulation.7 The pathogenesis of fluid accumulation is not clear, but some researches have proposed antilymphangiogenic activity of mTOR inhibitors or vasculitis leading to lymphatic or capillary obstruction as the cause.7 The use of compression devices can be beneficial in these patients.

Renal transplant patients on sirolimus have a high rate of nail dystrophy, including longitudinal ridging, distal onycholysis, erythema, splinter hemorrhages, onychomalacia, onychorrhexis, onycholysis, and transverse leukonychia.1,7 Periungual disorders such as perionyxis, nail ingrowth, whitlow, nail fissuring, and mycoses may also be seen.7 Other side effects include poor wound healing due to impaired signal transduction of fibroblasts and endothelial growth factors, mild alopecia, and facial hypertrichosis. Generally, sirolimus is not discontinued before minor cutaneous surgery, but surgeries involving staged reconstruction and flaps may require temporary suspension of sirolimus therapy. One benefit of the mTOR inhibitor class is an observed reduction in cutaneous malignancies. Multiple studies have shown that mTOR inhibitors significantly lower the incidence of both actinic keratoses (AK) and squamous cell carcinomas (SCCs) through a direct antiproliferative effect and indirect antiangiogenic effect on tumor growth.8 In studies, the greatest reduction in the development of future SCCs was at 1 and 2 years after conversion to sirolimus, respectively, and was observed in patients who had developed a single SCC before conversion to sirolimus. Conversely, there was a non-significant reduction of subsequent SCCs in patients who had numerous SCCs before conversion to sirolimus, or those with catastrophic cutaneous carcinomatosis. These studies suggest that conversion to sirolimus should be considered earlier than previously proposed by guidelines of the International Transplant Skin Cancer Collaborative, and possibly after the development of a single SCC.8 In addition, mTOR inhibitors are may induce complete remission of Kaposi sarcoma (KS) in patients on chronic immunosuppression.2 Therefore, it may be prudent to consider addition of an mTOR inhibitor to an immunosuppressive regimen in setting of cutaneous neoplasms.

Azathioprine Azathioprine is a purine antagonist, which disrupts the production of nucleic acids and proteins. Lymphocytes rely on de novo synthesis of purines, because they lack a purine salvage pathway; therefore, azathioprine is considered to be relatively selective to lymphocytes.9 The most prominent cutaneous side effect of azathioprine is the increased incidence of skin cancers, particularly SCC.2 This occurs due to a synergistic effect between azathioprine

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Section 4: Disorders of Immunity, Hypersensitivity and Inflammation Aphthous ulcers are frequently seen and, as mentioned above, are more pronounced when combination therapy of mycophenolate salts and an mTOR inhibitor is used.1,6 An increased incidence of herpetic viral infections, most commonly herpes zoster, has been reported, as well as CMV infection and verrucae.10

GRAFT VERSUS HOST DISEASE

Fig. 11.1: Azathioprine-related skin changes. Numerous verrucous keratoses and actinic keratosis on the background of a reticular hyperpigmented patch on the anterior chest of a male OTR receiving azathioprine (OTR: organ transplant recipient).

and UVA irradiation.2,9 Fair skin, excess sun exposure, and duration of allograft are important risk factors in the development of SCC.9 Azathioprine hypersensitivity, characterized by an allergic contact dermatitis, has been described in patients who come in direct contact with azathioprine tablets. This generally occurs within 4 weeks of initiation of therapy and can be confirmed with patch testing. More severe systemic hypersensitivity, such as anaphylaxis, occurs very rarely.9 Less troubling cutaneous effects include alopecia, hypotrichosis, verrucae, herpes zoster, and hyperpigmentation (Fig. 11.1).1,9 There are reports of crusted scabies, cytomegalovirus (CMV) infection, dermatomycoses, and KS in OTRs treated with azathioprine.9

Mycophenolate Salts Mycophenolate salts, such as mycophenolate mofetil, have multiple effects on the immune system that contribute to their immunosuppressant activity. Most notably, they selectively inhibit purine biosynthesis through the enzyme inosine monophosphate dehydrogenase (IMPDH), thereby disrupting purine synthesis. Compared to azathioprine, these agents are less oncogenic, because they cause a reversible inhibition of an enzyme, unlike the direct DNA damage and mutagenesis induced by azathioprine.10 A large study of renal transplant patients showed no increased risk of malignancy for patient treated with mycophenolate salts, as compared to other immunosuppressive regimens.10

Graft-versus-host disease (GvHD) occurs when donor immune cells attack host tissue and organs. Despite advances in transplantation medicine, the incidence of GvHD has remained unchanged and is a leading cause of morbidity in OTRs.11 A detailed discussion of GvHD can be found in Chapter 12.

INFECTIOUS LESIONS Chronic immunosuppression is commonly complicated by cutaneous infections, which occur in 55%–97% of OTRs.2 OTRs are at risk of invasion and propagation of common pathogens and atypical or unusually severe clinical variants. Rare pathogens and suspicion of disseminated disease must remain at the forefront of a clinician’s mind, as infection causes morbidity and mortality for OTRs.3 Fungal infections, folliculitis, and viral warts are the most common skin infections described in OTRs.1 Within the first year after transplantation, most cutaneous infections are caused by Staphylococcus aureus, candida, and herpes simplex virus (HSV). The risk of skin infection is related to the type and intensity of immunosuppression.1 Cutaneous infections observed in OTRs and therapeutic options are discussed briefly below and summarized in Table 11.2.

Fungal Infections Fungal infections in OTRs may be due to endemic pathogens, such as Coccidioides and Histoplasma, or opportunistic organisms, including Aspergillus, Candida, and Cryptococcus.3 Lesions may be typical appearing or nonspecific and ambiguous. Numerous antifungal agents have significant interactions with immunosuppressive regimens;2 therefore, clinicians should use careful consideration before prescribing these medications. Among the superficial cutaneous fungal infections, mucocutaneous candidiasis is particularly frequent in the first year after transplantation likely due to higher doses of immunosuppressive medications.1 Disseminated

Chapter 11: Transplant Dermatology Table 11.2: Infectious lesions in OTRs and therapeutic options. Type of infection Therapeutic options Fungal Mucocutaneous candidiasis Oral fluconazole Pityriasis versicolor Imidazole cream or selenium sulfate shampoo Onychomycosis Topical antifungal agents, oral terbinafine Primary cutaneous aspergillosis IV amphotericin B, voriconazole, posaconazole Cutaneous cryptococcosis IV amphotericin B ± flucytosine, surgical removal of cryptococcal foci Cutaneous histoplasmosis Itraconazole, voriconazole Cutaneous alternaria Wide excisional removal, prolonged itraconazole course Chromomycosis Itraconazole, posaconazole Cutaneous zygomycosis (mucormycosis) IV amphotericin B followed by posaconazole Viral Herpes simplex Valacyclovir, acyclovir, famciclovir Varicella zoster Valacyclovir, acyclovir, famciclovir Cytomegalovirus Valganciclovir, ganciclovir Molluscum contagiosum Immunosuppression reduction, local reduction methods (e.g., cryotherapy) Bacterial Folliculitis, abscess, cellulitis Antibiotic determined by organism and sensitivities (e.g., amoxicillin/clavulanic acid, clindamycin, cephalexin) Necrotizing fasciitis Debridement of necrotic tissue and high-dose IV antibiotics Cutaneous nocardiosis Long-term trimethoprim–sulfamethoxazole Mycobacterial Cutaneous tuberculosis Combination therapy (e.g., isoniazid, rifampin, ethambutol, streptomycin) Nontuberculous mycobacterial infections Regimen determined by organism and sensitivities (OTR: organ transplant recipient)

candidiasis can be difficult to diagnose as blood cultures are positive in only 25% of samples; however, hematogenous spread of Candida organisms resulting in cutaneous lesions may aid the diagnosis. These lesions have great morphological variability, but generally occur in the setting of fever unresponsive to antibiotics.3 Oral fluconazole may be used as antifungal prophylaxis in high-risk patients and is generally continued until myeloid reconstitution or ≥75 days following hematopoietic stem cell transplant. Guidelines for antifungal prophylaxis in solid organ transplantation are not well established. Of note, fluconazole lacks antimold coverage and candida species are becoming resistance to this agent, creating a shift toward broader spectrum antifungal agents, such as voriconazole. Invasive and disseminated aspergillosis is one of the most significant opportunistic infections affecting OTRs often with significant pulmonary involvement.2,12,13 Early

administration of IV amphotericin B or antimold azoles, such as voriconazole or posaconazole, is recommended due to the high mortality rate. Of note, administration of voriconazole leads to development of SCCs in a duration-dependent manner. There have also been reports of increased incidence of basal cell carcinoma (BCC) and melanoma; however, these associations have significantly less evidence than that seen with SCCs.13 Cutaneous cryptococcosis is more often disseminated in OTRs and generally involves the lower extremities. Nodules, maculopapules, ulcers, pustules, abscesses, and cellulitis have been reported.1,3 IV amphotericin B with or without flucytosine is generally used for severe and disseminated infections; however, surgical removal of cryptococcal foci can also be beneficial.1,3 Reactivation and dissemination of endemic agents, such as Histoplasma capsulatum and Coccidioides

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Section 4: Disorders of Immunity, Hypersensitivity and Inflammation immitis, occur at times when immunosuppression is greatest, which is within the first 6 months after transplantation.1,14 Early cutaneous histoplasmosis present as painless large erythematous and infiltrative plaques, while older lesions may ulcerate and drain. Disseminated disease may resemble erysipelas and cause mucosal ulceration as well. Drugs of choice are for histoplasmosis includes itraconazole and voriconazole.1 Pheohyphomycoses, such as cutaneous alternaria and chromomycosis, caused by dematiaceous (pigmented) fungi and cutaneous zygomycosis (mucormycosis) are rare. Pheohyphomycoses are generally treated with itraconazole with or without surgical removal of infectious foci, while zygomycosis is treated with IV amphotericin B followed by oral posaconazole.1,12

Viral Infections The major viral infections affecting the skin of OTRs are those caused by the herpes viruses and human papillo­ mavirus (HPV). Reactivation of latent viral infections caused by HSV and varicella zoster virus (VZV), often occur in settings of high-dose immunosuppression.2 Herpes simplex and herpes zoster may present as localized disease with painful grouped vesicles (HSV) and dermatomal distribution of painful vesiculobullous eruption (VZV), but in severe cases, they may develop as multifocal or widespread extensive hemorrhagic and ulcerative lesions with significant mucosal and/or systemic (pneumonia, myocarditis, hepatitis, and encephalitis) involvement.1,2,12 There is an increased incidence of postherpetic neuralgia, and prolonged infections have been reported in OTRs.3 Treatment includes valacyclovir and acyclovir, or famciclovir in the context of acyclovir resistance. In severe cases, withdrawal of immunosuppression is required.1,3,12 CMV infection may present as a reactivation of prior infection or new infection introduced by the transplanted organ. Cutaneous manifestations of CMV are extremely rare and include indurated hyperpigmented nodules or plaques, vesiculobullous eruption, and necrotic purpuric papules. Cutaneous and mucosal ulcerations may develop and disseminated disease, including fever, leukopenia, hepatitis, retinitis, enterocolitis, and interstitial pneumonitis.1,3,12 CMV is more likely to be resistant to acyclovir-based regimens than HSV and VZV, and therefore, ganciclovir and valganciclovir are traditionally used.12 Notably, there is experimental and clinical evidence that mTOR inhibitors may inhibit the replication of several member of herpesviridae, including CMV.1

Viral Warts Warts and condylomas are frequent in OTRs, affecting approximately 90% at 5 years post-transplant.2 Verruca vulgaris present as pink to flesh-colored verrucous or flattopped papules mainly located on sun-exposed areas.3 In severe cases, extension of disease may be so widespread as to constitute general verrucosis.2 Verrucae in OTRs are generally caused by HPV and are considered potential predictors for the development of coincidental non-melanoma skin cancer (NMSC). Additionally, there is an increased tendency for progression of these lesions to cutaneous malignancy.3 In OTRs, HPV has also been linked to the development of periungual SCC, anorectal carcinoma, and implicated as a cocarcinogen in the development of cutaneous SCCs, though evidence is mixed. HPV also causes anogenital warts, condylomas acuminate, and acquired epidermodysplasia verruciformis. Epidermodysplasia verruciformis is a precancerous condition characterized by susceptibility to HPV infection resulting in widespread keratotic, flat, wart-like papules, and tinea versicolor-like hypopigmented macules.3 There is no definitive treatment for epidermodysplasia verrucifomis, but topical glycolic acid, imiquimod, and systemic retinoids have been use with limited success. Close monitoring of patients with acquired epidermodysplasia verruciformis for development of cutaneous malignancy is recommended. Standard treatment of verrucae and condyloma applies to OTRs, with conventional ablative therapies, topical keratolytic agents and retinoic acid as the treatments of choice. Intralesional bleomycin, or topical imiquimod and cidofovir may be used in setting of recalcitrant lesions. HPV vaccination following transplantation is controversial, with one study reporting suboptimal immune response to vaccination, though no adverse events were noted. Ultimately, conversion of immunosuppressive regimen to include an mTOR inhibitor may be a useful strategy for recalcitrant cutaneous viral warts in OTRs.3

Bacterial Infections Bacterial infections that arise in transplant patients resemble those of immunocompetent persons; however, more serious infections caused by both Gram-positive and Gram-negative organisms may develop in the long term.1 Necrotizing fasciitis is a rare and sometimes fatal disease characterized by extensive necrosis of the skin and soft tissue and is caused by variety of organisms such as Group A streptococcus, Clostridium spp., or most

Chapter 11: Transplant Dermatology commonly polymicrobial pathogens. OTRs most likely to develop necrotizing fasciitis renal transplant patients on high-dose steroids with nephrotic syndrome. Prompt recognition and aggressive treatment with surgical intervention and high-dose IV antibiotics are paramount, as mortality rates range from 33% to 73% in these patients.1 Nocardiosis produces disseminated cutaneous pathology through hematogenous spread from pulmonary infection or primary cutaneous pathology through direct inoculation of bacteria. Lesions may present as pustules, abscesses, subcutaneous nodules, cellulitis, or ulcerations. In severe cases involvement of the lymphatic system occurs, creating a lymphocutaneous infection. Long-term antibiotic therapy with trimethoprim–sulfamethoxazole is recommended to prevent recurrence.3,12,14

Mycobacterial Infections Mycobacterium tuberculosis infection is more common in OTRs due to immunosuppression and occurs in roughly 1% of solid-OTRs in North America and Europe.12 Cutaneous manifestations of mycobacterial infection are diverse, and include spreading cellulitis around joints, cutaneous or subcutaneous nodules, and indurated plaques and ulcerations.1 Tuberculin skin testing will be negative the majority of OTRs; therefore, diagnosis depends on clinical suspicion and isolation of organisms via acid-fast staining and fungal culture, which may take up to 6 weeks for growth.12 Nontuberculous mycobacteria that commonly give rise to cutaneous lesions include Mycobacterium abscessus, Mycobacterium marinum, Mycobacterium kansasii, and Mycobacterium fortuitum, among others. Cutaneous lesions are generally painful erythematous or violaceous subcutaneous nodules which may progress to ulcerations or abscess and have underlying bone involvement.12 Treatment is complex due to drug interactions between antimycobacterial and immunosuppressive agents; however, generally active tuberculosis is treated with ≥12 months of combination therapy (isoniazid, rifampin, ethambutol, streptomycin) while atypical mycobacterial infections have no clear guidelines.12

NEOPLASTIC LESIONS There is a threefold increase in the prevalence of various malignancies, including cutaneous malignancies, in OTRs compared to age-matched control groups.3 This is due in part to the lack of continuous immune surveillance of the

skin due to chronic immunosuppression.2 Both benign and malignant lesions are discussed below, but a particular focus is placed on NMSC due to its frequency in clinical practice and related implications for OTRs’ health and quality of life. Neoplastic lesions and therapeutic options are detailed below and summarized in Table 11.3.

Benign Lesions Benign lesions such as seborrheic keratosis sebaceous hyperplasia may be found in greater number and in more severe forms in OTRs.

Malignant Tumors Skin cancers are the most common malignant condition in transplant recipients, with over 90% of these lesions accounted for by SCC and BCC. A 65–250-fold and 10–16fold increase in the prevalence of SCC and BCC, respectively, has been reported, ultimately affecting over 50% of all Caucasian OTRs.15,16 The magnitude of this increased risk of NMSC correlates with the amount and duration of immunosuppression among transplant recipients (e.g., heart and lung transplants have higher incidence of NMSC than kidney and liver transplants presumably due to a more intensive immunosuppressive regimen), as well as cumulative sun exposure.2,17 Other skin cancers, such as melanoma, primary cutaneous lymphomas, Merkel cell carcinoma (MCC), and KS, are also seen with greater incidence in OTRs.

Epidermal Dysplasia and Actinic Keratosis Keratotic skin lesions, including AK, porokeratosis, warts, and papillomas, are associated with solar damage and represent clinical and subclinical lesions of epidermal dysplasia.18 AK are a partial thickness proliferation of aty­ pical keratinocytes confined to the epidermis, that present as scaly red or flesh-colored papules or plaques on sunexposed skin. Of clinical significance, AK has the potential for malignant transformation to SCC. Warts, AK, and porokeratoses should be treated aggressively. A biopsy to evaluate for malignancy should be considered if a lesion has an atypical appearance or does not respond to usual therapy. When a large surface area is affected by carcinogenic alterations, this is known as field cancerization and is addressed with topical treatment of the entire affected area (aka. field therapy).18 Approved field therapies include 5-fluorouracil (0.5%, 1%, and 5% applied once to

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Section 4: Disorders of Immunity, Hypersensitivity and Inflammation Table 11.3: Neoplastic lesions in OTRs and therapeutic options. Neoplastic lesion Therapeutic options Benign lesions Viral warts and condylomas Conventional ablative therapies (e.g., topical keratolytic agents, retinoic acid), topical imiquimod, and cidofovir for recalcitrant lesions Malignant lesions Actinic keratosis and Local therapies (e.g., cryotherapy), field therapies (e.g., topical 5-fluorouracil, epidermal dysplasia diclofenac, imiquimod, ingenol mebutate, or photodynamic therapy), chemoprevention (e.g., systemic retinoids, nicotinamide, capecitabine) Squamous cell carcinoma— Mohs micrographic surgery or clear margin excision ± field therapy, aggressive low risk electrodessication and curettage Squamous cell carcinoma— Mohs micrographic surgery or clear margin excision ± sentinel lymph node biopsy high risk and adjuvant radiation therapy, chemoprevention, reduction of immunosuppression Basal cell carcinoma Mohs micrographic surgery or clear margin excision Melanoma Wide local excision ± sentinel lymph node biopsy and tumor staging evaluation, reduction of immunosuppression Merkel cell carcinoma Mohs micrographic surgery or wide local excision ± sentinel lymph node biopsy and adjuvant radiation, reduction of immunosuppression Kaposi sarcoma Local therapies (e.g., cryotherapy), reduction of immunosuppression ± interferon therapy or chemotherapy (OTR: organ transplant recipient)

twice daily for 4 weeks), diclofenac 3% (applied twice daily for 60–90 days), imiquimod (2.5% and 3.75% applied once daily and 5% applied twice weekly for 16 weeks), ingenol mebutate (0.015% and 0.05% applied daily to face/scalp or trunk/extremities, respectively, for 2–3 days), and photodynamic therapy. These methods provide noninvasive alternative treatment modalities that are more applicable to larger treatment areas and may be used in cyclic rotation with early biopsy of any lesions that persists despite topical therapy.18 In the setting of low-risk patients with limited number of AK, the recommended treatment is cryotherapy, though this local destructive method does not prevent the occurrence of new lesions nor local recurrence of the treated lesion. Sun protective measures are paramount to disease prevention. The use of chemoprevention with systemic retinoids (acitretin and isotretinoin), nicotinamide (500 mg twice daily), and capecitabine (500–1,500 mg/m2 twice daily on days 1–14 in a 21-day cycle) have also been shown to reduce the incidence of precancerous and SCC lesions. It should be noted their effect is only exerted during therapy and long-term use may be limited by adverse side effects.2,18,19 Major side effects of systemic retinoids include hepatotoxicity, hyperlipidemia, teratogenicity, dry skin, and rebound effect (rapid development of multiple aggressive SCCs after discontinuation of retinoid), while

side effects of capecitabine include fatigue, gout, palmarplantar erythrodysesthesia, gastrointestinal distress and reduced renal function.16

Squamous Cell Carcinoma Immunosuppression not only disproportionately increases the incidence of SCC, it also increases aggressive tendencies. SCCs in OTR (Figs. 11.2 to 11.4) grow more rapidly, are more likely to metastasize, and tend to infiltrate blood vessel walls and perineural sheaths.2 HPV DNA is detected in 65%–90% of SCCs from OTRs, supporting the notion that HPV has an active role in the pathogenesis of cutaneous malignancies. Mechanisms of carcinogenesis are attributed to the oncogenic proteins E6 and E7 of HPV. E6 protein inhibits cellular apoptosis in response to UV light, while E7 protein inactivates the tumor suppressor, pRb. Both of these effects lead to alterations in the normal differentiation and proliferation cycles of keratinocytes.17 The increased risk of cutaneous malignancy associated with long-term CSA use in transplant populations is well described. In skin tumor models, CSA has been shown to enhance the induction of skin tumors by UV irradiation, increase formation of reactive oxygen species which promote transformation to malignancy, and inhibit

Chapter 11: Transplant Dermatology

Fig. 11.2: Squamous cell carcinoma. Several red and pink scaly hyperkeratotic papules consistent with SCC found on the forehead of a male OTR on the background of prominent sun damage and several well-healed scars (OTR: organ transplant recipient; SCC: squamous cell carcinoma).

Fig. 11.3: Squamous cell carcinoma and epidermal dysplasia. One small red scaly hyperkeratotic papule consistent with SCC found on the medial wrist of an OTR on the background of prominent sun damage with numerous small thinly scaled erythematous papules, hyperpigmented and hypopigmented macules and patches (OTR: organ transplant recipient; SCC: squamous cell carcinoma).

DNA repair by inducing apoptosis in activated T cells.5 The addition of an mTOR inhibitor, such as sirolimus, to an existing CSA monotherapy regimen significantly lowers the incidence of cutaneous malignancies (22% with combination therapy vs 39% with CSA monotherapy) and extends the mean latency of development of cutaneous SCC (15 months with combination therapy vs 7 months with CSA monotherapy).2

Fig. 11.4: Keratoacanthoma of the forearm. One large dome-shaped shiny pink tumor with keratin-filled core found on the extensor surface of an OTR’s forearm consistent with keratoacanthoma, a low-grade variant of SCC (OTR: organ transplant recipient; SCC: squamous cell carcinoma).

In all OTRs with biopsy-proven SCC, Mohs micrographic surgery (MMS) or excision with clear surgical margins is the recommended treatment. Field therapy in addition to surgical therapy may be implemented, especially for large surface areas of field cancerization. Aggressive electrodessication and curettage (ED&C) may be used for low-risk SCC where there are multiple lesions or where ED&C is easier for patients to tolerate than multiple surgical procedures.16,17 High-risk SCC is characterized by: a high-risk location (ears, perioral, periorbital, temple, scalp, etc.), large size (>2  cm) or depth, poor differentiation, rapid growth, and often recurrent with perineural involvement.16 Aggressive surgical therapy for high-risk lesions with MMS is warranted in OTRs. Excision with margin assessment may be considered if MMS is not available; however, margins of ≥6–10 mm are recommended. Before surgery, high-risk SCCs should be evaluated for metastatic potential (>6 mm in thickness, desmoplastic growth), where sentinel lymph node biopsy is considered in suspicious cases. Adjuvant radiation therapy is indicated if perineural involvement is noted.16 Chemoprophylaxis with systemic retinoids, nicotinamide, or capecitabine may be considered in patients who develop between 5 and 10 SCCs annually.17 Revision of immunosuppression may be also be considered in patients with high SCC tumor burden. Calcineurin inhibitors (CSA and tacrolimus) and azathioprine are associated with increased risk of skin cancers, while the mTOR inhibitors and mycophenolate mofetil have been associated

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Fig. 11.5: Treatment algorithm for SCC in OTRs. A suggested treatment algorithm for SCCs in OTRs based on tumor behavior and annual number of SCCs (OTR: organ transplant recipient; SCC: squamous cell carcinoma).

with decreased risk of NMSCs.16,17 Lastly, in the case of catastrophic skin cancer, radical reduction or complete discontinuation of immunosuppressive medications should be considered. Figure 11.5 illustrates a treatment algorithm for SCC in OTRs based on tumor behavior and annual number of SCCs.

Basal Cell Carcinoma It is well recognized that the SCC:BCC ratio of 1:4 is reversed in transplant recipients as compared to immunocompetent patients.15 BCCs in OTRs do not appear to be more aggressive, and metastasis is extremely rare, as opposed to SCCs. Therefore, treatment for BCC in OTRs is similar to immunocompetent patients and largely achieved through surgical removal.2 Vismodegib, a smoothened receptor inhibitor and Hedgehog signaling pathway targeting agent, has been approved by the FDA for the use in metastatic and locally invasive BCC; however, this drug has not been studied in an immunosuppressed population.

Malignant Melanoma The incidence of melanoma in OTRs is increased three to five fold, when compared to the non-OTR population. Risk factors for melanoma in OTRs are similar to those in the

general population: the presence of multiple nevi (also associated with immunosuppression), fair skin, and history of sunburns.3 Melanoma may present as one of three scenarios: de novo development of a lesion, recurrence of previous melanoma, or as a donor-transmitted cancer. Classically, melanoma presents as an atypical pigmented lesion most often on the trunk, followed by upper extremities, head and neck in OTRs. The mean duration after transplant to the development of melanoma is 5 years.16 Treatment of melanoma in OTRs is similar to immunocompetent patients, including wide excision with or without sentinel lymph node biopsy and evaluation for tumor staging work-up. Systemic therapy options, such as ipilimumab and nivolumab, for advanced or metastatic melanoma have not been fully validated in OTRs; however, several case reports of their success have been published.20–23

Merkel Cell Carcinoma MCC is caused by Merkel cell polyomavirus. Epidemiologic data on MCC in OTRs is limited due to its rarity, but the incidence is estimated to be five to ten times greater than the general population. In OTRs, MCCs occur more commonly in males, predominantly on the head and neck on a background of field cancerization, approximately 7–8 years after transplantation. MCC lesions present as a

Chapter 11: Transplant Dermatology rapidly enlarging irregular solitary erythematous nodule that may ulcerate. Prognosis is generally poor, with tumors maintaining aggressive behavior with metastasis to lymph nodes in 68% of cases, and a high mortality rate, causing death in 56% of cases.16 For local disease, wide local excision with 2.5–3-cm margins or MMS is utilized. Sentinel lymph node biopsy with or without complete dissection as well as adjuvant radiation to the primary site and affected lymph nodes is also recommended due to risk of metastasis and poor prognosis, especially in the immunosuppressed population. The likelihood of recurrence is based on the status of the sentinel lymph node (60% if positive, 20% if negative).16 As with melanoma and high-risk SCC, reduction of immunosuppression is recommended for OTRs with MCC when possible.

Kaposi Sarcoma KS is a vascular malignancy caused by the human herpesvirus-8 (HHV-8) primarily involving the skin, but may involve visceral organs. The incidence of KS appears to vary geographically; however, there have been reports of an 84–500-fold increase in the incidence of KS in OTRs as compared to the general population.16,24 Risk factors for developing KS include immunosuppression (particularly with calcineurin inhibitors) and seropositive status at the time of transplantation, though some patients acquire the HHV-8 virus from the transplanted tissue.24 There are four types of KS; however, the iatrogenic form due to immunosuppression largely seen in the OTR population will only be discussed. KS lesions present early in the course of immunosuppression as red to violaceous macules, papules, and nodules. These lesions may disseminate, ulcerate, and become painful. Treatment of KS is through reduction of immunosuppression in conjunction with interferon therapy or chemotherapy.16 Transition from a calcineurin inhibitor to an mTOR inhibitor can be very beneficial in the setting of extensive KS disease, though the risk of graft rejection should be weighed. Individual lesions that are painful or cosmetically unappealing may be treated with local measures, such as cryotherapy, surgical excision, and laser therapy.24

EDUCATION AND MANAGEMENT OF OTRs Management of OTRs is an interdisciplinary challenge, with a focus on the prevention and treatment of infectious

diseases and cancer. Skin cancer education should be integrated into the care of the transplant recipient, including the use of self-examination for suspicious lesions and palpation of draining lymph nodes for high-risk patients.25 Counseling on sun protection, appropriate sunscreen use, use of protective clothing, and avoidance of indoor tanning should also be important mainstays of post-transplant care.2 Dedicated transplant dermatology clinics have shown to improve patient compliance with photoprotective practices and overall skin cancer awareness. Proposed follow-up intervals for total body skin examinations for OTRs include no skin cancer/field disease (12 months), field disease (3–6 months), one NMSC (3–6 months), multiple NMSC (3 months), high-risk SCC or melanoma (3 months), and metastatic SCC or melanoma (1–3 months).25

REFERENCES 1. Ponticelli C, Bencini PL. Nonneoplastic mucocutaneous lesions in organ transplant recipients. Trans Internat 2011;24:1041–50. 2. Ulrich C, Arnold R, Frei U, et al. Skin changes following organ transplantation. Dtsch Arztebl Int 2014;111:188–94. 3. Abel E. Cutaneous manifestations of immunosuppression in organ transplant recipients. J Am Acad Dermatol 1989;21:167–79. 4. Madan V, Griffiths CEM. Systemic ciclosporin and tacrolimus in dermatology. Dermatol Ther 2007;20:239–50. 5. Ryan C, Amor KT, Menter A. The use of cyclosporine in dermatology: Part II. J Am Acad Dermatol 2010;63: 949–72. 6. Campistol JM, de Fijter JW, Flechner SM, Langone A, Morelon E, Stockfleth E. mTOR inhibitor-associated dermatologic and mucosal problems. Clin Transpl 2010;24: 149–56. 7. Zaza G, Tomei P, Ria P, et al. Systemic and nonrenal adverse effects occurring in renal transplant patients treated with mTOR inhibitors. Clin Dev Immunol 2013;2013:1–13. 8. Colegio OR, Hanlon A, Olasz EB, Carucci JA. Sirolimus reduces cutaneous squamous cell carcinomas in transplantation recipients. J Clin Oncol 2013;31:3297–8. 9. Patel AA, Swerlick RA, McCall CO. Azathioprine in dermatology: the past, the present, and the future. J Am Acad Dermatol 2006;55:369–89. 10. Zwerner J, Fiorentino D. Mycophenolate mofetil. Dermatol Ther 2007;20:229–38. 11. Hausermann P, Walter RB, Halter J, et al. Cutaneous Graft-versus-host disease: a guide for the dermatologist. Dermatology 2008;216:287–304. 12. Patel R, Paya CV. Infections in solid-organ transplant recipients. Clin Microbiol Rev 1997;10:86–124. 13. Williams K, Mansh M, Chin-Hong P, Singer J, Arron ST. Voriconazole-associated cutaneous malignancy: a literature review on photocarcinogenesis in organ transplant recipients. Clin Infect Dis 2014;58:997–1002.

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Section 4: Disorders of Immunity, Hypersensitivity and Inflammation 14. Snydman DR. Infection in solid organ transplantation. Transpl Infect Dis 1999:1:21–8. 15. Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation. N Eng J Med 2003;348:1681–91. 16. Zwald FO, Brown M. Skin cancer in solid organ transplant recipients: advanced therapy and management: Part I. Epidemiology of skin cancer in solid organ transplant recipients. J Am Acad Dematol 2011;65:253–61. 17. Chockalingam R, Downing C, Tyring SK. Cutaneous squamous cell carcinomas in organ transplant recipients. J Clin Med 2015:4:1229–39. 18. Ulrich C, Kanitakis J, Stockfleth E, Euvrard S. Skin cancer in organ transplant recipients—where do we stand today? Am J Transpl 2008;8:2192–8. 19. Berg D, Otley CC. Skin cancer in organ transplant recipients: epidemiology, pathogenesis, and management. J Am Acad Dermatol 2002;47:1–17. 20. Ranganath HA, Panella TJ. Administration of ipilimumab to a liver transplant recipient with unresectable metastatic melanoma. J Immunother 2015;38:211.

21. Lipson EJ, Bodell MA, Kraus ES, Sharfman WH. Successful administration of ipilimumab to two kidney transplantation patients with metastatic melanoma. J Clin Oncol 2014;32:e69–71. 22. Morales RE, Shoushtari AN, Walsh MM, et al. Safety and efficacy of ipilimumab to treat advanced melanoma in the setting of liver transplantation. J Immunother Cancer 2015;3:22. 23. Herz S, Hofer T, Papapanagiotou M, et al. Checkpoint inhibitors in chronic kidney failure and an organ transplant recipient. Eur J Cancer 2016;67:66–72. 24. Hosseini-Moghaddam SM, Soleimanirahbar A, Mazzulli T, Rotstein C, Husain S. Post renal transplantation Kaposi’s sarcoma: a review of its epidemiology, pathogenesis, diagnosis, clinical aspects, and therapy. Transpl Infect Dis 2012;14:338–45. 25. Zwald FO, Brown M. Skin cancer in solid organ transplant recipients: advances in therapy and management: Part II. Management of skin cancer in solid organ transplant recipients. J Am Acad Dermatol 2011;65:263–79.

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Graft-versus-host Disease Ann M John, Babar K Rao

INTRODUCTION Graft-versus-host disease (GVHD) occurs after the administration of foreign immunologically competent cells to an individual who is immunologically compromised. Most commonly, it occurs after allogeneic hematopoietic stem cell transplantation (HSCT), affecting between 40% and 60% of patients.1 However, it can also occur after solid organ transplantation, autologous stem cell transplants, and rarely, blood transfusions.2,3 Usually, in the case of solid organ transplantation, the host or recipient recognizes the “foreign” donor tissue and attempts to reject the non-self-tissue—a host-versus-graft reaction. However, when the graft contains immunologically competent cells, these transplanted or transfused cells may identify the host as “foreign” and mount an immune response directed against host cells—a graft-versus-host reaction.4,5 The principal organs involved in GVHD are the gastrointestinal tract, the liver, and the skin. Clinically and histologically distinct acute and chronic forms of GVHD are recognized.6–8

ETIOLOGY Bone marrow transplantation for the treatment of leukemia, aplastic anemia, and congenital immunodeficient states provides the most frequent clinical setting for the development of GVHD. The greatest risk for the development of GVHD is human leukocyte antigen mismatch. However, minor differences in other histocompatibility antigens also contribute to the development of GVHD. In addition, older recipient age, gender disparity between host and donor, donor multiparity, use of peripheral blood stem cells as the graft source, and pretransplant conditioning methods promote the systemic manifestations of GVHD.1,9–11 The use of umbilical cord blood as a source for transplantation is protective against the development of GVHD; however, it is associated with increased failure of transplantation and often requires two cord blood units.12

More recently, other variations in HSCT have altered the presentation of GVHD. These include T-cell depletion prior to transplantation, which decreases the risk of GVHD but also increases cancer recurrence. The use of non-myeloablative but reduced preconditioning chemotherapy regimens has allowed for the use of HSCT in older patients with fewer preconditioning adverse effects. Finally, the use of donor lymphocyte infusions after HSCT to strengthen the antitumor activity has delayed the presentation of acute GVHD.13 Although pretransplantation preparatory regimens and post-transplantation care vary from institution to institution, the basic technique for bone marrow transplantation is relatively standardized. Bone marrow obtained from a histocompatible donor (usually a sibling) is intravenously infused into the recipient. The transfused bone marrow “homes in” to the recipient’s marrow cavities where, under ideal conditions, there is replication of stem cells and the production of erythrocytes, leukocytes, and platelets.14 In order to prevent rejection of the marrow by the host, the recipient is immunosuppressed both before and after transplantation. Immunocompetent lymphoid cells are present in the transfused marrow. These cells recognize antigens in the host and initiate the graftversus-host reaction. The paucity of cells presenting histologically in both the acute and the chronic phases of GVHD implicates that there are factors such as cytokines that are also involved in the pathogenesis of this reaction. Acute GVHD is associated with tumor necrosis factor-α (TNF-α), interferon-γ (INF-γ), interleukin-1 (IL-1), and nitric oxide. Chronic GVHD is associated with INF-γ, regulatory T cells, and IL-2 receptor subunit α (IL-2Rα) when present before 9 months and with B-cell-activating factor of the TNF family, Toll-like receptor 9 highly expressing B cells, and a lack of Th2 shift when present after 9 months.13 Furthermore, the fact that GVHD may occur after bone marrow transplantation between identical twins or reinfusion of the patient’s own marrow suggests that there are antigens present that are recognized by autocytotoxic lymphocytes or

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factors other than transplant antigens, such as TNF, play an important role in the pathogenesis of GVHD.15–20 Graft-versus-host disease also occurs in situations other than bone marrow transplantation. Transfusion GVHD is being more frequently recognized; it usually occurs in immunosuppressed patients and in most cases, is fatal. Sufficient numbers of viable, immunocompetent T lymphocytes may be present in erythrocyte or platelet transfusions, if they are not irradiated, to cause GVHD.21,22 Interestingly, patients with HIV/AIDS do not seem to be at risk for the disease, and occasional patients who are immunocompetent have developed transfusion GVHD.23 Why it does not occur in one setting and does in the other is not known. Immunocompetent T lymphocytes may also be present in solid organ transplants analogous to the transfusion setting.

CLASSIFICATION Graft-versus-host disease is typically classified as acute or chronic depending on its time of onset after HSCT, with symptoms within the first 100 days representing acute onset and symptoms after the first 100 days representing chronic onset. However, newer techniques of transplantation have blurred the line between acute and chronic GVHD, often delaying symptoms of acute GVHD until after the first 100 days. Acute GVHD may be present after the first 100 days, especially with the use of donor lymphocyte infusions after the first 100 days. Per the revised guidelines by the National Institutes of Health working group from 2005 and confirmed in 2014 by the NIH Chronic GVHD Diagnosis and Staging Consensus, acute GVHD is divided into “classic acute GVHD” if present within the first 100 days and “persistent, recurrent, or late-onset acute GVHD” if present after the first 100 days. Chronic GVHD is divided into “classic chronic GVHD” if symptoms of chronic GVHD are present at any time or “overlap syndrome” if symptoms of both acute and chronic GVHD are present.6,24

CLINICAL MANIFESTATIONS As the skin is the most frequently affected organ in acute and chronic GVHD, dermatologists often play a major role in recognition of GVHD.13

Acute Cutaneous GVHD The classic triad of rash, diarrhea, and bilirubinemia presents in acute GVHD, representing involvement of skin, the GI tract, and the hepatobiliary systems.8 Skin involvement is marked by a faint, blanchable macular follicular erythema or morbilliform eruption that appears on the hands, feet, palms, soles, forearms, and upper trunk within the first 4–6 weeks. This eruption is frequently accompanied by localized or generalized pruritus and characteristic dysesthesia of the palms and soles. Except for the distribution involving the face, palms, and soles, this mild form of acute cutaneous GVHD may be difficult to distinguish from a drug eruption or viral exanthema.8 The erythema may spontaneously fade, or it may progress to a more papular eruption. Dermoscopy of these lesions demonstrate well-demarcated pink to red papules with telengiectasias.25 The papular eruption, in turn, may remain localized or may progress to widespread erythroderma. Epidermolysis mimicking toxic epidermal necrolysis (TEN) may also occur.14 It is important to note that a more severe, hyperacute form presenting within the first 2 weeks after HSCT is marked by more frequent and severe skin involvement with an associated higher mortality.26 In addition, mucosal involvement, including erythema and ulcerations, is rare in acute GVHD but may indicate a more severe disease course.27 The extent and severity of acute GVHD may be staged on a scale from 1 to 4 using the modified Seattle Glucksberg criteria (Table 12.1). These criteria take into account both cutaneous and systemic manifestations.28 Stage 1 involves

. Table 12.1: Acute GVHD staging system. Stage Skin 1 Maculopapular rash, 50% BSA 4 Erythroderma, bullae formation

GI Nausea, diarrhea >500 mL/day Nausea, diarrhea >1,000 mL/day Nausea, diarrhea >1,500 mL/day Severe abdominal pain; possible ileus

(BSA: body surface area; GVHD: graft-versus-host disease; GI: gastrointestinal)

Hepatobiliary Bilirubin 2–3 mg/dL Bilirubin 3–6 mg/dL Bilirubin 6–15 mg/dL Bilirubin >15 mg/dL

Chapter 12: Graft-versus-host Disease 50% BSA with possible progression to generalized erythroderma. Stage 4, with the worst prognosis, presents with erythroderma and bulla formation, resembling TEN.13 Systemic involvement may occur concomitantly with or independently of the cutaneous changes. Signs and symptoms most frequently observed are nausea, vomiting, diarrhea, fever, elevation of serum bilirubin, transaminitis, and cholestasis.8,28 Other diagnoses that must be considered when evaluating a patient for acute GVHD include drug eruption, viral exanthem, chemotherapy-induced toxic erythema, and photo-induced rashes.13

Chronic Cutaneous GVHD Chronic GVHD can affect any organ, although the skin remains the most commonly affected site. Acute GVHD remains a huge risk factor for the development of chronic GVHD. In the past, two forms of chronic GVHD have been described—the early lichenoid and the later sclerodermoid forms. However, with more information regarding cutaneous manifestations, these terms are often inadequate to describe the breadth of expression and should ideally be reserved for histological terms. Of note, the earlier lichenoid form may evolve into the sclerodermoidlike phase.6,24,29 The earlier lichenoid form often begins as erythematous to violaceous polygonal papules (lichen-planus like) that coalesce to form larger plaques (Figs. 12.1 and 12.2). They are seen most commonly on the distal extremities, especially the palms and soles, but may occur anywhere on the body. The lesions may appear on clinically normal skin or in previously inflamed areas. It may be difficult to distinguish from lichen planus; however, the lesions in chronic GVHD tend to involve the face, ears, palms, and soles, which are not typical for the distribution in lichen planus. Poikiloderma is another typical skin manifestation presenting with skin atrophy and telangiectasia. Dyshidrotic palmar lesions may be found. Oral mucosal lesions similar to lichen planus are frequent and may occur in the absence of cutaneous lesions. The lesions have a white reticulate pattern and may be associated with erosions, ulcerations, mucoceles, pseudomembranes, and symptoms of sicca syndrome. Wickham striae are not observed and the borders of individual lesions of lichenoid GVHR are less sharply defined than those seen in classic idiopathic lichen planus. If the eruption is controlled at this

Fig. 12.1: Plaques and residual macular hyperpigmentation in a patient who underwent bone marrow transplant. Courtesy: Dr Babar Rao, MD. Robert Wood Johnson Medical School, New Brunswick, USA

Fig. 12.2: Plaques and residual macular hyperpigmentation in a patient who underwent bone marrow transplant. The biopsy site scar can be seen at the 7-cm mark. Courtesy: Dr Babar Rao, MD. Robert Wood Johnson Medical School, New Brunswick, USA

stage, a residual macular hyperpigmentation frequently occurs which resolves over several months. Vitiligo, alopecia, lupus-, dermatomyositis-, and epidermolysis-bullosalike lesions have also been described.30–32 The later sclerotic form of GVHD may be preceded by the lichenoid lesions or present independently as lichen sclerosis-like, morphea-like, or scleroderma-like eruptions. Lichen sclerosis-like lesions resemble shiny gray-white plaques, usually on the upper back with or without follicular plugging. Morphea-like lesions present

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Section 4: Disorders of Immunity, Hypersensitivity and Inflammation with induration and atrophy, often at site of skin injury or increased friction. Scleroderma-like lesions present with deeper dermal involvement including skin stiffening and dyspigmentation of the overlying skin. Alopecia, ulcers, decreased motion of the mouth, decreased chest wall expansion, vaginal stenosis, contractures, and decreased range of motion of involved joints may also result due to skin thickening. An even deeper variant mimics eosinophilic fasciitis, presenting with skin rippling and a firm, nodular involvement of skin in addition to muscle cramping and loss of range of motion. The “groove sign,” or linear depressions demonstrating vascular structures, can accompany skin ulceration. Minor infections and trauma may result in superficial ulcerations, which, even with optimal topical care, are extraordinarily slow in healing. The sclerotic changes are generally most pronounced centrally, over the buttocks and trunk; however, the face and scalp are often involved. An unusual reticulated poikilodermatous hyperpigmentation is commonly seen in association with the sclerosis. In addition to diffuse hair loss, there is evidence of adnexal involvement with sweat gland impairment and diminished to absent sweating.4,13,24,33 Diagnostic criteria that establish chronic GVHD diagnosis include poikiloderma, lichen planus-like features of the skin, lichen planus-like changes of the mouth, lichen sclerosis-like features, morphea-like features, and sclerotic features. Distinctive criteria that may suggest diagnosis of chronic GVHD include depigmentation, papulosquamous lesions, nail dystrophy, nail longitudinal ridging, splitting, or brittle features, onycholysis, pterygium unguis, symmetric nail loss, xerostomia, mucoceles, mucosal atrophy, and oral ulcers.6

is not specific for GVHD, and the histological differential diagnosis includes viral exanthema, drug eruption, and eruption of lymphocyte recovery. However, clinical suspicion, especially in the face of gastrointestinal tract and hepatobiliary involvement may indicate the need for treatment. As the eruption becomes more scaly, erythematous, and papular, histopathological findings include keratinocyte necrosis, basal layer degeneration, dyskeratosis of individual epidermal cells, haphazard arrangement of the epidermal cells in the lower half of the epidermis (loss of polarity), and band-like lymphohistiocytic infiltrate in the upper dermis are present. A sparse perivascular lymphocytic infiltrate is present in the papillary dermis. The lymphocytes migrate into the lower layers of the epidermis and frequently are found adjacent to dyskeratotic cells. The presence of these satellite lymphocytes is common in lichenoid tissue reactions and is not specific for GVHD. Similar involvement of the eccrine duct and hair follicle epithelium may be seen. With continued progression of the reaction, the basal vacuoles coalesce to form small subepidermal clefts and ultimately bullae. Subepidermal blister formation corresponds to the TEN-like form of acute GVHR. The paucity of dermal infiltrate differentiates GVHD from erythema multiforme. Histopathological grading is of little use to predicting clinical severity.35,36 In chronic GVHD, the histology is divided into the lichenoid (epidermal) and sclerotic (dermal) variants. In the lichenoid variant (Fig. 12.3), more extensive vacuolization of the basal layer is accompanied by keratinocyte

HISTOPATHOLOGY The histological findings in cutaneous GVHD vary somewhat with the appearance of the clinical lesion. It is interesting to note that surveillance skin biopsies of clinically normal skin obtained at regular intervals after bone marrow transplantation reveal subtle histologic abnormalities several days before an eruption may be clinically apparent. These may be helpful in predicting the early onset of cutaneous GVHD and may signal subclinical involvement of the skin when the gastrointestinal tract or liver is concomitantly involved.34 In acute GVHD, the earliest detectable pathological alteration, which may be seen in grossly normal skin or in the faint macular erythema, consists of a vacuolar interface dermatitis with focal basal vacuolization. This finding

Fig. 12.3: This H&E stain displays interface vacuolar change accompanied by necrotic keratinocytes in the epidermis, consistent with chronic graft-versus-host-disease. Courtesy: Dr Jisun Cha, MD and Robin Burger, MD of Rutgers, Robert Wood Johnson Medical School, New Brunswick, USA.

Chapter 12: Graft-versus-host Disease apoptosis and necrosis in the epidermis and along adnexa, orthokeratosis, focal hypergranulosis, irregular acanthosis, and dyskeratosis. A band-like, more impressive, lymphocytic infiltrate is accompanied by pigment dropout and accumulation of melanophages in the papillary dermis. The histological features may be indistinguishable from lichen planus, but usually there are fewer inflammatory cells in lichenoid cutaneous GVHD. The lesions may also be difficult to distinguish from acute GVHD. The lichenoid oral mucosal lesions also have a pattern indistinguishable from lichen planus. In addition, the minor salivary glands show the pattern of Sjögren syndrome with a lymphocyte and plasma cell infiltrate involving the ducts and acinar tissue. There is degeneration of the ducts and loss of acinar tissue with replacement by fibrosis. The sclerodermoid phase is histologically characterized by thickening and sclerosis of the reticular dermis with a proliferation of broad eosinophilic, slightly hyalinized collagen bundles. Fibrosis of the dermis, subcutaneous tissue, and fascia in addition to thickening of fat septae with a panniculitis is often seen. Involvement of appendageal epithelium may occur. In the upper dermis, there is a mild perivascular lymphocytic infiltrate as well as free and phagocytized melanin in early stages. Later stages show widening of collagen fibers and loss of adnexal structures and fat lobuli. The sclerosis seems to develop in a direction from the upper dermis to the lower dermis. Pilosebaceous units are usually absent, and there is entrapment of eccrine glands by the collagen. It may be impossible to histologically differentiate chronic cutaneous GVHD from morphea or progressive systemic sclerosis. Per the NIH working group, diagnosis of chronic GVHD must show apoptotic keratinocytes in the basal layer, stratum spinosum, external hair root sheath of the hair follicle, or acrosyringium in addition to lichenoid band-like infiltrate, vacuolar changes, and satellite necrosis.20,35,37 Immunofluorescence of acute lesions has shown occasional deposition of immunoglobulins (IgG, IgM) and complement at the dermal–epidermal junction. In chronic lesions, the deposition of globular or linear IgM along the dermal–epidermal junction is a fairly constant finding.36,38

TREATMENT The treatment and prevention of GVHD, including the drugs utilized and their doses, vary among different transplant centers. Cyclosporine is used as a prophylactic agent. If stage 1 and/or 2 acute GVHD develops, first line therapy is topical corticosteroids with topical emollients and

oral antihistamines. Topical calcineurin inhibitors can be used for resistant local cases or on sites where medium to high potency topical corticosteroids should be avoided, including intertriginous areas and the face. In addition, phototherapy, particularly with UVA or UVB, may be employed to disease isolated to the skin. However, most patients require systemic therapy with oral prednisone or intravenous methylprednisolone at a dose of 2 mg/kg/day, added to cyclosporine. If the patient responds to therapy, then both drugs are tapered until the oral route of administration is possible. If the patient does not respond, defined as progressive symptoms after 3 days or no response in 5–7 days to the use of both methylprednisolone and cyclosporine, mortality is high, but additional agents have been tried, including mycophenolate mofetil, TNF-α inhibitors such as etanercept and infliximab, IL-2 inhibitors such as daclizumab, antithymocyte globulin, and extracorporeal photophoresis. Cyclosporine is often limited by its renal toxicity, especially as most patients additionally require amphotericin. Even if the patient responds completely to therapy, it does not seem to alter their probability of developing chronic GVHD. Patients with stage 4 cutaneous GVHD have features similar to a burn and should be managed as such.39–47 Localized lichenoid chronic GVHD may be managed with medium to high potency topical corticosteroids and topical calcineurin inhibitors. These can often be combined with phototherapy, although there is an increased risk for the development of skin cancer given concomitant immunosuppression. Use of emollients with urea and glycerol are also effective as adjunctive treatment. Oral lesions can be treated with high potency topical steroids, intralesional steroids, topical calcineurin inhibitors, and phototherapy. Extensive lichenoid chronic GVHD and sclerodermoid GVHD are usually managed initially with systemic prednisone; cyclosporine is sometimes added. As chronic GVHD is slow to respond, it requires long-term therapy and prednisone and cyclosporine are subsequently switched to alternate-day administration to decrease side effects. If therapy is tapered too quickly or discontinued too soon, relapses are common. Six to nine months of therapy are warranted. For those who fail this therapy, there is no other standard salvage therapy, although options include hydroxychloroquine, mycophenolate mofetil, imatinib, rituximab, rapamycin, low-dose methotrexate, acitretin, basiliximab, and extracorporeal photophoresis. In addition, physical therapy, local ulcer care, emollients, adequate nutrition, and treatment of cutaneous bacterial infections are all important. Despite

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REFERENCES 1. Jagasia M, Arora M, Flowers ME, et al. Risk factors for acute GVHD and survival after hematopoietic cell transplantation. Blood 2012;119:296–307. 2. Murali AR, Chandra S, Stewart Z, et al. Graft versus host disease after liver transplantation in adults: a case series, review of literature, and an approach to management. Transplantation 2016;100:2661–70. 3. Fidler C, Klumpp T, Mangan K, et al. Spontaneous graft versus host disease occurring in a patient with multiple myeloma after autologous stem cell transplant. Am J Hematol 2012;87:219–21. 4. Hymes SR, Alousi AM, Cowen EW. Graft-versus-host disease: Part I. Pathogenesis and clinical manifestations of graft-versus-host disease. J Am Acad Dermatol 2012;66:515. e1–18; quiz 33–4. 5. Zeiser R, Penack O, Holler E, Idzko M. Danger signals activating innate immunity in graft-versus-host disease. J Mol Med 2011;89:833–45. 6. Jagasia MH, Greinix HT, Arora M, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transplant 2015;21:389–401.e1. 7. Penas PF, Zaman S. Many faces of graft-versus-host disease. Australas J Dermatol 2010;51:1–10; quiz 1. 8. Byun HJ, Yang JI, Kim BK, Cho KH. Clinical differentiation of acute cutaneous graft-versus-host disease from drug hypersensitivity reactions. J Am Acad Dermatol 2011;65:726–32. 9. DiRienzo CG, Murphy GF, Jones SC, Korngold R, Friedman TM. T-cell receptor Valpha spectratype analysis of a CD4mediated T-cell response against minor histocompatibility antigens involved in severe graft-versus-host disease. Biol Blood Marrow Transplant 2006;12:818–27. 10. Cutler C, Giri S, Jeyapalan S, et al. Acute and chronic graft-versus-host disease after allogeneic peripheral-blood stem-cell and bone marrow transplantation: a meta-analysis. J Clin Oncol 2001;19:3685–91. 11. James E, Chai JG, Dewchand H, et al. Multiparity induces priming to male-specific minor histocompatibility antigen, HY, in mice and humans. Blood 2003;102:388–93. 12. Pidala J, Anasetti C, Kharfan-Dabaja MA, et al. Decision analysis of peripheral blood versus bone marrow hematopoietic stem cells for allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 2009;15:1415–21. 13. Cowen, EW. Graft-versus-Host-Disease. In: Bologna, K, ed. Dermatology, Third Edition. Elsevier 2012;753–60. 14. Ferrara JL, Levine JE, Reddy P, Holler E. Graft-versus-host disease. Lancet (London, England) 2009;373:1550–61.

15. MacDonald KP, Shlomchik WD, Reddy P. Biology of graftversus-host responses: recent insights. Biol Blood Marrow Transplant 2013;19(1 Suppl):S10–4. 16. MacDonald KP, Hill GR, Blazar BR. Chronic graft-versushost disease: biological insights from preclinical and clinical studies. Blood 2017;129:13–21. 17. Yu Y, Wang D, Liu C, et al. Prevention of GVHD while sparing GVL effect by targeting Th1 and Th17 transcription factor T-bet and RORgammat in mice. Blood 2011;118:5011–20. 18. Beres AJ, Haribhai D, Chadwick AC, et al. CD8+ Foxp3+ regulatory T cells are induced during graft-versus-host disease and mitigate disease severity. J Immunol 2012;189:464–74. 19. Bruggen MC, Klein I, Greinix H, et al. Diverse T-cell responses characterize the different manifestations of cutaneous graft-versus-host disease. Blood 2014;123:290–9. 20. Wu PA, Cowen EW. Cutaneous graft-versus-host disease—clinical considerations and management. Curr Probl Dermatol 2012;43:101–15. 21. Ruhl H, Bein G, Sachs UJ. Transfusion-associated graft-versus-host disease. Transfus Med Rev 2009;23:62–71. 22. Molaro GL, De Angelis V. [Graft versus host disease after transfusion of blood and its products]. Riv Emoter Immunoematol 1984;31:107–23. 23. Ammann AJ. Hypothesis: absence of graft-versus-host disease in AIDS is a consequence of HIV-1 infection of CD4+ T cells. J Acquir Immune Defic Syndr 1993;6:1224–7. 24. Filipovich AH, Weisdorf D, Pavletic S, et al. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 2005;11:945–56. 25. Kaminska-Winciorek G, Czerw T, Kruzel T, Giebel S. Dermoscopic follow-up of the skin towards acute graftversus-host-disease in patients after allogeneic hematopoietic stem cell transplantation. BioMed Res Int 2016;2016:4535717. 26. Saliba RM, de Lima M, Giralt S, et al. Hyperacute GVHD: risk factors, outcomes, and clinical implications. Blood 2007;109:2751–8. 27. Ion D, Stevenson K, Woo SB, et al. Characterization of oral involvement in acute graft-versus-host disease. Biol Blood Marrow Transplant 2014;20:1717–21. 28. Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus conference on acute GVHD grading. Bone Marrow Transplant 1995;15:825–8. 29. Martires KJ, Baird K, Steinberg SM, et al. Sclerotic-type chronic GVHD of the skin: clinical risk factors, laboratory markers, and burden of disease. Blood 2011;118:4250–7. 30. Brassat S, Fleury J, Camus M, Monegier du Sorbier C, Guillet G. [Epidermolysa bullosa acquisita and graft-versushost disease]. Ann Dermatol Venereol 2014;141:369–73. 31. Hu SW, Myskowski PL, Papadopoulos EB, Busam KJ. Chronic cutaneous graft-versus-host disease simulating hypertrophic lupus erythematosus—a case report of a new morphologic variant of graft-versus-host disease. Am J Dermatopathol 2012;34:e81–3.

Chapter 12: Graft-versus-host Disease 32. Arin MJ, Scheid C, Hubel K, et al. Chronic graft-versus-host disease with skin signs suggestive of dermatomyositis. Clin Exp Dermatol 2006;31:141–3. 33. Chu GY, Lin HL, Chen GS, Wu CY. Eosinophilic fasciitis following allogeneic bone marrow transplantation in a patient with acute myeloid leukaemia. Acta Derm Venereol 2014;94:221–2. 34. Vassallo C, Brazzelli V, Alessandrino PE, et al. Normallooking skin in oncohaematological patients after allogenic bone marrow transplantation is not normal. Br J Dermatol 2004;151:579–86. 35. Ziemer M. Graft-versus-host disease of the skin and adjacent mucous membranes. J Dtsch Dermatol Ges 2013;11:477–95. 36. Wu YH, Lin YC. Cytoid bodies in cutaneous direct immunofluorescence examination. J Cutan Pathol 2007;34:481–6. 37. Shulman HM, Kleiner D, Lee SJ, et al. Histopathologic diagnosis of chronic graft-versus-host disease: National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: II. Pathology Working Group report. Biol Blood Marrow Transplant 2006;12:31–47. 38. Girolomoni G, Pincelli C, Zambruno G, et al. Immunohistochemistry of cutaneous graft-versus-host disease after allogeneic bone marrow transplantation. J Dermatol 1991;18:314–23. 39. Dignan FL, Clark A, Amrolia P, et al. Diagnosis and management of acute graft-versus-host disease. Br J Haematol 2012;158:30–45. 40. Kunitomi A, Iida H, Kamiya Y, Hayashi M, Sao H. Successful treatment using tacrolimus ointment for cutaneous graftversus-host disease. Int J Hematol 2008;88:465–7. 41. Rashidi A, DiPersio JF, Sandmaier BM, Colditz GA, Weisdorf DJ. Steroids versus steroids plus additional agent in frontline treatment of acute graft-versus-host disease: a systematic review and meta-analysis of randomized trials. Biol Blood Marrow Transplant 2016;22:1133–7. 42. Knobler R, Berlin G, Calzavara-Pinton P, et al. Guidelines on the use of extracorporeal photopheresis. J Eur Acad Dermatol Venereol 2014;28 Suppl 1:1–37. 43. Hattori K, Doki N, Kurosawa S, et al. Mycophenolate mofetil is effective only for involved skin in the treatment

for steroid-refractory acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Ann Hematol 2017;96:319–21. 44. Nogueira MC, Azevedo AM, Pereira SC, et al. Anti-tumor necrosis factor-a for the treatment of steroid-refractory acute graft-versus-host disease. Braz J Med Biol Res 2007;40:1623–9. 45. Tao T, Ma X, Yang J, et al. Humanized anti-CD25 monoclonal antibody treatment of steroid-refractory acute graftversus-host disease: a Chinese single-center experience in a group of 64 patients. Blood Cancer J 2015;5:e308. 46. Nishimoto M, Nakamae H, Koh H, et al. Response-guided therapy for steroid-refractory acute GVHD starting with very-low-dose antithymocyte globulin. Exp Hematol 2015;43:177–9. 47. Garbutcheon-Singh KB, Fernandez-Penas P. Phototherapy for the treatment of cutaneous graft versus host disease. Australas J Dermatol 2015;56:93–9. 48. Wolff D, Gerbitz A, Ayuk F, et al. Consensus conference on clinical practice in chronic graft-versus-host disease (GVHD): first-line and topical treatment of chronic GVHD. Biol Blood Marrow Transplant 2010;16:1611–28. 49. Ballester-Sanchez R, Navarro-Mira MA, de UnamunoBustos B, et al. The role of phototherapy in cutaneous chronic graft-vs-host disease: a retrospective study and review of the literature. Actas Dermosifiliogr 2015;106:651–7. 50. Flowers ME, Martin PJ. How we treat chronic graft-versushost disease. Blood 2015;125:606–15. 51. Greinix HT, van Besien K, Elmaagacli AH, et al. Progressive improvement in cutaneous and extracutaneous chronic graft-versus-host disease after a 24-week course of extracorporeal photopheresis—results of a crossover randomized study. Biol Blood Marrow Transplant 2011;17:1775–82. 52. Baird K, Comis LE, Joe GO, et al. Imatinib mesylate for the treatment of steroid-refractory sclerotic-type cutaneous chronic graft-versus-host disease. Biol Blood Marrow Transplant 2015;21:1083–90. 53. Arai S, Pidala J, Pusic I, et al. A randomized phase II crossover study of imatinib or rituximab for cutaneous sclerosis after hematopoietic cell transplantation. Clin Cancer Res 2016;22:319–27.

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Immunodeficiency Syndromes (except HIV) Danielle Tartar

INTRODUCTION Immunodeficiency often presents with cutaneous manifestations that can provide clues to the diagnosis.1 Immunodeficiencies can be primary or secondary. Primary immunodeficiency disorders result from inherited mutations that affect the development or function of an aspect of the immune system. As such, clinical manifestations are heterogeneous and depend largely on the involved arm of the immune system, though recurrent infections in early childhood are a shared feature.2 Many primary immunodeficiencies additionally present with atopy, lymphoproliferation, autoimmunity, or malignancy.3,4 Secondary immunodeficiency states result from other conditions or disorders such as age, medication, infection, malnutrition, or metabolic disorders that again affect function of the immune system.3,5 This chapter will focus on primary, or congenital immunodeficiencies (PID). The immune system can broadly be broken into the innate and adaptive components, which can be variably affected in PID. The innate immune system is non-antigen specific and encompasses phagocytic cells, complement, and other germ-line encoded receptors such as Toll-like receptors (TLRs).1 The adaptive immune system is antigenspecific and is composed of B- and T-lymphocytes.1 The most obvious sign of PID is often early, recurrent, and often overwhelming infections. The type of immune deficiency will often dictate the nature of the infection. For example, recurrent pyogenic infections with pus-forming bacteria occur in the setting of defects in antibodies, complement, or phagocytic cells,1,3 while defects in T cells are more likely to result in persistent fungal skin infections such as cutaneous candidiasis or with recurrent viral infections.1 Combined B- and T-cell deficiencies often present with diverse infections with bacteria, viruses, and fungi.3 Additional manifestations may include autoimmunity, which will again occur variably with the defect; autoimmune cytopenias can result from B-cell defects while systemic lupus erythematosus (SLE) is linked to complement

deficiencies.3 Malignancies, often lymphomas and leukemias, are associated with lymphoproliferative immunodeficiencies, while granulomatous complications in the skin, lungs, or gastrointestinal (GI) tract are linked to immunodeficiencies such as chronic granulomatous disease.3 Atopic features such as asthma, allergy, and atopic dermatitis have been associated with T-cell defects.3 It is therefore obvious that defects in different immune cells and pathways result in susceptibility to varying pathogens and clinical presentations. These will be discussed in this chapter with an emphasis on cutaneous manifestations, which, along with other systemic symptoms, can indicate an underlying immunodeficiency. For the purposes of this chapter, PID will be grouped into antibody defects, combined immunodeficiencies, and phagocytic defects.

ANTIBODY DEFECTS (TABLE 13.1) Defects in antibodies are heterogeneous and can range from absence of any circulating antibody to variable functional antibody changes.3 Patients most commonly present with recurrent pyogenic bacterial infections1 but can also include infections with viral or protozoan pathogens.3 X-linked agammaglobulinemia (XLA), or Bruton agammaglobulinemia, is caused by an X-linked recessive defect in BTK, a protein tyrosine kinase which signals through the pre-BCR, which is necessary for the maturation of pre-B cells to mature B cells.4,5 Additional autosomal recessive defects in other components of the pre-BCR cause congenital agammaglobulinemia similar to XLA include the IGHM gene, which encodes the µ heavy chain, λ5 (IGLL1), Igα (CD79a), and Igβ (CD79B).1 XLA is a PID with severe hypogammaglobulinemia and decreased or absent circulating B cells.3,4 Without plasma cells, patients are unable to produce circulating antibody or mount humoral responses.4 T-cell number remains unaffected, though the size of both tonsils and lymph nodes is decreased in the absence of B cells.4 In affected males, clinical manifestations typically begin in the first 6–12 months of life, when maternal

Chapter 13: Immunodeficiency Syndromes (except HIV) Table 13.1: Primary immunodeficiencies related to antibody defects. PID Summary Cutaneous findings Cutaneous infections XLA • Affects males (XLR ) • Presents upon weaning/withdrawal of (Pseudomonas aeruginosa and Campylobacter jejuni) maternal immunoglobulin • Small/rudimentary peripheral lymphoid organs such as lymph nodes and tonsils • Otitis media, pneumonia, sinusitis, chronic/recurrent diarrhea, conjunctivitis, cellulitis are common. Can also present with meningitis/ encephalitis, sepsis, septic arthritis, hepatitis, osteomyelitis • Cutaneous infections CVID • Males and females affected • Granulomas and lymphoid • Highly heterogeneous clinical proliferations presentation based on number of genetic defects • Only 10% of patients have known mutations • Common mutations include CD19, CD20, CD21, CD81, TNFRSF13B, TNFRSF13C, ICOS • Sinopulmonary infections common in addition to recurrent or chronic diarrhea • Associated with autoimmune disease (most commonly autoimmune hemolytic anemia and idiopathic thrombocytopenic purpura) • Associated with malignancy (most commonly lymphoma, leukemia, colon cancer)

Laboratory evaluation • Severely reduced or absent B cells (5%) • Eosinophilia • Eosinophilia (>1.5 × 109/L) • Thrombocytopenia Lymphadenopathy HHV-6 reactivation European Registry of Severe Cutaneous Adverse Reaction (RegiSCAR) requires rash, suspected drug etiology, and hospitalization, plus three additional criteria. The Japanese Research Committee on Severe Cutaneous Adverse Reaction (J-SCAR) requires all seven criteria for a diagnosis of typical drug-induced hypersensitivity syndrome. Atypical drug-induced hypersensitivity syndrome requires only the first five criteria.

noted with dapsone. In addition to prominent liver impairment with minocycline, heart and lung toxicity has been observed. While systemic involvement is common in both DRESS and SJS, a difference exists in that endocrine abnormalities can arise as late sequelae in DRESS. Thyroid abnormalities are most common and can lead to hypothyroidism or hyperthyroidism. Pancreatic involvement can occur in the form of pancreatitis or type 1 diabetes mellitus, and the salivary glands can become infiltrated with resultant xerostomia. Syndrome of inappropriate secretion of antidiuretic hormone has also been reported. Most commonly, endocrine abnormalities such as hypothyroidism or insulin disturbances have been reported several months after the disappearance of the rash. The pathogenesis of DRESS is not clearly elucidated but likely involves a combination of factors. Defective drug detoxification enzymes can lead to accumulation of toxic and active drug metabolites responsible for altering the immune response and inducing viral reactivation. Immune response based on HLA expression and cytokine release has also been implicated. The reactivation of herpesviruses, primarily HHV6 as well as CMV, EBV, and HHV7, may also contribute to the clinical picture. Diagnosis of DRESS is established through clinical and laboratory criteria. The European registry of severe cutaneous adverse reaction study group outlines seven criteria for diagnosis.20 Similar diagnostic criteria were outlined by the J-SCAR study group24 (Table 16.1). Skin biopsy is often more helpful in ruling out other

serious drug eruptions. The most common histopathology finding is a dense, perivascular lymphocytic dermal infiltrate with extravasated red blood cells, eosinophils, and dermal edema. The infiltrate tends to be more dense than other drug reactions. Histopathologic examination of involved organs may also be nonspecific. Patch testing and lymphocyte transformation testing have limited sensitivity and are rarely used. Treatment goals are early recognition, withdrawal of the offending agent, and initiation of systemic steroids. Systemic steroids are the mainstay of treatment with doses of at least 1  mg/kg/day. Clinical and serologic improvement occurs within days. Steroids should be tapered slowly over 3–6 months to prevent rebound. Steroid-recalcitrant cases have responded to IVIg (2  g/kg for 2 days) but not consistently. Plasmapheresis, plasma exchange, and other immunosuppressive drugs such as cyclophosphamide and cyclosporine have been used.25,26 N-acetylcysteine may aid in drug detoxification. Most patients recover completely, but they should be screened for late endocrine sequelae for months after the eruption has cleared. Overall mortality is 10% with hepatic necrosis and sepsis associated with poor prognosis.

NEUTROPHILIC DRUG ERUPTIONS There are several distinct types of neutrophilic drug eruptions including acute generalized exanthematous pustulosis (AGEP), neutrophilic eccrine hidradenitis (NEH), and drug-induced Sweet syndrome.

Chapter 16: Drug Eruptions

A

B Figs. 16.7A and B: (A) Acute generalized exanthematous pustulosis. (B) Pustules rapidly coalesce into flaccid sheets of pus. Courtesy: (A) R Corey Rougelot, MD, New Orleans, LA, USA.

Acute Generalized Exanthematous Pustulosis AGEP is a cutaneous adverse reaction most commonly associated with pristinamycin (an antistaphylococcal medication used in Europe), aminopenicillins, quinolones, hydroxychloroquine, sulfonamides, terbinafine, diltiazem, ketoconazole, and fluconazole.27 This eruption is characterized by sudden onset within 48  h of drug exposure and is commonly accompanied by fever. The eruption appears as numerous small sterile non-follicular based pustules with widespread underlying erythema on the trunk and intertriginous areas (Figs. 16.7A and B). The pustules rapidly coalesce into flaccid sheets of pus. The skin is often intensely pruritic or painful. Additional cutaneous features include marked

facial edema and purpuric lesions on dependent areas. Mucous membranes are most often spared, but focal mucosal involvement has been reported in up to 20% of cases. Systemic symptoms include leukocytosis with elevated neutrophils, fever, transaminitis, hepatomegaly, bilateral pulmonary effusions, hypoxemia, renal involvement, and disseminated intravascular coagulation. Pathogenesis is unknown. Interestingly, elevated Th17 cells are seen in peripheral blood as well as elevated IL-22, suggesting a role of activated Th17 cells in the pathogenesis. Workup includes total body skin and mucosal examination, biopsy, complete blood count (CBC) with differential, complete metabolic panel, chest X-ray, and coagulation panel. Histologic examination will reveal subcorneal sterile pustules with neutrophils and papillary dermal edema. Thirty percent of cases have eosinophils present. A diagnostic score for AGEP was proposed in the EuroSCAR study that includes histopathologic criteria and disease course.28 This can be helpful retrospectively but may not be useful in the acute setting. Patients often require management in an intensive care unit when multiorgan involvement is present. The main differential diagnosis includes pustular psoriasis, DRESS syndrome, and TEN. Mortality is SJS (SJS: Stevens-Johnson syndrome; TEN: toxic epidermal necrolysis)

Fig. 17.6: Toxic erythema necrolysis: intense bullae formation positive for Nikolsky and Asboe-Hansen sign on a background of erythema.

targetoid morphology and are primarily located on the extremities. The degree of epidermal necrosis and bullae formation is far less than that seen in SJS/TEN. In addition, history of an infection, especially herpes simplex virus, should prompt consideration of EMM. SSSS can be differentiated from SJS/TEN by the absence of mucous membrane involvement and superficial, as opposed to full-thickness, epidermal blistering on histology. Drug-induced linear IgA bullous dermatosis typically occurs within two weeks of vancomycin exposure and presents with tense bullae in annular or herpetiform arrangement with or without mucositis. Targetoid

Fig. 17.7: Histological features of SJS/TEN: full-thickness epidermal necrosis, a subepidermal split, and scant inflammatory infiltrate in the upper dermis (hematoxylin-eosin stain; original magnification: -100). (SJS/TEN: Stevens-Johnson syndrome/toxic epidermal necrolysis). Courtesy: Reprinted with permission from Schwartz RA, McDonough PH, Lee BW. “Toxic epidermal necrolysis: part II. Prognosis, sequelae, diagnosis, differential diagnosis, prevention, and treatment.” J Am Acad Dermatol 2013;69:187.e1–16; quiz 203–4.

lesions resembling EM or SJS/TEN may be seen.56 Immunofluorescence studies are critical to the diagnosis and show linear deposits of IgA at the basement membrane. Acute GvHD occurs approximately two weeks following bone marrow or hematopoietic stem cell transplant. Clinically, it appears as a symmetric morbilliform or lichenoid eruption with folliculocentric distribution of

Chapter 17: Erythema Multiforme, Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Table 17.4: SCORTEN.84 Criteria: 1 point per condition Age >40 years Heart rate >120 beats per minute Comorbid malignancy Epidermal detachment >10% body surface area on day 1 Blood urea nitrogen >28 mg/dL Glucose >252 mg/dL Bicarbonate 2 g/kg) or low dose of IVIG. Although high-dose

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Section 5: Drug Reactions Table 17.6: Differential diagnosis of TEN.19 Disease Erythema multiforme major

Staphylococcal scalded skin syndrome Drug-induced linear IgA Severe acute graft versus host disease Acute generalized exanthematous pustulosis

Clinical differentiation from TEN Typical target lesions or atypical targetoid papules; symmetric acral predominance; most commonly caused by infections; minimal epidermal exfoliation and bullae No mucositis; superficial epidermal peeling

Histological differentiation from TEN Should rely primarily on clinical features to make the distinction; epidermal cell death far less extensive; scattered necrotic keratinocytes Intraepidermal blistering

Rare mucositis; annular distribution of bullae

Direct immunofluorescence reveals linear deposits of IgA along basement membrane Folliculocentric distribution of eruption; acral to Indistinguishable proximal spread of bullae Pustules; Rare, nonerosive mucous membrane Intraepidermal pustules; focal necrotic involvement keratinocytes

(TEN: toxic epidermal necrolysis)

recipients were shown to have a lower mortality rate, a multivariate logistic regression model eliminated this difference.79 A recent meta-analysis found that high dose IVIG significantly decreased mortality in patients with SJS/ TEN.78 In another recent open-label, multicenter, singlearm study in Japan, consecutive administration of IVIG, in addition to systemic steroid therapy, resulted in markedly improved symptoms in eight patients.80,81 However, multicenter, randomized controlled trials are needed to obtain robust level of evidence to make definitive recommendations regarding the use of IVIG. Additional therapies such as TNF-α inhibitors, granulocyte colony–stimulating factors (GCSF), N-acetylcysteine (NAC), and cyclosporine have also been used in the treatment of SJS/TEN. Cyclosporine, a calcineurin inhibitor that inhibits T-cell function, has shown promise in the treatment of SJS/TEN. A study in which 29 patients were treated with cyclosporine for at least 10 days documented in rapidly halted disease progression, no mortality, and no associated increased rate of infection.82 Several case reports have shown efficacy of TNF-α, GCSF, and NAC; however, additional studies are required to validate efficacy.83–90

Prognosis Patient mortality in SJS/TEN is high, although there is some variability. Some older studies have reported a relatively good prognosis for SJS and a 20%–30% mortality rate for TEN.91 A large cohort study of 379 cases disclosed mortality rates of 13% for SJS, 21% for SJS/TEN overlap, and 39% for TEN.92 More recently, a cohort study

of 460 cases reported mortality at 6 weeks after onset of SJS/TEN: 12% for SJS, 29% for SJS/TEN overlap, and 46% for TEN.63 These data indicate that the mortality rate for SJS/TEN may be higher than historically reported. Sepsisinduced multiorgan failure is the primary cause of death in these patients.20 Prognosis in patients with SJS/TEN can be predicted with the Severity of Illness Score for Toxic Epidermal Necrolysis (SCORTEN), a severity of illness score that came into use over a decade ago (Table 17.6).17 The scoring system allots 1 point to 7 prognostic factors: (1) age >40 years; (2) heart rate >120 beats per minute; (3) comorbid malignancy; (4) epidermal detachment >10% of BSA on day 1; (5) blood urea nitrogen >28 mg/dL; (6) glucose >252  mg/dL; and (7) bicarbonate 5 points. The value of SCORTEN is optimized when performed on days 1 and 3 after admission and is a reliable instrument to predict mortality. An important limitation to this tool is that it does not account for respiratory involvement and may underestimate mortality in patients with this complication.23 SCORTEN was not designed to predict long-term sequelae.21

Immunopathogenesis While the precise pathophysiological mechanism is unknown, the clinical, histopathological, and immunological findings in SJS/TEN have provided evidence for an immune mediated disease that results in keratinocyte

Chapter 17: Erythema Multiforme, Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis apoptosis.21,43,93 Blister fluid of patients with SJS/TEN has shown a predominance of activated CD8+ T lymphocytes, granulysin, and other molecules such as natural killer cells.19,94,95 Additionally, markers such as killer inhibitory receptor, killer activating receptor (KIR/KAR), and CD56 have been demonstrated on the surface of CD8+ cells found in blister fluid. Several pathways are thought to be responsible for the keratinocyte apoptosis that occurs in SJS/TEN, including Fas-FasL, perforin/granzyme B, and granulysin pathways.95 FasL, a molecule found in cellular lysosomes, is transported to the cell surface following T-cell activation.95 Patients with SJS/TEN were found to have elevated serum FasL levels as compared to other drug-induced reactions, in which levels were normal.95 Early in the disease process, soluble FasL is secreted by T cells and NK cells and binds to Fas on the surface of affected keratinocytes. The Fas-FasL complex then recruits Fas-associated death domain protein, triggering apoptosis via the caspase cascade. One study demonstrated apoptosis of cultured keratinocytes when exposed to serum from SJS/TEN patients and a reduction in apoptosis when antiFasL antibody inhibitor was added to culture.95 The perforin/granzyme B pathway has also been implicated in keratinocyte apoptosis. These molecules, stored in granules within CD8+ T cells and NK cells, are released when an antigen-presenting cell (presenting the implicated drug or metabolite) directly contacts a T cell. Through a calcium-dependent mechanism, perforin creates pores through the target cell membrane and granzyme B enters the cell to activate caspases directly to cause apoptosis. Granzyme B can also activate caspaseindependent pathways via Bid, a proapoptotic protein that increases permeability of the mitochondrial outer membrane, which causes leaking of mediators that ultimately activate caspase. Apoptosis of keratinocytes by perforin/ granzyme B was demonstrated in vitro.95 Recent evidence has suggested granulysin as a key mediator in the extensive epidermal necrosis of SJS/TEN. Granulysin is a protein released by cytotoxic T cells and NK cells that induces an immune response by recruiting and activating antigen-presenting cells. In a study by Chung et al.,94 high levels of granulysin were found in blister fluid of patients with TEN, and keratinocyte apoptosis was induced when granulysin was injected into mouse skin. In gene expression profiling of SJS/TEN blister fluid, concentrations of granulysin were two to four orders of magnitude higher than perforin/granzyme B or soluble FasL, making granulysin the most highly expressed cytotoxic molecule.94,95 In addition, granulysin demonstrated

dose dependent toxicity, causing apoptosis of the majority of keratinocytes. In contrast, FasL, perforin/granzyme B caused a relatively minor amount of apoptosis of keratinocytes. The mechanism by which drug ingestion causes release of granulysin is not understood but may involve increased intracellular calcium, which has been implicated in necrosis and apoptosis.95 Thus, granulysin may represent a marker to alert clinicians to the development or enhanced risk of developing SJS/TEN. TNF-α is another immunologic mediator implicated in the immunopathogenesis of SJS/TEN. TNF-α is postulated to cause apoptosis by upregulation of Fas/FasL and activation of TNF-related apoptosis-inducing ligand and TNF-receptor 1.95 TNF-α increases nitric oxide, which produces reactive oxygen species, leading to oxidative stress, necrosis and enhanced FasL expression. However, TNF-α has also been shown to upregulate NF-κB, an apoptotic inhibitor, making its role in the pathogenesis of SJS/TEN unclear. Recently identified mediators in keratinocyte apoptosis include annexin A1 and miR-18-a-5p. Annexin A1 binds to its receptor (formyl peptide receptor 1 receptor) to induce keratinocyte death in a mouse model and was upregulated in the supernatant of peripheral blood smears from SJS/TEN patients.96 In addition, miR-18a-5p levels were increased in skin samples from patients with SJS/TEN. This molecule is believed to downregulate the expression of an anti-intrinsic apoptotic protein known as B-cell lymphoma/leukemia-2-like protein 10, thereby inducing intrinsic keratinocyte apoptosis.97

CONCLUSION SJS and TEN are rare, idiosyncratic usually drug induced hypersensitivity reactions associated with a mortality that may be as high as 30%, particularly with TEN. They are characterized by bullae and mucocutaneous denudation, with TEN a prominent example of sloughing of “skin, oral and internal mucosa” often with devastating consequences. The association between particular HLA allotypes and the hypersensitivity reaction places certain populations at greater risk for developing this condition. Certainly, physicians treating epileptics of Han Chinese origin should be aware of an increased risk in this population. In addition, the 1,000 times increased risk of TEN in patients with HIV disease should be widely recognized. Although several immune mediators have been identified in the pathogenesis of SJS/TEN, granulysin appears to be the primary mediator of keratinocyte apoptosis and continues

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Section 5: Drug Reactions to be studied for possible use as a marker for early TEN. Current treatment involves withdrawal of the offending medication and supportive therapy with comprehensive, long-term, and multidisciplinary follow-up.

REFERENCES 1. Von Hebra F. On diseases of the skin, including the exanthemata Bd 1. London: Hilton Fagge; 1866. p. 42. 2. Thomas BA. So-called Stevens–Johnson syndrome. Br Med J 1950;1:1393. 3. Auquier-Dunant A, Mockenhaupt M, Naldi L, et al. Correlations between clinical patterns and causes of erythema multiforme majus, Stevens–Johnson syndrome, and toxic epidermal necrolysis: results of an international prospective study. Arch Dermatol 2002;138:1019–24. 4. Duvic M, Reisner EG, Dawson DV, et al. HLA-B15 association with erythema multiforme. J Am Acad Dermatol 1983;8:493–6. 5. Khalil I, Lepage V, Douay C, et al. HLA DQB1* 0301 allele is involved in the susceptibility to erythema multiforme. J Invest Dermatol 1991;97:697–700. 6. Aurelian L, Ono F, Burnett J. Herpes simplex virus (HSV)associated erythema multiforme (HAEM): a viral disease with an autoimmune component. Dermatol Online J 2003; 9(1):1. 7. Howland WW, Golttz LE, Weston WL, et al. Erythema multiforme: clinical, histopathologic, and immunologic study. J Am Acad Dermatol 1984;10:438–46. 8. Brice SL, Leahy MA, Ong L, et al. Examination of non– involved skin, previously involved skin, and peripheral blood for herpes simplex virus DNA in patients with recurrent herpes–associated erythema multiforme. J Cutan Pathol 1994;21:408–12. 9. Joseph RH, Haddad FA, Matthews AL, et al. Erythema multiforme after orf virus infection: a report of two cases and literature review. Epidemiol Infect 2015;143:385–90. 10. Sokumbi O, Wetter DA. Clinical features, diagnosis, and treatment of erythema multiforme: a review for the practicing dermatologist. Int J Dermatol 2012;51:889–902. 11. Huff JC, Weston WL, Tonnesen MG. Erythema multiforme: a critical review of characteristics, diagnostic criteria, and causes. J Am Acad Dermatol 1983;8:763–75. 12. Tatnall FM, Schofield JK, Leigh IM. A double–blind, placebo–controlled trial of continuous acyclovir therapy in recurrent erythema multiforme. Br J Dermatol 1995;132:267–70. 13. Bean SF, Quezada RK. Recurrent oral erythema multiforme: clinical experience with 11 patients. JAMA 1983;249: 2810–2. 14. Stevens AM, Johnson FC. A new eruptive fever associated with stomatitis and ophthalmia; report of two cases in children. Am J Dis Child 1922;24(6):526–33. 15. Lyell A. Toxic epidermal necrolysis (the scalded skin syndrome): a reappraisal. Br J Dermatol 1979;100:69–86. 16. Dmochowski M, Schwartz RA. Erythemamultiforme, Stevens-Johnsonsyndrome, andtoxic epidermal necrolysis.

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In: Clinical Dermatology. D.J. Demis (Ed.), Lippincott Williams & Wilkins, Philadelphia, 1999, Unit 7–3, 1–20. Schwartz RA, McDonough PH, Lee BW: Toxic epidermal necrolysis. Part I. Introduction, history, classification, clinical features, systemic manifestations, etiology, and immunopathogenesis. J Am Acad Dermatol 2013;69:173–84. Mittmann N, Knowles SR, Koo M, et al. Incidence of toxic epidermal necrolysis and Stevens–Johnson syndrome in an HIV Cohort. Am J Clin Dermatol 2012;13(1):49–54. Harr T, French LE. Toxic epidermal necrolysis and Stevens– Johnson syndrome. Orphanet J Rare Dis 2010;5:1–11. Schwartz RA, McDonough PH, Lee BW. Toxic epidermal necrolysis: part II. Prognosis, sequelae, diagnosis, differential diagnosis, prevention, and treatment. J Am Acad Dermatol 2013;69:187.e1–16; quiz 203–4. Mockenhaupt M. Stevens–Johnson syndrome and toxic epidermal necrolysis: clinical patterns, diagnostic considerations, etiology, and therapeutic management. Semin Cutan Med Surg 2014;33:10–6. McCormack M, Alfirevic A, Bourgeois S, et al. HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans. N Engl J Med 2011;364:1134–43. Ellender RP, Peters CW, Albritton HL, et al. Clinical considerations for epidermal necrolysis. Ochsner J 2014;14: 413–7 Creamer D, Walsh SA, Dziewulski P, et al. UK guidelines for the management of Stevens–Johnson syndrome/toxic epidermal necrolysis in adults 2016 (print summary—Full guidelines available at http://dx.doi. org/10.1016/j.bjps.2016.01.034). J Plast Reconstr Aesthet Surg 2016;69:736–41. Revuz J, Penso D, Roujeau JC, et al. Toxic epidermal necrolysis. Clinical findings and prognosis factors in 87 patients. Arch Dermatol 1987;123(9):1160-5. Lebargy F, Wolkenstein P, Gisselbrecht M, et al. Pulmonary complications in toxic epidermal necrolysis: a prospective clinical study. Intensive Care Med 1997;23(12):1237-44. Avakian R, Flowers FP, Araujo OE, et al. Toxic epidermal necrolysis: a review. J Am Acad Dermatol 1991;25: 69–79. Blum L, Chosidow O, Rostoker G, et al. Renal involvement in toxic epidermal necrolysis. J Am Acad Dermatol 1996;34:1088–90. Michel P, Joly P, Ducrotte P, et al. Ileal involvement in toxic epidermal necrolysis (Lyell syndrome). Dig Dis Sci 1993;38: 1938–41. Dasgupta A, O’Malley J, Mallya R, et al. Bronchial obstruction due to respiratory mucosal sloughing in toxic epidermal necrolysis. Thorax 1994;49:935–6. Wallis C, McClymont W. Case reports toxic epidermal necrolysis with adult respiratory distress syndrome. Anaesthesia 1995;50:801–3. Dolan PA, Flowers FP, Araujo OE, et al. Toxic epidermal necrolysis. J Emerg Med 1989;7(1):65–9. Kohanim S, Palioura S, Saeed HN, et al. Stevens–Johnson syndrome/toxic epidermal necrolysis—a comprehensive review and guide to therapy. I. Systemic disease. Ocul Surf 2016;14:2–19.

Chapter 17: Erythema Multiforme, Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis 34. Chang YS, et al. Erythema multiforme, Stevens–Johnson syndrome, and toxic epidermal necrolysis: acute ocular manifestations, causes, and management. Cornea 2007;26:123–9. 35. Sotozono C, Ueta M, Koizumi N, et al. Diagnosis and treatment of Stevens–Johnson syndrome and toxic epidermal necrolysis with ocular complications. Ophthalmology 2009;116(4):685–90. 36. Yamane Y, Aihara M, Ikezawa Z. Analysis of Stevens– Johnson syndrome and toxic epidermal necrolysis in Japan from 2000 to 2006. Allergol Int 2007;56:419–25. 37. Saeed H, Mantagos IS, Chodosh J. Complications of Stevens–Johnson syndrome beyond the eye and skin. Burns 2016;42:20–7. 38. Ducic I, Shalom A, Rising W, et al. Outcome of patients with toxic epidermal necrolysis syndrome revisited. Plast Reconstr Surg 2002;110(3):768–73. 39. Sedghizadeh PP, Kumar SK, Gorur A, et al. Toxic epidermal necrolysis with a rare long-term oral complication requiring surgical intervention. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008;105(4):e29–33. 40. Schwartz RA. Toxic epidermal necrolysis. Cutis 1997; 59:123–8. 41. Murata J, Abe R, Shimizu H. Increased soluble Fas ligand levels in patients with Stevens–Johnson syndrome and toxic epidermal necrolysis preceding skin detachment. J Allergy Clin Immunol 2008;122(5):992–1000. 42. Caproni M, Antiga E, Parodi A, et al. Elevated circulating CD40 ligand in patients with erythema multiforme and Stevens–Johnson syndrome/toxic epidermal necrolysis spectrum. Br J Dermatol 2006;154:1006–7. 43. Heng YK, Lee HY, Roujeau JC. Epidermal necrolysis: 60 years of errors and advances. Br J Dermatol 2015;173:1250–4. 44. Fritsch PO, Sidoroff A. Drug-induced Stevens–Johnson syndrome/toxic epidermal necrolysis. Am J Clin Dermatol 2000;1:349–60. 45. Mockenhaupt M, Viboud C, Dunant A, et al. Stevens– Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. The EuroSCARstudy. J Invest Dermatol 2008;128(1):35–44. 46. Miliszewski MA, Kirchhof MG, Sikora S, et al. Stevens– Johnson syndrome and toxic epidermal necrolysis: an analysis of triggers and implications for improving prevention. Am J Med 2016;129(11):1221–5. 47. Roujeau JC, Stern RS. Severe adverse cutaneous reactions to drugs. N Engl J Med 1994;331(19):1272–85. 48. Rodriguez G, Trent JT, Mirzabeigi M, et al. Toxic epidermal necrolysis in a mother and fetus. J Am Acad Dermatol 2006;55:S96–8. 49. Roujeau JC, Kelly JP, Naldi L, et al. Medication use and the risk of Stevens–Johnson syndrome or toxic epidermal necrolysis. N Engl J Med 1995;333(24):1600–7. 50. Guillaume J, Roujeau JC, Revuz J, et al. The culprit drugs in 87 cases of toxic epidermal necrolysis (Lyell’s syndrome). Arch Dermatol 1987;123:1166–70. 51. Sassolas B, et al. ALDEN, an algorithm for assessment of drug causality in Stevens–Johnson syndrome and toxic

epidermal necrolysis: comparison with case–control analysis. Clin Pharmacol Ther 2010;88:60–68. 52. Hosaka H, Ohtoshi S, Nakada T, et al. Erythema multiforme, Stevens–Johnson syndrome and toxic epidermal necrolysis: frozen-section diagnosis. J Dermatol 2010;37:407–12. 53. Posadas SJ, Padial A, Torres MJ, et al. Delayed reactions to drugs show levels of perforin, granzyme B, and Fas-L to be related to disease severity. J Allergy Clin Immunol 2002;109(1):155–61. 54. Fujita Y, Yoshioka N, Abe R, et al. Rapid immunochromatographic test for serum granulysin is useful for the prediction of Stevens– Johnson syndrome and toxic epidermal necrolysis. J Am Acad Dermatol 2011;65(1):65–8. 55. Nakajima S, Watanabe H, Tohyama M, et al. High-mobility group box 1 protein (hmgb1) as a novel diagnostic tool for toxic epidermal necrolysis and Stevens–Johnson syndrome. Arch Dermatol 2011;147:1110–2. 56. Janniger CK, Wiltz H, Schwartz RA, et al. Adult linear IgA bullous dermatosis: a polymorphic disorder. Cutis 1990;45:37–42. 57. Szatkowski J, Schwartz RA. Acute generalized exanthematous pustulosis (AGEP): a review and update. J Am Acad Dermatol 2015;73:843–8. 58. Husain Z, Reddy BY, Schwartz RA. DRESS syndrome: part I. Clinical perspectives. J Am Acad Dermatol 2013;68:693. e1–14; quiz 706–8. 59. Janniger CK, Gascon P, Schwartz RA. Erythroderma as the initial presentation of the acquired immunodeficiency syndrome. Dermatologica 1991;183:143–5. 60. Schwartz RA, Leevy CM, Cohen PJ, et al. Erythroderma and fulminant hepatitis: a possible association. Cutis 1986;37: 56–58. 61. Papadopoulos AJ, Schwartz RA, Fekete Z, et al. Pseudoporphyria: an atypical variant resembling toxic epidermal necrolysis. J Cutan Med Surg 2001;5:479–85. 62. Sekula P, Dunant A, Mocheknhaupt M, et al. Comprehensive survival analysis of a cohort of patients with Stevens– Johnson syndrome and toxic epidermal necrolysis. J Investig Dermatol 2013;133:1197–204. 63. Kim KJ, Lee DP, Suh HS, et al. Toxic epidermal necrolysis: analysis of clinical course and SCORTEN-based comparison of mortality rate and treatment modalities in Korean patients. Acta Derm Venereol 2005;85:497–502. 64. Gueudry J, Roujeau JC, Binaghi M, et al. Risk factors for the development of ocular complications of Stevens–Johnson syndrome and toxic epidermal necrolysis. Arch Dermatol 2009;145:157–62. 65. Hazin R, Ibrahimi OA, Hazin MI, et al. Stevens–Johnson syndrome: pathogenesis, diagnosis, and management. Ann Med 2008;40(2):129–38. 66. Downey A, Jackson C, Harun N, et al. Toxic epidermal necrolysis: Review of pathogenesis and management. J Am Acad Dermatol 2012; 66(6):995–1003. 67. Oplatek A, Brown K, Sen S, et al. Long-term follow-up of patients treated for toxic epidermal necrolysis. J Burn Care Res 2006;27(1):26–33. 68. Sanmarkan AD, Sori T, Thappa Dm, et al. Retrospective analysis of Stevens– Johnson syndrome and toxic epidermal

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Section 5: Drug Reactions necrolysis over a period of 10 years. Indian J Dermatol 2011;56:25–9. 69. Patel T, Barvaliya MJ, Sharma D, et al. A systematic review of the drug-induced Stevens–Johnson syndrome and toxic epidermal necrolysis in Indian population. Indian J Dermatol Venereol Leprol 2013;79:389–98. 70. Herndon DN, Tompkins RG. Support of the metabolic response to burn injury. Lancet 2004;363:1895–902. 71. Abela C, Hartmann CE, De Leo A, et al. Toxic epidermal necrolysis (TEN): the Chelsea and Westminster Hospital wound management algorithm. J Plast Reconstr Aesthet Surg 2014;67(8): 1026–32. 72. Li X, Wang D, Lu Z. Answer to ‘Toxic epidermal necrolysis with failure of re-epithelialization. Could umbilical cord mesenchymal stem cell transplantation have a role?’. J Eur Acad Dermatol Venereol 2013;27:925. 73. Huang SH, Wu SH, Sun IF, et al. AQUACEL Ag in the treatment of toxic epidermal necrolysis (TEN). Burns 2008;34(1):63–6. 74. de Prost N, Ingen-Housz-Oro S, Duong Ta, et al. Bacteremia in Stevens–Johnson syndrome and toxic epidermal necrolysis: epidemiology, risk factors, and predictive value of skin cultures. Medicine (Baltimore) 2010;89:28–36. 75. Shiga S, Cartotto R. What are the fluid requirements in toxic epidermal necrolysis? J Burn Care Res 2010;31:100–4. 76. Ruiz-Maldonado R. Acute disseminated epidermal necrosis types 1, 2, and 3: study of sixty cases. J Am Acad Dermatol 1985;13:623–35. 77. Halebian PH, Cirder VJ, Madden MR, et al. Improved burn center survival of patients with toxic epidermal necrolysis managed without corticosteroids. Ann Surg 1986;204(5):503–12. 78. Barron SJ, Del Vecchio MT, Aronoff SC. Intravenous immunoglobulin in the treatment of Stevens–Johnson syndrome and toxic epidermal necrolysis: a meta-analysis with meta-regression of observational studies. Int J Dermatol 2015;54:108–15. 79. Huang YC, Li YC, Chen TJ. The efficacy of intravenous immunoglobulin for the treatment of toxic epidermal necrolysis: a systematic review and meta-analysis. Br J Dermatol 2012;167:424–32. 80. Kinoshita Y, Saeki H. A review of toxic epidermal necrolysis management in Japan. Allergol Int 2017;66(1):35–41 81. Aihara M, Kano Y, Fujita H, et al. Efficacy of additional i.v. immunoglobulin to steroid therapy in Stevens–Johnson syndrome and toxic epidermal necrolysis. J Dermatol 2015;42:768–77. 82. Valeyrie-Allanore L, Wolkenstein P, Brochard L, et al. Open trial of ciclosporin treatment for Stevens–Johnson syndrome and toxic epidermal necrolysis. Br J Dermatol 2010;163(4):847–53.

83. Fischer M, Fiedler E, Marsch WC, et al. Antitumour necrosis factor-α antibodies (infliximab) in the treatment of a patient with toxic epidermal necrolysis. Br J Dermatol 2002;146(4):707–9. 84. Kreft B, Wohirab J, Bramsiepe I, et al. Etoricoxib-induced toxic epidermal necrolysis: successful treatment with infliximab. J Dermatol 2010;37(10):904–6. 85. Gubinelli E, Canzona F, Tonanzi T, et al. Toxic epidermal necrolysis successfully treated with etanercept. J Dermatol 2009;36:150–3. 86. Roujeau JC. Treatment of severe drug eruptions. J Dermatol 1999;26:718–22. 87. de Sica-Chapman A, Williams G, Soni N, et al. Granulocyte colony-stimulating factor in toxic epidermal necrolysis (TEN) and Chelsea & Westminster TEN management protocol [corrected]. Br J Dermatol 2010;162(4):860–5. 88. Goulden V, Goodfield MJD. Recombinant granulocyte colony-stimulating factor in the management of toxic epidermal necrolysis. Br J Dermatol 1996;135:305–6. 89. Vélez A, Moreno JC. Toxic epidermal necrolysis treated with N-acetylcysteine. J Am Acad Dermatol 2002;46: 469–70. 90. Saavedra C, Cardenas P, Castellanos H, et al. Cephazolininduced toxic epidermal necrolysis treated with intravenous immunoglobulin and N-acetylcysteine. Case Rep Immunol 2012;2012:4. 91. Roujeau JC, Chosidow O, Saiag P, et al. Toxic epidermal necrolysis (Lyell syndrome). J Am Acad Dermatol 1990;23(6 Pt 1):1039–58. 92. Schneck J, Fagot JP, Sekula P, et al. Effects of treatments on the mortality of Stevens–Johnson syndrome and toxic epidermal necrolysis: a retrospective study on patients included in the prospective EuroSCAR Study. J Am Acad Dermatol 2008;58(1):33–40. 93. Chung WH, Wang CW, Dao RL. Severe cutaneous adverse drug reactions. J Dermatol 2016;43:758–66. 94. Chung WH, Hung Si, Yang JY, et al. Granulysin is a key mediator for disseminated keratinocyte death in Stevens– Johnson syndrome and toxic epidermal necrolysis. Nat Med 2008;14(12):1343–50. 95. Saeed HN, Chodosh J. Immunologic mediators in Stevens– Johnson syndrome and toxic epidermal necrolysis. Semin Ophthalmol 2016;31:85–90. 96. Saito N, Qiao H, Yanagi T, et al. An annexin A1-FPR1 interaction contributes to necroptosis of keratinocytes in severe cutaneous adverse drug reactions. Sci Transl Med 2014;6:245ra95. 97. Ichihara A, Wang Z, Jinnin M, et al. Upregulation of miR18a-5p contributes to epidermal necrolysis in severe drug eruptions. J Allergy Clin Immunol 2014;133(4): 1065–74.

Chapter

18

Erythroderma Sandipan Dhar, Amrinder Jit Kanwar

INTRODUCTION Erythroderma is an inflammatory cutaneous reaction pattern characterized by diffuse erythema and scaling. More than 80%–90% of the body surface area is involved. The term erythroderma was introduced in 1868 by Hebra. Though most of the available articles designated it as disorder; the phrase cutaneous reaction pattern is more appropriate for this condition due to diverse underlying etiologies which manifest similarly. Erythroderma poses a significant diagnostic challenge because of this etiological diversity. Only subtle differences in clinical presentation, appropriate history taking, necessary investigations, and clinicopathological correlation help the clinician arrive at a proper diagnosis. Idiopathic cases, known as “red man syndrome,” make the job of the treating physician exceptionally difficult, in spite of all diagnostic efforts. Erythroderma is also associated with significant morbidity and mortality as most patients are elderly, skin involvement is extensive, and associated metabolic complications may be fatal. Therefore, timely diagnosis is very important in order to initiate proper management and save the patient from this life-threatening condition.

EPIDEMIOLOGY Exact incidence of erythroderma is difficult to ascertain. Most of the studies describe an annual incidence of 1–2 per 1,000,000 people.1 A large prospective study from India shows an increased number in comparison to other studies; 35 per 1,000,000 dermatological outpatients.2 Almost all studies report a male predilection, with a male-tofemale ratio ranging from 2:1 to 4:1.3–5 Mean age of occurrence is from the fourth to sixth decade.

PATHOPHYSIOLOGY The pathophysiologic processes resulting in erythroderma vary depending on the underlying etiology. The pathophysiology of erythroderma is not well-understood, and disease

can arise de novo or as a flaring and generalization of preexisting inflammatory skin conditions. However, common to all conditions is an increased rate of skin turnover. In erythrodermic skin, there is an increased expression of adhesion molecules; which, along with their ligands, play a significant role in the pathogenesis. There is a complex interaction of these cellular adhesion molecules (VCAM-1, ICAM-1, E-selectin, and P-selectin) with cytokines such as interleukin-1, -2, and -8, and tumor necrosis factor resulting in a significantly elevated epidermal turnover rate. The number of basal precursor skin cells, as well as their proliferation rate, is increased in erythrodermic skin. As a result, epidermal transit time of cells is also truncated and turnover rate is increased. As a result, the exfoliated scales are immature, are incompletely keratinized, and contain material normally retained by the skin. Proteins, amino acids, and nucleic acids are shed, which may result in a negative nitrogen balance6,7 and hypoalbuminemia. The amount of scale lost varies, depending on the underlying condition, and its severity and it may be up to 20–30 g/ day. Incomplete keratinization results in impaired barrier function of skin, which in turn may increase the transcutaneous absorption of topically applied medicines. Another pathophysiologic process common to all forms of erythroderma is increased cutaneous blood flow, which, in combination with impaired skin barrier function, results in increased insensible fluid loss through transpiration, with consequent systemic dehydration and reflex tachycardia. Severe cases may be complicated with high-output cardiac failure. Increased cutaneous blood flow also leads to increased heat loss, which may lead to a compensatory hypermetabolism and cachexia.

ETIOLOGY The greatest challenge is to establish the underlying cause of erythroderma. In most of the cases, the reaction results from generalization of pre-existing inflammatory dermatoses, cutaneous T-cell lymphoma (CTCL), or drug reactions.

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Section 5: Drug Reactions Box 18.1: Medications commonly associated with erythroderma. • Allopurinol • β-lactam antibiotics • Carbamazepine • Gold • Phenobarbital • Phenytoin • Sulfasalazine • Sulfonamides • Zalcitabine • Angiotensin converting enzyme (ACE) inhibitors and calcium channel blockers (CCBs) • Dapsone • Isoniazid • Lithium • Minocycline • Vancomycin

In approximately one-quarter of the patients, no specific etiology is found, and these cases are called idiopathic erythroderma. There is difference in the etiology according to age group. In adults, the single most common cause is pre-existing dermatosis.1,2,8,9 Though a number of dermatoses may progress to erythroderma, psoriasis and eczema account for most of the cases.4,8,10 In most of the Indian study, psoriasis was found to be the single most common cause of erythroderma in adults and accounting for approximately 10%– 50% of all cases.3–5,8,11 Eczematous conditions that culminate into erythroderma or exfoliative dermatitis (ED) include atopic dermatitis, contact dermatitis, seborrheic dermatitis, and chronic actinic dermatitis. Introduction of several newer medications has been reflected based off of an apparent increase in the incidence of erythroderma. With the introduction of several newer medications for various diseases the chances and actual incidence of drug-induced erythroderma has apparently gone high. Not only in adults, but also in children the possibility of drug-induced erythroderma should be entertained. Morbilliform, lichenoid, or urticarial drug reactions may terminate into severe ED. Common drugs implicated in ED are given in Box 18.1. Erythroderma may be a cutaneous manifestation of malignancy. Around 1% of cases are linked to internal malignancy.11 Reticuloendothelial neoplasms, hematological malignancies and lymphomas, and visceral neoplasms such as laryngeal, thyroid, lung, esophageal, gallbladder, gastric, colon, fallopian tube, and prostate carcinomas and may manifest as erythroderma.12–18 Other less common causes of ED are ichthyoses, bullous dermatoses (usually pemphigus foliaceus), pityriasis rubra pilaris, Ofuji papuloerythroderma, and connective

tissue diseases (dermatomyositis, subacute cutaneous lupus erythematosus), dermatophytosis, crusted scabies, histoplasmosis, mastocytosis, hepatitis, renal failure, AIDS, and other immunodeficiency syndromes, sarcoidosis, graftversus-host disease, hypereosinophilic syndrome, etc. Among infants, the major causes of ED are ichthyoses, immunodeficiencies, psoriasis, dermatitis, and infection (e.g., staphylococcal scalded skin syndrome).

CLINICAL FEATURES By virtue of the definition of erythroderma, there is significant erythema, scaling, and edema involving at least 90% of the body surface area (Figs. 18.1 to 18.7). In acute ED, erythema gives way to exfoliation 2–6 days after first presentation. Erythroderma can be acute, erupting suddenly,

Fig. 18.1: Erythroderma in a 7-year-old boy with Netherton syndrome.

Fig. 18.2: Sézary syndrome manifesting as erythroderma in a 70-yearold man.

Chapter 18: Erythroderma

Fig. 18.3: Erythroderma in a 2-month-old baby diagnosed as Omenn syndrome.

Fig. 18.5: In a 2-month-old baby, non-BIE. (BIE: bullous ichthyosiform erythroderma)

Fig. 18.4: Erythroderma in a 4-year-old girl suffering from Stevens– Johnson syndrome.

Fig. 18.6: In a 2-month-old baby, nonbullous ichthyosiform erythroderma, view of trunk.

or chronic, developing over a course of weeks-to-months. Even though there is involvement of most of the body surface area, characteristic sparing of nose and paranasal areas has been described in many studies and it has been termed as the “Pavithran nose sign.”19,20 The exact reason for this phenomenon is not known, but suggested hypotheses are; greater exposure of the area to sunlight leading to presumptive antimitotic activity, or nervous habit of frequent rubbing of nose, leading to removal of the scale. The nature of the exfoliated scale changes with the course of the disease process; scales are large and crusted in the acute stage; fine, smaller, and anhydrous during the later stage of disease. The character of the scale may also provide clues to the underlying etiology: fine scale is

typically associated with atopic dermatitis, greasy scale in seborrheic dermatitis, large exfoliative scale in drug reactions, and crusted in pemphigus foliaceus (Tables 18.1 and 18.2). Pruritus is the most common symptom and is observed in up to 90% cases; others are constitutional symptoms such as chill and malaise. Patients may develop thickened, lichenified skin secondary to chronic excoriation. Other cutaneous findings, especially of chronic erythroderma, are dyspigmentation (hyperpigmentation being more common than hypo/depigmentation), palmoplantar keratoderma (seen in around 30% cases), non-scarring alopecia (in 20% cases), and multiple seborrheic keratosis.4,21 Nail changes have been observed in approximately

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Fig. 18.7: Close-up of face of a 2-month-old baby with BIE. (BIE: ­bullous ichthyosiform erythroderma).

40% of patients. Nails discoloration, brittleness, changes in luster, subungual hyperkeratosis, Beau’s lines, paronychia, and splinter hemorrhages can be seen. Eventually, there may be total shedding of nails.2 Other changes described in drug-induced erythroderma are alternate bands in nail plates and leukonychia.22 Erythroderma may be complicated by secondary cutaneous infection, mainly by Staphylococcus aureus, as a result of impaired barrier function. Bilateral ectropion and purulent conjunctivitis are some of the ocular complications. Bacterial sepsis may be fatal and is more common in AIDS-induced and CTCL-associated erythroderma. In addition to the aforementioned general clinical findings, there may be some additional, specific clinical features indicative of underlying etiology (described in Tables 18.1 and 18.2).

Table 18.1: Common causes of erythroderma in adults with clinical clues. Underlying disease Diagnostic clues Psoriasis • Pre-existing psoriatic plaques • Often spares the face • Associated nail changes (oil-drop, pits, onycholysis) and inflammatory arthritis • Personal or family history of psoriasis • Withdrawal of corticosteroids or methotrexate Atopic dermatitis • Pre-existing lesions • Fine scaling • Severe pruritus • Associated features like lichenification, prurigo nodularis • Personal and/or family history of atopy • Elevated serum IgE Drug reactions • Preceded by morbilliform or scarlatiniform exanthem or lichenoid or urticarial reactions • Facial edema • Lesions may become purpuric • Temporal association with drug intake and resolution usually within 2–6 weeks of drug withdrawal Idiopathic • Elderly men • Chronic, relapsing course • Severe pruritus • Palmoplantar keratoderma • Dermatopathic lymphadenopathy CTCL • Sézary syndrome more common than erythrodermic mycosis fungoides • Intense pruritus • Painful, fissured palmoplantar keratoderma • Alopecia and characteristic leonine facies • Characteristic histopathological and immunophenotypic findings Chronic actinic dermatitis • Initial lesions are in photodistribution • Positive photopatch testing Pityriasis rubra pilaris • Salmon-colored erythema • Nappes claires • Waxy keratoderma • Perifollicular keratotic papules • Cephalocaudal progression • Exacerbation on sun exposure (Contd...)

Chapter 18: Erythroderma (Contd...) Underlying disease Paraneoplastic

Bullous dermatoses Pemphigus foliaceus

Bullous pemphigoid

Paraneoplastic pemphigus

Papuloerythroderma of Ofuji GvHD

Diagnostic clues • Fine scaling • Melanoerythroderma • Cachexia • Insidious development • Progressive decompensation • Refractoriness to standard therapy • Absence of prior skin pathology • Flaccid vesicles and impetigo like erosion • Crusting with corn flake scaling • Characteristic histopathological findings of subcorneal acantholysis and classical immunofluorescence findings • Elderly patients • Urticarial plaques • Tense bulla • Subepidermal bulla on histopathology • Characteristic immunofluorescence findings • Recalcitrant mucosal erosions and hemorrhagic crusts • Polymorphic cutaneous lesions including flaccid and tense bullae, erythema multiforme like or lichenoid lesions • Seen in elderly male • Starts as flat topped red papules • Sparing of abdominal folds (Deck-chair sign) • Fever, pancytopenia, hepatic insufficiency, and diarrhea • May be fatal

(CTCL: cutaneous T-cell lymphoma; GvHD: graft versus host disease)

Table 18.2: Causes of erythroderma in neonates and infants. Underlying cause Diagnostic clue Inherited ichthyosis and ichthyosiform syndrome Bullous congenital • Formation of superficial blisters and erosions in the first days of life ichthyosiform erythroderma • Corrugated hyperkeratosis in flexures develop later • Epidermolytic hyperkeratosis on histopathology Nonbullous congenital • Presents as collodion baby ichthyosiform erythroderma • Associated findings: cicatricial alopecia, nail dystrophy, ectropion, eclabium Netherton syndrome • Erythroderma in neonates • Failure to thrive • AD like skin lesions • Immunodeficiency • Bamboo hair or trichorrhexis invaginata Immunodeficiencies Omenn syndrome • Onset in neonatal period • Diffuse alopecia • Lymphadenopathy and hepatosplenomegaly • Recurrent infections • Hypogammaglobulinemia • Elevated serum IgE levels (Contd...)

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Primary dermatoses AD

Seborrheic dermatitis

Psoriasis

Infections and infestations SSSS

Congenital cutaneous candidiasis

Scabies

Diagnostic clue • Primarily affects boys • Bleeding diathesis • Atopic-like dermatitis • Recurrent sinopulmonary infections • Abnormal immunoglobulin profile • Microthrombocytopenia • Typical distribution over the extensors and face • Severe pruritus • Positive family history • Onset during first 2 months • Sparing of diaper area • Greasy scale • Distributed mainly over scalp and body folds • Diaper area involved • Early onset • Absence of pruritus • Well-demarcated scaly, erythematous plaques over typical distribution • Nail changes • Onset later • May start as napkin dermatitis • Presents with facial and flexural erythema which rapidly generalizes to erythroderma • Extremely tender skin • Fever and a rapid decline of general condition • Large, flaccid, rapidly eroding bullae • Radiating perioral scale-crusts • Positive Nikolsky sign • Neonates present with maculopapular, sometimes pustular or bullous exanthema • Whitish macules on placenta and umbilical cord • Initial involvement of palms, soles, and umbilical region • Sparing of oral cavity and diaper area • Paronychia • Rare • Multiple micropustules and papules on the trunk, extremities, scalp, face, and palm-soles • Secondary eczematization • Bacterial superinfection

Other rare causes • PRP • Diffuse cutaneous mastocytosis • Ectodermal dysplasia • GvHD • Inborn errors of metabolism; Sjögren-Larsson syndrome, holocarboxylase synthetase deficiency, amino acid disorders (AD: atopic dermatitis; SSSS: Staphylococcal scalded skin syndrome; PRP: pityriasis rubra pilaris)

Lymphadenopathy is the most common extracutaneous finding and has been found in 21%–33% cases.5,10,23 Some other studies documented much higher incidence of lymphadenopathy (>50%).4,24 In the confirmed absence of underlying lymphoproliferative disease, this phenomenon is termed reactive dermopathic lymphadenopathy.

Reactive lymphadenopathy should be differentiated from lymphoproliferative disease by histology and immunophenotyping. Hepatosplenomegaly may also be a finding in these patients. It is better to describe erythroderma as a systemic illness because of the potential systemic hazards associated with

Chapter 18: Erythroderma it. Increased cutaneous blood flow leads to thermoregulatory imbalance which in turn is reflected as hyperthermia or hypothermia. Chronic heat loss leads to a state of compensatory hypermetabolism with consequent cachexia. Tachycardia seen in around 40% cases results from cutaneous vasodilation. Erythroderma may be complicated by high output cardiac failure, especially in elderly or in individual with pre-existing compromised cardiac status. Pedal and pretibial edema has been observed in 50%–70% cases1,2,4,24,25 and it is consequent upon fluid shift into extracellular spaces secondary to hypoproteinemia. Druginduced erythroderma is typified by facial edema. Another frequent association is anemia, which may be due to iron deficiency or may be classified as anemia of chronic disease. Gynecomastia has been reported in some patients, reflecting a hyperestrogenic state.26

LABORATORY FINDINGS Laboratory tests are usually guided by the clinical profile and history of the patients. Laboratory findings are not very supportive in establishing an underlying diagnosis and are mostly non-specific. The common findings with variable incidence are anemia, leukocytosis, eosinophilia, and elevated erythrocyte sedimentation rate. Though eosinophilia is a non-specific finding, a high level should raise the suspicion of lymphoma. Eosinophilia should also prompt consideration of DRESS (drug rash with eosinophilia and systemic symptoms) or drug hypersensitivity syndrome. Chemistry panel may demonstrate hypernatremia and prerenal azotemia with elevated levels of blood urea and serum creatinine. This is specially seen in the context of pre-existing diabetes. Hypoproteinemia with altered albumin-to-globulin ratio arises after protein loss through scaling, chronic malnutrition, or hypervolemia. Many studies document serum electrolyte imbalance in the form of hyponatremia, hypokalemia, and hypochloremia. There may be an abnormal serum protein electrophoresis with raised gamma globulins and IgE levels. Circulating Sézary cell count 20%, the possibility of Sézary syndrome should be considered.26,27 Urinalysis, blood cultures may be obtained if there is suspicion of infection as a cause of exacerbation of pre-existing skin disease. Skin swabs of the nostrils or areas of secondary impetiginization of the skin may be important to administer appropriate topical or systemic antimicrobial agents. In Norwegian scabies, the mites can be identified from direct examination of the skin with the dermatoscope or from skin scrapings. Similarly,

fungal elements can be identified with potassium hydroxide mounts microscopically, or culture can be performed for diagnostic confirmation. Human immunodeficiency virus testing is important with a high index of suspicion or in high-risk populations.

PATHOLOGY Although findings may be subtle, skin biopsy is the only relevant investigation as the histopathological features of underlying disease is identifiable in more than half of the patients. Comprehensive clinicopathological correlation is of considerable importance for etiological diagnosis. But clinicopathological correlation is not an easy task as specific histological features of underlying dermatoses are usually veiled by the non-specific features like hyperkeratosis, parakeratosis, acanthosis, spongiosis, and a chronic perivascular inflammatory infiltrate, with or without eosinophilic infiltrates. Clinicopathological correlation has been successfully established mostly in cases of psoriasis, drug-induced erythroderma, seborrheic, and other dermatitis and less frequently in case of pemphigus foliaceus.9,28–30 Serial biopsy should be considered in the context of idiopathic erythroderma because it should be differentiated from lymphomatous conditions. Immunohistochemistry may not be always helpful in differentiating between CTCL and non-CTCL erythrodermas, since the infiltrate is generally composed of mature CD4+ and CD8+ T cells. To discuss the histopathology of individual etiology is beyond the scope of this chapter. Lymph node biopsy is indicated if there is prominent lymph node enlargement and clinical profile is suggestive of lymphoma.

PROGNOSIS AND CLINICAL COURSE These are dependent on underlying etiology. Druginduced erythroderma improves quickly with discontinuation of offending agent with the exception of drug-induced hypersensitivity reaction where ED may persist even weeks after discontinuation of culprit agent and are usually complicated by hepatic and renal dysfunction. A slower course is observed in case of exacerbation of pre-existing dermatoses like psoriasis or atopic dermatitis. Recurrence of psoriatic ED occurs in 1.5% of patients after initial resolution. The course is progressive when associated with lymphoma, leukemia, and contact allergies. Malignancy-related ED is most often chronic and refractory. Favorable prognostic factors for CTCL related ED include age younger than 65 years, symptom duration of

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Section 5: Drug Reactions greater than 10 years before diagnosis, absence of evidence of nodal lymphoma, and the absence of circulating Sézary cells in mycosis fungoides. The course is unpredictable in idiopathic erythroderma, and is marked by multiple exacerbations. Patients with chronic idiopathic ED are at increased risk of evolution to CTCL. Mortality rate in ED has ranged from 3.7 to 64%.8,10,31–33 Early series of ED reported high mortality rates due to severe drug reactions, lymphoproliferative malignancy, pemphigus foliaceus, and idiopathic ED. The rate has since been reduced due to advancement in diagnosis and therapy. The most common causes of death in patients with erythroderma are pneumonia, septicemia, and heart failure. Elderly patients of ED with complications such as infection, fluid/electrolyte imbalances, and cardiac failure are at higher risk of mortality. Recent studies documented deaths mostly in association with malignancy and are mainly attributed to underlying disease progression, treatment complications, or sepsis.

TREATMENT As erythroderma poses a serious medical threat to patients, immediate hospitalization with early institution of treatment and supportive care is mandatory. There should be no delay in establishing the underlying cause, although the initial management is usually same despite the various etiologies of ED. This should include nutritional status assessment, replacement of sensible and insensible losses, correction of electrolyte imbalances, and prevention of hypothermia. Serum protein, electrolytes, and blood urea should be monitored periodically. Topical, as well as systemic, antibiotics are required for patients with evidence of 1ocalized and systemic secondary infection. It is better to administer antibiotic based on a culturesensitivity report. Patient should be kept in warm and humid environment for patient comfort and skin moisture, as well as to prevent hypothermia. Local skin-care measures should be employed such as oatmeal baths and wet dressings to weeping or crusted sites. These practices should be followed by the application of bland emollients and low-potency corticosteroids. High-potency topical corticosteroids should be reserved for lichenified areas, and prolonged application over extensive areas should be avoided, as there is increased chance of percutaneous absorption of the drug. Known and suspected precipitants and irritants should be avoided. Sedative oral antihistamines may ameliorate the intense pruritus. Symptomatic treatment includes diuretics for dependent edema that is refractory to leg

elevation. Hemodynamic or metabolic instability should be addressed adequately. After initial quelling of the general condition, an attempt should be made to address the underlying disorder. Cases refractory to local therapy and general measures may require systemic dermatologic therapy directed at the underlying etiology, if known. Treatment of the underlying illness is crucial since ED resists treatment until the basic disease is addressed. The role of systemic corticosteroids in the management of ED remains controversial, but it has a definite role in idiopathic erythroderma, ED due to atopic dermatitis, and in erythroderma due to drug reaction. A starting dose of 1–2 mg/kg/day of prednisone is beneficial in achieving rapid and often continued clearance of the erythroderma. Systemic corticosteroids should be avoided when there is suspicion of psoriatic erythroderma. In case of psoriatic erythroderma, preferred agents are methotrexate, acitretin, cyclosporine, or biologic agents. For severe drug reactions, besides the aforementioned therapeutic measures, intravenous immunoglobulin may be another useful option. For recalcitrant cases of idiopathic ED, cyclosporine has been used successfully, with an initial dosage of 5  mg/kg/day, and a subsequent reduction to 1–3  mg/kg/day. PRP usually responds to systemic retinoids or methotrexate. After achieving initial control of erythroderma due to CTCL, it may be treated according to the stage of disease with topical corticosteroids, psoralen plus ultraviolet A, total skin electron beam irradiation, systemic chemotherapy, extracorporeal photochemotherapy, bexarotene, or biologics. It is better to avoid immunosuppressive therapy until CTCL is ruled out. Management of neonatal and infantile erythroderma is a challenging task because this demographic is more vulnerable to fluid and electrolyte imbalances and consequent hypernatremic dehydration. Management is same as that of the adult, but special caution should be entertained while prescribing topical medications because of a higher rate of percutaneous absorption through the tender and immature skin.

REFERENCES 1. Sigurdsson V, Stegmans PH, van Vloten WA. The incidence of erythroderma: a survey among all dermatologists in the Netherland. J Am Acad Dermatol 2001;45:675–8. 2. Shegal VN, Srivastava G. Exfoliative dermatitis: a prospective study of 80 patients. Dermatologica 1986;173:278–84. 3. Chaudhary A, Gupte PD. Erythroderma: a study of incidence and aetiopathogenesis. Indian J Dermatol Venereol Leprol 1997;63:38–9. 4. Pal S, Haroon TS. Erythroderma: a clinico-etiologic study of 90 cases. Int J Dermatol 1998;37:104–7.

Chapter 18: Erythroderma 5. Bandyaopadhyay D, Chowdhury S, Roy A. Seventy five cases of exfoliative dermatitis. Indian J Dermatol 1999;44:55–7. 6. Salami TA, Enahoro Oziegbe O, Omeife H. Exfoliative dermatitis: patterns of clinical presentation in a tropical rural and suburban dermatology practice in Nigeria. Int J Dermatol 2012;51:1086–9. 7. Kanthraj GR, Srinivas CR, Devi PU, et al. Quantitative estimation and recommendations for supplementation of protein lost through scaling in exfoliative dermatitis. Int J Dermatol 1999;38:91–5. 8. Rym BM, Mourad M, Bechir Z, et al. Erythroderma in adults: a report of 80 cases. Int J Dermatol 2005;44:731–5. 9. Akhyani M, Ghodsi ZS, Toosi S, Dabbaghian H. Erythroderma: a clinical study of 97 cases. BMC Dermatol 2005;5:5. 10. Botella-Estrada R, Sanmartin O, Oliver V, Febrer I, Aliaga A. Erythroderma: a clinicopathological study of 56 cases. Arch Dermatol 1994;130:1503–7. 11. Chakraborty. Lymphoma as a cause of exfoliative dermatitis. Indian J Dermatol 1983;28:121–3. 12. Nishijima S. Papuloerythroderma associated with hepatocellular carcinoma. Br J Dermatol 1998;139:1115–6. 13. Axelrod JH, Herbold DR, Freel JH, Palmer SM. Exfoliative dermatitis: presenting sign of fallopian tube carcinoma. Obstet Gynecol 1988;71:1045–7. 14. Deffer TA, Overton-Keary PP, Goette DK. Erythroderma secondary to esophageal carcinoma. J Am Acad Dermatol 1985;13:311–3. 15. Harper TG, Latuska RF, Sperling HV. An unusual association between erythroderma and an occult gastric carcinoma. Am J Gastroenterol 1984;79:921–3. 16. Kameyama H, Shirai Y, Date K, et al. Gallbladder carcinoma presenting as exfoliative dermatitis (erythroderma). Int J Gastrointest Cancer 2005;35:153–5. 17. Nousari HC, Kimyai-Asadi A, Spegman DJ. Paraneoplastic dermatomyositis presenting as erythroderma. J Am Acad Dermatol 1998;39:653–4. 18. Bittencourt AL, Barbosa H, Brites C, Ferraz N. Clinicopathological aspects of HTLV-1 positive and negative T-cell lymphoma. Eur J Dermatol 1997;7:283–9. 19. Kanwar AJ, Dhar S, Ghosh S. ‘Nose sign’ in dermatology. Dermatology 1993;187:278.

20. Agarwal S, Khullar R, Kalla G, Malhotra YK. Nose sign of exfoliative dermatitis: a possible mechanism. Arch Dermatol 1992;128:704. 21. Sterry W, Steinhoff M. Erythroderma. In: Bolognia JL, Jorizzo JL, Schaffer JV, editors. Dermatology. 3rd ed. Elsevier Limited New York; 2012. p. 171–81 . 22. Shelley WB, Shelley ED. Shoreline nails: sign of drug-induced erythroderma. Cutis 1985;35:220–2. 23. Kimgai-Asadi A, Freedberg IM. Exfoliative dermatitis. In: Freedberg IM, Eisen AZ, Wolff K, Austen KF, Goldsmith LA, Katz SI, editors. Fitzpatrick’s dermatology in general medicine. 6th ed. New York: McGraw-Hill; 2003. p. 436–41. 24. Hulmani M, NandaKishore B, Bhat MR, et al. Clinicoetiological study of 30 erythroderma cases from tertiary center in South India. Indian Dermatol Online J 2014;5:25–9. 25. Wong KS, Wong SN, Than SN, Giam YC. Generalised exfoliative dermatitis—a clinical study of 108 patients. Ann Acad Med Singapore 1988;17:520–3. 26. Sigurdsson V, Toonstra J, Hezemans-Boer M, van Vloten WA. Erythroderma: a clinical and follow-up study of 102 patients, with special emphasis on survival. J Am Acad Dermatol 1996;35:53–7. 27. Sigurdsson V, Toonstra J, van Vloten WA. Idiopathic erythroderma: a follow-up study of 28 patients. Dermatology 1997;194:98–101. 28. Jowker F, Aslani FS, Shafiee M. Erythroderma: a clinicopathological study of 102 cases. J Pak Assoc Dermatol 2006;16:129–33. 29. Banerjee S, Ghosh S, Mandal RK. A study of correlation between clinical and histopathological findings of erythroderma in North Bengal population. Indian J Dermatol 2015;60:549–55. 30. Sudho R, Hussain SB, Bellraj E, et al. Clinicopathological study of exfoliative dermatitis. Indian J Dermatol Venereol Leprol 2003;69:30–1. 31. Karakayli G, Beckham G, Orengo I, Rosen T. Exfoliative dermatitis. Am Fam Physician 1999;59:625–30. 32. Wilson DC, Jester JD, King Jr LE. Erythroderma and exfoliative dermatitis. Clin Dermatol 1993;11:67–72. 33. Nicolis GD, Helwig EB. Exfoliative dermatitis: a clinicopathologic study of 135 cases. Arch Dermatol 1973;108:788–97.

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19

Figurate Erythemas Andrew J Peranteau, Ashley Eryn Pezzi, Tiffany Hinojosa, Stephen K Tyring*

INTRODUCTION The figurate erythemas are a group of cutaneous eruptions characterized by annular, circinate, arciform, or polycyclic configurations, which can be either fixed or migratory. Diagnosing and distinguishing these lesions can be challenging. These conditions have numerous synonyms and variations, often with overlapping clinical features and frequently changing nomenclature. Clinical features that may aid in diagnosis include the area of involvement, expansion rate, characteristics of the border, and histology. While numerous skin conditions can present with annular or polycyclic lesions, the most distinctive figurate erythemas are discussed in this chapter: erythema annulare centrifugum (EAC), erythema marginatum, erythema migrans, and erythema gyratum repens (EGR).1,2

ERYTHEMA ANNULARE CENTRIFUGUM EAC refers to chronic, annular, and erythematous lesions with a characteristic trailing scale. These lesions typically enlarge rapidly, fade, and then disappear as new lesions appear.

History Although clinically similar figurate or gyrate erythemas had been described previously under other names, Darier first used the term “erythema annulare centrifugum” in 1916.3 Two distinct forms are described in literature, a superficial and deep form, and there remains some controversy and contradiction among authors as to whether the superficial (pruritic, scaling) and deep (non-pruritic, non-scaling) forms represent different clinical entities that as such should be referred to by different names or whether they are merely variants of one another.1,2

*Senior author

Epidemiology EAC is an uncommon disorder. Although cases can occur at any age, EAC is most common in middle age and has no particular predilection for sex or race.4 Lesions may occur transiently or last for decades, with a mean duration of 11 months. The majority of cases resolve within 3 years.4 Several case reports describe an annually recurring form of EAC.5

Etiology and Pathogenesis Although the exact etiology of EAC is unknown, it is believed to be a hypersensitivity reaction caused by foods (tomatoes, blue cheese), drugs, neoplasms (leukemia, lymphoma, breast cancer), infection, and various systemic and autoimmune diseases. Reports have demonstrated that injections of tuberculin, Candida albicans, Trichophyton, and tumor extract have induced EAC, supporting a type IV hypersensitivity reaction as a possible mechanism for its development.8 Others suggest that EAC represents a Th1-mediated reaction with elevated levels of IL-2 and TNF-α. This theory was supported by a case report documenting complete clearance of lesions after etanercept administration and subsequent relapse following its discontinuation.9 The annular spread and peripheral migration of lesions is thought to be due to migration of foreign antigens through the skin.10 The most common underlying association is concurrent infection. Viral (Epstein-Barr virus, varicellazoster virus, HIV), bacterial (streptococcal infections, Escherichia coli), fungal (dermatophytes), parasitic, and mycobacterial triggers have been reported. In one study of 66 adults with a clinical or histopathological diagnosis of EAC, 72% had concurrent illnesses, including cutaneous fungal infections (48%), systemic diseases (21%), and

Chapter 19: Figurate Erythemas

Fig. 19.1: Erythema annulare centrifugum: superficial form displaying arcuate plaques with fine scale on inner margin of the advancing edge (trailing scale). Courtesy: Roberto Arenas, MD. Mexico City, Mexico.

internal malignancy (13%).6 The majority of EAC cases, however, are idiopathic.7 None of these reported associations are definitively proven to be causative. Despite this fact, numerous case reports describe the resolution of lesions once the inciting factor was either stopped or the underlying condition treated successfully.3,6,7

Fig. 19.2: Erythema annulare centrifigum: deep form demonstrating polycyclic plaques with elevation of the advancing edge without scale.

lesional sites should be performed to eliminate the presence of fungal hyphae. Lyme antibody titers can exclude erythema migrans. Antinuclear antibody tests may be performed in the appropriate setting to evaluate for underlying lupus erythematosus. Additional tests to consider include a complete blood count, complete metabolic panel, purified protein derivative or quantiferon test, and stool for ova and parasites.

Clinical Features

Histology

Polycyclic annular plaques arise from pink papules that develop and enlarge at a rate of 2–5 mm/day, rarely reaching >10  cm in diameter. The lesions expand peripherally while clearing centrally, producing arcuate, annular, figurate, or polycyclic plaques. A characteristic trailing scale may be seen on the inner aspect of the advancing edge (Fig. 19.1).8 Lesions may be pruritic or asymptomatic and resolve without scarring but may leave postinflammatory hyperpigmentation. In deep EAC, there is a lack of scale or pruritus, however these lesions are characterized by their peripheral expansion and figurate shapes (Fig. 19.2). There is a predilection for the thighs and the legs, but they may occur on the upper extremities, trunk, or face. There is no mucosal involvement.8

Superficial EAC has parakeratosis, spongiosis, and a superficial perivascular infiltrate. There is papillary dermal edema. A characteristic finding is lymphohistiocytic infiltrates organized tightly around blood vessels forming a “coat sleeve” (Fig. 19.3). The deep form demonstrates “coat sleeve” infiltrates in the middle and lower dermis and lacks epidermal changes.

Laboratory Findings Although there are no diagnostic laboratory tests for EAC, some studies are useful to exclude other diagnoses and should be guided by the patient’s history and physical examination. Potassium hydroxide (KOH) examination of

Differential Diagnosis Diagnostic considerations should include tinea corporis, annular psoriasis, pityriasis rosea, subacute cutaneous lupus, secondary syphilis, erythema migrans, urticarial eruptions, sarcoidosis, cutaneous T-cell lymphoma, and granuloma faciale.

Treatment and Prognosis The first step in the management of EAC is to exclude or treat any underlying disorder. If a triggering condition is identified and eliminated, skin lesions often resolve.

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Epidemiology

Fig. 19.3: Erythema annulare centrifigum: slight parakeratosis along with tight perivascular lymphocytic cuffing of dermal vessels can be seen, known as the “coat sleeve” anomaly.

A mid-strength to potent topical corticosteroid or topical calcipotriene may be effective. Topical tacrolimus and phototherapy are considered second-line treatments. Systemic steroids have also been used and can be effective but lesions recur once the treatment is discontinued. For symptomatic relief of pruritus, topical antipruritics and sedating antihistamines can be used. Isolated case reports have detailed successful treatment of refractory EAC with etanercept, metronidazole, oral fluconazole, and interferon-α, however, systemic therapy is rarely needed.8,11,12 EAC has a chronic and highly variable disease course, where the patient may experience many remissions and exacerbations. This pattern may last months, years, or decades before resolving spontaneously.

ERYTHEMA MARGINATUM Erythema marginatum is a figurate erythema and a diagnostic criterion for rheumatic fever. Rheumatic fever is the leading cause of acquired heart disease in children and young adults worldwide and follows group A streptococcal pharyngitis.12 Other diagnostic criteria for rheumatic fever include carditis, migratory polyarthritis, Sydenham chorea, subcutaneous nodules, fever, arthralgias, and abnormal laboratory findings (ESR, CRP, or prolonged PR interval on ECG). In 1944, Jones stated that erythema marginatum was by far the most significant cutaneous manifestation of rheumatic fever and he named it as one of the major Jones criteria for diagnosing acute rheumatic fever (ARF).13,14

Approximately 1%–3% of untreated patients with group A βeta–hemolytic streptococcal throat infections can go on to develop ARF. In developing areas of the world, this condition is more common and is the leading cause of cardiovascular death during the first five decades of life.15 Conservatively, there are approximately 470,000 new cases and 230,000 deaths due to ARF per year.15 The mean incidence of ARF is 19 per 100,000 school-aged children worldwide.16 These cases occur mostly in developing countries where the incidence of ARF and RHD can be >60 times higher than in developed countries.17 Of patients with ARF, 50% of patients experience these symptoms.66 A nonerosive, nondeforming oligoarthritis affecting the knees, ankles, and wrist is most common amongst Behçet’s patients. Joint manifestations may also be the initial sign of disease in up to 20% of patients.66 Children are more likely than adults to experience joint manifestations and polyarthritis. Fortunately, the arthritis typically resolves within 2 months. Rheumatologic referral is warranted for patients experiencing any of these symptoms that have known or suspected BD.

Gastrointestinal Manifestations Gastrointestinal manifestations of BD are associated with increased morbidity and mortality. Patients may experience severe debilitating abdominal pain that can be difficult to distinguish from IBD. Hemorrhage can occur and ulceration can develop anywhere within the gastrointestinal (GI) tract. The small bowel is most commonly affected (particularly the ileocecal region), but the transverse and ascending colon and esophagus can also be affected.67 BD does not display the granulomas that are commonly seen in IBD.67

decreased compared to BD patients without arterial lesions.70

Associated Syndromes MAGIC syndrome (mouth and genital ulcers with inflamed cartilage) is described as patients with features of both BD and relapsing polychondritis.71

Pathology Histopathological findings in BD vary based on age of lesion. Findings of vasculopathy can occur in all sizes of blood vessels within the dermis and subcutis. Aphthous ulcers tend to display lymphocytes, macrophages, and neutrophils at the base of the ulcer. Plasma cells can also be seen and are common in older lesions. Erythema nodosum like lesions display a perivascular pattern of inflammation in the deep dermis and subcutis. Lymphocytes may also be present in the vessel wall, but there is no fibrinoid necrosis present.

Differential Diagnosis and Workup

Neurologic manifestations are seen in 20%–40% of cases of BD.68 A male predominance has been observed and it is associated with a poor prognosis. The most common symptoms include headache, gait ataxia, cranial nerve dysfunction, and sensory deficits.69 These symptoms tend to occur within 10 years of disease onset.68,69

Although Behçet syndrome has a unique presentation, the initial differential diagnosis may include aphthous stomatitis, PG, chancroid, syphilis, herpes simplex virus, systemic lupus erythematosus, sarcoidosis, polyarteritis nodosa, and IBD. Initial workup for a suspected case of BD should include radiograph or CT scan of the sacrum, radiographs of the peripheral joints that exhibit signs of tenosynovitis, brain CT or MRI, and Doppler ultrasound to evaluate for deep vein thrombosis. Angiography may be warranted to evaluate for aneurysms.

Vascular Manifestations

Treatment

Vascular disease can affect veins, arteries, and capillaries of all size in BD.70 Veins are most commonly affected, and deep vein thrombosis is the most common vascular finding.60 Arterial involvement is present in 3%–5% of cases and is more common amongst males.70 Superficial thrombosis has also been reported but typically occurs ≥1 year after disease onset. Other serious vascular manifestations include arterial aneurysms, occlusive arterial disease, and arterial stenosis that may require surgical bypass or emergency intervention. Unfortunately, the 20-year survival rate for BD patients with arterial lesions is significantly

There is no cure for BD. Management of disease is difficult due to extreme variability in disease progression, but recent advances in pathogenesis of disease have yielded better management options. Furthermore, BD must be treated aggressively at onset due to its frequently relapsing course. In addition to systemic therapy, symptomatic management of disease to improve quality of life is essential. The mainstays of therapy are immunosuppressive agents like corticosteroids, azathioprine, and interferon. Colchicine (1 mg/day) is the first-line treatment for mucocutaneous lesions.60 Rheumatology, ophthalmology,

Neurologic Manifestations

Chapter 28: Neutrophilic Dermatoses and gastroenterology should generally be consulted for further workup and treatment of disease.72 The European League Against Rheumatism created recommendations for the treatment of BD in 2008 (Table 28.8).73 Most of the recommendations related to the treatment of dermatologic, ocular, and rheumatologic complications of disease are evidence based, but recommendations for the neurological, vascular, and gastrointestinal involvement are based mainly on observational studies, retrospective analyses, and expert opinion.73 It is also of note that the guidelines are almost 10 years old and newer trials are available to aid in the management of BD. These studies have primarily assessed the use of biologics for the treatment of disease. TNF-α antagonists are increasingly used for treatment of BD that is inadequately controlled by standard immunosuppressive regimens. Infliximab has been most widely studied,74 but adalimumab has proved successful in cases refractory to both conventional therapy and infliximab.75 Advantages of adalimumab over infliximab include the ability to self-administer at home and a better side effect profile.74 In a multicenter study of the use of TNF-α antagonists [mainly infliximab (62%) and adalimumab (30%)] for treatment of severe and/or refractory BD in 124 patients, clinical response rates with particular organ involvement were as given (Table 28.7).76 Furthermore, the incidence of BD flares was significantly decreased when patients were initiated on antiTNF therapy.76 However, biologic therapy should only be initiated if a patient has severe or refractory disease, as there is an increased incidence of serious adverse effects (Table 28.8).76

Key Points • Characterized by clinical triad of recurrent oral ulcers, recurrent genital ulcers, and uveitis • Most common in young adults 20–30 years old • Prevalence highest in Turkey and along the ancient Silk Road, which spans from Japan to the Mediterranean Sea • Genetic, environmental, viral, and bacterial factors contribute to the development of Behçet disease • Ocular, gastrointestinal, rheumatological, neurological, and vascular manifestations of disease can occur • No cure for disease, although biologic therapies are increasingly used with good efficacy

Table 28.7: Clinical response rate (complete and partial) following anti-TNF-α therapy for BD.76 Manifestation of disease Clinical response rate (%) Ocular 96.3 Mucocutaneous 88 Joint 70 GI 77.8 CNS 92.3 Cardiovascular 66.7 (BD: Behçet disease; GI: gastrointestinal; CNS: central nervous system)

Table 28.8: Summary of recommended treatment for BD.72,73 Manifestation Treatment Mucocutaneous   Mild Topical steroids Moderate to severe Initial:   Systemic steroid   Colchicine   Refractory case:   Azathioprine   Interferon-α Eye Initial:   Systemic steroid + azathioprine   Refractory case:   (1st) Cyclosporine A + steroid + azathioprine   (2nd) Interferon-α +/- systemic steroid Arthritis (1st) Colchicine   Nonsteroidal anti-inflammatory drug   (2nd) Azathioprine   Interferon-α Vessels   Deep venous Azathioprine thrombosis Cyclosporine A Cyclophosphamide (larger vessels)    Arterial aneurysm Neurological   Gastrointestinal    

Cyclophosphamide + systemic steroid Cyclophosphamide (drug of choice) Cyclosporine A (contraindicated) Systemic steroid Sulfasalazine Azathioprine

(BD: Behçet disease) Source: Table reprinted under the Creative Commons Attribution License. Leonardo and McNeil.77

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SYNOVITIS, ACNE, PUSTULOSIS, Clinical Manifestations HYPEROSTOSIS, AND OSTEITIS (SAPHO) Patients with SAPHO syndrome typically present with a variety of cutaneous manifestations, arthritis, and musSYNDROME The entity of synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome represents a heterogeneous disorder that includes aseptic neutrophilic dermatoses and aseptic osteoarticular findings. The lesions tend to have distinctive radiologic and histologic findings. Although SAPHO syndrome is rare, the incidence of disease has been increasing due to growing awareness amongst physicians.

History Chamot first described SAPHO syndrome in 1987.78 He introduced the acronym as a way to designate the five frequently combined disorders of synovitis, acne, pustulosis, hyperostosis, and osteitis into one disorder.78 The disorder is somewhat similar to chronic recurrent multifocal osteomyelitis (CRMO), which was described in 1972.79

Epidemiology SAPHO syndrome is a rare disease with an estimated incidence of 1 in 10,000. SAPHO syndrome can occur across all age groups, but the disease tends to primarily affect children and middle-aged adults. Mean age is 40.71 years.80 The elderly are rarely affected, and the disease is uncommon after the sixth decade of life. There is a female predilection of disease, and the majority of cases have been reported in Japan and Northern Europe.80

culoskeletal findings. The most common dermatologic manifestation of SAPHO syndrome is palmar plantar pustulosis,88 a neutrophilic dermatosis that presents as localized pustular psoriasis on the palms and soles. Extensive acneiform eruptions (acne conglobata) can also be seen in SAPHO syndrome and can be cosmetically disfiguring80 (Fig. 28.21). Acne conglobata often presents with numerous painful interconnecting abscesses and sinus tracts that leave irregular scars after healing. Cases of acne fulminans have also been associated with SAPHO syndrome.86 Hyperostosis and osteitis are the most prominent orthopedic findings in SAPHO syndrome.87 Clinically, bony tenderness is also prevalent, especially over the larger joints such as the wrists, hips, knees, and ankles. The anterior chest wall is affected in 70% of patients.88 An additional 24% of patients reported inflammatory back pain, and 56% of patients reported dermatologic manifestations of disease.88 The pattern of osteoarticular involvement seems to be age dependent and occurs more frequently in young and middle-aged adults.89 Inflammatory markers such as erythrocyte sedimentation rate and C-reactive protein can be elevated but are usually within normal limits.

Radiologic Findings Radiologic findings of SAPHO syndrome include osteosclerosis, cortical thickening, and narrowing of the medullary canal. This most often occurs at the sternum, ribs,

Pathogenesis The pathogenesis of SAPHO syndrome is not completely understood although two hypotheses are most commonly cited. Many hypothesize that there is an infectious cause of disease as Propionibacterium acnes has been found in up to 67% of needle biopsy specimens.81 P. acnes has also been found to have strong immunomodulatory activity and is essential to the activation of IL-8 and complement activation.82,83 Others believe that SAPHO syndrome is an autoimmune disorder with hyperstimulation of the innate immune response and increased levels of IL-8 and TNF-α by neutrophils in response to ex vivo stimulation.84,85 A genetic source of disease has also been postulated since numerous genetic abnormalities have been identified in patients with SAPHO syndrome.

Fig. 28.21: SAPHO syndrome: papulopustular acne on chest wall. (SAPHO: synovitis, acne, pustulosis, hyperostosis, and osteitis). Courtesy: Mehmet Özen, MD. Özen and Kalyoncu, Department of Internal Medicine, Hacettepe University Faculty of Medicine, Ankara, Turkey.98

Chapter 28: Neutrophilic Dermatoses jaw, and sternum.93 Majeed syndrome should also be considered in children and is characterized by neutrophilic dermatosis, multiple osteitic lesions (CRMO), and abnormalities of erythropoiesis.94 Majeed syndrome is known to result from mutation in the LPIN2 gene that provides instructions for making a protein called lipin-2.94 Majeed syndrome is inherited in an autosomal recessive fashion.94 The absence of skin lesions does not exclude SAPHO syndrome. The interval between onset of skin manifestations and osteoarticular lesions is generally 50, with good UVA protection and tinted sunscreens for protection against visible light. † UV screens should be replaced every 5 years as their protective value might be reduced by photodegradation. ‡ Not enough evidence. § Still under investigations.

ACTINIC PRURIGO AP is an idiopathic photodermatosis of children with a higher prevalence in the American continent. A relation to HLA-DR4, and especially to the rare subtype DRB1*0407, has been advocated. Lesions arise on sun-exposed areas and arise in the form of pruritic erythematous papules and nodules, which may leave superficial, pitted scars. Cheilitis and conjunctivitis are common, especially in Latin Americans with AP.21

Epidemiology AP probably occurs in most parts of the world. The highest prevalence occurs in Native Americans of South, Central, and North America and Latin American Mestizos (individuals with a mixed Caucasian and Native American ancestry). It is far less common in Europe, Australia, and Asia. Prevalence ranges from 0.003% in Scotland to 8% in the indigenous Chimila of Colombia. The disease affects people in higher altitudes, skin phototypes III–V, and females more than males, except in the Chimila and in Asians. It usually begins in children 60% of AP patients.24

Treatment Photoprotection is a very important step. Like PMLE, phototherapy to induce hardening in patients with chronic disease is useful. In mild-moderate cases, topical corticosteroids or topical tacrolimus are helpful. In resistant cases, it is best to use oral thalidomide (50–100 mg at night) administered for several weeks until remission is achieved, which is then tapered to as low of a maintenance dose as possible, such as 50 mg every second or third night. Thalidomide inhibits TNF-α production in peripheral monocytes, modulates the production of interferon gamma by CD3 cells, and suppresses the ability of Langerhans cells to present antigens to T-helper 1 lymphocytes, among other actions. However, the risks of teratogenicity and peripheral neuropathy require very careful patient selection and monitoring.25 Pentoxifylline

has anti-TNF-α effects and may be considered before thalidomide because of its greater availability and superior safety profile.26 Other possible systemic therapies include corticosteroids, azathioprine, and cyclosporine (Table 32.8).

SOLAR URTICARIA SU describes the development of wheals shortly after sun exposure, usually in association with burning, stinging, or itching.

Epidemiology SU most commonly affects females in their fourth or fifth decade and occurs worldwide. In a study from Singapore, SU represented 0.08% of urticaria cases and 7% of photodermatosis cases.27

Etiopathogenesis Primary SU is due to type I hypersensitivity reaction, which refers to IgE-mediated mast cell stimulation. Antigens, whether in serum or in the skin, that result in mast cell degranulation, are activated by sun exposure. Two types of primary SU have been described.28 In type 1, a new antigen is formed due to solar exposure, and an antibody is generated against it. In type 2, an antibody is formed against an antigen that is commonly induced upon UV exposure in most normal individuals. In the past, passive transfer tests were positive in type 2, but rarely in type 1. Secondary SU is a rare form described in association with drug-induced photosensitivity notably to quinolones, tetracyclines, non-steroidal anti-inflammatory drugs (NSAIDs), chlorpromazine, and it is also associated with porphyria and SLE.

Action Spectrum Varying action spectra have been reported in different studies, depending on the ethnicity and the country of the study. Most commonly reported spectra lie in the UVA and/or visible light range, UVB being less commonly involved.29 Inhibition and augmentation spectra, as their names imply, will inhibit or augment the effect of the action spectrum, respectively. They have been described in some studies of SU.30,31 Some patients will get the attacks after moving to the shade, which can be explained by the theory of the inhibition spectrum.

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Clinical Picture As most physical urticarias, the wheals develop within minutes of sun exposure and resolve within an hour or two. Rarely, patients describe itching without whealing on sun exposure. In rare instances, lesions may develop hours after sun exposure and might last up to 24  h. The previously described delayed SU, which lasts >24  h, probably represents a form of PMLE. Lesions typically occur on arms and décolleté area, while sites that are routinely exposed to the sun, such as the face and the hands, are less commonly involved. In rare cases, the lesions might occur in a fixed site with each sun exposure, a phenomenon known as fixed solar urticaria.32 As in other urticarias, systemic symptoms like malaise, nausea, and bronchospasm may be associated with extensive whealing attacks and are very rarely life threatening.

Differential Diagnosis

Other therapeutic alternatives for resistant cases include IVIG, plasmapheresis, afamelanotide, antimalarials, and cyclosporine A29 (Table 32.8).

HYDROA VACCINIFORME HV is a rare photodermatosis, predominantly affecting children. It is characterized by the formation of papulovesicular eruptions on sun-exposed areas, which heal leaving vacciniforme (pox-like) scars.

Epidemiology HV has a low prevalence of 0.34 cases per 100,000 people.35 It has been reported mainly in Europe, the United States, and Japan. The condition shows a slight female preponderance but is more severe in males. HV appears early in life and remits in adolescence. A rare HV-like variant (see below) has been described in adults and worsens with age.36

Refer Table 32.7 for details.

Action Spectrum

Histopathology

Phototesting is usually negative, but provocation testing with UVA doses in the 320–390-nm range might provoke characteristic lesions.37

Histological features are similar to other forms of urticaria and are characterized by dermal vasodilatation and edema, perivascular neutrophilic and eosinophilic infiltrate.

Investigations Phototesting is performed to confirm the diagnosis and to determine the minimal urticarial dose (Tables 32.2 and 32.8).

Treatment The first-line treatment consists of oral antihistamines, ideally taken continuously. Alternatively, they could be taken on demand 30  min before sun exposure in patients with infrequent attacks. Updosing of antihistamines, as tolerated, could be done in resistant cases. Photoprotection should be employed as well (Table 32.8). Sunscreens are rarely of help as their protective value against UVA, and visible light is usually low. Hardening with UVA phototherapy could be used as a preventive tool, but should be done with caution due to the possible risk of anaphylaxis. Interestingly, based on the inhibition spectrum theory, NB-UVB was successful in treating SU cases induced by UVA as proven on phototesting.33 In resistant cases, omalizumab given 150–300 mg on monthly basis has proven of benefit in recent reports.34

Etiopathogenesis The pathogenesis of HV is unclear. No chromophore has been identified yet. In spite of the clear relationship to UV exposure and the early disease onset, the presence of scarring and the resistance to treatment speaks against HV being a form of PMLE. The relationship to Epstein Barr virus (EBV) infection is evident for HV-like eruption. EBV nucleic acid has been detected in skin biopsies taken from lesional skin of classic HV in a Japanese study.38 HV and HV-like eruption might represent a disease spectrum.29

Clinical Picture The classic form of HV presents 15 min to 24 h after sun exposure by erythema and swelling, accompanied by stinging and pruritus. Within the next 24 h, a tender pinkto-purple papule appears on top of the erythematous area. Within the next 3 days, a painful, tense umbilicated, sometimes hemorrhagic vesicle develops. A crust forms and detaches leaving pox-like scar with variable telangiectasias (Figs. 32.3A and B). The lesions affect the cheeks, nose, V-shaped area of the neck, and the dorsa of hands. In addition to the classic form of HV, another more severe variant has been described in adults (HV-like eruption).36 HV-like eruption is characterized by larger and

Chapter 32: Photodermatoses

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Figs. 32.3A and B: (A) Hydroa vacciniforme: a 9-year-old girl showing typical papulovesicular eruption with some crusts on sun-exposed areas; (B) Hydroa vacciniforme: closer view showing typical papulovesicular eruption and crusts on the forehead with evident scarring. Courtesy: Dr Nada Eltayeb, Cairo, Egypt.

deeper lesions, which might become worse with age. The lesions may involve sun-protected areas, are not always associated with photosensitivity, and may not show seasonal variation. HV-like eruption is commonly associated with systemic symptoms like fever, malaise, weight loss, hepatosplenomegaly, headache, and hypersensitivity to insect bites.36 Patients might progress to EBV-associated T-cell lymphoma and/or NK-cell lymphoma.38 Ocular involvement and oral lesions have been reported in HV and HV-like eruption, respectively.39

Differential Diagnosis Refer Table 32.7 for details.

Histopathology Early lesions show reticular keratinocyte degeneration, spongiosis, and perivascular mononuclear cell infiltrate. In later lesions, intraepidermal vesicles, confluent epidermal necrosis, and ulceration may be seen (Fig. 32.4). HV-like eruption may show dense dermal and subcutaneous lymphocytic infiltrate with few atypical cells.

Investigations Laboratory tests are necessary to exclude other differential diagnoses (Table 32.2) and to test for T-cell receptor rearrangement in suspicious severe cases.

Fig. 32.4: Hydroa vacciniforme Histology: H&E section showing keratinocyte reticular degeneration with formation of intraepidermal multilocular vesicles, confluent keratinocyte necrosis, and a dense papillary dermal mononuclear infiltrate (×400 magnification). Courtesy: Dr Nada Eltayeb, Cairo, Egypt.

Treatment HV is refractory to most treatment modalities. Strict photoprotection is the most useful measure. Treatments like PUVA, UVB, antimalarials, azathioprine, thalidomide, and systemic corticosteroids could be tried (Table 32.8). In cases associated with chronic EBV infections, antiviral

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Section 10: Photosensitivity treatment may be of benefit in reducing the frequency and severity of the attacks.40

CHRONIC ACTINIC DERMATITIS Lim et al.41 suggested the unifying term “chronic actinic dermatitis”, previously coined by Hawk and Magnus,42 to describe a number of overlapping conditions, such as “photosensitive dermatitis,” “photosensitive eczema,” “eczematous PLE,” and “actinic reticuloid.”

Epidemiology CAD is more common in men over 50 years of age, especially those who spend too much time outdoors. HIV patients were found to develop CAD at a younger age.43

Action Spectrum The most common action spectrum that elicits CAD is UVB and UVA, and rarely UVA alone, UVB alone, or visible light.

Etiopathogenesis CD8 cells are found commonly in the dermal infiltrate. The pattern of adhesion molecule activation makes CAD very similar to allergic contact dermatitis. It is possible that ultraviolet radiation might induce the formation of

A

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endogenous neoantigens in the skin, resulting in DTH.12 In a study from the United Kingdom, CAD patients were found to have airborne contact or photocontact allergy to exogenous allergens called compositae oleoresins, to which they were exposed during gardening.44 Positive patch and photopatch testing has been reported to fragrance in CAD.45 Contact allergy sometimes precedes the development of CAD.46 CAD might represent the endstage of different conditions including photoallergic contact dermatitis, allergic contact dermatitis to substances with phototoxic potential, endogenous eczema, and HIV infection.47

Clinical Picture Patients present with eczematous lichenified pruritic patches and plaques on sun exposed areas, with sparing of nasolabial folds, submental chin, and upper eyelids (Figs. 32.5A to D). A sharp cutoff is frequently seen between exposed and non-exposed areas like at the cuff and collar of shirts in men. In severe cases, sun-protected areas might be involved, and in more severe cases, erythroderma and palmoplantar hyperkeratosis might be observed. Spontaneous resolution occurs in 10%, 20%, and 50% over 5, 10, and 15 years, respectively.46 There is no evidence that CAD is premalignant; however, longterm immunosuppressant therapy might increase the risk of malignancy.

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Figs. 32.5A to D: Chronic actinic dermatitis: typical scaly erythematous eruption with evident lichenification on sun-exposed areas [face (A), hands (B), V-area of the neck (C)]. Notice sharp cutoff at V-area of the neck (C) and at collar of T-shirt (D). Courtesy: A to C Ahmed Zidan, MD, Cairo, Egypt.

Chapter 32: Photodermatoses radiation due to the presence of chemical agent or a metabolite. Photosensitivity is subdivided into phototoxicity and photoallergy. Phototoxicity is the result of tissue damage induced by a chemical, a drug, or its metabolites with the help of ultraviolet radiation, and any individual may be affected. In contrast, photoallergy is a DTH reaction that affects sensitized people only. Systemically administered substances generally cause phototoxicity, while topically applied substances more commonly cause photoallergy. Exceptions to the rule exist. Porphyrins are the best-known endogenous phototoxic agents. According to the half-life of the drug or its metabolites, the patient may continue to suffer from photosensitivity for extended periods after cessation of drug intake.48 Fig. 32.6: Chronic actinic dermatitis histology: hyperkeratosis with parakeratosis, irregular acanthosis, spongiosis, pandermal perivascular lymphohistiocytic inflammatory infiltrate.

Differential Diagnosis Refer Table 32.7 for details.

Histopathology Histology shows a spongiotic dermatitis with lymphohistiocytic infiltrate (Fig. 32.6). The infiltrate is sometimes brisk, and there is evidence of exocytosis with some atypia, a picture that might mimic cutaneous T-cell lymphoma (CTCL). The presence of erythroderma along with T-cell exocytosis and atypia makes the diagnosis highly likely. However, immunohistochemical testing as well as T-cell clonality will differentiate between CAD and CTCL.

Epidemiology The real prevalence of drug-induced photosensitivity is not known and could be largely underdiagnosed. In a recent Tunisian study, it was found to be the third most common drug reaction.49 In tertiary photodermatology centers, its incidence has been estimated to be between 2% and 15%. There is no gender predilection, and older patients, especially those on polypharmacy, are more prone for druginduced photosensitivity.48

Action Spectrum Most agents react with UVA range; exceptions include sulfonamides and ranitidine which react in the UVB spectrum. Fluorescein, other dyes, and porphyrins react mainly in the visible light spectrum.

Etiopathogenesis

Treatment

Phototoxicity

Mild cases are treated with photoprotection and topical steroids or calcineurin inhibitors. Severe and refractory cases might necessitate the introduction of immunosuppressants like systemic steroids, cyclosporine, mycophenolate mofetil, and azathioprine for several weeks. Low-dose PUVA with initial systemic and topical steroids coverage may be tried (Table 32.8).

Phototoxicity may be induced by a vast number of drugs, especially in genetically prone individuals (Table 32.9). The most notorious substances are NSAIDs (with the exception of indomethacin) (Figs. 32.7A and B), cardiac drugs (amiodarone, quinidine), antimicrobials (tetracyclines, quinolones, sulfonamides), diuretics (thiazides, furosemide), and phenothiazines in addition to psoralens. Topical phototoxic agents include furocoumarins (e.g., psoralens) in plants (lime, parsley, parsnip, celery, figs), which can induce phytophotodermatitis, ending in berloque dermatitis with pigmentation (Figs. 32.8A and B). Rose bengal used in ophthalmologic examination and tar used by roofers and road workers can also lead to phototoxicity.

DRUG- AND CHEMICALLY-INDUCED PHOTOSENSITIVITY Drug-induced and chemically-induced photosensitivity represent an abnormal skin reaction to ultraviolet

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Section 10: Photosensitivity Table 32.9: Phototoxic agents. Topical phototoxic agents: Furocoumarins Rose bengal Coal tar Fluorouracil* Retinoids* Systemic phototoxic agents: Antianxiety drugs Alprazolam Chlordiazepoxide Anticancer drugs Fluorouracil Methotrexate Vinblastine Dacarbazine Antidepressants Tricyclics: amitriptyline, imipramine, desipramine Antimalarials Chloroquine Quinine Antimicrobials Griseofulvin Quinolones Sulfonamides Tetracyclines Trimethoprim Antipsychotics Phenothiazines Cardiac drugs Amiodarone Quinidine Diuretics Furosemide Thiazides Dyes Fluorescein Methylene blue Furocoumarins 8-Methoxypsoralen 5-Methoxypsoralen 4,5,8-Trimethylpsoralen Hypoglycemics Sulfonylureas Non-steroidals Diclofenac Mefenamic acid Ibuprofen Ketoprofen Naproxen Piroxicam Celecoxib Retinoids Acitretin† Isotretinoin† Others Flutamide Pyridoxine (B6) Hypericin Ranitidine Eculizumab (anti C5) *

Phototoxicity due to their irritant effect. Phototoxicity due to thinning of the epidermis.

†

Pathogenetic mechanisms entail that the drug or its metabolite get activated by ultraviolet radiation, mainly UVA, and through a series of reactions, ROS are generated, which result in host cytotoxic tissue effects. Other mechanisms of phototoxicity include formation of photoadducts (psoralens), the generation of stable photoproducts (tetracyclines, chlorpromazine), and the production of inflammatory mediators (porphyrins).50

Photoallergy The most common topical photoallergic agents, at present, are the organic UV filters used in sunscreens, especially benzophenone-3 and octocrylene, and topical NSAID such as ketoprofen. Patients who develop photoallergic contact dermatitis to ketoprofen often develop a photoallergy to octocrylene, benzophenone, or both.51 In the past, fragrances (musk ambrette) and disinfectants (salicylanilides) have been implicated in photoallergic dermatitis5 (Table 32.10). The pathogenesis of photoallergy development is essentially a DTH reaction. On exposure of the photosensitizer to ultraviolet radiation, the molecule gets excited and then reverts to the ground state by releasing its energy. In this process, it binds to an endogenous carrier protein to become a complete antigen. Another mechanism may involve formation of a stable photoproduct on exposure to ultraviolet radiation, which then binds to the carrier protein becoming a complete antigen. The rest of the process is similar to that of allergic contact dermatitis.50

Clinical Picture Phototoxicity Systemic Phototoxic Agents The classical clinical presentation of a phototoxic reaction is an exaggerated form of acute sunburn reaction, with burning and stinging sensation, erythema, edema, and possibly blistering, which is followed by hyperpigmentation (Figs. 32.7A and B, and 32.8A and B). Manifestations appear within a few hours on sunexposed areas and are drug-dose, as well as ultraviolet radiation-dose-dependent. Less commonly, slate gray pigmentation (amiodarone, diltiazem and tricyclic antidepressants), lichenoid eruption (quinine and quinidine), pseudoporphyria (NSAID

Chapter 32: Photodermatoses

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Figs. 32.7A and B: Phototoxic eruption: erythema and edema of sun-exposed areas in a 27-year-old man. Patient complained of burning and stinging sensation. Patient gave history of non-steroidal anti-inflammatory drug intake [(A) face, (B) hands]. Courtesy: Assem Farag, MD, Cairo, Egypt.

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Figs. 32.8A and B: Phototoxic eruption (phytophototoxic eruption) ending in hyperpigmentation. (A) After hair removal using sugar and lemon juice (using lemon juice to prevent sugar from crystallization); (B) After splashing lime juice at a pool party.

especially naproxen), photo-onycholysis (psoralens, tetracyclines, fluoroquinolones, benoxaprofen), and photodistributed telangiectasia (levofloxacin, calcium channel blockers) may occur.50,52

Photoallergy Photoallergy is an eczematous reaction similar to allergic contact dermatitis, but it is present in exposed areas. Lesions erupt 24–48  h after sun exposure. Less commonly, the eczema may extend to covered areas, being less

intense than in exposed areas. Rarely, a lichenoid reaction can develop.48

Long-term Effects of Phototoxic Agents Evolution into CAD, sometimes even after cessation of the photosensitizer, has been reported with drugs inclusive of thiazides, quinine, and quinidine. Long-term use of psoralens and voriconazole produces phototoxic reactions together with an increased risk for actinic keratoses, squamous cell carcinoma, and

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Section 10: Photosensitivity Table 32.10: Photoallergic agents. Topical photoallergens Sunscreens Benzophenone 3 Octocrylene Butyl methoxydibenzoylmethane, Isoamyl-p-methoxycinnamate, ethylhexyl methoxycinnamate PABA derivatives Benzyl salicylates Non-steroidal Ketoprofen anti-inflammatory Etofenamate drugs Diclofenac Piroxicam Fragrances 6-Methylcoumarin Musk ambrette Sandalwood oil Antimicrobial Bithionol agents Chlorhexidine Fenticlor Hexachlorophene Triclosan Salicylanilides Systemic photoallergens Non-steroidal Ketoprofen anti-inflammatory Piroxicam Drugs Antimicrobials Quinolones Sulfonamides Antifungals Griseofulvin Antimalarials Quinine Antiarrhythmics Quinidine

perhaps melanoma. BRAF inhibitors, especially vemurafenib, used to treat melanoma may be associated with increased risk of squamous cell carcinoma.52

Histopathology Phototoxic reactions are characterized by individual necrotic keratinocytes (sun-burn cells), and in severe cases, necrotic epidermis. This may be accompanied by dermal edema, a mild infiltrate of lymphocytes, neutrophils, and macrophages. In slate-gray pigmentation, a dermal deposition of melanin with or without dermal deposition of the drug or its metabolite is seen. Photoallergic reactions show a typical picture of spongiotic dermatitis.50

Differential Diagnosis Refer Table 32.7 for details.

Investigations Patients with phototoxic dermatitis usually have a lowered MED for UVA and/or UVB (Table 32.2). Diagnosis of a photoallergic reaction is done by photopatch testing1 (Tables 32.3 to 32.5).

Treatment Avoiding the insulting drug/chemical and implementing its replacement by non-photoallergic drugs, whenever possible, is invaluable. Sometimes, this is not possible, and strict sun protection is needed. Further treatment measures are similar to that of other photosensitive disorders (Table 32.8). Treatment should continue for some time after drug avoidance, according to the half-life of the photosensitizing drug or its metabolite.48

PHOTOAGGRAVATED DISEASES Cutaneous diseases classically treated with UV therapy could sometimes be aggravated by UV exposure. The list includes diseases like seborrheic dermatitis, psoriasis, atopic dermatitis, lichen planus actinicus, and others (Table 32.1). The clinical picture depends on the condition, with photoexposed areas being more severely involved. PMLE might coexist with lupus erythematosus (LE) (49%) and psoriasis.53–55 PMLE may precede the onset of LE by years. Psoriasis may be aggravated by sun exposure in 5%–20% of cases.54,55 This usually occurs in elderly women who have had psoriasis for a long time. The differential diagnosis of patients presenting with dermatitis in sun-exposed areas include photoaggravated atopic dermatitis, drug-induced photosensitivity, and CAD. Phototesting is usually positive in CAD. Phototesting is not usually of assistance due to the delay between UV exposure and the development of the lesions, which may last for weeks. LE is most commonly exacerbated by a combination of UVA and UVB, Darier disease, and psoriasis (without PMLE) usually by UVB. Treatment is given according to the disease condition. In addition, photoprotection should be advocated along with vitamin D supplementation if necessary. Phototherapy, in diseases showing good therapeutic response, is not strictly contraindicated but should be used at a lower setting.

REFERENCES 1. Choi D, Kannan S, Lim HW. Evaluation of patients with photodermatoses. Dermatol Clin 2014;32:267–75.

Chapter 32: Photodermatoses 2. Bylaite M, Grigaitiene J, Lapinskaite GS. Photodermatoses: classification, evaluation and management. Br J Dermatol 2009;161(Suppl. 3):61–8. 3. Lim HW, Hawk J. Evaluation of the photosensitive patient. In: Lim HW, Hönigsmann H, Hawk J, editors. Photodermatology. New York: Informa Healthcare USA; 2007. p. 139–48. 4. Gonçalo M. Photopatch testing. In: Johansen JD, Frosch PJ, Lepoittevin JP, editors. Contact dermatitis. 5th ed. Berlin Heidelberg: Springer-Verlag; 2010. Chapter 29. p. 519–32. 5. Gonçalo M, Ferguson J, Bonevalle A, et al. Photopatch testing: recommendations for a European photopatch test baseline series. Contact Dermatitis 2013;68:239–43. 6. Eberlein-König B, Fesq H, Abeck D, et al. Systemic vitamin C and vitamin E do not prevent photoprovocation test reactions in polymorphous light eruption. Photodermatol Photoimmunol Photomed 2000;16:50–2. 7. Gruber-Wackernagel A, Byrne SN, Wolf P. Polymorphous light eruption: clinic aspects and pathogenesis. Dermatol Clin 2014;32:315–34. 8. Pao C, Norris PG, Corbett M, Hawk JL. Polymorphic light eruption: prevalence in Australia and England. Br J Dermatol 1994;130:62–4. 9. Rhodes LE, Bock M, Janssens AS, et al. Polymorphic light eruption occurs in 18% of Europeans and does not show higher prevalence with increasing latitude: multicenter survey of 6,895 individuals residing from the Mediterranean to Scandinavia. J Invest Dermatol 2010;130:626–8. 10. Ortel B, Tanew A, Wolff K, Hönigsmann H. Polymorphous light eruption: action spectrum and photoprotection. J Am Acad Dermatol 1986;14(5 Pt 1):748–53. 11. Das S, Lloyd JJ, Walshaw D, Farr PM. Provocation testing in polymorphic light eruption using fluorescent ultraviolet (UV) A and UVB lamps. Br J Dermatol 2004;151: 1066–70. 12. van de Pas CB, Kelly DA, Seed PT, et al. Ultravioletradiation-induced erythema and suppression of contact hypersensitivity responses in patients with polymorphic light eruption. J Invest Dermatol 2004;122:295–9. 13. Norris PG, Morris J, McGibbon DM, Chu AC, Hawk JL. Polymorphic light eruption: an immunopathological study of evolving lesions. Br J Dermatol 1989;120:173–83. 14. Norris PG, Barker JN, Allen MH, et al. Adhesion molecule expression in polymorphic light eruption. J Invest Dermatol 1992;99:504–8. 15. Stratigos AJ, Antoniou C, Katsambas AD. Polymorphous light eruption. J Eur Acad Dermatol Venereol 2002;16:193–206. 16. Jansén CT, Karvonen J. Polymorphous light eruption. A seven-year follow-up evaluation of 114 patients. Arch Dermatol 1984;120:862–5. 17. Epstein JH. Polymorphous light eruption. Dermatol Clin 1986;4:243–51. 18. Rücker BU, Häberle M, Koch HU, et al. Ultraviolet light hardening in polymorphous light eruption—a controlled study comparing different emission spectra. Photodermatol Photoimmunol Photomed 1991;8:73–8.

19. Collins P, Ferguson J. Narrow-band UVB (TL-01) phototherapy: an effective preventative treatment for the photodermatoses. Br J Dermatol 1995;132:956–63. 20. Fesq H, Ring J, Abeck D. Management of polymorphous light eruption: clinical course, pathogenesis, diagnosis and intervention. Am J Clin Dermatol 2003;4:399–406. 21. Valbuena MC, Muvdi S, Lim HW. Actinic prurigo. Dermatol Clin 2014;32:335–44. 22. Hojyo-Tomoka MT, Vega-Memije ME, Cortes-Franco R, Dominguea-Soto L. Diagnosis and treatment of actinic prurigo. Dermatol Ther 2003;16:40–4. 23. Hönigsmann H, Hojyo-Tomoka MT. Polymorphous light eruption, hydroa vacciniforme, and actinic prurigo. In: Lim HW, Hönigsmann H, Hawk J, editors. Photodermatology. New York: Informa Healthcare; 2007. p. 149–68. 24. Ferguson J, Ibbotson S. The idiopathic photodermatoses. Semin Cutan Med Surg 1999;18:257–73. 25. Estrada-G, Garibay-Escobar A, Núñez-Vázquez A, et al. Evidence that thalidomide modifies the immune response of patients suffering from actinic prurigo. Int J Dermatol 2004;43:893–7. 26. Torres-Alvarez B, Castanedo-Cazares JP, Moncada B. Pentoxifylline in the treatment of actinic prurigo. A preliminary report of 10 patients. Dermatology 2004;208:198–201. 27. Chong WS, Khoo SW. Solar urticaria in Singapore: an uncommon photodermatoses seen in a tertiary dermatology center over a 10-year period. Photodermatol Photoimmunol Photomed 2004;20:101–4. 28. Leenutaphong V, Holzle E, Plewig G. Pathogenesis and classification of solar urticaria: a new concept. J Am Acad Dermatol 1989;21(2 Pt 1):237–40. 29. Nitiyarom R, Wongpraparut C. Hydroa vacciniforme and solar urticaria. Dermatol Clin 2014;32:345–53. 30. Hasei K, Ichihashi M. Solar urticaria. Determinations of action and inhibition spectra. Arch Dermatol 1982;118:346–50. 31. Horio T, Fujigaki K. Augmentation spectrum in solar urticaria. J Am Acad Dermatol 1988;18(5 Pt 2):1189–93. 32. Reinauer S, Leenutaphong V, Holzle E. Fixed solar urticaria. J Am Acad Dermatol 1993;29(2 part 1):161–5. 33. Wolf R, Herzinger T, Grahovac M, Prinz JC. Solar urticaria: long-term rush hardening by inhibition spectrum narrow-band UVB 311 nm. Clin Exp Dermatol 2013;38: 446–7. 34. Aubin F, Avenel-Audran M, Jeanmougin M, et al.; Société Française de Photodermatologie. Omalizumab in patients with severe and refractory solar urticaria: a phase II multicentric study. J Am Acad Dermatol 2016;74:574–5. 35. Gupta G, Man I, Kemmett D. Hydroa vacciniforme: a clinical and follow-up study of 17 cases. J Am Acad Dermatol 2000;42(2 Pt 1):208–13. 36. Cho KH, Lee SH, Kim CW, et al. Epstein-Barr virus associated lymphoproliferative lesions presenting as a hydroa vacciniforme-like eruption: an analysis of six cases. Br J Dermatol 2004;151:372–80. 37. Sonnex TS, Hawk JL. Hydroa vacciniforme: a review of ten cases. Br J Dermatol 1988;118:101–8.

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Section 10: Photosensitivity 38. Iwatsuki K, Satoh M, Yamamoto T, et al. Pathogenic link between hydroa vacciniforme and Epstein-Barr virus-associated hematologic disorders. Arch Dermatol 2006;142:587–95. 39. Yamamoto T, Hirai Y, Miyake T, et al. Oculomucosal and gastrointestinal involvement in Epstein-Barr virus-associated hydroa vacciniforme. Eur J Dermatol 2012;22:380–3. 40. Lysell J, Wiegleb Edström D, Linde A, et al. Anti-viral therapy in children with hydroa vacciniforme. Acta Derm Venereol 2009;89:393–7. 41. Lim HW, Buchness MR, Ashinoff R, Soter NA. Chronic actinic dermatitis. Study of the spectrum of chronic photosensitivity in 12 patients. Arch Dermatol 1990;126:317–23. 42. Hawk JL, Magnus IA. Chronic actinic dermatitis—an idiopathic photosensitivity syndrome including actinic reticuloid and photosensitive eczema [proceedings]. Br J Dermatol 1979;101(Suppl 17):24. 43. Meola T, Sanchez M, Lim HW, Buchness MR, Soter NA. Chronic actinic dermatitis associated with human immunodeficiency virus infection. Br J Dermatol 1997;137:431–6. 44. Frain-Bell W, Johnson BE. Contact allergic sensitivity to plants and the photosensitivity dermatitis and actinic reticuloid syndrome. Br J Dermatol 1979;101:503–12. 45. Addo HA, Ferguson J, Johnson BE, Frain-Bell W. The relationship between exposure to fragrance materials and persistent light reaction in the photosensitivity dermatitis with actinic reticuloid syndrome. Br J Dermatol 1982;107:261–74. 46. Dawe RS, Crombie IK, Ferguson J. The natural history of chronic actinic dermatitis. Arch Dermatol 2000;136: 1215–20.

47. Hönigsmann H. Mechanisms of phototherapy and photochemotherapy for photodermatoses. Dermatol Ther 2003;16:23–7. 48. Dawe RS, Ibbotson SH. Drug-induced photosensitivity. Dermatol Clin 2014;32:363–8. 49. Chaabane H, Masmoudi A, Amouri M, et al. Cutaneous adverse drug reaction: prospective study of 118 cases. Tunis Med 2013;91:514–20. 50. Lim HL. Abnormal responses to ultraviolet radiation: photosensitivity induced by exogenous agents. In: Wolff K, Goldsmith L, Katz S, et al., editors. Fitzpatrick’s dermatology in general medicine. 7th ed. New York, Chicago, San Francisco: McGraw Hill; 2008. p. 828–34. 51. de Groot AC, Roberts DW. Contact and photocontact allergy to octocrylene: a review. Contact Dermatitis 2014; 70:193–204. 52. Ibbotson S, Dawe R. Cutaneous photosensitivity diseases. In: Griffiths CEM, Barker J, Bleiker T, Chalmers R, editors. Rook’s textbook of dermatology. 9th ed. The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK: Blackwell Publishing, Ltd. John Wiley & Sons, Ltd.; 2016; 127.1. 53. Nyberg F, Hasan T, Puska P, et al. Occurrence of polymorphous light eruption in lupus erythematosus. Br J Dermatol 1997;136:217–21. 54. Ros AM, Eklund G. Photosensitive psoriasis. An epidemiologic study. J Am Acad Dermatol 1987;17(5 Pt 1): 752–8. 55. Rutter KJ, Watson RE, Cotterell LF, et al. Severely photosensitive psoriasis: a phenotypically defined patient subset. J Invest Dermatol 2009;129:2861–7.

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Connective Tissue Diseases

Chapter

33

Lupus Erythematosus Jose Dario Martinez, Dionicio Angel Galarza, Jesus Alberto Cardenas, Miryam Eguia

INTRODUCTION Lupus erythematosus (LE) is a chronic autoimmune disease with a broad range of cutaneous and systemic manifestations, which predominantly affects the skin and joints. Skin manifestations of LE have been classified in two broad categories: specific LE skin lesions and nonspecific LE skin lesions. Nonspecific LE lesions are found in other diseases and include scarring alopecia, Raynaud’s phenomenon, cutaneous vasculitis, urticarial vasculitis, oral ulcers, periungual telangiectasia, and livedo reticularis (Table 33.1). Specific LE skin lesions are classified into acute cutaneous lupus (ACLE), subacute cutaneous lupus (SCLE), and chronic cutaneous lupus (CCLE). The Düsseldorf classification added two more categories in 2004, intermittent cutaneous lupus (ICCL), which includes the variant lupus erythematosus tumidus (LET), formerly included in CCLE and bullous LE.

EPIDEMIOLOGY The epidemiology of cutaneous LE is variable depending on the population described. In 2009, a study of a predominantly Caucasian population in the United States reported an incidence of 4.3/100,000 for cutaneous LE, 3.56/100,000 for discoid lupus erythematosus (DLE), and 0.63/100,000 for SCLE, with progression to systemic lupus erythematosus (SLE) in 12%.1 In men, the incidence of cutaneous LE is higher than that of SLE with a peak incidence in older adults.2 The estimated incidence of cutaneous LE in a cohort in Sweden was 4 cases per 100,000, with the most common subtypes being DLE (80%) and SCLE (15.7%). Mean age at diagnosis was 54 years with a female/male ratio of 3:1. At the time of diagnosis of cutaneous LE, 24% had a diagnosis of SLE, and an additional 18% were diagnosed with SLE during a 3-year follow up.3

Table 33.1: Specific and nonspecific skin manifestations of lupus erythematosus. LE-specific skin disease LE-nonspecific skin disease Photosensitivity Chronic cutaneous lupus erythematosus (CCLE) Diffuse non-scarring alopecia – Discoid lupus erythematosus (DLE) Scarring alopecia – Hypertrophic/verrucous variant Raynaud’s phenomenon – Lupus erythematosus profundus (LEP; lupus panniculitis) Cutaneous vasculitis – Chillblain lupus (CHLE) Oral ulcers Subacute cutaneous lupus erythematosus (SCLE) Periungual telangiectasies – Annular Livedo racemosa – Papulosquamous/psoriasiform Livedo reticularis Acute cutaneous lupus erythematosus (ACLE) Cutaneous calcinosis – Localized form Erythema multiforme – Generalized form Thrombophlebitis Intermittent cutaneous lupus erythematosus (ICLE) Rheumatoid nodules – Lupus erythematosus tumidus (LET) Urticaria Erythromelalgia LE–nonspecific bullous lesions Papulo nodular mucinosis Atrophie blanche

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CHRONIC CUTANEOUS LUPUS ERYTHEMATOSUS Chronic cutaneous lupus erythematosus (CCLE) includes discoid lupus erythematosus (DLE), lupus erythematosus profundus (LEP), also known as lupus panniculitis, chilblain LE (CHLE), and lupus erythematosus tumidus (LET).

DISCOID LUPUS ERYTHEMATOSUS DLE represents 70% of cases of cutaneous LE, and more than 90% of CCLE. Prevalence is higher in women (female to male ratio 3:1) between the fourth and sixth decades of life with a mean age at diagnosis of 41 years.4 It is present in 25% of individuals diagnosed with SLE. Unlike the variants ACLE and SCLE, it progresses to systemic disease less frequently (5–10%).5 Smoking, autoantibodies, gender, ultraviolet radiation, and specific alleles such as HLA DQA1 and DRB1 have been implicated in the pathogenesis of DLE.6

A

Clinical Features According to its distribution, DLE can be classified into two forms: localized with lesions above the neck and disseminated with lesions above and below the neck. The localized form accounts for 80% of DLE and mainly affects the scalp, face, and pinnae (especially the conchal bowl) (Figs. 33.1A and B). The disseminated form also affects the trunk and upper extremities. The risk of progression to SLE is higher in disseminated DLE than in localized DLE. The hallmark lesion of DLE is an infiltrated, welldelimited, coin-shaped erythematous plaque covered by scale. When this scale is removed, “keratotic spikes” can be observed, which is known as the “carpet tack sign.” Plaques may appear or worsen after sunlight exposure or trauma (Koebner phenomenon). Upon resolution of plaques, residual scarring, atrophy, telangiectasia, and pigmentary changes may be noted. Involvement of hair follicles may cause scarring alopecia (Fig. 33.2). Photosensitivity is present in 25 to 90% of DLE cases. In a cohort including more than 300 patients with CCLE, positivity for antinuclear antibodies (ANA) was found in 53%, anti-SSA (Ro) antibodies in 22%, and antiSSB (La) in 7% of cases. Positivity for anti-dsDNA was reported in 18% and 7% for anti-Sm.4

B Figs. 33.1A and B: (A) Discoid lupus erythematosus on the face; (B) Discoid lupus erythematosus on the pinnae.

Histopathology DLE histopathology reveals interface dermatitis with pronounced lymphocytic infiltrate in the dermoepidermal

Fig. 33.2: Scarring alopecia in discoid lupus erythematosus.

Chapter 33: Lupus Erythematosus sarcoidosis, cutaneous tuberculosis, lichen planus, squamous cell carcinoma, and lymphoproliferative lesions of the skin. Squamous cell carcinoma may develop from long-standing DLE lesions and biopsy is essential if neoplastic transformation is suspected.

Treatment and Prognosis

Fig. 33.3: Panoramic view of (5×) epidermal atrophy with degeneration of basal layer, periadnexal lymphocytic infiltrate and marked thickening of the basement membrane in a patient with discoid lupus erythematosus.

Sun protection and avoidance is essential in the treatment of DLE. Topical corticosteroids have a well-established use in the treatment of DLE. The potency of the topical steroid should be tailored to the affected site. Topical calcineurin inhibitors (tacrolimus and pimecrolimus) have been used with success in DLE and are steroid sparing.8 First-line systemic therapy for DLE is antimalarials: hydroxychloroquine, cloroquine, and quinacrine. Hydroxychloroquine 200–400 mg at night is preferred because of its lower rate of adverse effects including retinopathy. Second-line systemic treatments that have shown variable success include systemic corticosteroids, metothrexate, dapsone, thalidomide, and lenalidomide (thalidomide analogue). Third-line therapy includes abatacept and, for selected localized lesions, pulsed dye laser.

HYPERTROPHIC LUPUS ERYTHEMATOSUS Clinical Features

Fig. 33.4: Basal membrane vacuolar degeneration in discoid lupus erythematosus.

junction as well as around blood vessels and hair follicles (Figs. 33.3 and 33.4). Hyperkeratosis and follicular plugging is present. Lesional skin lupus band test (deposits of immunoreactants) is positive in approximately 60% of cases and may be more prominent around hair follicles.7 Direct immunofluorecence (DIF) shows granular deposits, primarily of IgG and IgM, at the dermoepidermal junction.

Differential Diagnosis The differential diagnosis of DLE includes other types of cutaneous lupus, psoriasis, rosacea, tinea faciei,

Hypertrophic (or verrucous) lupus erythematosus (HLE) is a rare variety of DLE characterized by hyperkeratotic, erythematous warty, indurated plaques.9 It may also present with hyperkeratotic papules resembling keratoacanthomas. Most patients with HLE report the simultaneous presence of classic DLE lesions. The most common locations are sun-exposed areas.9

Histopathology Histopathology shows a dense band-shaped infiltrate with pseudoepitheliomatous hyperplasia engulfing elastotic material and vacuolar interface changes.10 Additional findings include marked hyperkeratosis with focal parakeratosis, a perivascular and periadnexal lymphocytic infiltrate and basal cell atypia. Keratoacanthoma-like lesions show a crateriform lesion with central keratin, a squamous epithelial proliferation and a lichenoid reaction in the dermoepidermal junction.9,10

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Differential Diagnosis Differential diagnosis includes keratoacanthoma, cutaneous neoplasms, and pseudoepitheliomatous hyperplasia.

Treatment and Prognosis HLE tends to chronicity, recurrence and resistance to treatment.9 Utility of topical or systemic retinoids, antimalarials, thalidomide, and systemic steroids have been reported.11 Effective treatment with ustekinumab, a monoclonal antibody directed against IL-12 and IL-23, has been reported in a patient with psoriasis and hypertrophic DLE.12

LUPUS ERYTHEMATOSUS PROFUNDUS Clinical Features LEP, also known as lupus panniculitis, is an uncommon form of CCLE. It presents as painful, indurated subcutaneous nodules primarily on the face, arms, thighs, and torso (Figs. 33.5 and 33.6). The course is characterized by intermittent remissions and exacerbations. Lesions resolve with atrophic deep scars.13 LEP may be accompanied by DLE. Around 10 to 20% of patients will develop SLE.

provide additional information to differentiate LEP from other entities.

Differential Diagnosis Main differential diagnoses of LEP are T-cell lymphomas (particularly subcutaneous panniculitis-like T-cell lymphoma) and other connective tissue panniculitis.

Treatment and Prognosis Topical or intralesional corticosteroid therapy has a limited role in LEP. Systemic therapy with antimalarials, particularly hydroxychloroquine, represents the first-line treatment. In case of intolerance to or lack of response to antimalarials, thalidomide can be used. Oral steroids, mycophenolate mofetil, dapsone, azathioprine, cyclophosphamide, and rituximab can be used in refractory cases.

CHILBLAIN LUPUS ERYTHEMATOSUS Clinical Features

Biopsy is essential for diagnosis and shows lobular pannic­ ulitis with an infiltrate consisting of plasma cell and lymphocytes, lymphoid follicles with germinal centers, and mucin deposits between adipocytes.12 Immunofluorescence can

LE associated with erythema pernio (chilblain LE or CHLE) is a subtype of CCLE reported in about 70 cases.14 It presents as pruritic and painful popular, erythematous lesions usually located on the dorsal hands, fingers and feet. Occasionally, ulcers and Raynaud’s phenomenon are seen. CHLE appears more commonly in cold or humid climates. CHLE may present in association with DLE and approximately 18% of cases progress to SLE.13

Fig. 33.5: Lupus profundus affecting the face.

Fig. 33.6: Lupus profundus affecting the arms.

Histopathology

Chapter 33: Lupus Erythematosus The diagnosis is made based on diagnostic criteria developed by the Mayo Clinic.15 Two major and at least one minor criterion are required. The two major criteria are: skin lesions in acral locations induced by exposure to cold and evidence of LE based on histopathologic examination or direct immunofluorescence study. Minor criteria include coexistence of SLE or DLE lesions, response to LE therapy, and negative results of cryoglobulin and cold agglutinin studies.

Histopathology

Differential Diagnosis

Treatment includes preventive measures (avoid sunlight exposure, sunscreen with SPF of 50 or higher and smoking cessation), topical steroids, antimalarials, methotrexate, and systemic steroids in refractory cases.

Differential diagnosis includes erythema nodosum, chilblains, and lupus pernio.

Treatment and Prognosis Treatment includes physical protection against cold temperatures, topical steroids, and calcium channel blockers. In recalcitrant cases immunosuppressants can be used, such as mycophenolate mofetil, tacrolimus, and sirolimus.13

LUPUS ERYTHEMATOSUS TUMIDUS Clinical Features LET is a rare subtype of CCLE. Some authors have suggested categorizing it as a different entity under the term Intermittent Cutaneous Lupus. There is no gender predilection. It usually appears between the fourth and fifth decades. It presents as urticarial, erythematous, and edematous plaques located mainly on the face and truck that resolve without scarring (Fig. 33.7). It has a polycyclic course and marked photosensitivity.

Histopathology shows a periadnexal and perivascular lymphocytic infiltrate with interstitial mucin deposits in the papillary and reticular dermis. The epidermis is usually intact although mild changes like focal vacuolization of the basal layer can be found.

Treatment and Prognosis

SUBACUTE CUTANEOUS LUPUS Epidemiology SCLE represents 8–16% of cutaneous LE.16 The mean age at presentation is 51 years and there is a male to female ratio of 4:1.4 SCLE is present in about 10% of patients diagnosed with SLE and approximately 50% of patients diagnosed with SCLE fulfill at least four of the ACR classification criteria for SLE.16 The presence of SCLE has been associated with a less aggressive course of SLE. Nonspecific LE lesions are present in 41% of the cases.4 The most frequent extracutaneous manifestations are arthralgia, arthritis, and musculoskeletal symptoms. Renal and central nervous system (CNS) involvement is rare (10%). Other associated autoimmune diseases include Sjögren syndrome, autoimmune thyroiditis, and overlap syndromes. Genetic factors that are involved include HLA-A1, B8, DR2, DR3, TNF-α,308A promoter polymorphism, and C1QA single-nucleotide polymorphism.17,18 Smoking contributes to the risk of SCLE, leads to exacerbations and decreases response to treatment.

Clinical Features

Fig. 33.7: Lupus tumidus on the V-neck area.

SCLE can be classified according to its clinical presentation into annular and papulosquamous (psoriasiform) subtypes, which each account for 50% of cases. Most patients have only one clinical variant. Sun-exposed areas including the V-neck area, shoulder, arm, forearm, and dorsum of hands and fingers (sparing the knuckles) are susceptible. Unlike ACLE and CCLE, it rarely affects the face.19 The annular form presents with symmetric and confluent annular or polycyclic plaques with central hypopigmentation, occasionally with erythematous margins.

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Treatment and Prognosis

Fig. 33.8: Subacute cutaneous lupus erythematosus psoariasiform type.

The papulosquamous variety is characterized by plaques with a psoriasiform appearance (Fig. 33.8). Lesions resolve without scarring, however, vitiligo-like hypopigmentation may occur. SCLE lesions are very photosensitive to both ultraviolet light A (UVA) and ultraviolet light B (UVB).19 Medications that have been associated with the onset of and exacerbation of SCLE include diuretics (hydrochlorothiazide), antihypertensives (ACE inhibitor blockers, calcium channel blockers), antifungal agents (terbinafine, griseofulvin), antineoplastic (docetaxel), antimalarials (hydroxychloroquine), non-steroidal anti-inflammatory drugs (naproxen, piroxicam), and statins, among others.19 Serological findings include positivity for ANA in 73%, anti-Ro/SS-A in 72%, anti-La/SS-B in 36%, anti-dsDNA in 11.6%, and anti-Sm in 3.8%.4

Histopathology Histopathological findings are similar to those of ACLE. Epidermal atrophy and vacuolar degeneration of the basal membrane are more accentuated than in ACLE. Positive lesional lupus band test (DIF) is found in approximately 60% of cases.7

Differential Diagnosis The differential diagnosis depends on the morphologic variant of SCLE and should include psoriasis, dermatophytosis, mycosis fungoides, drug-induced rash, seborrheic dermatitis, dermatomyositis, figurate or gyrate erythemas, pityriasis rubra pilaris, sarcoidosis, polymorphous light

SCLE is highly photosensitive. Sunscreens and sun avoidance are essential for disease control. The first-line topical treatment includes topical steroids, which typically lead to an excellent response. A minority of patients who fail to respond to topical steroids may benefit from a combination of topical calcineurin inhibitors (tacrolimus or pimecrolimus) and topical steroids or intralesional triamcinolone. The first-line systemic therapy for SCLE is antimalarial medication, especially hydroxychloroquine. Smoking cessation is important because response to antimalarials is hindered during tobacco use. In selected cases, thalidomide, leflunomide, and mycophenolate mofetil may be used. In cases of drug-induced SCLE, the suspected drug must be discontinued.

ACUTE CUTANEOUS LUPUS ERYTHEMATOSUS Epidemiology ACLE represents approximately 30% of cutaneous LE. It is the variant that is most closely associated with SLE. In some cases it may precede systemic manifestations of SLE for weeks or months.12 Women represent 82% of cases. The age of onset is usually between the second and third decades. It is associated with SCLE in 13% and DLE in 30%. Nonspecific LE skin lesions are present in half of all cases.4 Butterfly erythema occurs in 20–60% of patients with SLE.

Clinical Features A localized variant of ACLE consists of a malar rash, which is classically described as “butterfly rash,” involving both cheeks and the bridge of the nose with well-defined edges (Fig. 33.9). Unlike the facial erythema seen in seborrheic dermatitis and dermatomyositis, the malar rash does not affect the nasolabial folds. In some cases this rash may be accompanied by edema, telangiectasias, atrophy, and erosions. Usually, it appears after exposure to sunlight. In cases of SLE, the malar rash may be associated with increased systemic disease and exacerbations of renal or pulmonary involvement. Skin lesions resolve without scarring.

Chapter 33: Lupus Erythematosus

A Fig. 33.9: Acute cutaneous lupus presenting as malar rash in a patient with systemic lupus erythematosus.

B

Fig. 33.10: Generalized morbiliform rash in systemic lupus erythematosus.

The generalized form of ACLE is rare. It is characterized by a symmetric morbiliform or maculopapular rash principally affecting upper limbs and chest (Fig. 33.10). Typically, it does not affect knuckles, which distinguishes it from dermatomyositis.

Diagnosis Histopathology reveals interface dermatitis with scarce vacuolar degeneration in the dermoepidermal junction and a lymphocytic perivascular infiltrate. Epidermal atrophy and dermal mucin deposits may be seen. Follicular plugging is not observed. DIF of affected skin may depict

Figs. 33.11A and B: (A) Panoramic and close-up view revealing focal parakeratosis with spongiosis, Civatte bodies and a perivascular lymphocyte and histiocytic infiltrate; (B) Direct immunofluorescence with focal positivity for IgG and IgM in a linear and granular pattern in the basal membrane. Courtesy: Dr Horacio Decanini Arcaute from Hospital Christus Muguerza, Monterrey, Mexico.

granular deposits of immunoglobulin (IgG and IgM) and sometimes complement deposits in a band-like pattern (lesional lupus band test) in approximately 90% of cases (Figs. 33.11A and B). Positive lupus band test in nonsun exposed skin may indicate more severe systemic involvement.7

Differential Diagnosis The differential diagnosis for the malar rash of ACLE should include other causes of facial erythema including seborrheic dermatitis, atopic dermatitis, contact dermatitis, rosacea, tinea faciei, erysipelas, dermatomyositis,

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Section 11: Connective Tissue Diseases mastocytosis, carcinoid, and psychosomatic flushing should be considered. The differential diagnosis of the generalized form should include drug-induced reactions, viral rash, dermatomyositis, erythema multiforme and toxic epidermal necrolysis.

Treatment and Prognosis Lifestyle modifications (smoking cessation), clothing covering sun-exposed areas, and sunscreens are encouraged. Topical steroids and topical calcineurin inhibitors (tacrolimus) are recommended. Systemic steroids and hydroxychloroquine represent first-line systemic treatments. Vitamin D supplementation is important because of its role in immune response. The adult dose of vitamin D varies between populations but it is usually estimated around 1000–2000 IU/daily.

SYSTEMIC LUPUS ERYTHEMATOSUS Epidemiology The prevalence of SLE ranges from 20 to 70/100,000 cases with a yearly incidence of 1 to 10/100,000 depending on the population evaluated. In recent years, the incidence has almost tripled due to an earlier diagnosis and better antibody determination techniques. SLE prevalence and severity is higher among African-Americans, Hispanics, and Caucasians compared to other ethnic groups. The female to male ratio is 9:1. Disease onset is most common during the second and fourth decades. Compared to women, men are usually older, less photosensitive and more likely to have serositis.

Pathogenesis SLE is a multifactorial disease in which two main factors have been implicated: genetics and environment (Fig. 33.12). HLA class II alleles –DR and –DR3 have been implicated. Mutations in complement factors and TREX1 have been showed to confer increased susceptibility. Environmental agents like UV exposure, infections, and smoking have been related to disease development and flares. Estrogen and other hormones are implicated in the increased prevalence in women and pregnancy-related exacerbations. Organ and tissue damage in SLE is linked primarily to immune complex (Gell and Coombs type III). Immune deposits activate complement, leading to tissue damage. B-lymphocytes play an important role in lupus pathogenesis and are a novel therapeutic target. Their role

Fig. 33.12: Systemic lupus erythematosus pathogenesis. Defective clearance of apoptotic bodies exposes nuclear antigens and leads to activation of antigen-presenting cells changes by costimulation and autoreactive B lymphocytes synthesize autoantibodies. Immune complexes are formed and have the capacity to activate complement and cause tissue damage. Activation of dendritic cells also produces IFN-α, which promotes B-cell differentiation to antibody producing plasma cells, T-cell activation and dendritic cell maturation. (B: B lymphocyte; BAFF-R: B-cell activating factor receptor; BCR: B-cell receptor; CD40L: CD40 ligand; IFN-α: inferferon; MHC: major histocompatibility complex; NETs: neutrophil extracellular traps; T: T lymphocyte; TCR: T-cell receptor; TLR: toll-like receptor).

includes autoantibody and cytokine production, antigen presentation, and impaired cell tolerance. In the skin, keratinocytes exposed to UV light may undergo apoptosis which liberates nuclear material and may stimulate the autoimmune response.

Diagnostic Criteria In clinical practice, disease activity and severity are assessed using a combination of clinical history, physical examination, and laboratory and imaging studies for specific organs involvement, and serologic tests. Lupus criteria can be accumulative and need not be present concurrently. Systemic Lupus International Collaborating Clinics (SLICC) 2012 SLE criteria requires four or more including at least one clinical and one laboratory criteria or biopsy-proven lupus nephritis with ANA or anti-dsDNA (Table 33.2).20

Chapter 33: Lupus Erythematosus Table 33.2: Systemic Lupus International Collaborating Clinics (SLICC) 2012 SLE criteria. Clinical criteria Immunological criteria 1. Acute cutaneous lupus 1. ANA 2. Chronic cutaneous lupus 2. Anti-dsDNA 3. Oral or nasal ulcers 3. Anti-Sm 4. Non-scarring alopecia 4. Antiphospholipid antibodies (lupus anticoagulant or anticardiolipin antibody or β2-glycoprotein) 5. Low complement; C3, C4, CH50 5. Arthritis (synovitis involving 2 or more joints) 6. Serositis (pleurisy, pericarditis) 6. Direct Coombs test (without hemolytic anemia) 7. Renal (500 mg protein/24 hours or red blood cell casts) 8. Neurologic manifestations 9. Hemolytic anemia 10. Leukopenia ( neck extensor (c) Myositis-specific antibodies detected in (d) Rash typical of DM: heliotrope (purple) periorbital serum edema; violaceous papules (Gottron’s papules) or macules (Gottron’s sign), scaly if chronic, at 4. Muscle biopsy inclusion and exclusion criteria metacarpophalangeal and interphalangeal joints and (a)  Endomysial inflammatory cell-infiltrate (T-cells) other bony prominences; erythema of chest and neck surrounding and invading non-necrotic muscle (V-sign) and upper back (shawl sign) fibers (b)  Endomysial CD8 +T-cells surrounding, but not Exclusion criteria definitely invading non-necrotic muscle fibers, or (a) Clinical features of IBM: asymmetric weakness, wrist/ ubiquitous MHC-1 expression finger flexors same or worse that deltoids; knee (c) Perifascicular atrophy extensors and/or ankle dorsiflexors same or worse (d)  MAC depositions on small blood vessels, or reduced than hip flexors) capillary density, or tubuloreticular inclusions in (b) Ocular weakness, isolated dysarthria, neck extensor > endothelial cells on EM, or MHC-1 expression of neck flexor weakness perifascicular fibers (c) Toxic myopathy (e.g. recent exposure to myotoxic (e) Perivascular, perimysial inflammatory cell infiltrate drugs), active endocrinopathy (hyper-or hypothyroid, (f)  Scattered endomysial CD+ T-cells infiltrate hyperparathyroid), amyloidosis, family history of that does not clearly surround or invade muscular dystrophy or proximal motor neuropathies muscle fibers 2. Elevated serum creatine kinase level (g) Many necrotic muscle fibers as the predominant abnormal histological feature. Inflammatory cells 3. Other laboratory criteria are sparse or only slight perivascular; perimysial (a) Electromyography: infiltrate is not evident. MAC deposition on small Inclusion criteria blood vessels or pipestem capillaries on EM may (I)  Increased insertional and spontaneous activity in the be seen, but tubuloreticular inclusions in endothelial form of fibrillation potentials, positive sharp waves, or cells are uncommon or not evident complex repetitive discharges (h) R  immed vacuoles, ragged red fibers, cytochrome (II) Morphometric analysis reveals the presence of short oxidase-negative fibers that would suggest IBM duration, small amplitude, polyphasic MUAPs (i)  MAC deposition on the sarcolemma of non-necrotic Exclusion criteria fibers and other indications of muscular dystrophies (I)  Myotonic discharges that would suggest proximal with immunopathology myotonic dystrophy or other channelopathy (ENMC: European Neuromuscular Centre; DM: dermatomyositis; MAC: membrane attack complex; IBM: inclusion body myositis; MUAPs: motor unit action potentials; MHC: major histocompatibility complex; STIR: short tau inversion recovery)

elevated. ALT and AST elevations on their own are unspecific, but together with CK elevation they are evidence of the diagnosis of DM. Aldolase might be elevated too, especially if the fascia is affected.5,7 The antibodies that are associated with the IIM are subcategorized in myositis-specific antibodies (MSA) and myositis-associated antibodies (MAA) and are clinically useful biomarkers to aide in the diagnosis of DM. Some antibodies are associated with a particular subset of DM, which adds to their utility in predicting and

monitoring specific clinical manifestations. The antibody anti-Mi-2 is the most frequent MSA in classic DM; however, there are new autoantigens that are linked to ILD and cancer. These autoantibodies are outlined in detail in Tables 34.6 to 34.8.5,19,23 Electromyography is a functional evaluation of muscular damage. The alterations that can be identified are an increase in the spontaneous and insertional activity with fibrillations, complex repeated electrical discharges, positive sharp waves, and small and polyphasic potentials of

Chapter 34: Dermatomyositis Table 34.6: Autoantibodies and myositis.20 Myositis-specific Type of autoantibodies antibodies (MSA) Autoantibody specificities Classic MSA: Jo-1, PL-7, PL-12, EJ, OJ, Mi-2, SRP New antibodies that can be considered MSA: KS, TIF1γ/α, TIF1β, MJ/NXP-2, MDA5/CADM-140, SAE Association with SARD PM/DM, PM/DM-overlap syndrome Detection in non-PM/DM Uncommon (anti-ARS can be in overlap syndrome and idiopathic ILD) Association with myopathy Yes when found in non-PM/DM Prevalence In general Almost none population

Myositis-associated antibodies (MAA) PM-Scl, Ku, U1RNP, U1/ U2RNP, U3RNP

Other autoantibodies often found in myositis Ro52, Ro60

PM/DM, PM/DM-overlap Syndrome, SSc, SLE Not uncommon

Various SARD

Yes

No or not established

PM-Scl, Ku, U1/U2RNP— almost none; U1RNP, ~0.1%

Relatively common (0.5–1%)

Often

(SARD: systemic autoimmune rheumatic diseases; PM: polymyositis; DM: dermatomyositis; SSc: systemic sclerosis; SLE: systemic lupus erythematosus; ILD: interstitial lung disease)

Table 34.7: Dermatomyositis and autoantibodies.5 Clinical association Frequency in DM Classical DM 20–30% ADM, severe ILD 50% Adult DM 5–8% Cancer associated DM 40–75% Adult DM 20–25% Juvenile DM, no cancer 30% Juvenile DM, severe cases with 25% calcinosis Anti-synthetase syndrome 5–10% High frequency of arthritis and ILD Rare Adult DM Rare Anti-synthetase syndrome MCTD Scleromyositis

19% 8% 2% 1%

Myositis-specific autoantibodies (MSA) Anti-Mi-2 Anti-CADM-140 (MDA5) Anti-SAE Anti-p155/140

Anti-MJ (NXP-2) Anti-RNA synthetase, Anti-Jo1 Anti-PMS1 Myositis-associated autoantibodies (MAA) Anti-Ro/SSA Anti-U1RNP Anti PM/Scl (75 and 100 Kda) Anti-Ku

(DM: dermatomyositis; ILD: inflammatory lung disease; ADM: amyopathic DM; MCTD: mixed connective tissue disease)

motor units. In the later stage of disease, the insertional activity decreases as a consequence of the muscular fibrosis. These alterations are not specific and occur in 70–90% of the patients.5,7 Magnetic resonance (MR) is considered the gold standard imaging study for muscular diseases that is

sensitive (70%) but not specific for the diagnosis of myositis. It is possible to see edematous muscular areas in active disease and fat atrophy of the muscle in the chronic stage. MR may also help to determine the best location for biopsy. When MR is unavailable, ultrasound is useful to evaluate acute muscular inflammation.5,7

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Section 11: Connective Tissue Diseases Table 34.8. Autoantibodies and cutaneous sign in DM24 Cutaneous sign Autoantibodies Hair loss Anti-MDA5 Oral ulcers Anti-MDA5 Photosensitivity Anti-Mi-2, anti-TIF1 V-neck sign, shawl sign Anti-Mi-2 anti-TIF1 (scalp, face, neck, back; erythroderma) Cuticular overgrowth Anti-Mi-2, anti-TIF1 (JDM) Nailfold hemorrhage Anti-Mi-2 Mechanic’s hands Anti-ARS(>Jo-1), anti-MDA5, anti-PM/Scl Skin ulcer Anti-MDA5 (digital pulp/ periugual) anti-TIF1 (JDM) Calcinosis Anti-NXP2 (JDM)

Fig. 34.23: Skin biopsy (H&E 20 and 40x): Interface dermatitis and thickening of the basement membrane (arrow). Courtesy: Gisela Navarrete MD.

HISTOPATHOLOGY Histopathological findings of the skin in DM are not specific. In the acute phase, there are some changes that are indistinguishable from lupus erythematosus, including: hyperkeratosis, epidermal atrophy, interface dermatitis, and thickening of the basement membrane. In the upper dermis, there is edema and melanophages, with perivascular lymphocytes infiltration (Figs. 34.23 and 34.24).1,5,25 Muscle biopsy should be obtained from proximal muscles. Histologically, there is a lymphocytic infiltrate and the muscle fibers show perivascular atrophy and necrosis. Complement deposits can be detected around the vessels. The infiltrate is composed of CD20+ B cells, macrophages, and CD4+ T cells (Fig. 34.25).5,41,42

Fig. 34.24: Gottron’s papule biopsy (H&E. 20x): Interface dermatitis and vasodilation. Courtesy: Gisela Navarrete MD.

TREATMENT AND PROGNOSIS Treatment of DM involves halting cutaneous and systemic disease activity with immunosuppression, maintaining muscular health with physical therapy, and avoiding potential complications (Fig. 34.26).7,43 Physical and chemical photoprotection is essential in the treatment of DM. Patients should be educated about clothing (long sleeves, turtlenecks, and hats with a 7.5 cm brim) and also about the use of a broad-spectrum sunscreen (SPF of 50+), which should be reapplied every three hours.1,7,43 Topical corticosteroids can be used to treat cutaneous manifestations of DM. They are useful to reduce erythema

Fig. 34.25: Muscle biopsy (H&E 20 and 40x): Lymphocytic infiltrate that is perifascicular, interfascicular, and perivascular. Courtesy: Gisela Navarrete MD.

Chapter 34: Dermatomyositis

Fig. 34.26: Therapeutic scheme for DM (step by step).45

and itching.1,43 Alternatively, topical calcineurin inhibitors, including tacrolimus 0.1% and pimecrolimus 1%, are reported to be helpful and may be preferred as they are steroid sparing.43 Hydroxychloroquine may be used as a systemic treatment for cutaneous DM. Lesions improve in 41–75% of the cases treated with hydroxychloroquine 6.5 mg/kg/ day.1,2,43,44 For muscle involvement, systemic corticosteroids are first line in treatment with a recommended dose of prednisone 1–2 mg/kg/day for 2 to 4 weeks or until the symptoms are controlled and muscle enzymes normalize. It is recommended to slowly taper corticosteroid therapy, rather than to abruptly discontinue treatment. In patients with severe cases or with involvement of respiratory muscles, methylprednisolone must be used in 3 to 5 pulses of 0.5–1 g followed by oral prednisone. Oral pulses with dexamethasone are an alternative to oral prednisone or prednisolone, which is safer but the relapse time is shorter.1,43,44,45 Second-line systemic treatments include methotrexate (7.5–20 mg per week), azathioprine, mycophenolate (2–3 g/day) and IVIG, tacrolimus, rituximab, cyclosporine (3–4 mg/kg/day), and cyclophosphamide (1–2 mg/kg/day orally or 0.75–1 g/m2.IV per month for 5–6 months). These can be added after systemic corticosteroids in patients that have not responded to the treatment or as steroid

sparing agents. They may also be used immediately in cases of respiratory insufficiency, dysphagia, or extramuscular manifestations including ILD. Cyclophosphamide is reserved for severe cases only. Azathioprine is effective after 4–8 months of treatment and its maximum effect is reached after 1–2 years. Intravenous immunoglobulin is for patients with a resistant disease and reportedly benefits 92% of treated patients. Third-line treatments include rituximab, abatacept, and Anakinra (Table 34.9).45,46 Finally, exercise and physical therapy are important in the treatment and rehabilitation of DM patients to assist in the avoidance of muscular atrophy.43 DM is generally regarded as a chronic disease with associated morbidity and mortality. In one case series, only 20–40% of the patients achieved remission, while 60–80% had a chronic and intermittent course, and 80% of treated patients had some form of disability with an impact on their quality of life.6,47,48 Recent studies report a survival rate of 72–85%, 34–75%, and 42–85% in 2, 5, and 10 years, respectively. In JDM, the mortality rate is 0–1.5%.2,6,47 While the advances in the treatment of DM with the use of immunosuppressives and biological therapy have improved the prognosis, the mortality still occurs in cases with severe myopathy and visceral involvement (Table 34.2).

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Section 11: Connective Tissue Diseases Table 34.9: Treatment of DM and future therapeutic options.46 Treatment Mechanism of action IVIg Hypothesized to downregulate pro-inflammatory cytokines, neutralize autoantibodies, decrease complement, and decrease MAC deposition Subcutaneous IVIg Rituximab Chimeric monoclonal ab against CD+20 B cells Anakinra Recombinant IL-1 receptor antagonist Apremilast Phospodiesterase-4 Inhibitor Infliximab Chimeric monoclonal ab against TNF-α Etanercept Fusion protein that binds soluble TNF-α Adalimumab Human monoclonal ab against TNF-α Ruxolitinib JAK 1 and 2 selective inhibitor Tocilizumab Human monoclonal ab against IL-6 receptor Abatacept Inhibits T cell activation Sifalimumab Interferon-α monoclonal ab BAF312 (siponimod) Selective S-1-P receptor modulator that inhibits lymphocyte trafficking Belimumab Human monoclonal ab specific for BLyS

Level of evidence 1,2,3 2 1a,2b,3,4 2 2 2b,3,4 1b,2b,4b 4 4 4,6 4 6 6 6

(Keys: (1) randomized controlled trial; (2) prospective or open label trial; (3) retrospective study; (4) small case series or case reports; (5) abstract; (6) current trial; a cutaneous disease response not included, Worsening or no clinical improvement of cutaneous disease ab antibody, MAC: membranolytic attack complex, IL: interleukin, JAK: janus kinase, S-1-P: spingosine 1-phosphate, Blys: B lymphocyte stimulator protein)

REFERENCES 1. Jurado F. Manifestaciones cutáneas de las enfermedades colágenovasculares. En: Torres V, Camacho F, Mihm M, González S, Jurado F y Sánchez Carpintero I, editores. Dermatología práctica ibero-latinoamericana. México, D.F.: Encuentros Científicos Académicos, S.C. 2012. 2. Dourmishev LA, Dourmishev AL. Dermatomyositis: advances in recognition, understanding and management. Berlin, Heidelberg: Springer-Verlag; 2009. 3. Mammen AL. Dermatomyositis and polymyositis: clinical presentation, autoantibodies, and pathogenesis. Ann NY Acad Sci 2010;1184:134–53. 4. Findlay AR, Goyal NA, Mozaffar T. An overview of polymyositis and dermatomyositis. Muscle Nerve 2015;51: 638–56. 5. Iaccarino L, Ghirardello A, Bettio S, et al. The clinical features, diagnosis and classification of dermatomyositis. J Autoimmun 2014;48–49:122–7. 6. Robinson, AB, Reed AM. Clinical features, pathogenesis and treatment of juvenile and adult dermatomyositis. Nat Rev Rheumatol 2011;7:664–75. 7. Dalakas MC. Inflammatory muscle diseases. N Engl J Med 2015;372:1734–47. 8. Ceribelli A, De Santis M, Isailovic N, et al. The immune response and the pathogenesis of idiopathic inflammatory myositis: a critical review. Clin Rev Allergy Immunol 2017; 52:58–70. doi:10.1007/s12016-016-8527-x. 9. Ye Y, van Zyl B, Varsani H, Wedderburn LR, Ramanan A, Gillespie KM. Maternal microchimerism in muscle biopsies from children with juvenile dermatomyositis. Rheumatology 2012;51:987–91.

10. Prieto S, Grau JM. The geoepidemiology of autoimmune muscle disease. Autoimmun Rev 2010;9:A330–A334, doi:10. 1016/j.autrev.2009.11.006 11. Seidler AM, Gottlieb AB. Dermatomyositis induced by drug therapy: a review of case reports. J Am Acad Dermatol 2008;59:872–80. 12. Ali SS, Goddard Al, Luke JL, Donahue H, Derrick PA, Todd J, et al. Drug-associated dermatomyositis following Ipilimumab therapy. a novel immune-mediated adverse event associated with Cytotoxic T-Lymphocyte Antigen 4 Blockade. JAMA Dermatol 2015;151:195–9. 13. Lu X, Yang H, Shu X, et al. Factors predicting malignancy in patients with polymyositis and dermatomyostis: a systematic review and meta-analysis. PLoS ONE 2014;9:e94128. doi:10.1371/journal.pone.0094128 14. Prohic´ A, Hadžimuratovic´ A, Kuskunovic´-Vlahovljak S, Jogunc´ic´ A. Risk factors associated with malignancy in paraneoplastic dermatomyositis. Medical J 2015; 21:13–6. 15. Jakubaszek M, Kwiatkowska B, Mas´lin´ska M. Polymyositis and dermatomyositis as a risk of developing cancer. Reumatologia 2015; 53(2):101–5. 16. Greenberg SA. Sustained autoimmune mechanisms in dermatomyositis. J Pathol 2014;233:215–16. 17. Hornung T, Wenzel J. Innate immune-response mechanisms in dermatomyositis: an update on pathogenesis, diagnosis and treatment. Drugs 2014;74:981–98. 18. Venalis P, Lundberg IE. Immune mechanisms in polymyositis and dermatomyositis and potential targets for therapy. Rheumatology 2014;53:397–405. 19. Olazagasti J, Niewold TB, Reed AM. Immunological biomarkers in dermatomyositis. Curr Rheumatol Rep 2015;17:68–73. doi: 10.1007/s11926-015-0543-y.

Chapter 34: Dermatomyositis 20. Satoh M, Tanaka S, Ceribelli A, Calise J, Chan EK. A comprehensive overview on myositis-specific antibodies: new and old biomarkers in idiopathic inflammatory myopathy. Clin Rev Allergy Immunol 2017;52:1–19. DOI 10.1007/ s12016-015-8510-y 21. Bohan A, Peter JB. Polymyositis and dermatomyositis (part 1). N Engl J Med 1975;292:344–7. 22. Bohan A, Peter JB. Polymyositis and dermatomyositis (part 2). N Engl J Med 1975;292:403–7. 23. Hoogendijka JE, Amatob AA, Leckyc BR, et al. 119th ENMC International Workshop: trial design in adult idiopathic inflammatory myopathies, with the exception of inclusion body myositis, 10–12 October 2003, Naarden, The Netherlands. Neuromuscular Disorders 2004;14:337–45. 24. Muro Y, Sugiura K, Akiyama M. Cutaneous manifestations in dermatomyositis: key clinical and serological features—a comprehensive review. Clin Rev Allergy Immunol 2016;51:293–302. doi: 10.1007/s12016-015-8496-5 25. Navarrete G, Jurado Santa-Cruz F, Maya S. Pápulas de Gottron. Alteraciones histológicas. Dermatol Rev Mex 2013;57:95–8. 26. Russo T, Piccolo V, Ruocco E, Baroni A. The heliotrope sign of dermatomyositis: the correct meaning of the term heliotrope. Arch Dermatol 2012;148. 27. Zaiac MN, Walker A. Nail abnormalities associated with systemic pathologies. Clin Dermatol 2013;31:627–49. 28. García-Arpa M, Ramírez-Huaranga MA, Ramos-Rodríguez C, Flores Terry MA. Mechanic hands and feet: a clinical sign of systemic disease. Piel (Barc) 2016;31:250–3. 29. Gitiaux C, De Antonio M, Aouizerate J, et al. Vasculopathyrelated clinical and pathological features are associated with severe juvenile dermatomyositis. Rheumatology 2016;55:470–9. 30. Hughes M, Herrick AL, Raynaud’s phenomenon, best practice & research. Clin Rheumatol 2016;30:112–132. doi: http://dx.doi.org/10.1016/j.berh.2016.04.001 31. Callen JP, Wortmann RL. Dermatomyositis. Clin. Dermatol. 2006;24,363–73. 32. Valenzuela A, Chung L, Casciola-Rosen L, Fiorentino D. Identification of clinical features and autoantibodies associated with calcinosis in dermatomyositis. JAMA Dermatol. 2014;150:724–9. 33. Wang J, Guo G, Chen G, et al. Meta-analysis of the association of dermatomyositis and polymyositis with cancer. Br J Dermatol 2013;169:838–47. 34. Requena C, Alfaro A, Traves V, et al. Paraneoplastic dermatomyositis: a study of 12 cases. Actas Dermosifiliogr. 2014;105:675–82.

35. Galimberti F, Li Y, Fernandez AP. Clinically amyopathic dermatomyositis: clinical features, response to medications and malignancy-associated risk factors in a specific tertiarycare-centre cohort. Br J Dermatol 2016;174:158–64. 36. Aguayo R, Casanova JM. Amyopathic dermatomyositis. Piel (Barc) 2012;27:77–81. 37. Wang Y, Wu Y, Chen T. Overlap syndrome of type Wong variant dermatomyositis and rheumatoid arthritis. Dermatologica Sinica 2014;32: 58–61. 38. Lobato-Berezo A, Martínez-Pérez M, Imbernón-Moya A, et al. Flagellate erythema: a rare presentation of dermatomyositis. Piel (Barc) 2014;29:347–49. 39. Eirís N, González-Lara L, Vázquez-López F, Pérez-Oliva N. Cutaneous mucinosis as the initial sign of paraneoplastic dermatomyositis: case presentation and literature review. Piel (Barc) 2015;30:95–8. 40. Hozumi H, Enomoto N, Kono M, et al. Prognostic significance of anti-aminoacyltRNA synthetase antibodies in polymyositis/dermatomyositis-associated interstitial lung disease: a retrospective case control study. PLoS ONE 2015:1–14. doi:10.1371/journal.pone.0120313. 41. Vattemi G, Mirabella M, Guglielmi V, et al. Muscle biopsy features of idiopathic inflammatory myopathies and differential diagnosis. Autoimmun Highlights 2014; 5: 77–85. 42. Karri SB, Muthu Kannan MA, Rajashekhar L, Uppin MS, Challa S. Clinico pathological study of adult dermatomyositis: importance of muscle histology in the diagnosis. Ann Indian Acad Neurol 2015;18:194–9. 43. Iorizzo III LJ, Jorizzo JL. The treatment and prognosis of dermatomyositis: an updated review. J Am Acad Dermatol 2008;59:99–112. 44. Rodriguez-Caruncho C, Bielsa Marsol I. Antimalarials in dermatology: mechanism of action, indications, and side effects. Actas Dermosifiliogr. 2014;105:243–52. 45. Needham M, Mastaglia FL. Immunotherapies for immune-mediated myopathies: a current perspective. Neurotherapeutics 2016;13:132–46. 46. Wright NA, Vleugels RA, Callen JP. Cutaneous dermatomyositis in the era of biologicals. Semin Immunopathol 2016;38:113–21. 47. Marie I. Morbidity and mortality in adult polymyositis and dermatomyositis. Curr Rheumatol Rep 2012;14: 275–85. 48. Ishizuka M, Watanabe R, Ishii T, et al. Long-term follow-up of 124 patients with polymyositis and dermatomyositis: statistical analysis of prognostic factors. Mod Rheumatol 2016;26:115–120. doi: 10.3109/14397595.2015.1054081

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35

Scleroderma Sara Hogan, Anthony Fernandez

EPIDEMIOLOGY AND GENETICS Systemic sclerosis (SSc) is a rare, chronic autoimmune disease primarily affecting connective tissue and microvasculature. It is characterized by fibrosis of the skin, lungs, heart, kidneys, and gastrointestinal tract. Estimated prevalence is 276 cases per million adults and annual incidence is 20 new cases per million adults per year, with higher numbers in the United States compared to Europe and Japan.1 Onset is typically during the fourth to sixth decades, but may begin in childhood or late adulthood. The femaleto-male ratio is 3–4:1, but males tend to have more severe disease and have higher risk of diffuse cutaneous subtype, digital ulcers, and cardiopulmonary involvement.2 African-American patients are almost twice as likely to have diffuse disease compared to White patients, and have a younger age of onset.1 Cochtaw Native Americans have one of the highest prevalence rates of SSc, with 14 cases per 21,255 Cochtaw individuals.3 There is less than 1.6% frequency of disease among first-degree relatives, but family history of SSc is regarded as the strongest risk factor for this condition. Family history increases the risk of developing the disease by 13 to 15 times in first-degree relatives, and 15 to 19 times in siblings.4–7 Molecular genetic studies have identified susceptibility factors via genome scanning on three chromosomes outside of human leukocyte antigen (HLA) regions: fibrillin on chromosome 15, SPARC on chromosome 5, and topoisomerase I on chromosome 20.3,8 Other susceptibility genes associated with development of disease include signal transducer and activator of transcription-4 (STAT4), interferon regulatory factor-5 (IRF5), and B cell scaffold protein with ankyrin repeats-1 (BANK-1).9,10 Certain HLA subtypes, including HLA-DPB1 and -DPB2 have been associated with risk in some populations.11

PATHOGENESIS Like most autoimmune diseases, SSc onset is hypothesized to occur in genetically susceptible individuals

after some external trigger. The initiating trigger(s) is usually unclear, but may include infectious organisms [parvovirus, cytomegalovirus (CMV)], or underlying malignancies. Once initiated, the pathogenesis of SSc is hypothesized to involve three mechanisms: (1) vascular abnormalities resulting in endothelial destruction, (2) altered T- and B-cell immune functions resulting in autoantibody production, and (3) fibroblast dysfunction leading to increased extracellular matrix (ECM) deposition8 (Fig. 35.1). The exact interactions among these three disease mechanisms that lead to clinical manifestations of SSc also remains uncertain. Early SSc pathogenesis is hypothesized to involve endothelial injury caused by endogenous or exogenous factors. Vascular abnormalities include underproduction of nitrous oxide (NO) and overproduction of vasoconstrictor endothelin-1, which likely contributes to local ischemia and vasospastic episodes.12 Subsequent increased expression of proangiogenic factors [i.e. vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), smooth muscle derived growth factor-1 (SDGF1), tumor growth factor beta-β (TGF-β), endothelin-1] then causes vascular permeability.13 This can precede fibrosis by months-to-years, and manifests clinically as tissue edema and nailfold capillary changes.13 Despite the presence of proangiogenic factors, SSc tissue paradoxically displays impaired and abnormal angiogenesis, possibly due to decreased numbers of endothelial progenitor cells.13–15 Potent vascular smooth muscle activators are upregulated, causing fibrointimal proliferation and contributing to vasospastic episodes. In small vessels, this corresponds clinically with Raynaud’s phenomenon and tissue ischemia; in larger vessels, this manifests as pulmonary arterial hypertension (PAH) or scleroderma renal crisis (SRC).14 Repetitive ischemia-reperfusion episodes result in formation of reactive oxygen species.16 Microvascular damage incites platelet activation and thrombi formation, perpetuating ischemia.17,18 Chemokines upregulated at sites of microinjury promote both B-cell maturation and autoantibody formation, as

Chapter 35: Scleroderma

Fig. 35.1: Pathogenesis of systemic sclerosis. © Cleveland Clinic Foundation.

well as T-cell differentiation into Th2 subsets, which are thought to play a major role in fibrosis.14 In the later phase of scleroderma, fibroblasts are recruited by cytokines (e.g. IL-13) and growth factors [e.g. connective tissue growth factor (CTGF), PDGF] to differentiate into myofibroblasts, which in the setting of increased TGF-β signaling, increase collagen and ECM protein synthesis to cause tissue fibrosis.14,19 Once initiated, fibrosis is escalated through multiple feed-forward amplification loops, resulting in a vicious cycle.12,20 A growing body of evidence suggests SSc pathogenesis is partly mediated by circulating progenitor cells (CPCs), specifically of endothelial origin. During SSc pathogenesis, CPCs mobilize from bone marrow and migrate through blood vessels to tissue, where they secrete signaling proteins directing cell differentiation. Characterization of CPC populations corresponds with the degree of fibrosis and vascular involvement in different clinical SSc

phenotypes.13,21 Additionally, DNA microarrays of skin biopsies from SSc patients found a wide diversity of genes expressed based on differing SSc phenotypes, suggesting some degree of pathophysiologic diversity among SSc patients.22

CLINICAL MANIFESTATIONS SSc is divided into three clinical subsets based on the extent of skin fibrosis: diffuse cutaneous systemic sclerosis (dcSSc), limited cutaneous systemic sclerosis (lcSSc), and sine scleroderma.

Diffuse Cutaneous Systemic Sclerosis Diffuse cutaneous systemic sclerosis (dcSSc) is typically heralded by arthralgias, edematous hands, feet, and/ or legs, and positive antinuclear antibody (ANA) titer. Raynaud’s phenomenon typically develops within 1 year

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Section 11: Connective Tissue Diseases of symptom onset, but is usually not a prodrome to other symptoms. This is followed by skin thickening/induration involving fingers and hands, and extending proximally to the forearms, arms, legs, and trunk within several months.23 In dcSSc, any part of the skin may develop fibrosis. Internal organ dysfunction begins early, with severe dysfunction usually present within 3 years. Late stages of dcSSc are actually characterized by skin fibrosis regression. Following regression of proximal skin thickening, fatigue, arthralgias, and tendon rubs begin to subside. However, not all manifestations of SSc subside and complications resulting from visceral fibrosis often dominate the patient’s medical issues (pulmonary hypertension, esophageal strictures, malabsorption, and cardiac abnormalities).

Limited Cutaneous Systemic Sclerosis Limited cutaneous systemic sclerosis (lcSSc) was previo­ usly referred to as CREST (calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodacytly, telangiectasia) syndrome. Early lcSSc is characterized by Raynaud’s phenomenon with or without digital tip ulcerations, which are often present one to two decades before any other manifestations appear. Eventually patients develop mild digital swelling or heartburn, and these are often the reasons why they initially seek medical attention. Unlike in dcSSc, pulmonary fibrosis is uncommon in early stages, and myocardial or renal involvement is unusual. With time, skin fibrosis occurs but is limited in lcSSc to the distal extremities and does not occur proximal to the elbows or knees, though the head and neck may be affected.23 Late stages of lcSSc are characterized by stable skin fibrosis without further progression, but 85% of patients develop mat-like telangiectasias and many develop calcinosis cutis.23 Other common late-stage manifestations include digital tip ischemia/ulcerations, arthralgias, joint contractures, esophageal strictures, and pulmonary fibrosis. The most serious late-stage manifestation of lcSSc is the appearance of pulmonary artery hypertension, which most commonly presents as rapid progression of dyspnea on exertion over a several month period.

Evolution of Cutaneous Involvement Cutaneous involvement in SSc progresses through three stages.10,23–25 In the edematous phase patients display painless pitting edema of hands and fingers, which may also involve feet, legs, and forearms. Swelling lasts several weeks to months in those destined to develop dcSSc.

This is followed by the indurative phase, which may persist variably for many years and is characterized by slow (occasionally rapid) replacement of swelling with thickening and tightening of skin. The skin becomes shiny, taut, and adherent to the subcutis. It is during the indurative phase that patients are generally diagnosed with SSc. Finally, the atrophic phase occurs later in the disease course and here skin may revert to normal thickness or may atrophy, looking thin and tethered to underlying connective tissue. Although involvement of other organs can often lead to death, cutaneous involvement in SSc can have a tremendous negative impact on patients’ lives. Skin involvement is often associated with pain, pruritus, and limited range of motion. Pruritus is a particularly common symptom in SSc, affecting 42% of patients across the disease course, and is associated with the degree of both skin and gastrointestinal involvement.26 Pruritus can often be severe and generalized, and can affect to negative quality of life. Additionally, ischemic skin ulcerations can contribute to pain or lead to infections, which can be life threatening. The degree of skin involvement correlates with survival and prognosis: patients with higher peak Modified Rodnan Skin Scores (MRSSs; see below) have higher mortality.10,27,28 Additionally, extent of cutaneous involvement correlates with the impact on quality of life.10 SSc patients have significant morbidity, and the mortality rate is 2.7 times that of the general population.29 SSc has the highest case-specific mortality of any rheumatological disease, with a 10-year survival of 70–80%.30,31 Interstitial lung disease is the most common cause of death. Malignancy can also lead to death and SSc patients are at higher risk of many malignancies, specifically oropharyngeal (tongue) and esophageal cancers.32 Various mechanisms potentially underlie the relationship between SSc and malignancy, including (1) SSc occurring as a paraneoplastic phenomenon; (2) malignancy arising secondary to SSc-induced tissue changes; and (3) malignancy arising secondary to immunosuppressive SSc therapies.32 Risk of malignancy diagnosis peaks during the first 12 months after SSc diagnosis, and it is recommended that newly diagnosed patients receive age-appropriate malignancy screenings.33,34

DIAGNOSIS Skin involvement is often the first clinical sign leading to diagnosis, as cutaneous signs are usually at the forefront of patients’ complaints. The differential diagnosis for SSc includes metabolic conditions such as scleredema, scleromyxedema, and porphyrias; inflammatory conditions

Chapter 35: Scleroderma such as sclerodermoid graft-versus-host disease (GVHD), eosinophilic fasciitis (EF), and acrodermatitis chronica atrophicans; paraneoplastic conditions such as systemic amyloidosis, polyneuropathy, organomegaly, endocrinopathy, mono­clonal protein, skin changes (POEMS), and carcinoid tumor; as well as sclerosing conditions secondary to drugs and toxins such as nephrogenic systemic fibrosis (NSF) or toxic oil syndrome. A history and review of systems can often exclude many of these conditions. Since they are involved in all SSc patients, meticulous physical examination of the hands and fingers is particularly important in making a diagnosis. Enlarged proximal nailfold (PNF) capillary loops, hemorrhages, and areas of PNF avascularity (i.e. capillary dropout) are strongly suggestive of a SSc-spectrum disorder in the setting of Raynaud’s phenomenon.35–38 Capillaroscopy plays a key role in assessing PNF capillary abnormalities. Nailfold videocapillaroscopy (NVC) with magnification up to 200 times is the current gold standard.39 NVC requires specialized equipment that is not as readily available as the dermatoscope, which typically only has magnification of 10 times. Hughes et al. found the two techniques to be comparable, though NVC images were more classifiable and graded more severely.40 The authors typically use dermatoscopes to assess PNF changes in patients and find them to be useful and adequate. In 2013, the American College of Rheumatology published updated diagnostic criteria for SSc to include the following: skin thickening of fingers of both hands extending proximal to the metacarpophalangeal joint (9 points; sufficient for SSc diagnosis), skin thickening of fingers (2–4 points), Raynaud’s phenomenon (3 points), abnormal nailfold capillaries (2 points), fingertip lesions (e.g. digital ulcers or pitting scars (2–3 points), telangiectasias (2 points), pulmonary manifestations (e.g. interstitial lung disease, pulmonary hypertension) (2 points), SSc-specific autoantibodies (e.g. anticentromere, anti-Scl-70, antiRNA polymerase III) (3 points). A total score of ≥9 denotes a definitive diagnosis of SSc.39 Patients with skin thickening that spares the fingers are classified as not having SSc. Several items useful for recognizing SSc in clinical practice not included in the updated diagnostic criteria include calcinosis, flexion contractures of the fingers, tendon or bursal friction rubs, renal crisis, esophageal dysmotility, and dysphagia. These were considered but did not substantially improve sensitivity or specificity.39,41 Once a diagnosis is made, standardized palpation to assess thickness of skin (versus tethering of skin) is the preferred method of assessing disease involvement, though ultrasonographic scoring is more objective.42 The Rodnan

Fig. 35.2: Modified Rodnan Skin Score (MRSS). 17 anatomic locations on the skin (7 areas assessed bilaterally) are assessed for skin induration using a grading scale of 0 (uninvolved) to 3 (severe thickening). The scores of all 17 locations are then added together to achieve the MRSS. Source: Reprinted from Chatterjee, S. Systemic Scleroderma. The Cleveland Clinic Disease Management Project (www.clevelandclinicmeded.com) © Cleveland Clinic Foundation.

skin score, first developed in 1978, is a semiquantitative tool to measure disease activity that incorporated weighing skin biopsies to measure collagen content.24 In recent years, the MRSS was developed as a validated tool to assess SSc severity and response to treatment. Skin thickness is palpated in 17 surface anatomic areas of the body and rated using a scale from 0 (normal skin) to 3 (severe thickness, inability to pinch the skin into a fold) (Fig. 35.2). The sum of these ratings is defined as the total skin score.43

LABORATORY FINDINGS Ninety percent of SSc patients have a positive ANA, typically in a speckled or nucleolar pattern.14 Three major subclasses of SSc antibodies are observed, and are mutually exclusive: (1) anticentromere antibodies, (2) anti-RNA polymerase III antibodies, and (3) antitopoisomerase 1 (anti-Scl70) antibodies.14 Anticentromere antibodies are found in about 90% of lcSSc/CREST patients and are associated with higher risk of PAH.20,44 Anticentromere antibodies have a strong negative association with SSc-associated pulmonary fibrosis and SRC. Anti-RNA polymerase III antibodies occur in 20% of dcSSc patients, and carry higher risk of SRC; among this subset of patients, approximately 20% are also noted to have an increased risk of underlying malignancy.33,45,46 Anti-Scl70 antibodies occurs in 20% of dcSSc patients and predicts worse prognosis; it is associated with increased risk of pulmonary fibrosis and mortality.47

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A

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C

Figs. 35.3A to C: Histopathology of systemic sclerosis and localized scleroderma. (A) Low-power view of a punch biopsy from a patient with systemic sclerosis. Note the square shape due to the increased collagen content. The epidermis is normal, but significant increases in (eosinophilic) collagen content are noted, especially in the mid-to-deep dermis. An overall loss of adnexae and vascular structures can also be appreciated at this low power. There is a mild perivascular inflammatory infiltrate associated with structures in the superficial-to-mid dermis; (B and C) Highpower view. (B) Normal eccrine glands with abundant surrounding adipocytes; (C) Eccrine glands in a patient with systemic sclerosis. Note the thickened collagen, near complete loss of surrounding adipocytes, and the compression of eccrine structures, giving a “bunched up” appearance.

HISTOPATHOLOGY SSc and localized scleroderma (LS; also called morphea) have indistinguishable histological features. Skin biopsies of early SSc lesions are performed less frequently, and demonstrate apoptotic endothelial cells, and both papillary and reticular dermal edema.14 In early stages there also tends to be a superficial and deep perivascular inflammatory infiltrate composed of lymphocytes and plasma cells, occasionally with rare eosinophils.48 Collagen bundle thickening at this stage is subtle. Biopsies of late SSc lesions demonstrate a distinctive “square biopsy sign” on low power, where increased dermal thickness due to increased collagen deposition causes borders to be parallel (as opposed to tapered in normal tissue). On higher power, increased amounts of homogenized eosinophilic collagen is observed to extend from the dermis to the subcutaneous connective tissue septae. Other features include eccrine glands situated relatively high in the dermis, loss of adipocytes surrounding eccrine glands, and loss of blood and lymphatic vessels (rarefaction)12,24,49–51 (Figs. 35.3A to C).

TREATMENT Early diagnosis and prompt initiation of systemic therapies is key to effective treatment of SSc. Current consensus among experts suggests that methotrexate (MTX; 15–20 mg weekly) should be first line treatment. MTX

has been shown to improve MRSS in early dcSSc, though positive effects on involved visceral organs have not yet been established.52 If response is inadequate after 8–12 weeks, mycophenolate mofetil (MMF; 1000–1500 mg BID) should be added to MTX or switched to as a second line treatment. Cyclophosphamide (starting dose, 500 mg/m2, subsequent infusions increased to 750 mg/m2) is an appropriate third line treatment, but should be considered earlier in the treatment algorithm if there is concurrent lung disease.53 Other treatments include azathioprine (2.5 mg/kg), which when taken over 12 months, has been shown to sustain MRSS53 Intravenous Immunoglobulin (IVIG) (2 g/kg administered over 2–5 days for 6 months) has been shown to reduce MRSS, but evidence is limited; it may, however, be particularly useful in SSc patients with concurrent myositis.53 The use of systemic prednisone in SSc remains controversial as some evidence suggests administration can precipitate SRC. Recently, hydroxychloroquine has been demonstrated to have antifibrotic properties in vitro, but its clinical use in SSc has not been well studied.54–56 There is limited evidence that phototherapy can be efficacious in SSc. Morita showed that, among four SSc patients treated with medium ultraviolet A1 (UVA1) at 60 J/cm2 administered over 10–30 treatments, patients had softened forearm skin and increased joint mobility.57 Other studies have demonstrated significant improvements in MRSS in both dcSSc and lcSSc patients with UVA1 dosed 30–60 J/cm2.58,59 UVA1 also addresses microstomia in SSc

Chapter 35: Scleroderma

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Figs. 35.4A and B: (A) A young woman diagnosed with diffuse systemic sclerosis (negative anti-RNA pol III Ab) by the authors during the early indurative phase (2–3 months) of the disease. In addition to induration and dyspigmentation of the face, she had prominent induration of the forearms, hands, upper back, and chest. Upon diagnosis she was initiated promptly on 10 mg prednisone daily, mycophenolate mofetil 1.5 g twice daily, hydroxychloroquine 200 mg twice daily, and UVA-1 phototherapy 50 J/cm2 three times weekly; (B) After 10 weeks of treatment on this regimen her skin showed remarkable reversal of induration and dyspigmentation in all areas on her body, most notably the forearms and hands (not shown). Although she continues to have mild-to-moderate involvement of her GI tract, her skin has remained normal (MRSS essentially 0) since this treatment over 5 years ago.

by softening perioral skin.60 UVA1 appears to have no effect on visceral organ involvement, though. The authors believe skin fibrosis can definitely be reversed with aggressive combination therapy that includes UVA1 phototherapy if initiated early enough in the disease course based on their clinical experience (Figs. 35.4 and 35.5). Raynaud’s phenomenon treatment should begin when patients become symptomatic with pain and/or ulceration at involved sites. In patients with mild Raynaud’s phenomenon (RP) (3 cm), which become confluent and involve at least 2 of 7 anatomic sites (head/neck, each extremity, anterior trunk, posterior trunk) Pansclerotic Circumferential involvement of limb(s) affecting skin, subcutaneous tissue, muscle and bone. Lesions may involve other anatomic sites, but without internal organ involvement Mixed variant Combination of two or more previous subtypes

A

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Figs. 35.6A and B: Circumscribed localized scleroderma or plaque morphea on trunk.

have relapsing disease, occurring years after quiescence, and extracutaneous involvement.89,90 The frontal subtype of linear LS or “En Coup de Sabre” (ECDS) presents as a paramedian forehead streak. The term ECDS is derived from a French descriptive suggesting the clinical presentation resembles the shape of a sword strike. Progressive facial hemiatrophy, or Parry–Romberg syndrome, is a deep linear LS subtype. There is mild or absent involvement of the superficial skin, but there is sclerosis of dermis with extension to muscle and bone77 (Fig. 35.7). Arthralgias are the most common extracutaneous finding of linear LS, and may occur at joints unrelated to sites

of skin lesions.86 Facial linear LS (ECDS) can have ocular involvement (anterior uveitis, anterior segments inflammation), dental abnormalities and central nervous system (CNS) involvement leading to seizures.77,91 It is recommended that these patients undergo MRI imaging to determine presence and extent of CNS involvement (mani­fested as calcifications and hyperdensities in subcortical white matter), and ophthalmologic screening every 3–4 months during the first three years following diagnosis.92,93 Lichen sclerosus et atrophicus and atrophderma of Pasini and Pierini can be associated with previous subtypes but are not included in above classification.86

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Laboratory Findings

Fig. 35.7: Linear localized scleroderma, mild progressive facial hemiatrophy subtype (Parry–Romberg syndrome). Frontal view displaying atrophy of the forehead and subtle atrophy of the left infraorbital face.

Generalized LS initially begins as circumscribed LS with large individual plaques that coalesce to involve ≥3 contiguous or disparate anatomic sites (head and neck, extremities, and/or trunk). Unilateral generalized morphea is an exceedingly rare variant which has been described only in childhood.94 Panscrelotic LS is a rare, severe variant that involves full thickness fibrosis of the scalp, face, trunk, and extremities. It is differentiated from SSc by the lack of internal organ involvement. Pansclerotic LS is more common in children than adults. Extracutaneous manifestations include fatigue, myalgias, and arthralgias, which can precede skin manifestations by months. Affected patients are disabled and often develop ulcers at contracture sites. Approximately 7% of pansclerotic LS patients develop cutaneous squamous cell carcinomas, occurring both within ulcers and non-ulcerated sites.95,96

Diagnosis Diagnosis of LS typically is made with a skin biopsy showing histologic features of LS/SSc in the appropriate clinical setting. The differential diagnosis includes lichen sclerosus, but distinction can be made based on histologic differences. The differential diagnosis for generalized LS includes lipodermatosclerosis, sclerosis at injection sites, cutaneous malignancy, and radiationinduced sclerosis.48 Pansclerotic LS and generalized LS can be distinguished from SSc by absence of Raynaud’s phenomenon, PNF capillary changes, and lack of visceral organ involvement.

Adults and children with LS have an increased prevalence of autoimmune disorders in family members. Nearly half of generalized LS patient have other concurrent autoimmune disease, suggesting LS may in fact be a systemic autoimmune disease.79 ANA positivity (homogenous and speckled patterns) is most frequent in mixed and generalized LS subtypes. Anti-topoisomerase II-α antibodies are more prevalent in LS patients compared to other autoimmune diseases.97 Antihistone autoantibodies, in particular, are more prevalent in linear LS patients and is associated with increased lesional burden and functional impairment.98,99 Antisingle stranded DNA antibodies are also correlated with linear LS disease severity, and have significant association with extensive body surface area involvement.99

Treatment Treatment of LS ideally begins during the early inflammatory stages of the disease. The mainstay of treatment for circumscribed or limited plaque LS is skin-directed therapies, while linear, generalized, pansclerotic, and mixed variants typically require systemic therapies. Topical calcineurin inhibitors (e.g. tacrolimus) and corticosteroids are considered first-line therapy for LS patients with circumscribed lesions.100 Tacrolimus has been shown in several studies to promote resolution of early LS lesions and softening of late LS lesions with twice daily application.101–103 Calcipotriene and imquimod have been studied but do not appear to be effective treatments.104,105 Patients with more severe LS subtypes should be treated with glucocorticoids in combination with other systemic immunosuppressants. Zulian et al. evaluated pediatric LS patients treated with a 3-month course of prednisone, then with MTX 15 mg/m2 or placebo. MTX was associated with a significantly lower relapse rate compared to placebo.106 A study of pediatric LS patients given intravenous steroids dosed 30 mg/kg day for three days a month and MTX dosed 0.6 mg/kg per week revealed disease improvement by month 3, with disease staying inactive through 33 months follow up.107 Adults with LS receiving intravenous methylprednisolone 1000 mg/day × 3 days per month and MTX 15 mg/week also had improvement of disease.108 A retrospective study evaluating the combination of pulsed corticosteroids and MTX revealed significant clinical improvement at 3–8 months. However, relapse occurred in 44% of patients after ending treatment.109 Treatment

Chapter 35: Scleroderma should be initiated promptly in linear LS patients who have involvement of joints to minimize contractures. Generalized LS patients may benefit from the addition of MMF to the above combination therapy. Increasing evidence suggests phototherapy is an effective treatment for LS. UVA1 phototherapy, unlike UVB, penetrates skin to the mid and lower dermis where LS activity is prevalent. Kreuter et al. compared low-dose UVA1 (10–20 J/cm2), medium dose UVA1 (30–50 J/cm2), and narrowband UVB (311 nm) in limited LS and found that all three therapies improved modified skin scores, but medium dose UVA1 had significantly better results than other two modalities.110 A systemic review of 11 studies evaluating phototherapy in LS concluded that UVA1, psoralen with UVA (PUVA) and narrowband UVB are all effective for limited LS, with UVA1 and PUVA being particularly effective for circumscribed deep LS.111 This is hypothesized to be due to UVA1’s ability to induce T-cell apoptosis, stimulate collagenase mRNA expression, downregulate inflammatory cytokines IL-6 and IL-8 and promote neovascularization.112–116 There is no consensus regarding UVA1 dosing, but medium-dose UVA1 (40–80 J/cm2) may be more effective than low-dose UVA1 (≤40 J/cm2) in treatment of LS.117 The recommended UVA1 schedule for both LS and SSc is two to three times weekly, for a total 20 to 40 sessions.118 Improvement observed with UVA1 therapy continues for several months after treatment is stopped.119 Among LS patients treated successfully with UVA1, about 50% will have disease recurrence after three years, suggesting that maintenance therapy may be beneficial.119 Limitations of UVA1 include that it can be time consuming for patients and it is not widely available. In cases where UVA1 is not feasible, broadband UVB or PUVA could be used.100 There is ongoing debate whether UVA1 is effective among LS patients with dark skin tones (Fitzpatrick Types IV, V, IV).120, 121 It is interesting to note that given the high proportion of LS patients with ANA positivity, there are no reported photosensitivity problems among those treated with UV therapy.100 Extracorporeal photopheresis has good response in generalized LS, both with and without bullous changes, but evidence is limited to case reports and achieving insurance coverage approval is difficult.122–124

EOSINOPHILIC FASCIITIS (SHULMAN SYNDROME) EF is a rare sclerosing disorder that is closely related to deep LS. Classically, onset of EF is preceded by an episode

of rigorous physical activity. Clinical presentation varies, but typically EF presents as edema of distal extremities that progresses to peau d’orange appearance and hyperpigmentation, and finally to induration. The epidermis is spared and tethering of the deep dermis to the subcutis and muscle gives the appearance of venous furrowing, also known as the “river bed” or “groove” sign.125 EF can be distinguished from SSc by the absence of Raynaud’s phenomenon and hand involvement. Common laboratory findings in EF patients include peripheral eosinophilia and/or monoclonal gammopathy. Diagnosis is made by deep biopsy down to muscle. Histology shows thickened collagen bundles extending from the dermis to the subcutaneous connective tissue septae and fascia, and an infiltrate composed of lymphocytes, plasma cells and eosinophils.49,50 Systemic corticosteroids are the first line treatment, but variable response to treatment among EF patients often necessitates longterm therapy and the addition of other agents, like MTX.126 Like in SSc, the authors believe effective treatment is more often seen when aggressive combinations regimens are initiated relatively early in the fibrotic process. EF can lead to contractures and impairment of joint mobility. Routine MRI may be utilized to monitor disease progression and treatment response.127

LICHEN SCLEROSUS (LICHEN SCLEROSUS ET ATROPHICUS, KRAUROSIS VULVAE, BALANITIS XEROTICA OBLITERANS) Lichen sclerosus is an uncommon chronic inflammatory disease that occurs primarily in the anogenital region, with 6% of cases involving isolated extragenital skin.128 LS has an unknown prevalence. LS occur more frequently in females and with peak ages of presentation during prepuberty and postmenopause.128,129 Little is known about the etiology of LS, though elevated circulating IgG autoantibodies against ECM1 protein have been demonstrated in both females and male anogenital LS patients.130, 131 A current leading theory proposes that the chronic irritation of genital epithelium exposes epitopes, which leads to autoantibody formation in patients with autoimmune diathesis.131 LS typically presents as atrophic white or “porcelain” plaques, often with an erythematous to violaceous rim. Symptomatic patients experience significant pruritus, burning, and pain, prompting chronic scratching. This cycle results in lichen simplex, erosions, purpura, and even

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Section 11: Connective Tissue Diseases bullae. Chronic irritation of lesions places patients at risk of squamous cell carcinoma transformation. Most patients, however, are asymptomatic, and as such, diagnosis is often delayed in LS. In advanced disease, patients develop scarring and loss of vulvar architecture with narrowing of the introitus and flattening of the labina minora.128,129 Diagnosis of LS is mostly clinical. Differential diagnosis includes morphea, lichen planus, discoid lupus erythematosus, and acrodermatitis chronica atrophicans. Biopsy is performed in cases where diagnosis is not clear or there is question of malignant transformation. Histology of early LS lesions may be subtle. Histologic features of chronic LS lesions include hyperkeratosis, epidermal atrophy, and vacuolar interface changes.49,50 The mainstay of LS treatment is continued suppressive therapy with ultrapotent topical steroids, with increased frequency of application at times of inflammation. Patient should be advised to avoid irritants in personal products. In corticosteroid-resistant cases, topical calcineurin inhibitors, topical retinoids (especially in the case of hyperkeratotic lesions), and photodynamic therapy may be used.128 Long-term surveillance is necessary given the risk of SCC development in LS patients. Circumcision may be helpful in penile LS cases. Emerging therapies for vulvar LS include platelet-rich plasma therapy intralesional injections.132

NEPHROGENIC SYSTEMIC FIBROSIS NSF is an exceedingly rare condition, first reported in 2000 among a cohort of 14 renal disease patients who developed scleromyxedema-like skin changes after exposure to MRI gadolinium-based contrast agents (GBCA). Skin lesions can be “ameboid” patterned, fixed, red to violaceous plaques or markedly indurated, hyperpigmented, “bound down” plaques over the extremities. Joint contractures are noted, with loss of motion of the elbows, wrists, fingers, and knees or ankles. Patient may experience atypical, burning or “sizzling” pain requiring narcotics.133 Differential diagnosis includes LSc and SSc, lipodermatosclerosis, scleromyxedema, sclerodermoid porphyria cutanea tarda, EF, and Dupuytren’s contracture. Diagnosis of NSF is challenging, and relies upon clinicopathological correlation. Patients nearly always have a history of acute or chronic kidney injury, dialysisdependence, or renal transplantation. Cumulative lifetime exposure to GBCA is an independent risk factor for developing NSF, and gadolinium has been detected in tissue of those affected by NSF.133,134 Histological findings of NSF lesions include preserved elastic tissue (in contrast to LSc/

SSc) and thin and thick collagen bundles in the dermis, expansion of interlobular adipose septa by collagen, and osseous metasplasia around elastic fibers.133 NSF is a chronic, progressive condition for which there are few known effective therapies. Extracorporeal photopheresis, IVIG, UVA-1 and photodynamic therapy, all have been shown in case studies to provide some benefit. Lifelong avoidance of GBCA after NSF diagnosis is essential.

STIFF SKIN SYNDROME Stiff skin syndrome (SSS) is a rare scleroderma-like condition characterized by rock-hard skin, hypertrichosis, and restricted joint mobility with the absence of visceral or muscle involvement or serologic findings. The pathogenesis of SSS is unknown, but it is likely due to a primary fibroblast dysfunction or fascial dystrophy.135 Segmental and familial forms of SSS have been described, suggesting a possible genetic component. Onset typically occurs during infancy or early childhood. Body areas with abundant fascia, such as the legs and buttocks are most often involved.135 Histological findings include increased fibroblast cellularity in the deep reticular dermis and subcutaneous tissue and fascial sclerosis without associated inflammation.135 Differential diagnosis includes scleredema, deep LSc, and SSc. SSS is slowly progressive and non-fatal. Treatment focuses on slowing disease progression and addressing skin lesions and joint contractures, and includes physical therapy, systemic, intralesional and topical steroids, methotrexate, and PUVA.

EXOGENOUS SUBSTANCE-INDUCED SCLERODERMOID CHANGES Environmental and industrial exposures (silica, dust, organic solvents, vinyl chloride, contaminated rapeseed oil), and several drugs (bleomycin, cocaine, pentazocine) have all been reported to cause sclerodermoid skin changes in exposed individuals.136,137

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Section 11: Connective Tissue Diseases 40. Hughes M, et al. A study comparing videocapillaroscopy and dermoscopy in the assessment of nailfold capillaries in patients with systemic sclerosis-spectrum disorders. Rheumatology (Oxford) 2015;54:1435–42. 41. Alhajeri H, et al. 2013 American College of Rheumatology/ European League against rheumatism classification criteria for systemic sclerosis outperform the 1980 criteria: data from the Canadian Scleroderma Research Group. Arthritis Care Res (Hoboken) 2015;67:582–7. 42. Moore TL, et al. Seventeen-point dermal ultrasound scoring system–a reliable measure of skin thickness in patients with systemic sclerosis. Rheumatology (Oxford) 2003;42:1559–63. 43. Clements PJ, et al. Skin thickness score in systemic sclerosis: an assessment of interobserver variability in 3 independent studies. J Rheumatol 1993;20:1892–6. 44. Gabrielli A, Avvedimento EV, Krieg T, et al. N Engl J Med 2009;360:1989–2003. 45. Okano Y, Steen VD, Medsger Jr. TA. Autoantibody reactive with RNA polymerase III in systemic sclerosis. Ann Intern Med 1993;119:1005–13. 46. Parker JC, et al. Anti-RNA polymerase III antibodies in patients with systemic sclerosis detected by indirect immunofluorescence and ELISA. Rheumatology (Oxford) 2008;47:976–9. 47. Koenig M, Dieude M, Senecal JL. Predictive value of antinuclear autoantibodies: the lessons of the systemic sclerosis autoantibodies. Autoimmun Rev 2008;7:588–93. 48. Fett N, Werth VP, Update on morphea: part I. Epidemiology, clinical presentation, and pathogenesis. J Am Acad Dermatol 2011;64:217–28; quiz 229–30. 49. Patterson JW. Weedon’s skin pathology. 4th ed. Elsevier; 2015:305–309 50. McKee PH, Calonje E, Granter SR. Pathology of the skin: with clinical correlations. 3rd ed. (Eds:) McKee PH, Calonje E, Granter SR. Edinburgh, Philadelphia: Elsevier Mosby; 2005, v . 51. Czirjak L, Foeldvari I, Muller-Ladner U. Skin involvement in systemic sclerosis. Rheumatology (Oxford) 2008;47:v44–5. 52. Kowal-Bielecka O, et al. EULAR recommendations for the treatment of systemic sclerosis: a report from the EULAR Scleroderma Trials and Research group (EUSTAR). Ann Rheum Dis 2009;68:620–8. 53. Frech TMS, Shah VK, Assassi AA, et al. Treatment of early diffuse systemic sclerosis skin disease. Clin Exp Rheumatol 2013;31:166–71. 54. Oikarinen A. Hydroxychloroquine induces autophagic cell death of human dermal fibroblasts: implications for treating fibrotic skin diseases. J Invest Dermatol 2009;129:2333–5. 55. Ramser B, et al. Hydroxychloroquine modulates metabolic activity and proliferation and induces autophagic cell death of human dermal fibroblasts. J Invest Dermatol 2009;129:2419–26. 56. Walker KM, et al. Treatment of systemic sclerosis complications: what to use when first-line treatment fails–a consensus of systemic sclerosis experts. Semin Arthritis Rheum 2012; 42:42–55.

57. Morita A, et al. Ultraviolet A1 (340–400 nm) phototherapy for scleroderma in systemic sclerosis. J Am Acad Dermatol 2000;43:670–4. 58. Kreuter A, et al. Low-dose UVA1 phototherapy in systemic sclerosis: effects on acrosclerosis. J Am Acad Dermatol 2004;50:740–7. 59. Rose RF, et al. Low-dose UVA1 phototherapy for proximal and acral scleroderma in systemic sclerosis. Photodermatol Photoimmunol Photomed 2009;25:153–5. 60. Tewari A, et al. Successful treatment of microstomia with UVA1 phototherapy in systemic sclerosis. Photodermatol Photoimmunol Photomed 2011;27:113–4. 61. White B, et al. Cyclophosphamide is associated with pulmonary function and survival benefit in patients with scleroderma and alveolitis. Ann Intern Med 2000;132:947–54. 62. Wigley FA. Raynaud’s phenomenon. N Engl J Med 2002;3.47:1: 001–1008. 63. Uppal L, Dhaliwal K, Butler PE. A prospective study of the use of botulinum toxin injections in the treatment of Raynaud’s syndrome associated with scleroderma. J Hand Surg Eur Vol 2014;39:876–80. 64. Murata K, et al. Long-term follow-up of periarterial sympathectomy for chronic digital ischaemia. J Hand Surg Eur Vol 2012;37:788–93. 65. Frech T, et al. Low-dose naltrexone for pruritus in systemic sclerosis. Int J Rheumatol 2011; 2011:804296:1–5 66. Lafyatis R, et al. B cell depletion with rituximab in patients with diffuse cutaneous systemic sclerosis. Arthritis Rheum 2009;60:578–83. 67. Daoussis D, et al., Experience with rituximab in scleroderma: results from a 1-year, proof-of-principle study. Rheumatology (Oxford) 2010;49:271–80. 68. Bournia VK, Evangelou K, Sfikakis PP. Therapeutic inhibition of tyrosine kinases in systemic sclerosis: a review of published experience on the first 108 patients treated with imatinib. Semin Arthritis Rheum 2013;42:377–90. 69. Daniels CE, et al. Imatinib treatment for idiopathic pulmonary fibrosis: Randomized placebo-controlled trial results. Am J Respir Crit Care Med 2010;181:604–10. 70. Usategui A, et al. Topical vitamin D analogue calcipotriol reduces skin fibrosis in experimental scleroderma. Arch Dermatol Res 2014;306:757–61. 71. Cappelli S, et al. Is immunosuppressive therapy the anchor treatment to achieve remission in systemic sclerosis? Rheumatology (Oxford) 2014;53:975–87. 72. Bandinelli F, et al. Stiff skin syndrome and myeloma successfully treated with autologous haematopoietic stem cell transplantation (HSCT). Clin Exp Rheumatol 2013;31:181–3. 73. Fleming JN, et al. Is scleroderma a vasculopathy? Curr Rheumatol Rep 2009;11: 103–10. 74. Distler O, Cozzio A. Systemic sclerosis and localized scleroderma—current concepts and novel targets for therapy. Semin Immunopathol 2016;38:87–95. 75. Peterson LS, et al. The epidemiology of morphea (localized scleroderma) in Olmsted County 1960–1993. J Rheumatol 1997;24:73–80.

Chapter 35: Scleroderma 76. Murray KJ, Laxer RM. Scleroderma in children and adolescents. Rheum Dis Clin North Am 2002;28:603–24. 77. Zulian F, et al. Juvenile localized scleroderma: clinical and epidemiological features in 750 children. An international study. Rheumatology (Oxford) 2006;45:614–20. 78. Christen-Zaech S, et al., Pediatric morphea (localized scleroderma): review of 136 patients. J Am Acad Dermatol 2008;59:385–96. 79. Leitenberger J.J, et al. Distinct autoimmune syndromes in morphea: a review of 245 adult and pediatric cases. Arch Dermatol 2009;145:545–50. 80. Torrelo A, et al. Deep morphea after vaccination in two young children. Pediatr Dermatol 2006;23:484–7. 81. Alonso-Llamazares J, Ahmed I. Vitamin K1-induced localized scleroderma (morphea) with linear deposition of IgA in the basement membrane zone. J Am Acad Dermatol 1998;38:322–4. 82. Guidetti MS, et al. Sclerodermatous skin reaction after vitamin K1 injections. Contact Dermatitis 1994;31:45–6. 83. Prinz JC, et al. “Borrelia-associated early-onset morphea”: a particular type of scleroderma in childhood and adolescence with high titer antinuclear antibodies? Results of a cohort analysis and presentation of three cases. J Am Acad Dermatol 2009;60:248–55. 84. Pandey JP, LeRoy EC. Human cytomegalovirus and the vasculopathies of autoimmune diseases (especially scleroderma), allograft rejection, and coronary restenosis. Arthritis Rheum 1998;41:10–5. 85. Peroni A, et al. Drug-induced morphea: report of a case induced by balicatib and review of the literature. J Am Acad Dermatol 2008;59:125–9. 86. Laxer RM, Zulian F. Localized scleroderma. Curr Opin Rheumatol 2006;18:606–13. 87. Weibel L, Harper JI. Linear morphoea follows Blaschko’s lines. Br J Dermatol 2008;159:175–81. 88. Zulian F, et al. Congenital localized scleroderma. J Pediatr 2006;149:248–51. 89. Mertens JS, et al. Disease recurrence in localized scleroderma: a retrospective analysis of 344 patients with paediatric- or adult-onset disease. Br J Dermatol 2015;172: 722–8. 90. Zulian F, et al. Localized scleroderma in childhood is not just a skin disease. Arthritis Rheum 2005;52:2873–81. 91. Tollefson MM, Witman PM. En coup de sabre morphea and Parry-Romberg syndrome: a retrospective review of 54 patients. J Am Acad Dermatol 2007;56:257–63. 92. Zannin ME, et al, Ocular involvement in children with localised scleroderma: a multi-centre study. Br J Ophthalmol 2007;91:1311–4. 93. Kister I, et al. Neurologic manifestations of localized scleroderma: a case report and literature review. Neurology 2008;71: 1538–45. 94. Appelhans C, et al. Unilateral generalized morphea is a rare variant of localized scleroderma. Eur J Med Res 2006;11:152–6. 95. Wollina U, et al. Disabling pansclerotic morphea of childhood poses a high risk of chronic ulceration of the skin and

squamous cell carcinoma. Int J Low Extrem Wounds 2007; 6:291–8. 96. Petrov I, et al. Lower lip squamous cell carcinoma in disabling pansclerotic morphea of childhood. Pediatr Dermatol 2009;26:59–61. 97. Hayakawa I, et al. Anti-DNA topoisomerase IIalpha autoantibodies in localized scleroderma. Arthritis Rheum 2004;50:227–32. 98. Arkachaisri T, et al. Serum autoantibodies and their clinical associations in patients with childhood- and adult-onset linear scleroderma. A single-center study. J Rheumatol 2008; 35:2439–44. 99. Dharamsi JW, et al. Morphea in adults and children cohort III: nested case-control study—the clinical significance of autoantibodies in morphea. JAMA Dermatol 2013;149:1159–65. 100. Fett N, Werth VP. Update on morphea: part II. Outcome measures and treatment. J Am Acad Dermatol. 2011; 64:231–42; quiz 243–4. 101. Kroft EB, et al. Efficacy of topical tacrolimus 0.1% in active plaque morphea: randomized, double-blind, emollient-controlled pilot study. Am J Clin Dermatol 2009;10:181–7. 102. Mancuso G, Berdondini RM. Localized scleroderma: response to occlusive treatment with tacrolimus ointment. Br J Dermatol 2005;152:180–2. 103. Stefanaki C, et al. Topical tacrolimus 0.1% ointment in the treatment of localized scleroderma. An open label clinical and histological study. J Dermatol 2008;35:712–8. 104. Cunningham BB, et al. Topical calcipotriene for morphea/ linear scleroderma. J Am Acad Dermatol 1998;39:211–5. 105. Pope E, et al. Topical imiquimod 5% cream for pediatric plaque morphea: a prospective, multiple-baseline, open-label pilot study. Dermatology 2011;223:363–9. 106. Zulian F, et al. Methotrexate treatment in juvenile localized scleroderma: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2011;63:1998–2006. 107. Uziel Y, et al. Methotrexate and corticosteroid therapy for pediatric localized scleroderma. J Pediatr 2000;136:91–5. 108. Kreuter A, et al. Pulsed high-dose corticosteroids combined with low-dose methotrexate in severe localized scleroderma. Arch Dermatol 2005;141:847–52. 109. Weibel L, et al. Evaluation of methotrexate and corti costeroids for the treatment of localized scleroderma (morphoea) in children. Br J Dermatol 2006;155:1013–20. 110. Kreuter A, et al. A randomized controlled study of lowdose UVA1, medium-dose UVA1, and narrowband UVB phototherapy in the treatment of localized scleroderma. J Am Acad Dermatol 2006;54: 440–7. 111. Gordon Spratt EA, et al. Phototherapy, photodynamic therapy and photophoresis in the treatment of connective-tissue diseases: a review. Br J Dermatol 2015;173: 19–30. 112. Sakakibara N, Sugano S, Morita A. Ultrastructural changes induced in cutaneous collagen by ultraviolet-A1 and psoralen plus ultraviolet A therapy in systemic sclerosis. J Dermatol 2008;35:63–9.

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Section 11: Connective Tissue Diseases 113. Kreuter A, et al. Ultraviolet A1-induced downregulation of human beta-defensins and interleukin-6 and interleukin-8 correlates with clinical improvement in localized scleroderma. Br J Dermatol 2006;155:600–7. 114. Camacho NR, et al. Medium-dose UVA1 phototherapy in localized scleroderma and its effect in CD34-positive dendritic cells. J Am Acad Dermatol 2001;45:697–9. 115. Breuckmann F, et al. Modulation of endothelial dysfunction and apoptosis: UVA1-mediated skin improvement in systemic sclerosis. Arch Dermatol Res 2004;296:235–9. 116. Yin L, et al. The expression of matrix metalloproteinase-1 mRNA induced by ultraviolet A1 (340–400 nm) is phototherapy relevant to the glutathione (GSH) content in skin fibroblasts of systemic sclerosis. J Dermatol 2003;30:173–80. 117. Sator PG, et al. Medium-dose is more effective than lowdose ultraviolet A1 phototherapy for localized scleroderma as shown by 20-MHz ultrasound assessment. J Am Acad Dermatol 2009;60:786–91. 118. Zandi S, Kalia S, Lui H. UVA1 phototherapy: a concise and practical review. Skin Therapy Lett 2012;17:1–4. 119. Vasquez R, et al. Recurrence of morphea after successful ultraviolet A1 phototherapy: A cohort study. J Am Acad Dermatol 2014;70:481–8. 120. Jacobe HT, Cayce R, Nguyen J. UVA1 phototherapy is effective in darker skin: a review of 101 patients of Fitzpatrick skin types I–V. Br J Dermatol 2008;159:691–6. 121. Wang F, et al. Effect of increased pigmentation on the antifibrotic response of human skin to UV-A1 phototherapy. Arch Dermatol 2008;144:851–8. 122. Schlaak M, et al. Successful therapy of a patient with therapy recalcitrant generalized bullous scleroderma by extracorporeal photopheresis and mycophenolate mofetil. J Eur Acad Dermatol Venereol 2008;22:631–3. 123. Pileri A, et al. Generalized morphea successfully treated with extracorporeal photochemotherapy (ECP). Dermatol Online J 2014;20:21258:1–3 124. Neustadter JH, et al. Extracorporeal photochemother apy for generalized deep morphea. Arch Dermatol 2009;145:127–30.

125. Bischoff L, Derk CT. Eosinophilic fasciitis: demograph ics, disease pattern and response to treatment: report of 12 cases and review of the literature. Int J Dermatol 2008;47:29–35. 126. Wright NA, et al. Epidemiology and treatment of eosinophilic fasciitis: an analysis of 63 patients from 3 tertiary care centers. JAMA Dermatol 2016;152:97–9. 127. Baumann F, et al. MRI for diagnosis and monitoring of patients with eosinophilic fasciitis. AJR Am J Roentgenol 2005;184:169–74. 128. Fistarol SK, Itin PH. Diagnosis and treatment of lichen sclerosus: an update. Am J Clin Dermatol 2013;14:27–47. 129. Dinh H, et al. Pediatric lichen sclerosus: a review of the literature and management recommendations. J Clin Aesthet Dermatol 2016;9:49–54. 130. Oyama N, et al. Autoantibodies to extracellular matrix protein 1 in lichen sclerosus. Lancet 2003;362:118–23. 131. Edmonds EV, et al. Extracellular matrix protein 1 autoantibodies in male genital lichen sclerosus. Br J Dermatol 2011;165:218–9. 132. Goldstein AT, et al. Intradermal injection of autologous platelet-rich plasma for the treatment of vulvar lichen sclerosus. J Am Acad Dermatol 2017;76:158–160. 133. Girardi M, et al. Nephrogenic systemic fibrosis: clinicopathological definition and workup recommendations. J Am Acad Dermatol 2011;65:1095–1106 e7. 134. High WA, et al. Gadolinium is detectable within the tissue of patients with nephrogenic systemic fibrosis. J Am Acad Dermatol 2007;56:21–6. 135. Liu T, et al. The stiff skin syndrome: case series, differential diagnosis of the stiff skin phenotype, and review of the literature. Arch Dermatol 2008;144:1351–9. 136. Lunardi C, et al. Systemic sclerosis immunoglobulin G autoantibodies bind the human cytomegalovirus late protein UL94 and induce apoptosis in human endothelial cells. Nat Med 2000;6:1183–6. 137. Joseph CG, et al. Association of the autoimmune disease scleroderma with an immunologic response to cancer. Science 2014;343:152–7.

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36

Other Rheumatologic Disorders with Cutaneous Manifestations Jose Dario Martinez, Magda Arredondo, Jesus Alberto Cardenas

MIXED CONNECTIVE TISSUE DISEASE Mixed connective tissue disease (MCTD) is an autoimmune disease characterized by different features of systemic sclerosis, systemic lupus erythematosus (SLE), dermatomyositis/polymyositis, and rheumatoid arthritis (RA), accompanied by high titers of anti-U1 small nuclear antiribonucleoprotein (anti-U1-RNP). The existence of MCTD as a separate entity has been a matter of debate since its first description in 1972, mainly due to its difficulty in differentiating it from other rheumatologic conditions and the shift it may experience over time to other disease spectrum. Nonetheless, many reports have defended the distinct serological and clinical profile of MCTD and the different prognosis it entreats.

or dactylitis), and diffuse hand edema. Dystrophic calcification may lead to ulcers and subcutaneous nodules. Acrosclerosis and sclerodactyly may develop as disease progresses (Fig. 36.2). Nail fold capillaroscopy may reveal a pattern similar to that of systemic sclerosis in around half

Epidemiology MCTD has been linked to HLA-class II alleles like HLA-DR4, -DR1 and –DR2.1 MCTD incidence reports have ranged from 0.2 to 1.9 per 100,000 people. Like other connective tissue diseases, it is more frequent in females, with a female to male ratio of 5:1.2

Fig. 36.1: Raynaud’s phenomenon.

Clinical Features The most common clinical manifestations are polyarthritis/polyarthralgias, Raynaud’s phenomenon, proximal muscle weakness, esophageal dysmotility, interstitial lung disease, swollen hands, sclerodactyly, and sausage-like fingers.

Skin Connection Skin manifestations are habitually encountered at the moment of diagnosis. The most common dermatological manifestation is Raynaud’s phenomenon (Fig. 36.1). It is present in almost 90% of patients. It may progress to digital ulcers and gangrene. Another common finding is sausagelike fingers (edematous erythematous sausage-like fingers

Fig. 36.2: Acrosclerosis.

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Section 11: Connective Tissue Diseases of patients. Common findings are mega-capillaries, hemorrhages, and bushy capillaries. Photosensitivity, malar rash, and discoid lesions similar to those present in acute, subacute, and chronic lupus erythematosus may develop. Pigmentary changes, alopecia, and oral ulcers have also been reported.1,3

Systemic Involvement Other signs and symptoms found in MCTD include gastroesophageal reflux, diarrhea, headaches, peripheral neuropathies, glomerulonephritis, pericarditis, myocarditis, leucopenia/lymphopenia, and anemia. The most important factor for prognosis is the development of pulmonary hypertension, and mortality in MCTD patients is generally due to pulmonary hypertension, congestive heart failure, or infections. Systematic evaluation of pulmonary hypertension is mandatory for early diagnosis. Different screening tools are available and include echocardiography and high-resolution computed tomography. Right heart catheterization may be indicated when pulmonary arterial hypertension is highly probable.

Diagnosis Diagnosis of MCTD is difficult and often requires a multidisciplinary approach between rheumatologists, immunologists, and dermatologists. Several sets of diagnostic criteria have been developed including Sharp, Alarcon-Segovia, Kasukawa and Kahn.3 All of them require a high titer of anti-RNP antibody. AlarconSegovia and Villarreal criteria require an anti-RNP titer higher than 1:1600 plus three of the following: edema in hands, acrosclerosis, and Raynaud’s phenomenon with at least synovitis or myositis present. Histopathology is not pathognomonic and shares resemblance to other connective tissue diseases like lupus and systemic sclerosis. Other autoantibodies may show low titer positivity including rheumatoid factor, anti-Ro, anti-dsDNA, and anti-Sm. Antiphospholipid antibodies have been detected mainly in low titers.3

Differential Diagnosis The main differential diagnosis of MCTD are other connective tissue diseases including SLE, RA, polymyositis/ dermatomyositis, systemic sclerosis, spondyloarthropathies, and overlap syndromes.1,3

Treatment Treatment depends on extent of organ involvement and disease severity. Individual treatment schemes are necessary due to the variability of disease expression. Due to the relative rarity of MCTD diagnosis, no randomized controlled treatment trials have been published. Case series report that systemic steroids and hydroxychloroquine (HCQ) are the most frequently employed drugs.4 Non-steroidal antiinflammatory may be useful for myalgias, serositis, or fever. Low-dose oral steroids plus HCQ, may be effective for cutaneous and articular involvement, while higher steroid doses are needed for internal organ affliction. Immunosuppressive drugs like cyclophosphamide, azathioprine, mycophenolate mofetil, and methotrexate (MTX) may be required in resistant or severe cases. Raynaud’s phenomenon management includes wearing gloves and cold exposure avoidance. Nifedipine, a calcium channel blocker, is considered first-line treatment. Second-line treatment is sildenafil (cGMP-specific phosphodiesterase type 5 inhibitor). Lung involvement is a therapeutic challenge and requires a multidisciplinary management. Calcium channel blockers, prostacyclin inhibitors, and endothelin receptor antagonist (like bosentan) are part of the complex armamentarium available for lung involvement especially in pulmonary arterial hypertension.1 Specific organ involvement treatment is usually extrapolated from other connective tissue diseases.

Prognosis Prognosis of MCTD is considered better in comparison to other connective tissue diseases, although this remains a matter of debate. Pulmonary involvement carries a poor prognosis. Case series report progression from MCTD to other connective tissue diseases like systemic sclerosis, SLE or RA.1 Systematic evaluation of comorbidities and disease progression are necessary to establish early diagnosis, therapeutic interventions, and improve long-term prognosis.

Key Points •

• •

•

MCTD is characterized by different features of systemic sclerosis, SLE, dermatomyositis/polymyositis, and RA. Particularly presents high anti-RNP titers. Skin manifestations include Raynaud’s phenomenon, sausage-like fingers, hand edema, calcinosis, and acrosclerosis. Treatment is complex and depends on the clinical manifestations.

Chapter 36: Other Rheumatologic Disorders with Cutaneous Manifestations

RHEUMATOID ARTHRITIS The first description of rheumatoid arthritis (RA) ever acknowledged is found in the dissertation presented in 1800 by Agustin Jacob Landré-Beauvais, for his medical doctorate.5 In his dissertation, he presented “primary asthenic gout,” a disease that differed from the well-known gout. The main features of the disease included female predominance, polyarticular involvement, and a chronically progressive course.6 Categorizing RA as a relative of gout was inaccurate, and by the late 1800s, Alfred Garrod distinguished gout from other arthritides in his Treatise on Nature of Gout and Rheumatic Gout. There, he refers to RA as “rheumatic gout” and this becomes the groundwork for the consideration of RA as a distinct etiology. The first to ever use the term “Rheumatoid Arthritis” was Archibald Garrod, son of Alfred Garrod, in 1890 on his Treatise on Rheumatism and Rheumatoid Arthritis. The contemporary approach has focused on the pathogenesis from a molecular standpoint. The current hypothesis is that RA occurs as a response to environmental stimuli in genetically susceptible individuals.7 RA is a systemic disease with articular and extra-articular manifestations, dermatologic manifestations being the most common. Tokiyushi Yamamoto and his team proposed a classification of the RA skin manifestations in 1995, where they categorize them into specific and nonspecific.8 Later on, in 2003, a pathological classification was performed by Margo and Crowson, where they propose three histological patterns: diffuse interstitial granulomatous infiltrate, findings related to vasculopathy, and dermal neutrophilia.9 Now it has been found that the most specific cutaneous lesion of RA is the rheumatoid nodule, and that the related non-specific cutaneous RA manifestations are vasculitis, the granulomatous dermatitides, and the neutrophilic dermatitis.10 In this chapter, the lesions will be described as specific, non-specific, miscellaneous, therapy-induced, and related to juvenile rheumatoid arthritis (JRA).

Epidemiology RA is a disease that manifests worldwide. It affects nearly 1% of the US population. The Pima Indians show a higher incidence, while African populations show lower indices. A lower prevalence of RA was found in southern China, as well as a correlation of the rarity of human leukocyte antigen (HLA)-DR4, known genetic factor for RA.

The disease can present at any age, but it usually occurs between the fourth and eighth decades. It has a female predominance, being 2.5 times more common in women than in men.11 Around 40% of patients present with extraarticular­manifestations, the dermatologic findings among the most common. In 2015, Mirjana Zeimer and her team presented the results from a prospective study performed in 214 German patients with RA. In their study, they assessed the role of disease activity in cutaneous manifestations. The population evaluated had a mean age of 62.81 years, 69.2% were female and 30.8% were male. The mean disease duration was 15.5 years. To assess the disease activity, Disease Activity Score 28 (DAS28) was calculated. The study showed that 24.5% of the patients had high disease activity, 46.7% had moderate disease activity and 28.8% had low disease activity. In general, 87.4% showed skin lesions. Of those, 73.8% showed nonRA related lesions and 27.5% showed RA-associated skin lesions. The rheumatoid nodules were the most common cutaneous manifestation, with a prevalence of 26.6%.10 The prevalence is lower in Turkish (9%)12 and Japanese patients (2%).8

Pathogenesis RA is characterized by synovitis, the presence of rheumatoid factor (RF) and anticitrullinated protein antibody (ACPA), and systemic features. These characteristics prompt to question the genetic-environmental relationships, the articular localization preponderance, and the mechanism to produce a systemic illness. There is a well-established association with the HLA-DRB1 system. Individuals that have the shared epitope, an amino acid motif in the DRB1 region, are susceptible. This finding suggests that the autoimmune response elicited in RA is related to altered T-cell function, including repertoire selection, antigen presentation, peptide affinity, and cell senescence. It is known that genetic risk factors for ACPA-negative disease are as important as those for ACPA-positive RA. Patients with ACPA-positive RA have a less favorable prognosis, making the molecular subset differences clinically useful. Other factors include the interactions between the environment and the genetic predisposition as seen in smokers and patients with silicosis and susceptible HLA-DR4 alleles. Notwithstanding, smoking and HLA-DR1 increase the risk of having ACPA. Infectious agents such as Epstein-Barr virus, cytomegalovirus, and Escherichia Coli have been linked with RA, probably due to molecular mimicry. The

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Section 11: Connective Tissue Diseases explanation of why the systemic loss of tolerance leads to synovitis still needs to be resolved.13 It has been considered by convention that RA is mediated by T-helper lymphocytes. Synovial T-cell oligoclonality and B-cell hypermutation suggests an interaction between the two cell types. Nevertheless, besides the importance of T helper lymphocytes, attention has been given to type 17 helper T-cells (Th17). Th17 differentiation is induced by macrophage and dendritic cell-derived transforming growth factor β (TGF-β) and interleukin (IL)-1β, -6,-21, and-23. Th17 differentiation suppresses differentiation of regulatory T cells, shifting T-cell homeostasis toward inflammation.14 B cells perpetuate the immunologic process through antibody and cytokine formation. The role of CD20 positive B cells is confirmed by the notable response to Rituximab. Plasma cells are widely distributed in the synovium and are CD20-negative B cells. This suggests that RA goes further than antibody production and autoantigen presentation and cytokine production should be considered in addition. Cytokine production plays a central role in the pathogenesis of RA. The cytokine production patterns change throughout the progression of the disease. Tumor necrosis factor alpha (TNF-α) and IL-6 play a central role in the pathogenesis of RA. TNF-α promotes the activation and expression of cytokines and chemokines, the induction of pain, suppression of regulatory T-cells, and expression of endothelial adhesion molecules.15 On the other hand, IL-6 induces autoantibody production and also mediates systemic manifestations such as anemia, acute-phase responses, and cognitive dysfunction and fatigue. IL-1 family cytokines mediate the activation of leukocytes.16 The role of these molecules has been confirmed by the effect of the blockade by biologic drugs such as Infliximab and Adalimumab for TNF-α, Tocilizumab for IL-6R, and Anakinra for IL-1. Nonetheless, the clinical response to IL-1 inhibitors has been modest. RA patients also show extra-articular and systemic manifestations. Extra-articular manifestations include rheumatoid nodules, vasculitis, conjunctivitis sicca, uveitis, and rheumatoid lung disease.17 The induction of cytokines may explain the development of systemic manifestations in RA.

Diagnosis The diagnosis of RA is primarily clinical. The patient will have a highly suggestive presentation, with a polyarticular

symmetric synovitis that is insidious, commonly affects the wrists, the proximal interphalangeal joints (PIP), metacarpophalangeal joints (MCP), and metatarsophalangeal joints (MTP), sparing the distal interphalangeal joints (DIP). Supportive laboratory workup includes complete blood count (CBC) with differential, RF, erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP), and ACPA.18 ACPA has a specificity of 98% and a sensitivity of 68%.19 The American College of Rheumatology (ACR) criteria (Table 36.1) aids to attain a diagnosis and to follow the progression of patients through the course of the disease.20 Specific manifestations, such as rheumatoid nodules, are more common in patients with longstanding disease who are positive for RF and ACPA.10 The correct diagnosis of a skin lesion in a patient with RA is relevant because of the differences in management. Most of the skin lesions (73.8%) that appear on a patient with RA will be non-RA related, such as seborrheic dermatitis, solar lentigines, acrochordons,10 or other conditions such as fungal infections, urticaria, and eczema.8 The clinical and histopathological classifications of the RA-related skin conditions have helped establish which may benefit from

Table 36.1: The 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for rheumatoid arthritis (RA). A score of ≥6/10 is needed for Score classification of a patient as having definite RA A. Joint involvement 1 large joint 2–10 large joints 1–3 small joints 4–10 small joints >10 small joints

0 1 2 3 5

B. Serology (at least one test result is needed for classification) 0 Negative rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) Low-positive RF or low positive ACPA 2 High-positive RF or high-positive ACPA 3 C. Acute-phase reactants Normal C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) Abnormal CRP or ESR D. Duration of symptoms  +2 • Feature B: positive family history, with one or more first degree relatives independently meeting the current diagnostic criteria for hEDS • Feature C: musculoskeletal complications (must have at least one) Musculoskeletal pain in two or more limbs, recurring daily for at least 3 months Chronic, widespread pain for ≥3 months Recurrent joint dislocations or frank joint instability, in the absence of trauma (a or b) (a) Three or more atraumatic dislocations in the same joint or two or more atraumatic dislocations in two different joints occurring at different times (b) Medical confirmation of joint instability at two or more sites not related to trauma Criterion 3: All of the following must be met: • Absence of unusual skin fragility, which should prompt consideration of other types of EDS • Exclusion of other heritable and acquired connective tissue disorders, including autoimmune rheumatologic conditions. • Exclusion of alternative diagnoses that may also include joint hypermobility by means of hypotonia and/or connective tissue laxity. • Molecular basis: Unknown

Autosomal dominant: • Inheritance • Major criteria 1. Family history of vEDS with documented causative variant in COL3A1 2. Arterial rupture at a young age 3.  Spontaneous sigmoid colon perforation in the absence of known diverticular disease or other bowel pathology 4. Uterine rupture during the third trimester in the absence of previous C-section and/or severe peripartum perineum tears 5. CCSF formation in the absence of trauma • Minor criteria 1. Bruising unrelated to identified trauma and/or in unusual sites such as cheeks and back 2. Thin, translucent skin with increased venous visibility 3. Characteristic facial appearance 4. Spontaneous pneumothorax 5. Acrogeria 6. Talipes equinovarus 7. Congenital hip dislocation 8. Hypermobility of small joints 9. Tendon and muscle rupture 10. Keratoconus 11. Gingival recession and gingival fragility 12. Early onset varicose veins (under age 30 and nulliparous if female) • Minimal criteria suggestive for vEDS: A family history of the disorder, arterial rupture or dissection in individuals less than 40 years of age, unexplained sigmoid colon rupture or spontaneous pneumothorax in the presence of other features consistent with vEDS • Molecular basis Heterozygous mutation in the COL3A1 gene, encoding type III collagen. In very rare instances, biallelic pathogenic variants in COL3A1 may be identified.

Pseudoxanthoma Elasticum Pseudoxanthoma elasticum (Gronlad–Strandberg syndrome) is a rare heritable metabolic disease with a predominantly autosomal recessive inheritance, caused by mutations in the ABCC6 gene.50 The lack of functional ABCC6 protein leads to progressive mineralization of the elastic tissues of the skin, eyes and blood vessels. The term

Chapter 42: Disorders of Collagen, Elastin and Ground Substance pseudoxanthoma elasticum was coined by the French dermatologist Ferdinand-Jean Darier in 1896.51 The link between retinal angioid streaks and the skin features of PXE was reported by Gronblad and Strandberg in 1929.52,53 Prevalence rates are as high as 1:25,000–100,000.54 All skin types and ethnicities can be affected and there is a 2:1 female predominance. The prevalence seems higher in Afrikaners from South Africa because of a founder effect.55 The disease expression is heterogeneous in the extent and severity of involvement of skin, eyes and vasculature. Progressive involvement of the skin begins in childhood or adolescence with appearance of small yellow papules which may coalesce into plaques on the nape and sides of the neck, in flexural areas. The oral, vaginal and rectal mucosae may also be involved.56,57 The coalescence gives the skin a cobblestoned appearance. The skin becomes loose and wrinkled. The presence of horizontal and oblique mental creases before age 30 is specific for PXE.58 Eye changes include angioid streaks and degenerative chorioretinitis that may lead to blindness. Angioid streaks are not specific to PXE and may also be associated with Paget disease of bone, EDS, lead poisoning, sickle thalassemia trait and various hemoglobinopathies.59,60 In 2010, Plomp et al.61 proposed an updated classification system for PXE.

Major Criteria Skin • Yellowish papules or plaques on the sides of the neck and/or flexures • Increased morphologically altered elastic fibers with fragmentation, clumping and calcification Eye • Peau d’orange of retina • At least one angioid streak, each at least as long as one disk diameter • One or more comets of the retina • One or more wing signs in the retina Genetic • A mutation in both alleles of the ABCC6 gene

Minor Criteria Eye • One streak shorter than one disk diameter Genetic • First degree family member with definite diagnosis of PXE

• Mutation in one allele of ABCC6 gene Definite diagnosis of PXE: Major genetic criterion and one major non-genetic or three major criteria from eye and skin Probably diagnosis of PXE: Two major clinical criteria or one major criterion plus at least one minor criterion Possible diagnosis of PXE: Only one major criterion without minor criteria or only three minor criteria (Figs. 42.11A to C). The primary histologic feature of PXE is degeneration of elastic fibers in the mid-dermis, which undergo progressive calcification and fragmentation. Elastic fibers are easily identifiable on H&E stain. They are basophilic, thickened, fragmented, clumped and irregular. They stain with von Kossa stain due to the presence of phosphates or carbonates. Bruch’s membrane and vasculature in the myocardium and pericardium show similar calcifications (Figs. 42.12A and B).62 Histologic changes of PXE may be found in patients with angioid streaks and clinically normal skin.63 PXE is associated with mutations in the ABCC6 (ATP binding cassette subtype C number 6) gene. ABCC6 encodes the protein ABCC6 (also known as MRP6), a member of the large ATP-dependent transmembrane transporter family expressed predominantly in the liver and kidneys. At least one mutation of ABCC6 is found in 80% of patients.56,64 Mutations in ABCC6 are related to the ectopic mineralization in pseudoxanthoma elasticum and some forms of generalized arterial calcification of infancy. ABCC6 mediates cellular release of ATP, which is rapidly converted extracellularly into AMP and the mineralization inhibitor, inorganic pyrophosphate (PPi). Patients with PXE have low plasma levels of PPi.65–69 Decreased plasma levels of PPi is one of the strongest candidates for pathophysiology of PXE. Intravitreal injections with vascular endothelial growth factor inhibitors is an effective treatment for choroidal neovascularization.71–72 Yoo et al. demonstrated clinical improvement of skin lesions and histopathologic regression of skin disease as well as no progression of eye lesions after one year of treatment with a phosphate binder, aluminum hydroxide.73

Cutis Laxa Cutis laxa (CL) is a heterogeneous group of disorders of elastic connective tissue characterized by loose, prematurely

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A

C wrinkled, sagging, inelastic skin. CL does not have easy bruising or abnormal scarring. The inherited forms of the disease are rare and can have autosomal dominant, autosomal recessive or X-linked inheritance. The specific symptoms, severity and prognosis vary depending on the type of cutis laxa; acquired variants also exist. Abnormal skin may give affected individuals and children a prematurely aged appearance. In many cases, there is also a loss of elastic fibers in the lungs, gastrointestinal tract, joints and aorta, resulting in emphysema, hernias, diverticula, dislocations and aneurysms.74,75 CL is also known as generalized elastolysis, generalized elastorrhexis and generalized dermatochalasis. Eleven CL-related genes have been identified, which encode proteins within three groups.76 Elastin, fibulin-4, fibulin-5 and latent transforming growth factor-betabinding-protein 4 form elastic fibers and are involved in the sequestration and activation of transforming growth factor-beta (TGFβ). Proteins in the second group perform

B

Figs. 42.11A to C: Pseudoxanthoma elasticum. Yellowish papules or plaques on the sides of the neck and/or flexures. Courtesy: Rajendra Singh, MD (A and B), New York, USA and Ian McColl, MD (C), Tugun, Australia.

transport and membrane trafficking functions in modification and secretion of elastic fiber components. Proteins in the third group perform metabolic functions within the mitochondria, inhibiting accumulation of reactive oxygen species. CL affects approximately one in one million individuals in the general population. It has been reported in approximately 400 families worldwide. There is no gender or racial predilection. The inherited forms of cutis laxa usually manifest at birth or during infancy. In several cases of autosomal dominant type, the skin changes did not appear until adulthood. Acquired forms can appear at any age.

Clinical Manifestations The most characteristic clinical feature is laxity of the skin which hangs from the trunk, neck, extremities and genitalia in loose, wrinkled, pendulous, inelastic folds. The

Chapter 42: Disorders of Collagen, Elastin and Ground Substance

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A

B

B

Figs. 42.12A and B: Pseudoxanthoma elasticum. Degeneration of elastic fibers in the mid-dermis with progressive calcification and fragmentation. Courtesy: Ian McColl, MD, Tugun, Australia.

face is also affected with sagging jowls, lips and eyelids which give the patient a prematurely aged appearance. When stretched, inelastic skin returns to place abnormally slowly. Unlike similar skin disorders, easy bruising and scarring are generally not associated with cutis laxa. The joints are often abnormally loose (hypermobility) because of lax ligaments and tendons. The cutaneous findings are typically less severe in autosomal dominant than in autosomal recessive cutis laxa (Figs. 42.13A and B).77 All forms of cutis laxa have elastic tissue abnormalities. Histopathologic findings include loss of eulanin fibers and sparse, fragmented elastic fibers in the dermis. H&E stains are usually normal and elastic tissue stains are needed to demonstrate abnormalities (Table 42.2).

Figs. 42.13A and B: CL. A young child with loose, pendulous, wrinkled skin. Note the sagging jowls and eyelids giving a prematurely aged appearance. Courtesy: Samuel Freire da Silva, MD, Aracaju, Brazil.

DERMAL HYPERTROPHIES Hypertrophic Scars/Keloids Hypertrophic scars and keloids are two forms of abnormal wound healing which may result from any insult to the reticular dermis. Both involve excessive collagen deposition and can affect quality of life functionally, aesthetically or both. A hypertrophic scar is firm, raised within the site of injury, occasionally symptomatic and develops within 4–8 weeks of injury, typically in areas of high tension,85 such as extensor surfaces of extremities, shoulders, knees, ankles and neck. Hypertrophic scars may increase in size rapidly for 3–6 months, then tend to regress over time. When mature, hypertrophic scars have a raised, rope-like appearance with increased width.86

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Section 13: Disorders of the Dermis and Subcutaneous Tissue Table 42.2: Classification of Cutis Laxa. Type Clinical characteristics ADCL Onset congenital or neonatal period Generalized skin redundancy, pulmonary emphysema and aortic root dilatation.78 Skin is loose, redundant with slow recoil. Facial features include a premature aged appearance, long philtrum, high forehead, large ears and beaked nose.

Genetic defect Heterogeneous: Mutations in ELN Mutations in FBLN5 (heterozygous)

May also have hernias, cardiac valve abnormalities, pulmonary stenosis and gastrointestinal diverticuli. ARCL1A Also known as FBLN5-related cutis laxa

CL, early childhood-onset severe cardiopulmonary lesions, including pulmonary emphysema and/or supravalvular aortic stenosis, peripheral pulmonary artery stenosis, inguinal hernias and hollow viscus diverticula (e.g. intestine, bladder) (Murphy-Ryan et al.79 Van Maldergem and Loeys80).

*FBLN5-related cutis laxa may be inherited in AR or AD manner. AR is more common

Cardiorespiratory failure from complications of pulmonary emphysema (respiratory or cardiac insufficiency) is the most common cause of death

ARCL1B

CL and systemic involvement, most commonly arterial tortuosity, aneurysms, and stenosis; retrognathia; joint laxity; and arachnodactyly.81

Also known as EFEMP2-related cutis laxa and FBLN4-related cutis laxa ARCL1C Also known as LTBP4related cutis laxa and Urban–Rifkin–Davis syndrome

FBLN5 (homozygous) Previously known as EVEC or DANCE

EFEMP2/FBLN4

Severity ranges from perinatal death as a result of cardiopulmonary failure to manifestations limited to the vascular and craniofacial systems. May also include ocular hypertelorism, pulmonary emphysema, hypotonia, pectus excavatum and collagen-related abnormalities such as bone fragility and aneurysms of medium-size arteries.79 Skin findings may be mild. CL and severe complications affecting the pulmonary, gastrointestinal and urinary systems. Early childhood-onset pulmonary emphysema, peripheral pulmonary artery stenosis, inguinal hernias and hollow viscus diverticula (e.g. intestine, bladder). Other manifestations can include diaphragmatic hernias, congenital heart disease, intestinal malrotation, hydronephrosis and ectopic kidneys.82

LTBP4

Also, joint laxity, diminished muscle tone, growth delays and may have distinctive facial features including micrognathia, receding forehead, wide anterior fontanels, hypertelorism and, in some cases, prominent ears. Pulmonary emphysema is clinically evident during the first months of life, is often severe and is the most common cause of death. ARCL2A *Mutations in the ATP6V0A2 gene were found to underlie both, autosomal recessive cutis laxa type 2 (ARCL2), Debré type and wrinkly skin syndrome.

Generalized cutis laxa, persistent open fontanels, oxycephaly, hyperextensible joints, with varying neurological, facial and congenital abnormalities.83

ATP6V0A2

Neurologic abnormalities: developmental delays, intellectual disability, hypotonia, microcephaly, hearing loss, seizures, cobble-like dysgenesis. Eye abnormalities: myopia, strabismus Facial dysmorphic features: frontal bossing, reverse V eyebrows, down-slanting palpebral fissures, long philtrum, sagging cheeks, anteverted nares (Contd...)

Chapter 42: Disorders of Collagen, Elastin and Ground Substance (Contd...) Type ARCL2B

Clinical characteristics Intrauterine growth retardation, cutis laxa, more prominent on the arms and legs, particularly with wrinkling of dorsum of hands and feet, visible veins on the chest, congenital hip dislocations, hyperextensible joints and adducted thumbs.

Genetic defect PYCR1

Bone abnormalities include scoliosis, bowing of long bones of arms and legs, osteopenia, osteoporosis, congenital dislocation of the hip. Facial features: broad and prominent forehead, large ears, bulbous nose, prognathism, blue sclerae, aged appearance, triangular face and thin nose.83 Neurologic abnormalities: hypotonia, developmental delay, intellectual disability, dysgenesis or agenesis of corpus callosum. ARCL3

Skin symptoms of cutis laxa, growth deficiencies, moderate to severe intellectual disability, loose joints, cataracts and corneal abnormalities.84

ALDH18A1

May eventually develop dystonia. Individuals with this form of cutis laxa usually do not have cardiovascular or pulmonary complications. Many individuals with de Barsy syndrome were found to have a mutation in the ALDH18A1 gene. Note: X-linked recessive cutis laxa, which was previously classified as EDS type 9, also known as occipital horn syndrome, a mild form of Menkes disease, is characterized by connective tissue abnormalities and progressive neurodegeneration due to a copper transport defect.

Keloids are also raised, possibly painful or pruritic scars, which in contrast to hypertrophic scars, grow beyond the boundary of the original injury. They may develop up to one year after injury and do not regress on their own. Keloids may result from several types of skin injury such as surgery, piercings, burns, lacerations, abrasions, tattoos, insect bites, vaccinations and other inflammatory processes such as acne, varicella and folliculitis or may develop spontaneously.87 Shoulders, upper arms, anterior chest, upper back and earlobes are typical areas. Recurrence rates after surgical excision alone are 50–80%.88 Blackburn and Cosman reported that a clear-cut distinction between keloids and hypertrophic scars cannot be made in 5% of the scars.89 Hypertrophic scars and keloids are seen in all skin types and ethnicities. Keloids are most common in darker skin types, with 16% incidence in the African and Hispanic populations. Incidence is also increased during pregnancy and puberty. The highest occurrence is between ages 10 and 30 years old, with men and women affected equally.90–92 Patients with hypertrophic scarring tend to be somewhat older. In hypertrophic scars, there is an increase in the number of fibroblasts and density of collagen fibers.

Histopathologically, keloids are characterized by whorls and nodules of thick, hyalinized collagen bundles with mucinous ground substance and relatively few fibroblasts. Lee et al.93 found the following features were more commonly seen in keloids: a. No flattening of the overlying epidermis b. No scarring of the papillary dermis c. Presence of significant amount of keloidal collagen d. Absence of prominent vertically oriented blood vessels e. Presence of significant disarray of fibrocollagenous fascicles/nodules f. Presence of tongue-like advancing edge The association was statistically significant (p < 0.001) for features a, c, d and f. Well-formed keloidal collagen is the histologic hallmark of a keloid, however it may not be detected in all lesions potentially due to sampling error, or very young or old keloids (Figs. 42.14 and 42.15). Pathogenesis of abnormal scar formation has not been completely elucidated yet however an abnormal inflammatory response, cytokines, including IL-6, IL-8, IL-10, transforming growth factor β and platelet-derived growth factor as well as activation of fibroblasts have been implicated.95 Prevention must be emphasized for patients with keloids. All elective and/or cosmetic procedures should be

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Fig. 42.14: Hypertrophic scar histopathology. Flattening of the epidermis and replacement of papillary dermis by scar tissue with prominent vertically oriented blood vessels. Fibrous bundles are horizontal in the upper dermis and whorled in the deeper dermis.94 Courtesy: Rajendra Singh, MD, New York, USA.

Fig. 42.15: Keloid histopathology. Whorls and nodules of thick, hyalinized collagen bundles or keloidal collagen with mucinous ground substance and relatively few fibroblasts (Lee et al.94). Courtesy: Rajendra Singh, MD, New York, USA.

avoided. Patients must be aware of high rates of recurrence after procedures. When procedures cannot be avoided, prophylaxis to prevent recurrences should be utilized. The following therapies have been tried and/or are being developed for the treatment of keloids:95–103 • Occlusive dressings • Compression therapy • Intralesional corticosteroids • Surgical excision • Cryotherapy • Radiation therapy • Interferon • Imiquimod • 5-fluorouracil • Sirolimus • Tacrolimus • Bleomycin • Doxorubicin • Epidermal growth factors • Transforming growth factor β • Verapamil • Retinoic acid • Tamoxifen • Botulinum toxin A • Onion extract • Silicone-based camouflage • Hydrogen scaffold • Skin tension offloading device

Gold et al.104 proposed the following algorithm for the treatment of keloids. Prevention • For high-risk wounds, silicone gel or sheeting to be applied after re-epithelialization of the wound and maintained for at least 1 month • For lower risk wounds, options include silicone gel or sheeting, microporous tape or onion extract preparations • Strict sun protection to prevent hyperpigmentation Scar Treatment • For immature erythematous scars lasting longer than 1 month, pulse-dye laser or if unresponsive, fractional laser therapy • For linear hypertrophic scars from surgery or trauma, adjunctive use of intralesional corticosteroid or 5-fluorouracil injection • For minor keloids, combination of silicone gel or sheeting with monthly intralesional corticosteroid injections • For major keloids which are often refractory to treatment, monthly intralesional corticosteroids. If unresponsive, transition to monthly intralesional 5-FU and triamcinolone. Secondary treatments include laser treatments and excision with prophylactic radiation therapy.

Dupuytren’s Contracture Dupuytren’s disease is a common and benign fibromatosis of the hand which results from the progressive

Chapter 42: Disorders of Collagen, Elastin and Ground Substance

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B

Figs. 42.16A and B: Dupuytren’s contracture. Flexion contracture due to fibrous cords in the digital fascia. Courtesy: Mark Crowe, MD, Puyallup, USA.

thickening and shortening of the palmar fascia. The prevalence of Dupuytren’s contracture varies between 1–3% in the United States and 4–6% in Northern Europe.105 The incidence increases with age, usually starting with middle age. Men are more likely to be affected and have more severe disease than women. There is a striking genetic predisposition with 68% of male relatives of affected patients develop the disease. The palmar fibromatosis begins with skin pitting and small nodules at the distal ulnar aspects of one or both palms. Later, fibrous cords form by contraction of the affected bands of digital fascia, resulting in the flexion contracture as they cross joints, most frequently involving the fourth and fifth fingers. The natural history of the disease is variable. Leclercq divides the course of the disease into two different populations (Figs. 42.16A and B):106 • Those with late-onset disease (50s or 60s) with a single palmar nodule that evolves slowly into a thin cord with late contraction of the MP joint and then the PIP joint. • Those with early onset of disease with multiple palmar involvement, large nodules, massive skin adhesion and rapid progression to finger contracture. Plantar fibromatosis can also occur. The nodules of plantar fibromatosis may be single or multiple, unilateral or bilateral and painful or asymptomatic. They are found most often on the medial aspects of the soles. Patients may have both palmar and plantar lesions. Palmar and plantar fibromatosis may be associated with knuckle pads, which are fibrous thickenings over the dorsal metacarpophalangeal joints.

Established risk factors include genetic predisposition and ethnicity, as well as sex and age. Several environmental risk factors (some considered controversial) include smoking, alcohol intake, trauma, diabetes, epilepsy and use of anticonvulsant drugs, and exposure to vibration. Genetic analysis showed that Dupuytren’s disease risk loci contain genes that encode proteins in the Wnt signaling pathway.107 The Wnt signaling patient activates nuclear functions of beta-catenin, leading to altered cell proliferation and survival. Abnormal proliferation of fibroblasts is a key feature of early Dupuytren’s disease. People with Dupuytren’s contracture are at increased risk of developing other disorders in which similar connective tissue abnormalities affect other parts of the body. These include Garrod pads, which are nodules that develop on the knuckles; Ledderhose disease, also called plantar fibromatosis, in which contractures affect the foot; and, in males, Peyronie disease, which causes abnormal curvature of the penis.108,109 Histologically, there are multiple small nodules of spindle cells (fibroblasts) and blood vessels. In early nodules the fibroblasts are densely packed, and the amount of collagen is minimal. Older lesions show diminished cellularity and greater deposition and hyalinization of collagen. There is no curative treatment for Dupuytren’s disease. Treatments include intralesional triamcinolone injections, percutaneous needle fasciotomy, clostridial collagenase injection or surgical excision. While surgical

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Section 13: Disorders of the Dermis and Subcutaneous Tissue excision is initially helpful, there is a high percentage of recurrence.110,111 For early stage disease, radiation therapy may also be helpful.112

Cutis Verticis Gyrata Cutis verticis gyrata is a rare congenital or acquired skin condition characterized by deep furrows and convolutions that resemble the surface of the cerebrum. These folds and furrows form as a result of infiltration of cells or substances and the defined anatomy and attachments of the scalp. Unna113 was the first to use the term cutis verticis gyrata (CVG) in 1907. Polan and Butterworth114 were the first to divide CVG into primary (essential and nonessential) or secondary types. In primary CVG, the folds are usually symmetrical; histology is normal or there is an increase in connective tissue or epidermal appendages.115 It is further classified as essential and non-essential. Essential CVG is not associated with any other abnormalities. It is five times more prevalent in men than in women and starts during or after puberty, most commonly approximately 30 years of age. Primary non-essential CVG is associated with neurologic or ophthalmologic diseases,116,117 which include mental deficiency, cerebral palsy, epilepsy, schizophrenia, cranial abnormalities (microcephaly), deafness, ophthalmologic abnormalities (cataract, strabismus, blindness, retinitis pigmentosa) or a combination of these (Fig. 42.17). Secondary CVG is comprised of scalp diseases that manifest in the form of CVG. There is a local underlying

process. There is abnormal histology, folds are asymmetrical and onset can be at any age. There are no mental abnormalities. Causes of secondary CVG can be:118–137 • Inflammatory (eczema, psoriasis, folliculitis, impetigo, erysipelas, pemphigus, Darier disease, acne conglobata) • Nevi • Hamartomas (neurofibroma, fibroma, other tumors) • Acromegaly • Myxedema • Post-traumatic • Idiopathic hypertrophic osteohypertrophy (pachydermoperiostosis) • Amyloidosis • Syphilis • Leukemia • Fallopian tube carcinoma • Acanthosis nigrigans • Tuberous sclerosis • EDS • HIV-related lipodystrophy The estimated prevalence of CVG (with data from 1964) is up to 1 in 100,000 people in the general population.138 It has been estimated to occur in 0.5% (1 in 200) of people with intellectual disability in the United States. CVG has been described associated with fragile sites on chromosomes, including the fragile X-site, the sexlinked site for Fragile X syndrome.139 Several cases of primary non-essential CVG with autosomal dominant or recessive inheritance have been described.140,141 Treatment of primary CVG is primarily surgical and is predominantly for the correction of cosmetic disfigurement.

Juvenile Hyaline Fibromatosis and Infantile Hyalinosis

Fig. 42.17: Primary non-essential CVG. Folds and convolutions of scalp skin resembling the surface of the cerebrum. Courtesy: Nejib Doss, MD, Tunis, Tunisia.

Also known as Murray–Puretic–Drescher syndrome. Infantile systemic hyalinosis (ISH) and juvenile hyaline fibromatosis (JHF) are rare autosomal recessive diseases that arise from the mutation of the gene for anthrax toxin receptor-2 (ANTXR2), also known as capillary morphogenesis gene-2, located on chromosome 4q21.142 Since 2009, these two entities have been grouped together into the hyaline fibromatosis syndrome (65) with a spectrum of clinical features from a less severe (JHF) to a more severe and possibly lethal form (ISH).

Chapter 42: Disorders of Collagen, Elastin and Ground Substance A number of aspects, such as age of onset, types of cutaneous and visceral involvement, overlap, demonstrating that JHF and ISH represent different degrees of severity on the spectrum of this disorder.143,144 The condition is characterized by an abnormal growth of hyalinized fibrous tissue usually affecting subcutaneous regions on the scalp, ears, neck, face, hands and feet. The lesions appear as pearly papules or fleshy nodules. Age at presentation: The onset of clinical manifestations for JHF is in the first 3–4 months of life and for ISH in the first few weeks of life. In both cases, intellectual development is normal. The prevalence is less than 1/1,000,000. The hyaline fibromatoses present with a wide range of clinical features that range from limited skin involvement with normal survival to severe systemic involvement and death in the first two years of life.142 Both JHF and ISH present with painful fleshy papulonodular skin lesions, gingival hypertrophy, progressive joint contractures and bone lesions, such as osteolysis, osteopenia and osteoporosis. The main clinical features of ISH include early onset, diffusely thickened, inflexible skin, papulonodular skin lesions, hyperpigmented plaques over bony prominences, gingival hyperplasia, perianal nodules, limitation of joint motility, osteoporosis of bones, bone fractures, short stature, persistent diarrhea and protein-losing enteropathy, systemic involvement, recurrent infections, failure to thrive and death before two years of age. JHF has a later onset, pearly nodules on the face and neck, especially perinasal and retroauricular areas, large plaques and nodules on the scalp, trunk and limbs and perianal plaques and nodules, normal growth and prolonged survival. Histopathology analysis of involved tissues reveals cords of spindle-shaped cells embedded in an amorphous, hyaline material. In ISH there are deposits of this hyaline material in other organs such as the gastrointestinal tract, adrenals, bladder, skeletal muscle, thymus, parathyroid glands. The nature of the hyaline material is unclear (Fig. 42.18). The ANTXR2 gene encodes a transmembrane protein which binds to both laminin and collagen IV, suggesting that this protein plays a role in basement membrane matrix assembly and endothelial cell morphogenesis. It also functions as a receptor for the anthrax toxin.142,145–148 The differential diagnosis includes infantile multicentric neurofibromatosis, Winchester syndrome, lipoid proteinosis and mucopolysaccharidosis 2. No satisfactory treatment is available.

Fig. 42.18: juvenile hyaline fibromatosis (JHF). Cords of spindle-shaped cells embedded in an amorphous, hyaline material. Courtesy: Rajendra Singh, MD, New York, USA.

ELASTIC TISSUE-RELATED HYPERTROPHIES Elastic fibers are a vital component of dermal connective tissue that provides elasticity and resilience to the skin by forming a complex and extensive network of structural proteins and glycoproteins.149 Elastic fibers constitute less than 4% of the dry weight of the skin. Mature elastic fibers are composed of 90% elastin and are located in the mid and deep reticular dermis. Several acquired disorders in which accumulation or elastotic material have recently been described. They include elastoderma, linear focal elastosis and late-onset focal dermal elastosis (Table 42.3).150

Elastoderma Elastoderma is a rare acquired condition that affects the skin, characterized by localized increased laxity, extensibility and wrinkling of skin resembling cutis laxa.152,153 Decreased recoil of the skin has also been reported. Although any part of the body can be affected, the skin of the neck and extremities (arms and legs, especially at the elbows and/or knees) are most commonly involved. The human phenotype ontology provides a list of features that have been reported in people with this condition. Most frequent features include cutis laxa (100%), premature wrinkling (80–99%) and hyperesthesia. Histopathology reveals an increase of pleomorphic elastic fibers in the superficial and mid dermis. The fibers are thickened, fragmented and curled.154 There is no evidence of calcification. The histologic differential diagnosis includes penicillamine dermopathy.

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Section 13: Disorders of the Dermis and Subcutaneous Tissue Table 42.3: Disorders of increased connective tissue (adapted from Lewis et al.150). Disorder

Epidemiology

Clinical features

Histopathology

Late-onset focal dermal elastosis

65–85 years

Increased normal-appearing elastic fibers in the reticular dermis

Linear focal elastosis

M > F, 7–89 years, no ethnic predilection

Elastoderma

27–33 years

Asymptomatic or pruritic yellow papules coalescing into plaques on neck and flexural arms and legs Asymptomatic palpable yellow or red linear plaques across lumbar spine Localized areas of lax, pendulous skin primarily on the neck and flexural extremities

Elastofibroma

F > M 35–94 years 2/3 cases in Japanese patients Congenital or acquired (2nd or 3rd decade)

Elastoma

Slowly growing subcutaneous nodule at apex of scapula Ill-defined firm yellow papules, plaques or nodules on the trunk

The exact underlying cause is unknown. The condition generally occurs sporadically in persons without any family history of the disease, however a familial case (sisters) with lesions primarily in the acral location has been reported.155 Kornberg et al.156 postulated that in elastoderma there is an accumulation of elastin that results from increased synthesis rather than degradation. There is no standard therapy available for elastoderma. Some cases have been treated with surgical excision (removal of affected skin), but hyperlaxity of skin often returns following the surgery.

Late-onset Focal Dermal Elastosis A condition characterized by a localized increase of healthy-appearing elastic tissue in the mid and deep reticular dermis. The condition may mimic pseudoxanthoma elasticum and linear focal elastosis clinically. Late-onset focal dermal elastosis was first described by Tajima et al. in 1995.157 Clinically, it presents as firm yellow papules that coalesce into thickened plaques typically on the neck or flexural surfaces of arms and legs. Pruritus may or may not be present. Late-onset focal dermal elastosis has no associated systemic findings. Histologically the elastic fibers appear healthy with no evidence of calcification, elastolysis or extensive solar damage.

Linear Focal Elastosis First case of linear focal elastosis, also called elastotic striae, was described by Burket et al. in 1989.158 It presents

Numerous elongated wavy fragmented basophilic elastic fibers some with “paintbrush” ends Increased pleomorphic elastic fibers in the superficial and mid dermis. The fibers are thickened, fragmented and curled. No calcification Fragmented serrated-appearing elastic fibers admixed with collagen, fibroblasts and fat cells Increased broad, branching and interlacing elastic fibers in the mid and lower dermis151

as asymptomatic, palpable yellow lines in the lumbosacral region. Other sites may be affected. Although first described in three Caucasian men over age 60, later cases described both young men and women of various ethnic backgrounds. This condition has been compared to an extensive regenerative process such as a “keloidal” repair of striae distensae.159,160 Histologically there are numerous elongated, wavy elastic fibers in the mid-dermis.161 Splitting at the fiber ends given them a “paintbrush” appearance. There is no known treatment.

Elastofibroma Elastofibroma, also known as elastofibroma dorsi, was first described by Jarvi and Saxen162 in 1961 in four elderly persons who had subscapular tumors and a long history of manual labor. It is a slowly growing proliferation of collagen and abnormal elastic fibers in the subscapular region. Women are more commonly affected than men. There is a strong association with hard manual labor. Almost two thirds of the described cases were in Southern Japan.163 Pathogenesis is not known, however chromosomal instability and/or clonal changes have suggested a neoplastic process.164,165 Clinically elastofibroma is an asymptomatic or mildly tender, slowly growing submuscular 5–10 cm nodule most commonly adjacent to the apex of the scapula. Other sites have been described. Histologically, elastofibromas are unencapsulated lesions that blend in with surrounding fat and connective tissue. There is a mixture of swollen eosinophilic collagen

Chapter 42: Disorders of Collagen, Elastin and Ground Substance fibers intertwined with elongated, serrated elastic fibers along with fibroblasts and fat cells.166,167 The elastic fibers are large, swollen, coarse and deeply eosinophilic. They are studded with globular aggregates of elastic material giving a serrated appearance to the fibers. Treatment of elastofibroma is local excision.

Elastoma Elastoma, also known as elastic nevus or juvenile elastoma, is a form of connective tissue nevus that was first described by Weidman et al. in 1933.168 It is characterized by formation of yellow or flesh-colored papules, plaques and/or nodules which represent a focal increase in normal-appearing elastic tissue.169 Elastoma is typically diagnosed in children. The age of onset is approximately 6 years of age, the age at diagnosis at 24.170 Both congenital and acquired cases have been reported, although most cases are congenital. The lesions may be solitary or multiple. Multiple small foci of osteopoikilosis are often associated with multiple lesions of elastoma. This association is known as the Buschke–Ollendorff syndrome171 and the cutaneous lesions as dermatofibrosis lenticularis disseminata. Buschke–Ollendorff syndrome has autosomal dominant inheritance. It involves a loss-of-function mutation in the LEMD3 gene, also known as MAN1.172,173 Pathogenesis involves a three-to-seven-fold increase in elastin due to a faulty aggregation of elastin units.169 Histologically, there is an increase in dermal elastic tissue. The lesions are characterized by excessive amounts of broad, interlacing elastic fibers in the dermis. Major diagnostic features of Buschke–Ollendorff syndrome include connective tissue nevi, osteopoikilosis, LEMD3 mutation and family history. There may also be an association with short stature, scoliosis and cognitive delays necessitating an earlier diagnosis and possible intervention.170

ATROPHIES OF CONNECTIVE TISSUE Mid-dermal Elastolysis First described by Shelley and Wood in 1977,174 middermal elastolysis (MDE) is a rare acquired disorder of elastic tissue primarily manifesting as patches of fine wrinkling on the trunk and proximal extremities of young women or perifollicular papules in the same distribution. Approximately 80 cases of MDE have been described in the literature. MDE typically presents in healthy young or middleaged women.

The clinical appearance may include widespread patches of fine wrinkling, perifollicular papular protrusions and inflammatory skin changes like reticular erythema.175 Most frequently affected sites are the trunk and upper proximal extremities. Most described patients presented with asymptomatic, well-demarcated, symmetrical lesions of fine wrinkling (type I) and perifollicular papular protrusions with “peau d’orange” appearance (type II).176 Persistent reticular erythema has also been described. Fifty percent of the cases are preceded or accompanied by burning or urticaria. Lesions resolve leaving well-demarcated patches of finely wrinkled skin.150 There is a band-like or focal loss of elastic fibers in the mid-dermis. The papillary and deeper reticular dermis are not affected.177 The elastic tissue around appendages appears normal. Many specimens may appear normal on H&E stains. Elastophagocytosis may also be seen. In early lesions there may be a mild lymphohistiocytic infiltrate around the superficial plexus. Immunohistochemistry shows that elastin but not fibrillin staining is significantly decreased. Large cells located in the mid-dermis showed an intense staining for MMP-9, a gelatinase expressed primarily by macrophages, epithelial cells and fibroblasts that can degrade elastin.178 MMP-9 has been associated with anetoderma. There is a history of intense sun exposure in the majority of patients with reports of using a tanning bed or UVB phototherapy.178,179 There is also an association with pregnancy and smoking. There is no evidence of familial incidence. There are reported cases of MDE in association with autoimmune diseases such as systemic lupus erythematosus, Hashimoto’s thyroiditis and rheumatoid arthritis.175 Other associated conditions were urticaria, atopic dermatitis, granuloma annulare, Sweet’s syndrome, phototoxic dermatitis, elevated antinuclear antibodies and others.180 There is no effective treatment of MDE. Multiple treatments have been tried, including sunscreens, colchicine, chloroquine, vitamin E, topical corticosteroids and tretinoin, without success.

Anetoderma Anetoderma (macular atrophy) is an uncommon disorder of elastic tissue, characterized clinically by multiple small oval atrophic papules that herniate inward on palpation, and histologically by loss of dermal elastic tissue.181 Anetoderma was first described by Pellizzari in 1884 and subsequently by Jadassohn in 1892. Anetoderma was previously divided into two clinical types: (1) Schweninger–Buzzi

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Section 13: Disorders of the Dermis and Subcutaneous Tissue (arising on normal skin without preceding erythema) and (2) Jadassohn–Pellizzari (preceded by macular erythema, papular urticaria or other skin pathology).182 The exact prevalence is unknown. Women are affected more commonly than men and both children and adults can be affected. Onset of disease is most commonly in late adolescence and early adulthood. Familial cases have been described, but are rare.183 Anetoderma of Jadassohn–Pellizzari begins with erythematous or urticarial papules and macules. Gradual atrophy produces bulging or depressed, finely wrinkled papules that can be pushed inward easily with the tip of a finger. The most common sites are the neck, upper trunk and arms. Lesions vary in size from 0.5 to 2.0 cm. They are asymptomatic and persistent. The most consistently reported association of primary anetoderma is with a prothrombotic disorder, particularly antiphospholipid antibodies. Associations with other diseases, such as systemic lupus erythematosus, Sjogren’s syndrome, Addison’s disease and others have been reported in case reports or small studies. Other laboratory abnormalities include elevated antinuclear antibodies, rheumatoid factor and antithyroid antibodies.184–186 Secondary anetoderma occurs in areas of prior skin eruptions, such as acne, varicella, discoid lupus erythematosus, papular eruption of HIV, urticaria pigmentosa, Lyme disease, leprosy and numerous others (Figs. 42.19A and B). The primary histopathologic feature is loss of elastic tissue in the dermis. In early lesions, there may be a heavy perivascular infiltrate of lymphocytes.187–189 Eosinophils and plasma cells are occasionally present. In established lesions, the skin may appear normal on H&E sections. Scattered macrophages and giant cells may show elastophagocytosis. Ultrastructurally, there is fragmentation and eventually absence of elastin, without a decrease in fibrillin, and activation of multiple matrix metalloproteinases.190 There is no effective treatment for anetoderma.

Striae Striae distensae are an extremely common form of dermal scarring. They occur in pregnancy, puberty, obesity, numerous medical conditions including Cushing’s syndrome and Marfan’s, and post-treatment with certain medications. Striae have a high impact on the psychosocial quality of life.191,192 Striae appear as reddish or violaceous, occasionally pruritic streaks (striae rubra), then

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B Figs. 42.19A and B: Anetoderma. Multiple small oval atrophic outpouched papules that herniate inward on palpation. Courtesy: Ian McColl, MD, Tugun, Australia.

fade gradually and change into wrinkled, hypopigmented depressed scars that remain indefinitely (striae alba). Striae appear in approximately 11% of men and up to 90% of pregnant women.193–195 In adolescents, 40% of males and 70% of females are affected.196 Striae may also occur in HIV-positive patients taking protease inhibitors, such as indinavir (Fig. 42.20).197 Common locations include the abdomen, breasts, shoulders, medial upper arms, hips, lower back, buttocks and thighs. Striae are common in pregnant women, teenagers undergoing growth spurts and in overweight individuals. Striae occur in a symmetrical distribution and are usually oriented along skin tension lines. Yamaguchi et al.192 revealed a significant difference in the emotion score of a validated questionnaire, Skindex-29, in Japanese women with or without striae distensae.

Chapter 42: Disorders of Collagen, Elastin and Ground Substance

Fig. 42.20: Striae. Reddish and violaceous streaks on the legs. Courtesy: Mark Crowe, MD, Puyallup, USA.

Fig. 42.21: Linear focal elastosis. Yellowish, palpable linear plaques across the lower back. Courtesy: Mark Crowe, MD, Puyallup, USA.

Linear focal elastosis, yellowish, palpable linear plaques across the lower back is thought to represent excessive regeneration of elastic fibers, i.e. keloidal repair of striae distensae (Fig. 42.21).160,198 The diagnosis of striae is usually made clinically. Histologically, striae rubra resemble a scar. The early striae show a flattening of the epidermis with loss of rete ridges and fine straight dermal collagen bundles arranged parallel to the dermal–epidermal junction. The center of the striae show a decrease in normal collagen, elastin and fibrillin. At the periphery there are thick tortuous elastic fibers.199,200 Mature striae alba resemble an atrophic scar.

Pathogenesis of striae distensae is likely a combination of three components: 1. Genetic predisposition 2. Hormonal fluctuations 3. Mechanical stresses It has been postulated that changes in estrogens, androgens, glucocorticoids and their receptors modulate production of extracellular matrix components. A positive family history is a risk factor in both pregnant women and adolescents. The following conditions have also been linked with striae distensae: • Medical conditions, such as Cushing’s syndrome, Marfan’s syndrome, anorexia nervosa, obesity, chronic liver disease, pregnancy. • Medications, such as systemic and topical steroids, HIV therapy with protease inhibitors, chemotherapy, tuberculosis therapy, contraceptives, neuroleptics. Currently, there are no treatments that can provide significant improvement of striae distensae. Combinations of treatments are needed to achieve improvement. In a study that identified all available records of striae and related terminology from 1773 to 2016, Ross et al.200 recommends the following therapeutic algorithm for treatment of striae distensae. First line • Nonablative lasers, specifically 1540 non-ablative fractionated laser Second line • Retinoids • Chemical peels • Microdermabration • Microneedling • Radiofrequency devices Third line • Silicone • Infrared light devices • Intense pulsed light devices • Ultraviolet light devices • Ablative lasers • Fractionated microneedling • Ultrasound • Platelet rich plasma plus microneedling

Atrophoderma of Pasini and Pierini Idiopathic Atrophoderma of Pasini and Pierini (IAPP) is an uncommon disorder of dermal atrophy initially described by Pasini in 1923 and Pierini and Vivoli in 1936.201,202 It

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B Figs. 42.22A and B: Atrophoderma of Pasini and Pierini. Depressed hyperpigmented plaques with a “cliff-sign” step-off border. Courtesy: Jo Bohannon-Grant, MD, Midlothian, USA.

presents with distinctive, hyperpigmented, depressed oval or round plaques. The great majority of cases present after birth, usually in the second or third decade of life, and have a strong female predominance of 2–6:1. Only a few cases of congenital IAPP have been described.203 There is debate as to whether IAPP represents an atrophic form of morphea.204–206 The lesions present as hyperpigmented single or multiple depressed plaques with an abrupt “cliff sign” transition from normal to diseased skin. Areas of atrophy are smooth and soft and do not show inflammation. Size of the lesions varies from 2 to 15 cm in diameter. The predominant site affected was the back (82%), followed by the chest (39%), arms (30%), abdomen (30%) legs, hips, thighs and groin (Figs. 42.22A and B).207

H&E histology of IAPP often cannot be differentiated from normal tissue. On review of biopsy specimens from 11 patients, Vieira-Damiani et al.208 found no change in the content of collagen fibers or any morphologic change in elastic fibers by conventional microscopy, morphometry and multiphoton imaging. They concluded that the clinical atrophic appearance reflects a gradual change in organization and horizontal distribution of collagen fibers closer to the deep dermis. In contrast, Buechner et al. found that all 17 specimens showed various degrees of perivascular and interstitial inflammatory infiltrate of lymphocytes and histiocytes. Plasma cells were found in two patients. In all specimens, lesional skin showed varying degrees of homogenization and clumping of collagen bundles in the reticular dermis. Eccrine sweat glands, hair follicles and sebaceous glands were intact in 15 specimens. In Buechner’s study, 10 of the 26 patients tested had significantly elevated immunoglobulin G (IgG) titers against Borrelia burgdorferi, raising the possibility of relationship to Lyme disease. Given the positivity of B. burgdorferi infection, patients in Buechner’s study were treated with antibiotics and experienced clinical improvement207,209. Other treatments that have been tried included topical steroids, topical calcineurin inhibitors or hydroxychloroquine.210 However, there are no randomized trials to evaluate these therapies.

Follicular Atrophoderma Follicular atrophoderma presents as follicular funnelshaped “ice-pick” depressions without hairs on extensor surfaces of hands, arms and legs.211 A fissured tongue may also be found. When the lesions occur on the cheeks, it is called atrophoderma vermiculatum (Figs. 42.23A and B). Follicular atrophoderma does not occur alone, but is usually associated with other abnormalities. Follicular atrophoderma is primarily seen in the X-linked dominant form of chondrodysplasia punctata (Conradi– Hunermann–Happle syndrome) and in the X-linked dominant Bazex–Dupre–Christol syndrome, seen in males and females due to either autosomal dominant or X-linked dominant inheritance.212 Follicular atrophoderma also occurs in association with keratosis palmoplantaris dissipata, keratosis follicularis and hyperhidrosis palmoplantaris. In 1998, follicular atrophoderma was also described in siblings with congenital ichthyosis, hypotrichosis and hypohidrosis, where it may be inherited in an autosomal recessive manner.211

Chapter 42: Disorders of Collagen, Elastin and Ground Substance

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Figs. 42.23A and B: Follicular atrophoderma/atrophoderma vermiculatum with ice-pick depressions on the cheeks. Courtesy: Samuel Freire da Silva, Aracaju, Brazil.

Figs. 42.24A and B: Piezogenic papules. Yellowish papules on the heels. Courtesy: Mark Crowe, MD, Puyallup, USA.

Inoue et al.213 described eight members of a single family that presented with perioral pigmented follicular atrophoderma with numerous milia and epidermoid cysts. Histologic examination of follicular atrophoderma revealed proliferation of basaloid cells continuous with the epidermis, with coarse collagen fibers and decreased elastic fibers around the basaloid cells. The inheritance pattern in that family appeared to be autosomal dominant. In 2016, Neri et al.214 reported a novel mutation in the ST14 (suppressor of tumorigenicity 14) gene, which causes autosomal recessive congenital ichthyosis seen in two syndromes: IFAH (autosomal recessive congenital ichthyosis, follicular atrophoderma and hypotrichosis) and ARIH (autosomal recessive ichthyosis and hypotrichosis).

Piezogenic Papules Painful piezogenic pedal papules (PPPP) were initially described by Shelley and Rawnsley in 1968.215 The authors noted an unusual cause of painful feet which were small, papular herniations of subcutaneous tissue into the skin of the medial aspects of the heels, which occurred only on standing. In 90% of patients, piezogenic papules occur in healthy subjects and are asymptomatic.216 Piezogenic papules are small yellowish papules which may or may not be painful.217 They are common and become evident when pressure is applied to the heel. Piezogenic papules can also occur on the wrists.218 Laing and Fleischer classified piezogenic papules as a normal finding (Figs. 42.24A and B).

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Section 13: Disorders of the Dermis and Subcutaneous Tissue Schlappner found that histologically there is fat herniation into the dermis or loss of compartmentalization of subcutaneous fat with thickened, dense dermal tissue with homogenization of collagen. The pathogenesis of PPPP has been described as vigorous activity, years of repeated pressure in susceptible persons, hereditary factors and collagen defects in EDS.219 Laing and Fleischer did not find any relation of PPPP to age, sex, connective tissue disease in self or family. Not all subjects participated in physical activity. Altin et al.220 reported association of PPPP with MVP and recommended a cardiac examination for patients with PPPP. There is no effective medical therapy for PPPP. Rest, elevation and compression are recommended. Doukas et al.221 reported significant improvement in pain with three injections of equal parts betamethasone and bupivacaine in a male patient with EDS.

DEPOSITION OF GROUND SUBSTANCE Scleredema Scleredema is an uncommon disorder of connective tissue characterized by diffuse non-pitting swelling and woody induration of the skin without overlying skin changes, primarily in the cervical, deltoid and dorsal regions. The original description of scleredema was credited to Buschke. Scleredema is part of a group of cutaneous mucinoses and is classified into three subtypes by their associated conditions: 1. Type 1: Acute onset, days to weeks after a febrile illness caused by streptococci,222 mycoplasma or viruses, such as influenza, measles, CMV and HIV.223 This type is more prevalent in children and young adults. Spontaneous resolution is seen in about one third of patients. 2. Type 2: associated with paraproteinemias (monoclonal gammopathies), most commonly hypergammaglobulinemia involving IgG k. In 25–45% of patients, there is progression to multiple myeloma.224 This group usually has a chronic, progressive course. 3. Type 3: associated with both Type I and Type II diabetes mellitus.225 These patients are usually adult males with long-standing diabetes mellitus and poor glycemic control. There is no spontaneous resolution. There is also an idiopathic form, with slow onset without any predisposing illness and a protracted course. Some cases of scleredema in this category do go on to develop a monoclonal gammopathy.

Other disorders that have associated with scleredema include hyperparathyroidism, rheumatoid arthritis, Sjogren’s syndrome,226 malignant insulinoma, carcinoid and amyloidosis.224 The median age of patients at the time of onset is about 20 years. Approximately 50% of the cases occur in the pediatric age group. In most cases of scleredema there is a female preponderance (2:1) except diabetes-associated scleredema, where males outnumber females 10:1. There is no ethnic predilection. Patients present with poorly defined areas of woody skin induration that may have a peau d’orange appearance. Lesions are primarily found on the neck, upper back, shoulders and arms.227 There may be some restriction of motion. Unusual cases with limited site involvement, e.g. periorbital skin, have also been reported.228 The skin is pale and waxy or shiny because of the effacement of normal skin markings. There is occasional tightness of the skin, which causes difficulty with mobility or restrictive pulmonary defects.229 Some patients report dysphagia. Scleredema has also been associated with exophthalmos, edema of the eyelids, electrocardiographic abnormalities, cardiomyopathy, myositis, hepatomegaly and splenomegaly, and pleural, pericardial, peritoneal and joint effusions (Fig. 42.25).230,231 The epidermis is generally unaffected, except for a mild effacement of the rete ridge pattern, and occasionally, a mild basal hyperpigmentation. There is thickening of the reticular dermis, with collagen extending into the subcutis. The collagen fibers are swollen and separated from one another by prominent mucopolysaccharide deposits, but

Fig. 42.25: Scleredema. Poorly defined areas of woody skin induration with a peau d’orange appearance on the upper back. Courtesy: Ian McColl, MD, Tugun, Australia.

Chapter 42: Disorders of Collagen, Elastin and Ground Substance

Fig. 42.26: Scleredema. Thickening of the reticular dermis, with collagen extending also into the subcutis. Collagen fibers are separated by prominent mucopolysaccharide deposits but no increase in fibroblasts. Courtesy: Rajendra Singh, MD, New York, USA.

no increase in fibroblasts.232,233 The mucin deposits stain Alcian blue or toluidine blue (pH 5.0 or 7.0) or with colloidal iron, but may be difficult to find as they may only be present at the onset of the disease (Fig. 42.26). The pathogenesis of scleredema is unknown. There is an increased deposition of an acid mucopolysaccharide, hyaluronic acid, in the dermis. Electron microscopy shows thickened collagen fibers with widening of the interfibrillar spaces.234 There may also be abnormal glycosylation of collagen fibers in patients with poorly controlled diabetes. The main mechanism appears to be an accumulation of matrix components due to abnormal gene expression of extracellular protein (collagen types I and III and fibronectin.).235 Treatment of scleredema is difficult. Systemic steroids, methotrexate, thalidomide, cyclosporine, plasmapheresis have been tried with inconsistent success.236 Phototherapy with UVA-1 and radiation treatment, including electron beam, have been successful.237 Some benefit has been seen with tamoxifen and colchicine.238

ACKNOWLEDGMENTS My deepest appreciation to the contributors of exceptional clinical and histopathologic photographs for this chapter.

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Section 13: Disorders of the Dermis and Subcutaneous Tissue 169. Uitto J, Cruz DJ, Starcher BC, et al. Biochemical and ultrastructural demonstration of elastin accumulation in the skin lesions of the Buschke–Ollendorff syndrome. J Investig Dermatol 1981;76(4):284–7. 170. Pope V, Dupuis L, Kannu P, et al. Buschke–Ollendorff syndrome: a novel case series and systematic review. Br J Dermatol 2016;174(4):723–9. 171. Morrison GLJ, Jones WE, Macdonald DM. Juvenile elastoma and osteopoikilosis (the Buschke–Ollendorff syndrome). Br J Dermatol 1977;97(4):417–22. 172. Korman B, Wei J, Laumann A, et al. Mutation in LEMD3 (Man1) Associated with osteopoikilosis and late-onset generalized morphea: a new Buschke–Ollendorf syndrome variant. Case Rep Dermatol Med 2016;2016:9. https://doi. org/10.1155/2016/2483041. 173. Condorelli A, Musso N, Scuderi L, et al. Juvenile elastoma without germline mutations in LEMD3 gene: a case of Buschke–Ollendorff syndrome? Pediatr Dermatol 2017;34(6):e345–e346. 174. Shelley WB, Wood MG. Wrinkles due to idiopathic loss of mid-dermal elastic tissue. Br J Dermatol 1977;97(4):441–5. 175. Hardin J, Dupuis E, Haber RM. Mid-dermal elastolysis: a female-centric disease; case report and updated review of the literature. Int J Womens Dermatol 2015;1(3):126–30. 176. Gambichler T. Mid-dermal elastolysis revisited. Arch Dermatol Res 2010;302(2):85–93. 177. Neri I, Patrizi A, Fanti PA, et al. Mid-dermal elastolysis: a pathological and ultrastructural study of five cases. J Cutan Pathol 1996;23(2):165–9. 178. Patroi I, Annessi G, Girolomoni G. Mid-dermal elastolysis: a clinical, histologic, and immunohistochemical study of 11 patients. J Am Acad Dermatol 2003;48(6):846–51. 179. Barile M, Rivara GP, Parodi A, et al. Postinflammatory mid-dermal elastolysis. J Eur Acad Dermatol Venereol 1992;1, 281–3. 180. Cohen PR, Tschen JA. Linear lumbar localized lysis of elastic fibers: a distinctive clinical presentation of mid-dermal elastolysis. J Clin Aesthet Dermatol 2013;6(7):32–9. 181. Venencie PY, Winkelmann RK, Moore BA. Anetoderma. Clinical findings, associations, and long-term follow-up evaluations. Arch Dermatol 1984;120(8):1032–9. 182. Miller WN, Ruccles CW, Rist TE. Anetoderma. Int J Dermatol 1979;18(1):43–5. 183. Friedman SJ, Venencie PY, Bradley RR, et al. Familial anetoderma. J Am Acad Dermatol 1987;16(2 Pt 1):341–5. 184. Hodak E, David M. Primary anetoderma and antiphospholipid antibodies—review of the literature. Clin Rev Allergy Immunol 2007;32(2):162–6. 185. Hodak E, Shamai-Lubovitz O, David M, et al. Immunologic abnormalities associated with primary anetoderma. Arch Dermatol 1992;128(6):799–803. 186. Hodak E, Shamai-Lubovitz O, David M, et al. Primary anetoderma associated with a wide spectrum of autoimmune abnormalities. J Am Acad Dermatol 1991;25(2 Pt 2):415–8. 187. Kim JE, Sohn KM, Woo YJ, et al. A clinicoimmunohistopathologic study of anetoderma: is protruding type more advanced in stage than indented type? J Immunol Res 2016;2016:10. https://doi.org/10.1155/2016/4325463.

188. Lindstrom J, Smith KJ, Skelton HG, et al. Increased anticardiolipin antibodies associated with the development of anetoderma in HIV-1 disease. Military Medical Consortium for the Advancement of Retroviral Research (MMCARR). Int J Dermatol 1995;34(6):408–15. 189. Venencie PY, Winkelmann RK. Histopathologic findings in anetoderma. Arch Dermatol 1984;120(8):1040–4. 190. Ghomrasseni S, Dridi M, Gogly B, et al. Anetoderma: an altered balance between metalloproteinases and tissue inhibitors of metalloproteinases. Am J Dermatopathol 2002;24(2):118. 191. Kordi M, Rashidi Fakari F, Mazloum SR, et al. Quality of life evaluation in Iranian postpartum women with and without striae gravidarum. Iran J Psychiatry Behav Sci 2016;10(2):e3993. 192. Yamaguchi K, Suganuma N, Ohashi K. Prevention of striae gravidarum and quality of life among pregnant Japanese women. Midwifery 2014;30(6):595–9. 193. Kasielska-Trojan A, Sobczak M, Antoszewski B. Risk factors of striae gravidarum. Int J Cosmet Sci 2015;37(2): 236–40. 194. Elton RF. Striae in normal men. Arch Dermatol 1966;94(1): 33–4. 195. Farahnik B, Park K, Kroumpouzos G, et al. Striae gravidarum: risk factors, prevention, and management. Int J Women’s Dermatol 2017;3(2):77–85. 196. Cho S, Park ES, Lee DH, et al. Clinical features and risk factors for striae distensae in Korean adolescents. J Eur Acad Dermatol Venereol 2006;20(9):1108–13. 197. Darvay A, Acland K, Lynn W, et al. Striae formation in two HIV-positive persons receiving protease inhibitors. J Am Acad Dermatol 1999;41(3 Pt 1):467–9. 198. Tamada Y, Yokochi K, Ikeya T, et al. Linear focal elastosis: a review of three cases in young Japanese men. J Am Acad Dermatol 1997;36(2):301–3. 199. Al-Himdani S, Ud-Din S, Gilmore S, et al. Striae distensae: a comprehensive review and evidence-based evaluation of prophylaxis and treatment. Br J Dermatol 2014;170(3):527–47. 200. Ross NA, Ho D, Fisher J, et al. Striae distensae: preventative and therapeutic modalities to improve aesthetic appearance. Dermatol Surg 2017;43(5):635–48. 201. Pasini A. Atrophoderma idiopathica progressiva. G Ital Dermatol 1923;58:785. 202. Pierini LE, Vivoli D. Atrophodermia idiopathica progressiva. (Pasini). G Ital Dermatol 1936;77. 203. Handler M, Alshaiji JM, Shiman MI, et al. Congenital idiopathic atrophoderma of Pasini and Pierini. Dermatol Online J 2012;18(4):4. 204. Jablonska S, Blaszczyk M. Is superficial morphea synonymous with atrophoderma Pasini–Pierini? J Am Acad Dermatol 2004;50(6):979–80; author reply 980. 205. Kee CE, Brothers WS, New W. Idiopathic atrophoderma of Pasini and Pierini with coexistent morphea: a case report. Arch Dermatol 1960;82(1):100–3. 206. Kencka D, Blaszczyk M, Jabłon´ska S. Atrophoderma Pasini–Pierini is a primary atrophic abortive morphea. Dermatology, 190(3):203–6.

Chapter 42: Disorders of Collagen, Elastin and Ground Substance 207. Buechner SA, Rufli T. Atrophoderma of Pasini and Pierini. Clinical and histopathologic findings and antibodies to Borrelia burgdorferi in thirty-four patients. J Am Acad Dermatol 1994;30(3):441–6. 208. Vieira-Damiani G, Lage D, Christofoletti Daldon PE, et al. Idiopathic atrophoderma of Pasini and Pierini: a case study of collagen and elastin texture by multiphoton microscopy. J Am Acad Dermatol 2017;77(5):930–7. 209. Lee Y, Oh Y, Ahn SY, et al. A case of atrophoderma of Pasini and Pierini associated with borrelia burgdorferi infection successfully treated with oral doxycycline. Ann Dermatol 2011;23(3):352–6. 210. Carter JD, Valeriano J, Vasey FB. Hydroxychloroquine as a treatment for atrophoderma of Pasini and Pierini. Int J Dermatol 2006;45(10):1255–6. 211. Lestringant GG, Kuster W, Frossard PM, et al. Congenital ichthyosis, follicular atrophoderma, hypotrichosis, and hypohidrosis: a new genodermatosis? Am J Med Genet 1998;75(2):186–9. 212. Curth HO. The genetics of follicular atrophoderma. Arch Dermatol 1978;114(10):1479–83. 213. Inoue Y, Ono T, Kayashima K. et al. Hereditary perioral pigmented follicular atrophoderma associated with milia and epidermoid cysts. Br J Dermatol 1998;139(4):713–8. 214. Neri I, Virdi A, Tortora G, et al. Novel p.Glu519Gln missense mutation in ST14 in a patient with ichthyosis, follicular atrophoderma and hypotrichosis and review of the literature. J Dermatol Sci 2016;81(1):63–6. 215. Shelley WB, Rawnsley HM. Painful feet due to herniation of fat. JAMA 1968;205(5):308–9. 216. Rocha Bde O, Fernandes JD, Prates FV. Piezogenic pedal papules. An Bras Dermatol 2015;90(6):928–9. 217. Schlappner OL, Wood MG, Gerstein W, et al. Painful and nonpainful piezogenic pedal papules. Arch Dermatol 1972;106(5):729–33. 218. Laing VB, Fleischer AB. Piezogenic wrist papules: a common and asymptomatic finding. J Am Acad Dermatol 1991;24(3):415–7. 219. Kahana M, Feinstein A, Tabachnic E, et al. Painful piezogenic pedal papules in patients with Ehlers–Danlos syndrome. J Am Acad Dermatol 1987;17(2 Pt 1):205–9. 220. Altin C, Askin U, Gezmis E, et al. Piezogenic pedal papules with mitral valve prolapse. Indian J Dermatol 2016;61(2):234. 221. Doukas DJ, Holmes J, Leonard JA. A nonsurgical approach to painful piezogenic pedal papules. Cutis 2004;73(5):339. 222. Cron RQ, Swetter SM. Scleredema revisited. Clin Pediatr 1994;33(10):606–10. 223. Morais P, Almeida M, Santos P, et al. Scleredema of Buschke following Mycoplasma pneumoniae respiratory infection. Int J Dermatol 2011;50(4):454–7.

224. Dziadzio M, Anastassiades CP, Hawkins PN, et al. From scleredema to AL amyloidosis: disease progression or coincidence? Review of the literature. Clin Rheumatol 2006;25(1):3–15. 225. Cole GW, Headley J, Skowsky R. Scleredema diabeticorum: a common and distinct cutaneous manifestation of diabetes mellitus. Diabetes Care 1983;6(2):189–92. 226. Alves J, Judas T, Ferreira T, et al. Scleredema associated with Sjögren’s syndrome. An Bras Dermatol. 2015 May–Jun; 90(3 Suppl 1):81–3. 227. Meguerditchian C, Jacquet P, Béliard S, et al. Scleredema adultorum of Buschke: an under recognized skin complication of diabetes. Diabetes Metab. 2006;32(5 Pt 1):481–4. 228. Ioannidou DI, Krasagakis K, Stefanidou MP, et al. Scleredema adultorum of Buschke presenting as periorbital edema: a diagnostic challenge. J Am Acad Dermatol 2005;52(2 Suppl 1):41–4. 229. Ray V, Boisseau-Garsaud AM, Ray P, et al. Obesity persistent scleredema: study of 49 cases. Ann Dermatol Venereol 2002;129(3):281–5. 230. Rongioletti F, Kaiser F, Cinotti E, et al. Scleredema. A multicentre study of characteristics, comorbidities, course and therapy in 44 patients. J Eur Acad Dermatol Venereol 2015;29(12):2399–404. 231. Carrington PR, Sanusi ID, Winder PR, et al. Scleredema adultorum. Int J Dermatol 1984;23(8):514–22. 232. Cohn BA, Wheeler CE, Briggaman RA. Scleredema adultorum of buschke and diabetes mellitus. Arch Dermatol 1970;101(1):27–35. 233. Cole HG, Winkelmann RK. Acid mucopolysaccharide staining in scleredema. J Cutan Pathol 1990;17(4):211–3. 234. Ohta A, Uitto J, Oikarinen AI, et al. Paraproteinemia in patients with scleredema. Clinical findings and serum effects on skin fibroblasts in vitro. J Am Acad Dermatol 1987;16(1 Pt 1):96–107. 235. Lemes LR, Vilela GM, Duraes SM, et al. Scleredema of Buschke associated with difficult-to-control type 2 diabetes mellitus. Rev Assoc Med Bras (1992) 2016; 62(3):199–201. 236. Adam Z, Szturz P, Krejcˇí M, et al. Monoclonal immunoglobulin (M-Ig) and skin diseases from the group of mucinoses—scleredema adultorum Buschke and scleromyxedema. Description of four cases and an overview of therapies. Vnitr Lek 2015;61(12):1072-87. 237. Kokpol C, Rajatanavin N, Rattanakemakorn P. Successful treatment of scleredema diabeticorum by combining local PUVA and colchicine: a case report. Case Rep Dermatol 2012;4(3):265–8. 238. Alsaeedi SH, Lee P. Treatment of scleredema diabeticorum with tamoxifen. J Rheumatol 2010;37(12):2636–7.

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Diseases of Subcutaneous Tissue Sandipan Dhar, Ann M John, Amrinder Jit Kanwar

INTRODUCTION Panniculitis is the inflammation of subcutaneous fat. This group of disorders poses a significant diagnostic challenge to dermatologists and pathologists because of their clinical similarity and considerable histopathological overlap. Therefore, a good clinical–pathological correlation is of the utmost importance to reach a diagnosis. Most of the panniculitis disorders clinically present as subcutaneous nodules or indurated plaques, with or without tenderness. From a histopathological point of view, different panniculitis disorders may show similar histopathological features and histopathology of a particular panniculitis may change with the stage of the disease. There may be an overlap of septal panniculitis (predominantly septal inflammation) and lobular panniculitis (predominantly lobular inflammation), and different specimens from the same entity may show different pictures. At the end of the day, it is the predominant inflammation of a particular specimen that sheds light on the diagnosis. In spite of these confusing presentations, the most commonly used classification system is based on predominant histopathology, whether the pathology is septal or lobular. These two categories are further divided into the presence or absence of vasculitis. Therefore, an optimal biopsy technique with adequate sample depth is extremely important. Panniculitis may be classified as follows: Predominantly septal panniculitis without vasculitis, which includes erythema nodosum. Predominantly septal panniculitis with vasculitis, which includes cutaneous polyarteritis nodosa and superficial panniculitis. Lobular panniculitis with vasculitis, which includes only two entities: erythema induratum of Bazin and erythema nodosum leprosum. Lobular panniculitis without vasculitis encompasses several entities, including iatrogenic or traumatic panniculitis, cold panniculitis, and poststeroid panniculitis. Others include subcutaneous fat necrosis of the newborn, sclerema neonatorum, panniculitis associated with connective tissue

diseases, enzymatic panniculitis, calciphylaxis, lipodystrophy and lipoatrophy, infective panniculitis, sclerosing panniculitis, cytophagic histiocytic panniculitis, and subcutaneous panniculitis-like T-cell lymphoma. Here we give a brief account of some important forms of panniculitis.

PREDOMINANTLY SEPTAL PANNICULITIS WITHOUT VASCULITIS Erythema Nodosum Erythema nodosum (EN) is the most common form of panniculitis seen in adults and children. In adults, females in their third decade of life are the usual victim. However, it may occur in any age and gender without any racial or geographical preponderance. Etiologies vary from infectious, drug-induced, inflammatory, to cause secondary to malignancy. Therefore, it is better to designate EN as reaction pattern than as a specific entity to a variety of stimulus. In spite of several implicated etiological factors, many cases of EN remain idiopathic. Though primarily considered as a delayed-type hypersensitivity reaction, the role of other factors such as cytokines,1 estrogen, and immune complexes2 are yet to be confirmed. Beta-hemolytic streptococcal infection is the most common infection known to induce EN in the pediatric group.3,4 Tuberculosis is another important inciting infection. Several other infections such as intestinal infection by shigella sp., salmonella sp., systemic fungal infection by histoplasmosis, coccidioidomycosis, and hepatitis B virus infection have been implicated. Oral contraceptive pills and hormone replacement therapy are the most common culprit drugs. Other causative medications are antibiotics (penicillin, sulphonamides), the BCG vaccination, and iodides and bromides. In terms of irritable bowel disease, EN is more commonly associated with Crohn’s disease than ulcerative colitis. Among malignancies, Hodgkin’s lymphoma is

Chapter 43: Diseases of Subcutaneous Tissue commonly, but rarely, associated with EN both in children and adults.5 Sarcoidosis may present with fever, joint pain, hilar lymphadenopathy, uveitis, and EN. This constellation of symptoms is collectively known as Lofgren’s syndrome. EN is found to be associated with other autoimmune disorders and pregnancy. Erythema nodosum like lesions are associated with Behcet’s syndrome. These lesions can be differentiated from true EN as they are predominantly lobular panniculitis with leukocytoclastic vasculitis or lymphocytoclastic vasculitis.6 Clinically, lesions present as erythematous, warm, tender nodules, or plaques distributed bilaterally and symmetrically over anterior shins, ankle, and knees. Uncommonly, they involve calves, thighs, arms, and face. Gradually, the color changes from erythematous to ecchymotic like in appearance. The nodules heal completely within 2–6 weeks without any atrophy or scarring. Postinflammatory hyperpigmentation may occur in few cases. Acute EN is associated with or preceded by constitutional symptoms such as fever, malaise, headache, conjunctivitis, abdominal pain, vomiting, and arthralgia. Any joint of the upper or lower extremities can be involved. Chronic forms of EN do exist, and may be given a variety of titles such as chronic EN, erythema nodosum migrans, and subacute nodular migratory panniculitis. In chronic cases, the lesions are asymptomatic or minimally painful,7 are not associated with systemic symptoms except arthralgia usually start with a nodule that spreads peripherally to form annular lesions with central clearing,8 and tend to have a protracted course. On histological grounds, primarily EN is a septal panniculitis without vasculitis. Inflammation and thickening of fibrous septa is evident, and the characteristics of the inflammatory infiltrate changes with the stage of the disease. Initially, infiltrate is composed of neutrophils, followed by histiocytes, and multinucleated giant cells in older lesions. Miescher radial granulomas are characterized by an arrangement of histiocytes around a central cleft. This finding is characteristic9 but not diagnostic of EN.10 On occasion, thickening of fibrous septa and spillage of inflammatory cells in fat lobules make the diagnosis difficult to make in later stages of disease. Other than careful history taking, thorough clinical examination, and biopsy, few other tests are often required to arrive an etiological diagnosis. Based off of clinical suspicion, these include: complete blood count including erythrocyte sedimentation rate, antistreptolysin O titers, throat swab culture, chest X-ray, Mantoux test,

urine and stool culture, serological tests for bacterial, viral, and fungal infection, and serology, imaging, and/or biopsy if suspicion exists for inflammatory bowel disease. Management should be aimed at finding out an underlying etiology and treating accordingly. Supportive management, including complete bed rest and use of non-steroidal anti-inflammatory drugs (NSAIDs), is absolutely necessary. Systemic steroid use leads to rapid resolution of symptoms, but should only be employed after exclusion of underlying infection. Saturated solution of potassium iodide taken orally is a good choice, but should be used with caution in children due to its side effect profile. Other options include antimalarial medications and colchicine. Prognosis of acute EN is good, though recurrence is common. Recurrence and systemic symptoms11 are less common in children than in adults. Chronic EN requires further evaluation.

LOBULAR PANNICULITIS WITH VASCULITIS Erythema induratum of Bazin (EI) and nodular vasculitis are etiologically different entities, but clinically and histopathologically they are the same. When hypersensitivity reaction is due to tuberculosis, the entity is called EI. Though classically described in middle-aged women, EI can also occur in the pediatric population.12,13 Clinically, lesions are erythematous, tender nodules on the calves, which frequently ulcerate, lead to drainage of oily fluid. EI/ nodular vasculitis can be differentiated from EN as it develops on the posterior leg, is less tender, is prone to ulceration, heals with atrophic scarring, is devoid of systemic symptoms, and is recurrent in nature. Histopathologically, EI is a lobular panniculitis with vasculitis in most of the cases14 whereas EN is a septal panniculitis without vasculitis. Vasculitis may be absent in few cases. Involvement of vessels leads to ischemic necrosis of fat lobules. The initial predominant neutrophilic infiltration is subsequently replaced by granulomatous infiltration with the passage of time. Mantoux test is strongly positive in cases of nodular vasculitis of tubercular origin (EI). As Mycobacterium tuberculosis cannot be cultured, detection of bacterial DNA by polymerase chain reaction (PCR) is the indirect evidence of the same.15 PCR is not recommended in tuberculin skin test-negative cases. EI should be treated with antitubercular medications after confirmation. Nodular vasculitis due to other causes can be treated with systemic

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LOBULAR PANNICULITIS WITHOUT VASCULITIS Physical, Chemical, and Iatrogenic Panniculitis Cold Panniculitis Cold panniculitis occurs following exposure to cold temperature and more commonly occurs in infants and children. The underlying etiology is a higher content of saturated fat in infants with higher melting point.16 A slight decrease in temperature leads to solidification of the same. The gradual resistance to crystallization of subcutaneous fat with increasing age is due to an increase in the content of unsaturated fat.17 This entity is known by different terminologies according to the etiology. It can occur in children following suckling “popsicles” (Popsicle panniculitis),18 over exposed parts of the cheek and limbs in winter season, or following application of ice over the cheek in cases of supraventricular tachycardia. Scrotal cold panniculitis has been reported in prepubertal boys following swimming in cold water.19 Absence of fatty tissue in the adult scrotum protects it from cold panniculitis. Equestrian panniculitis refers to cold panniculitis in upper lateral thigh of women who ride horse in cold weather. Tight-fitting riding pants with lack of insulation is the most probable cause (Fig. 43.1). Clinically, lesions are ill-defined indurated plaques or nodules that appear 48–72 hours after cold exposure.

Cold panniculitis resolves spontaneously within few days to weeks without any atrophy or scarring. Slight postinflammatory hyperpigmentation may ensue. Diagnosis is mostly clinical with a definite history of cold exposure. Histopathology is non-specific. Histopathology reveals predominantly a lobular panniculitis with mixed infiltrate of lymphocytes, neutrophils and histiocytes, and plasma cells.20 Close differentials are cellulitis and poststeroid panniculitis, which are sometimes difficult to distinguish without an appropriate history.21

Traumatic Panniculitis Accidental blunt trauma may incite an inflammatory response following necrosis of subcutaneous fat. Usual affected sites are the trunk and breast in women. In pediatric cases, the cheek is the most common site of involvement, though other areas in close proximity to bony prominences can be affected.22 Clinically, patients present with firm-to-hard indurated subcutaneous nodules that may be mobile or fixed to the underlying structure. Close differentials are lipoma and carcinoma of breast. Interestingly, prior history of trauma usually cannot be recalled by the patient. The term Lipoatrophia semicircularis could be attributed to a semicircular band of fat atrophy in the upper anterolateral thigh, following accidental trauma with desk or chair. Histopathology reveals it to be a lobular panniculitis with fat necrosis and foamy histiocytes. Subcutaneous nodules usually resolve spontaneously. Sometimes, localized lipoatrophy ensues, leading to a cosmetic defect. Traumatic panniculitis can be factitious in origin, which will be discussed next.

Factitious Panniculitis

Fig. 43.1: Cold panniculitis.

Self-induced or factitious panniculitis results from injection of naturally occurring fluids such as feces, saliva, vaginal fluid, or organic materials into the subcutaneous tissue. Self-induced blunt trauma may lead to factitious panniculitis as well. The clinical pattern depends on the inciting agent, therefore presentation is very non-specific. Proper history taking and examination are very important to reach a conclusion. Inconsistent history, underlying psychological conflict, pattern unusual to any known form of panniculitis, and distribution in accessible areas are few important points to be considered. Histopathology varies with the stage of the lesion and causative agent. Mostly, it is a lobular panniculitis with variable inflammation and fat necrosis. Culture may reveal growth of fecal, oral, and vaginal flora. Special techniques such as

Chapter 43: Diseases of Subcutaneous Tissue polarization, radiography, and electron microscopy may be used to identify foreign material. Treatment options range from supportive to surgical care, avoidance of offending agent, and psychiatric consultation if needed.23,24

Poststeroid Panniculitis Poststeroid panniculitis occurs due to rapid withdrawal of high dose systemic corticosteroids used for other indications, where route of administration may vary. Though pathogenesis is cloudy, rapid withdrawal of systemic steroid leading to increased ration of saturated-to-unsaturated fatty acids, which favors crystal formation, could be a possible explanation.25 Clinically affected children manifest with erythematous, firm subcutaneous nodules predominantly over face, trunk, and proximal extremities, sites rich in subcutaneous fat. Histopathology reveals that it is a lobular panniculitis with necrosed adipocytes, foamy histiocytes, and needle shaped crystals within both types of cells. Most of the cases resolve spontaneously. Severe cases may require reinstitution of systemic corticosteroids, followed by slow tapering.

Sclerosing Lipogranuloma This specific entity, also known as paraffinoma or oil granuloma, results from a granulomatous and fibrotic reaction following injection of mineral or vegetable oil into the panniculus for various cosmetic and aesthetic purposes. Though introduction of silicon prosthesis has reduced the incidence of oil granuloma, this phenomenon may still occur infrequently. Clinically, lesions may appear months to years after injection. Sites of predilection are based off of desire for esthetic augmentation, and may include the breast, buttock, and penis.26-28 Firm, painless, indurated lumps with overlying hyper pigmented and erythematous skin is the usual presentation. Focal ulceration is not uncommon. Implanted material may persist indefinitely at the injection site or may migrate locally or distally into lymphoreticular system. Histopathology is characterized by a “Swiss cheese” appearance that denotes replacement of the panniculus with various sized vacuoles. As the material is washed out during tissue processing, only empty spaces persist. Cavities are surrounded by histiocytes with ingested materials, giving the cytoplasm a vacuolated appearance. Profound inflammation with little inflammation characterizes the histopathology. Surgical excision is needed if there is ulceration, necrosis, or malignant transformation.29

OTHER LOBULAR PANNICULITIS DISORDERS WITHOUT VASCULITIS Sclerema Neonatorum Sclerema neonatorum is a rare and life-threatening condition that affects severely ill and premature infants during the first few days of life. Associated conditions are hypothermia, hypoglycemia, sepsis, electrolyte imbalance, pneumonia, and intracranial hemorrhage.30-31 High content of saturated fatty acids in infants leads to rapid crystallization under certain conditions. The poorly developed neonatal enzyme system fails to convert saturated palmitic and stearic acid to oleic acid, which is further aggravated with associated comorbidities. Thickening of connective tissue septa due to edema also plays role.32 Diffuse, woody hardening starts from buttock, lower extremities and cheeks within first few days and gradually involves trunk. Acral surfaces and genitalia are spared. Skin is cold, hard, immobile, and bound down. Respiration and joint mobility are severely compromised and could be fatal. Discrepancies exist whether sclerema neonatorum and subcutaneous fat necrosis represent a spectrum of disease, where the former represents the severe form. There is significant clinical histopathological overlap between the two entities.32,33 Visceral fat may also be involved. Histopathology shows sparse or absent inflammation with radially arranged needle shaped clefts within the adipocytes representing empty spaces of lipid crystals. Treatment of the underlying cause is very essential. The role of systemic corticosteroids is controversial. Exchange transfusion might be beneficial.

Subcutaneous Fat Necrosis of Newborn Subcutaneous fat necrosis (SFN) is a benign and uncommon panniculitis that occurs during first few weeks of life in term or post-term infants. Among the associated perinatal complications, fetal asphyxia is most common.33 SFN can also be associated with meconium aspiration, hypothermia, sepsis, neonatal anemia, thrombocytopenia, seizures, or macrosomia. Among the associated maternal predisposing factors, gestational diabetes, pre-eclampsia, and maternal cocaine use are worth mentioning. Localization of SFN over bony prominences, which supports hypoxic fat necrosis following local trauma, could be a possible explanation. Other etiological explanations are high content of saturated fatty acid and immature neonatal fat metabolism system.34,35

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Section 13: Disorders of the Dermis and Subcutaneous Tissue Clinically, lesions are erythematous, painful, indurated subcutaneous nodules or plaques. On palpation, they are freely mobile, overlying fascia or muscle distributed over buttock, thigh, upper back, and cheek, preferentially sparing the anterior trunk. Lesions usually resolve within weeks-to-months without residual atrophy. Rarely, they can become calcified or fluctuant with liquefied fat, followed by spontaneous drainage and scar formation. In spite of these tender lesions, infants are usually well. Among the important metabolic complication that requires greatest consideration is hypercalcemia. Hypercalcemia may be completely asymptomatic or may lead to electrolyte imbalances and failure to thrive, hypotonia, seizures, renal failure, and cardiac arrest.36,37 Hypercalcemia may appear a few weeks-to-months after the appearance of skin lesions. Therefore, periodic serum calcium estimation for first 6 months is very important. Possible explanations are increased production of 1,25 dihydroxy vitamin D3 by macrophages, increased level of prostaglandin E2 and parathormone leading to bone resorption.38,39 Histo­ pathology shows lobular panniculitis with fat necrosis and mixed infiltrate with histiocytes, lymphocytes, and multinucleated giant cells. Radially arranged needle shaped clefts within histiocytes represent empty spaces for dissolved crystallized fat during tissue processing. No treatment is required for skin lesions. Treatment of the metabolic complications should be done as early as possible.

Infectious Panniculitis Infectious panniculitis commonly occurs in immuno­ compromised individuals, but may also affect immunecompetent people.40 Infectious etiology is diverse. Bacterial causes include Staphylococcus aureus, Streptococcus sp., Klebsiella sp., Pseudomonas sp.), atypical mycobacterial species. Fungal sources are Candida sp, Nocardia sp.), and viruses may cause panniculitis as well. Modes of transmission are primary inoculation, direct extension from underling infection, or hematogenous spread. Clinically, patients present with tender, erythematous subcutaneous nodules, usually confined to one area. However, dissemination is not uncommon. Ulceration and necrosis of the skin lesions may occur due to lodgment of septic emboli within blood vessels and lymphatics. Histopathology shows a mixed septal and lobular panniculitis with a neutrophilic predominance. Necrosis, hemorrhage, suppurative granuloma, and vasculitis are occasional findings. Special stains and culture of the biopsy specimen reveals

the causative organism. Sometimes it becomes difficult to distinguish infectious panniculitis from erythema nodosum, because the septum may also be predominantly involved in infectious panniculitis.41 However, the absence of an infectious organism may point toward erythema nodosum. Antibiotic/antifungal treatments based on culture report should be initiated early.

METABOLIC PANNICULITIS DISORDERS Pancreatic Panniculitis As the name suggests, this entity is typically associated with pancreatic disease; mainly acute or chronic pancreatitis or pancreatic carcinoma. Among the pancreatic carcinomas, acinar cell carcinoma is the most common association. Other pancreatic disorders such as drug-induced pancreatitis and pancreatic pseudocyst are hardly found to be in associated with pancreatic panniculitis. It is almost exclusively a disorder of the adult population. Release of different digestive enzymes (amylase, lipase, phosphorylase) leads to inflammation and subcutaneous fat necrosis. Cutaneous panniculitis may come as the inciting sign of pancreatic pathology, even before the manifestation of other organs is involved. Surprisingly, abdominal symptoms may be completely absent. Extracutaneous manifestations of pancreatic panniculitis is most commonly associated with arthritis, which may be monoarticular, polyarticular, migratory, or persistent. Joints in close proximity to the panniculitis are usually affected, such as ankles.42 Examination of the joint fluid aspirate reveals free fatty acids. Other internal organ manifestations are pleuritis, pericarditis, or hypocalcemia secondary to saponification. Lesions are ill defined, erythematous, tender nodules located in the distal extremities that may ulcerate leading oozing of oily fluid43 (Fig. 43.2). Histopathology shows lobular panniculitis without vasculitis. Coagulative necrosis of fat leads to ghost cell appearance of adipocytes with no nucleus and peripheral rim of cytoplasm.44 Dystrophic calcification in the form of fine granular basophilic substances is found within the cytoplasm of necrotic fat cells. Treatment is supportive and directed to the underlying cause.

Alpha-1 Antitrypsin Deficiency Panniculitis Alpha-1 antitrypsin is the most abundant serine protease inhibitor. This enzyme is synthesized by the liver

Chapter 43: Diseases of Subcutaneous Tissue exacerbate the condition. Replacement of the deficient enzyme, plasma exchange, liver transplantation, and gene therapy47 are other modes of treatment.

Cytophagic Histiocytic Panniculitis

Fig. 43.2: Pancreatic panniculitis over legs.

and circulates in the body. It is required to inactivate neutrophilic elastase, pancreatic elastase, trypsin, chymotrypsin, and several other enzymes. Deficiency of this enzyme leads to unopposed activation of proteases and inflammatory damage. Alpha-1 antitrypsin deficiency commonly manifests as emphysema, cirrhosis, or hepatitis. Cutaneous panniculitis is a rare manifestation of this deficiency. Deficiency of this enzyme is inherited in an autosomal dominant fashion. Sequela of this deficiency and resulting panniculitis is seen commonly in the third– fourth decade, but children can also be affected. Europeans and Caucasians are common victims. Panniculitis is most common in those who have a homozygotic deficiency of the Z allele. Patients usually present with painful subcutaneous nodules mimicking cellulitis following minor trauma. Lesions has predilection for the lower extremities, but the trunk and face may also be involved. They may ulcerate spontaneously, leading to drainage of oily fluid. For­ mation of draining sinuses and healing with atrophy are common sequelae.45 Histopathology changes with stage of the disease. Initial lesions show neutrophils scattered in between collagen bundles in the reticular dermis. Gradually, they invade into fat lobules through the fibrous septa, leading to extensive fat necrosis. Islands of normal fat float in the space provided by the destroyed septa. From a management point of view, avoidance of inciting factors such as trauma, smoking, debridement, and hepatotoxins is of utmost importance. Among the treatments available, dapsone, colchicine, and tetracyclines46 are found to be effective. Systemic corticosteroids may

The name cytophagic histiocytic panniculitis (CHP) was derived from its histopathological appearance, in which the lobules were found to be infiltrated with cytologically benign-appearing histiocytes filled with engulfed erythrocytes, neutrophils, platelets, lymphocytes, and nuclear debris. These phagocytic cells are hence named bean bag cells. Though bean bag cells are a consistent feature of CHP, they are not diagnostic of the same. Along with histiocytes, other features include infiltrated T cells, fat necrosis, and hemorrhage. In cases of hemophagocytic syndrome, presence of RBCs within phagocytes predominates the picture. The etiology is not yet described. However, cytokines released by T cells are considered to play some role.48 Important associations with CHP are Epstein-Barr virus (EBV) infection, human immunodeficiency (HIV) virus infection, and malignancies. According to some authors, CHP and subcutaneous panniculitis caused by T-cell lymphoma (SPTL) represent a spectrum of disease where CPH can progress to SPTL.49 Presence of atypical T cells or clonal proliferation of B/T cells supports the diagnosis of the latter. Clinically, patients present with erythematous, painful subcutaneous nodules, which may ulcerate. Associated systemic symptoms are fever, pancytopenia, hepatosplenomegaly, and liver failure. Though the disease commonly occurs in adults, children may also be affected. Treatment options are systemic corticosteroids, cyclosporine, high dose intravenous immunoglobulin, and other chemotherapeutic agents. Resistant cases should be treated with bone marrow transplantation.50

Subcutaneous Panniculitis-like T-cell Lymphoma This is a form of cutaneous lymphoma where there is proliferation of cytologically atypical malignant T cells within the subcutis, clinically mimicking inflammatory panniculitis. According to the WHO-EORTC classification (2005), SPTL denotes cases with alpha/beta positive T-cell receptor phenotypes.51 It can occur both in adults and children. Specific etiology is unknown. Previously, EBV was hypothesized to play some role. However, the new classification states that EBV hardly has a role in pathogenesis.51,52

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Section 13: Disorders of the Dermis and Subcutaneous Tissue Deep-seated subcutaneous nodules and plaques over the trunk and extremities is the usual presentation. Lesions may ulcerate. Fever, malaise, and weight loss are usually associated with subcutaneous panniculitis-like T-cell lymphoma and constitutional symptoms occur more commonly in children.53 Patients with hemophagocytic syndrome present with pancytopenia, hepatosplenomegaly and lymphadenopathy, and carry a poor prognosis. Histopathology reveals a lobular panniculitis dominated by atypical lymphocytes. They may rim the adipocytes, leading to a lace-like pattern that is a non-specific finding as it may be found in other lymphomas. Presence of the “bean bag cell” is not uncommon.54 T-cell gene receptor rearrangement studies are important in arriving at the correct diagnosis. Clonality does not always confer malignancy. Immunohistochemical staining reveals atypical lymphocytes that are CD3+, CD8+ positive and CD56 negative.55 Imaging studies are required to assess the extent of the disease. Treatment should be aggressive and should include systemic corticosteroids, cyclosporine, and other immunosuppressive agents.

CONNECTIVE TISSUE DISORDERASSOCIATED PANNICULITIS Lupus Panniculitis Lupus panniculitis, also known as lupus erythematous profundus, clinically presents as asymptomatic, erythematous nodules, or plaques, with a predilection for the face and proximal extremities (upper arms, shoulder, buttock, and thigh). Overlying skin may be normal or have associated features of discoid lupus erythematosus such as atrophy, scaling, and follicular plugging.56 It can occur both in adults and children, however, there is a limited number of reports in children.57 In adults, lupus panniculitis may present as an isolated finding or as a component of manifestations of discoid lupus erythematosus or systemic lupus erythematosus.58,59 Histopathology shows mainly a lobular panniculitis with predominance of lymphocytes and plasma cells. Lymphoid aggregates may develop with formation of germinal centers. Additional features like calcification and mucin deposition may also be present. Direct immunofluorescence reveals linear deposition of IgM and C3 along the dermoepidermal junction. Treatment options are corticosteroids, antimalarial agents, and other immunosuppressive drugs (Fig. 43.3).

Fig. 43.3: Lupus panniculitis.

Dermatomyositis Panniculitis While rare, panniculitis can be associated with dermatomyositis, particularly juvenile-onset dermatomyositis. Clinically, lesions present as tender, indurated, erythematous, subcutaneous plaques that often ulcerate and may lead to lipoatrophy. Lesions are primarily located on the buttocks, abdomen, and proximal extremities. Panniculitis can precede or follow other cutaneous manifestations of dermatomyositis. The pathology of dermatomyositis panniculitis is a predominantly lobular or mixed panniculitis with fat necrosis and an infiltrate of lymphocytes and plasma cells with some nodular lymphocytic aggregates. Lesions with evidence of lipomembranous changes may be associated with refractoriness to therapy. Calcification or vasculitis may be noted. In addition, vacuolar changes in the basal layer and mucinous or edematous changes in the dermis have been described. In juvenile dermatomyositis, panniculitis is associated with hypertriglyceridemia and insulin resistance. Treatment options include prednisone, hydroxychloroquine, and immunosuppressive drugs such as methotrexate, azathioprine, cyclosporine, mycophenolate mofetil, and IVIG. If there is evidence of infection, antibiotics should be added to the treatment regimen.60-64

Subcutaneous Sarcoidosis Subcutaneous sarcoidosis, also known as the DarierRoussy variant of sarcoidosis, presents with non-caseating

Chapter 43: Diseases of Subcutaneous Tissue granulomas constricted to the subcutaneous tissue. A rare variant, it has been reported in 1.4–6% of patients with systemic sarcoidosis.71 These often affect the extremities and trunk. Clinically, the lesions present as multiple asymptomatic subcutaneous nodules without epidermal changes. Histologically, this variant is a fibrosing panniculitis with non-caseating granulomas confined to the subcutaneous tissue, specifically the fat lobules. Multinucleated histiocytes containing asteroid bodies or Schaumann bodies may be found, although these are not specific for sarcoidosis. Necrosis and calcification may be present. Systemic treatment includes oral corticosteroids, hydroxychloroquine, minocycline, methrotrexate, thalidomide, allopurinol, isotretinoin, TNF-α inhibitors, PVA, leflunomide, mycophenolate mofetil. Intralesional steroids and intralesional chloroquine can also be considered.64,69-71 It is important to note that erythema nodosum (discussed previously) also represents a subcutaneous manifestation of sarcoidosis.

Fig. 43.4: Lipodermatosclerosis. Courtesy: Dr Ann John.

OTHER DISEASES OF SUBCUTANEOUS TISSUES Lipodermatosclerosis Lipodermatosclerosis represents a chronic fibrosing panniculitis in the setting of venous insufficiency, usually affecting middle aged to elderly women (Fig. 43.4). It has also been referred to as sclerosis panniculitis and hypodermitis sclerodermaformis. The acute and subacute phases clinically present as tender, erythematous, indurated plaques involving legs above the medial malleolus (Fig. 43.5). Eventually, this transforms into the chronic phase with well-demarcated, hyperpigmented, and depressed skin with skin tightening causing constriction of the ankle region and providing the classic “inverted champagne bottle” appearance. Ulceration can occur. The histopathology of lipodermatosclerosis also depends on the phase of the lesion. In the acute phase, lesions demonstrate septal lymphocytic infiltrate, ischemic necrosis within lobule, capillary congestion, and erythrocyte extravasation. As lesions progress, a mixed inflammatory cell infiltrate with lymphocytes and plasma cells develops with septal thickening, sclerosis within fat lobules, and lipophage formation. Eventually, sclerosis and lipomembranous changes with decreased inflammation is found. The dermis shows fibrosis, thickened veins, and perivascular inflammation.

Fig. 43.5: Lipodermatosclerosis in the setting of venous insufficiency. Courtesy: Dr Ann John.

Differentiation from cellulitis, erythema nodosum, stasis dermatitis, erythema induratum, morphea, scleromyxedema, and vasculitis must be undertaken. Treatment consists of leg elevation and compression stockings. Intralesional steroids, anabolic steroids such as danazol and oxandrolone, pentoxifylline, and surgery with fasciotomy or phlebectomy have also be used with success.64-68

Adiposis Dolorosa (Dercum’s Disease) Adiposis dolorosa, or Dercum’s disease, is a rare disorder that more commonly affects middle-aged women

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Section 13: Disorders of the Dermis and Subcutaneous Tissue with unknown etiology. The disease is characterized by multiple painful fatty masses lasting longer than three months and generalized obesity. Painful lipomas are usually located in the extremities, trunk, and buttocks, and the pain is characterized as burning and resistant to analgesics. Patients often have accompanying fatigue and depression. The disease is classified into the generalized diffuse (widespread painful adipose tissue without lipomas), generalized nodular (widespread painful adipose tissue with lipomas), localized nodular (painful lipomas), and juxta-auricular (painful fat deposits adjacent to joints) types. Histology shows bland fat cells and an acellular stroma. Other conditions that should be excluded include fibromyalgia, lipedema, panniculitis, Cushing’s syndrome, tumors of adipose tissue, and familial multiple lipomatosis. Treatment options include liposuction, lipectomy, oral analgesics, such as NSAIDs, lidocaine injections, methotrexate, infliximab, corticosteroids, interferon alpha, metformin, anticonvulsants such as pregabalin and oxcarbazepine, and rapid cycling hypobaric pressure.64,72-75

Lipodystrophy Syndromes Lipodystrophy syndromes represent a range of inherited and acquired forms of fat loss that can be subdivided into general, partial, and localized. These syndromes are often accompanied by insulin resistance and changes similar to metabolic syndrome due to a defect in adipocyte triglyceride storage. As a result, levels of adiponectin, which are inversely correlated with insulin resistance, are reduced. Congenital syndromes include congenital generalized lipodystrophy (Berardinelli–Seip syndrome), familial partial lipodystrophy (Kobberling–Dunnigan syndrome), and familial partial lipodystrophy with mandibuloacral dysplasia (MAD). Berardinelli–Seip syndrome is an autosomal recessive condition due to mutations in AGPAT2 (type 1) and BSCL2/seipin (type 2). Type 1 is categorized by decreased triglyceride and phospholipid synthesis and type 2 is characterized by defective production of lipid droplets. In some patients, a separate gene, CAV1, is mutated (type 3). Patients demonstrate loss of fat on the face, trunk, extremities, and viscera. Type 2 is further characterized by loss of fat in the palmoplantar and retroorbital areas. Moreover, patients have insulin resistance, diabetes, increased triglycerides, and anabolic syndrome. Patients may also experience hypertrophic cardiomyopathy, cirrhosis, pancreatitis, proteinuric nephropathy, and organomegaly. Type 2 patients are more likely to experience mental retardation and cardiomyopathy.

Kobberling–Dunnigan syndrome is an autosomal dominant condition characterized by mutations in LMNA, which encodes lamins, thus leading to premature apoptosis of adipocytes. Other subtypes demonstrate mutations in PPARG, which is essential for adipogenesis, and AKT2, protein kinase B, which assists in adipocyte differentiation, and PLIN1. Clinically, this syndrome presents during puberty with decreased fat on the extremities and trunk, increased fat on the face and neck, and muscular hypertrophy. The PPARG-associated subtype presents with decreased fat on the extremities and buttocks. Patients have insulin resistance, diabetes, increased triglycerides, and decreased HDL. In addition, patients experience acute pancreatitis, cirrhosis, and menstrual abnormalities. MAD is an autosomal recessive condition with mutations in LMNA (type A) or ZMPSTE24 (type B). This syndrome presents in childhood or puberty with decreased fat on extremities, although type B usually presents with generalized lipodystrophy. Patients present with insulin resistance, diabetes, increased triglycerides, and decreased HDL. Patients demonstrated premature aging, mandibular hypoplasia, short stature, mottled skin pigmentation, and hypoplasia of clavicles and terminal digits. Acquired forms of lipodystrophy include acquired generalized lipodystrophy (Lawrence syndrome), ac­quired partial lipodystrophy (Barraquer–Simons syndrome), and HIV/ART-associated lipodystrophy syndrome. Lawrence syndrome may be associated with an autoimmune condition, preceding panniculitis, or preceding viral/bacterial infection. This syndrome usually presents in childhood or adolescence with decreased fat on the face, trunk, and extremities. Patients have insulin resistance, diabetes, and increased triglycerides. Patients demonstrate low levels of leptin and adiponectin. Barraquer–Simons syndrome may be sporadic or autosomal dominant. Presenting in childhood or adolescence, patients demonstrate decreased fat in the face, upper extremities, and trunk, thus sparing the lower extremities. In addition, patients may have increased fat in the hips and legs. Patients have diabetes, increased triglycerides, low C3 levels, and circulating C3 nephritic factor. It is often preceded by a febrile illness and patients may demonstrate mesangiocapillary glomerulonephritis. HIV/ART-associated lipodystrophy syndrome is the most common non-localized form of acquired lipodystrophy that occurs 2 months to 2 years after antiretroviral therapy is started. Patients have decreased fat in their faces and extremities but increased fat in their trunks and breasts. Patients may also have buffalo humps and lipomas. They usually demonstrate insulin resistance, increased

Chapter 43: Diseases of Subcutaneous Tissue triglycerides and LDL, decreased HDL, and diabetes. They tend to incur cardiovascular disease. Localized lipodystrophy is often due to trauma, surgery, and injections. Most commonly, insulin and corticosteroid injections result in localized lipoatrophy. Antibiotics, growth hormone, heparin, iron, vaccines, exogenous material, methotrexate, and glatiramer acetate injections can also result in lipoatrophy. Lipoatrophy related to repetitive trauma or pressure is known as lipoatrophia semicircularis. Lipodystrophy can also be associated with glomerulonephritis and autoimmune conditions. The histology of lipodystrophy syndromes is noninflammatory. Generalized lipodystrophy shows a complete loss of subcutaneous fat. Acquired generalized lipodystrophy may demonstrate either non-inflammatory changes of fat or an inflammatory lobular panniculitis with lipophages, lymphocytes, and plasma cells. Involutional lipoatrophy can be characterized by lobules resembling embryonic fat and little inflammation or collapsed lobules with acid mucopolysaccharide deposition within lobules and fibrosis of the septa. Treatment targets cosmetic concerns as well as systemic associations. Localized lipodystrophy may resolve on its own after removing external sources such as trauma/injections. Surgical treatment, liposuction, use of fillers, midfacial implants, and fat transplantation have been used. Use of fibrates, thiazolidinediones, and omega 3 polyunsaturated fatty acids can target hypertriglyceridemia. Treatment with recombinant leptin has also targeted metabolic derangements. In patients with mesangiocapillary glomerulonephritis, IVIg is effective.64,76-79

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46. Ching WJ, Henderson CA. Suppurative panniculitis associated with alpha 1-antitrypsin deficiency (PiSZ phenotype) treated with doxycycline. Br J Dermatol 2001;144:1282–3. 47. Requena L, Sanchez Yus E. Panniculitis. Part II. Mostly lobular panniculitis. J Am Acad Dermatol 2001;45:325–61. 48. Yung A, Snow J, Jarrett P. Subcutaneous panniculitic T-cell lymphoma and cytophagic histiocytic panniculitis. Australas J Dermatol 2001;42:183–7. 49. Marzano AV, Berti E, Paulli M, Caputo R. Cytophagic histiocytic panniculitis and subcutaneous panniculitis-like T-cell lymphoma: report of 7 cases. Arch Dermatol. 2000;136:889–96. 50. Craig AJ, Cualing H, Thomas G, Lamerson C, Smith R. Cytophagic histiocytic panniculitis–a syndrome associated with benign and malignant panniculitis: case comparison and review of the literature. J Am Acad Dermatol 1998;39:721–36. 51. Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classifi cation for cutaneous lymphomas. Blood 2005;105:3768–85. 52. Gallardo F, Pujol RM. Subcutaneous panniculitic-like T-cell lymphoma and other primary cutaneous lymphomas with prominent subcutaneous tissue involvement. Dermatol Clin 2008;26:529–40. 53. Yim JH, Kim MY, Kim HO, et al. Subcutaneous panniculitis-like T-cell lymphoma in a 26-month-old child with a review of the literature. Pediatr Dermatol 2006;23:537–40. 54. Al Zolibani AA, Al Robaee AA, Qureshi MG, et al. Subcutaneous panniculitis-like T-cell lymphoma with hemophagocytic syndrome successfully treated with cyclosporine A. Skinmed 2006;5:195–7. 55. Takeshita M, Imayama S, Oshiro Y, et al. Clinicopathologic analysis of 22 cases of subcutaneous panniculitis-like CD56- or CD56+ lymphoma and review of 44 other reported cases. Am J Clin Pathol. 2004;121:408–16. 56. 4. Fraga J, Garcia-Diez A. Lupus erythematosus panniculitis. Dermatol Clin 2008;26:453–63. 57. Nitta Y. Lupus erythematosus profundus associated with neonatal lupus erythematosus. Br J Dermatol 1997;136:112–4. 58. Nousari HC, Kimyai-Asadi A, Santana HM, et al. Generalized lupus panniculitis and antiphospholipid syndrome in a patient without complement deficiency. Pediatr Dermatol 1999;16:273–6. 59. Kerstan A, Goebeler M, Schmidt E, et al. Lupus erythematosus profundus in an 8-year-old child. J Eur Acad Dermatol Venereol 2007;21:132–3. 60. Douvoyiannis M, Litman N, Dulau A, Ilowite NT. Panniculitis, infection, and dermatomyositis: case and literature review. Clinical rheumatology. 2009;28:S57–63. 61. Lowry CA, Pilkington CA. Juvenile dermatomyositis: extramuscular manifestations and their management. Curr Opin Rheumatol 2009;21:575–80. 62. Otero Rivas MM, Vicente Villa A, Gonzalez Lara L, et al. Panniculitis in juvenile dermatomyositis. Clinical and experimental dermatology. 2015;40:574–5.

Chapter 43: Diseases of Subcutaneous Tissue 63. Salman A, Kasapcopur O, Ergun T, Durmus Ucar AN, Demirkesen C. Panniculitis in juvenile dermatomyositis: report of a case and review of the published work. J. Dermatol 2016;43:951–3. 64. Bolognia JL, Jorizzo JJ, Schaffer JV, Dermatology 2012;753–60. 65. Caggiati A, Rosi C, Casini A, et al. Skin iron deposition characterises lipodermatosclerosis and leg ulcer. Eur J Vasc Endovasc Surg 2010;40:777–82. 66. Choonhakarn C, Chaowattanapanit S, Julanon N. Lipodermatosclerosis: a clinicopathologic correlation. Int J Dermatol 2016;55(3):303–8. 67. Walsh SN, Santa Cruz DJ. Lipodermatosclerosis: a clinicopathological study of 25 cases. J Am Acad Dermatol 2010;62:1005–12. 68. Wick MR. Panniculitis: a summary. Semin Diagn Pathol 2017;34:261–72. 69. Bosnic D, Baresic M, Bagatin D, et al. Subcutaneous sarcoidosis of the face. Intern Med (Tokyo, Jpn) 2010;49:589–92. 70. Marchetti M, Baker MG, Noland MM. Treatment of subcutaneous sarcoidosis with hydroxychloroquine: report of 2 cases. Dermatol Online J 2014;20:21250. 71. Marcoval J, Moreno A, Mana J, Peyri J. Subcutaneous sarcoidosis. Dermatol Clin 2008;26:553–6. 72. Hansson E, Svensson H, Brorson H. Liposuction may reduce pain in Dercum’s disease (adiposis dolorosa). Pain Med (Malden, Mass). 2011;12:942–52.

73. Hansson E, Svensson H, Brorson H. Review of Dercum’s disease and proposal of diagnostic criteria, diagnostic methods, classification and management. Orphanet J Rare Dis. 2012;7:23. 74. Lange U, Oelzner P, Uhlemann C. Dercum’s disease (Lipomatosis dolorosa): successful therapy with pregabalin and manual lymphatic drainage and a current overview. Rheumatol Int 2008;29:17–22. 75. Martinenghi S, Caretto A, Losio C, Scavini M, Bosi E. Successful Treatment of Dercum’s Disease by transcutaneous electrical stimulation: a case report. Medicine 2015;94:e950. 76. Bindlish S, Presswala LS, Schwartz F. Lipodystrophy: syndrome of severe insulin resistance. Postgrad Med 2015;127:511–6. 77. Chiquette E, Oral EA, Garg A, Araujo-Vilar D, Dhankhar P. Estimating the prevalence of generalized and partial lipodystrophy: findings and challenges. Diabetes, Metab Syndr Obes: Targets Ther 2017;10:375–83. 78. Finkelstein JL, Gala P, Rochford R, Glesby MJ, Mehta S. HIV/AIDS and lipodystrophy: implications for clinical management in resource-limited settings. J Int AIDS Soc 2015;18:19033. doi:10.7448/IAS.18.1.19033. eCollection 2015. 79. Kieselova K, Santiago F, Guiote V, Amado C, Henrique M. Fever, lipodystrophy and cutaneous lesions. Clin Exp Dermat 2017;42:939–41.

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Pigmentation Disorders

Chapter

44

Introduction to the Biology of the Pigmentary System

Šitum Mirna, Bulat Vedrana, Goren Andy, Kazandjieva Jana, Guleva Dimitrina, Kovacevic Maja, Lotti Torello

EMBRYONIC DEVELOPMENT AND DISTRIBUTION OF MELANOCYTES The regulation of the embryonic development of cutaneous melanocytes and their functions is a highly complex multistep process. The human genome contains multiple genes that directly or indirectly modify their development and activity, which suggests that the body highly values the functions of melanocytes and carefully regulates their numerous behaviors. Melanocytes are specialized dendritic cells and melanin, the natural pigment of the skin, synthesis is a well-known primary melanocyte function. However, there is increasing evidence that melanocytes are part of the peripheral nervous system (PNS) and that they have actions that are unrelated to melanin ­synthesis.1,2 During embryonic development, melanocytes, sensory neurons in the PNS, postsynaptic autonomic neurons, Schwann cells, adrenal medulla cells, arachnoid, and pia mater of meninges evolve from the same origin—the neural crest. Pigment precursor cells (melanoblasts) migrate along a dorsolateral pathway via the mesodermal layers to reach the basal layer (stratum basale) of the interfollicular epidermis and the bulge of hair follicles. Recently, it was shown that a substantial number of melanocytes arise from Schwann cell precursors associated with extending nerves, having migrated there by a ventral pathway. Significantly, it was also found that in the adult, mature Schwann cells also retain the ability to differentiate into melanocytes.3,4 Melanocytes are additionally found at many locations throughout the body such as in the inner ear (cochlea, vestibular system, utricle, ampullae), eye (uvea, iris, retina), arachnoid and pia mater of meninges, adipose tissue, bone, intestinal system, placenta, heart (valves, septa, atrium), pulmonary veins, and lungs where they serve primarily for action potential conduction (Fig.  44.1).5 Interactions between specific receptors on melanoblasts and extracellular signaling molecules are particularly important during embryonic melanocyte

migration to their target tissues, and for prevention of their premature terminal differentiation (Table 44.1).6 Endothelins (ETs) are important signaling molecules and include three members, ET1, ET2, and ET3. They bind and activate heptahelical transmembrane G protein-linked receptors EdnrA and B. Protein ET3 is encoded by EDN3 gene located on chromosome 20q13.2-q13.3. Protein ET3 and its EdnrB receptors are particularly required for embryonic melanocyte survival during their migration to the developing ectoderm.7 Mutations in either ET3 or EdnrB receptor genes can result in aberrant migration and prominent melanocyte loss within the inner ear, the iris, mid portions of skin and hair, and colon. These mutations lead to the development of the classic neurocristopathy– Waardenburg syndrome type 4 (WS4) that is characterized by congenital deafness, partial or total heterochromia iridis, frontal leukotrichia, depigmentation of the mid portions of the forehead and extremities, plus congenital megacolon.8 Four clinical subtypes of WS have been described. Several of the genes responsible for WS encode a group of proteins—transcription factors that can bind DNA and are able to regulate the complex interactions of sets of genes required during embryogenesis. The paired box 3 (PAX3) transcription factor is encoded by PAX3 gene on chromosome 2q35-q37.3 and is mutated in WS1 and WS3. PAX3 activates melanoblasts to proliferate and then migrate from the neural crest.9 The classic form (WS1) is characterized by several features: frontal leukotrichia, depigmentation of the mid portions of the forehead and extremities, congenital deafness, partial or total heterochromia iridis, medial eyebrow hyperplasia, a broad nasal root, and dystopia canthorum. FOXD3 is a gene located on chromosome 1p31.3-p32.2 which encodes an embryonic transcription factor that is a primary regulator of the differentiation and development of melanoblasts and some mesodermal elements, including pancreatic islet cells.10 In melanoblasts, the signaling molecule Wnt activates

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Fig. 44.1: Melanocytes within various tissues.

Table 44.1: Signaling molecules, their receptors, and the effect they have on melanocyte development. Signaling molecules Receptors Melanocytes Wnt Frizzled MITF transcription Survival BMPs BMP receptors Antidifferentiation Endothelin 3 EdnrB Migration Survival Steel factor c-Kit Migration Melanogenesis Survival FGFs FGF receptors Mitogen Survival Hepatocyte growth Met Proliferation factor Differentiation Survival Nerve growth factor p75NTR/TrkA Antiapoptotic Dendricity Neurotrophin 3 p75NTR/TrkC Survival Semaphorins β semaphorins Spreading Plexin Dendricity Neuropilin (BMP: bone morphogenetic protein; FGF: fibroblast growth factor; MITF: microphthalmia-associated transcription factor)

transmembrane heptahelical G protein-linked receptor frizzled which induces the transcription of regulatory protein—microphthalmia-associated transcription factor (MITF), leading to melanoblast differentiation into melanocytes through melanocyte survival and melanogenesis (the synthesis and distribution of pigment melanin).11,12 MITF is a protein coding gene located on chromosome 3p13. MITF comprises a family of nine isoforms: MITF-M, -A, -B, -C, -D, -E, -J, and -Mc. MITF-M expression is highly specific for melanocytes. MITF-M appears to promote melanocyte survival by upregulating the expression of a major antiapoptotic protein, bcl2. MITF-M also induces melanogenesis through the transcriptional induction of multiple pigment genes, including those that encode themajormelanogenicproteinssuchastyrosinase,tyrosinaserelated protein-1 (TRP1), and tyrosinase-related protein-2 (TRP2), Pmel17, and MART-1/Melan-A.13 The TYR gene is localized at chromosome 11q14.3 and it encodes tyrosinase, which is a melanosomal enzyme that catalyzes melanin biosynthesis; it is a major autoantigen in genera­ lized vitiligo.14 MITF activity is increased upon its

Chapter 44: Introduction to the Biology of the Pigmentary System phosphorylation by the mitogen-activated protein kinase-2, whose activity is in turn induced by binding of steel factor to c-Kit receptor. The expression of MITF gene is under the control of several transcription factors, including SOX10 [SRY (sex determining region Y)-box 10] and PAX3.8,15 The promoter region of the MITF gene contains a cAMP-response element (CRE) that interacts with transcription factor CRE binding protein when the cAMPdependent pathway is activated. Therefore, c-AMP-elevating agents like α-melanocyte stimulating hormone (α-MSH) induce the expression of MITF. MITF is also recognized as a potent melanocyte mitogen under certain conditions. MITF induces the expression of the cell cycle-associated kinase CDK2 required for progression of cells from G1 into S phase of the cell cycle, thus promoting melanocyte proliferation. MITF also suppresses the expression of p21, a protein that inhibits CDK2 activation.16 Mutations in the MITF gene can result in WS2, which lacks dystopia canthorum. Melanocytes also express MITF isoforms -A, -B, and -E, but their biological role in normal melanocytes has to be elucidated. Steel factor (also known as mast/stem cell factor, Kit-ligand, and CD117) is a cytokine expressed by epidermal keratinocytes that binds to the c-Kit receptor. The transcription factors SOX10 and PAX3 bind to the promoter of the MITF gene to express MITF, which in turn stimulates the expression of c-Kit. As soon as c-Kit receptors are expressed by melanoblasts, they begin their migration to their final destination in the skin.17 Migrating melanoblasts do not reach all body sites simultaneously. Mutations of c-Kit receptor or its ligand can lead to disturbed timing of melanoblast migration or failure of melanoblasts to migrate the necessary distance to the given skin site and survive there. This results in piebaldism, a rare autosomal dominant disorder.18,19 It has been linked to inactivating mutations or deletions of the c-Kit gene, which is mapped on chromosome 4q12, or of the SLUG gene, located on chromosome 8q11. Piebaldism has congenital, stable, circumscribed areas of leukoderma that favors the ventral trunk, mid-extremities, central forehead, and mid-frontal portion of the scalp with frontal leukotrichia. Interestingly, the ventral aspect of the body is more frequently affected than the dorsal aspect, probably because it is the area farthest from the dorsally located neural crest where melanoblast migration begins.18 During embryogenesis, melanocytes are first found diffusely throughout the dermis in the head and neck region at approximately 50 days of gestation.20 After 50 days of

gestation, the population density of the epidermal melanocytes increases, and in the second trimester, the population density peaks at around 2,300 cells/mm2. At the time of birth, it decreases in number so that the average density is about 800 cells/mm2. A substantial number of dermal melanocytes have diminished at this point, except in three anatomic locations: the head and neck, the dorsal aspects of the distal extremities, and presacral area. These are the most common sites for dermal melanocytes and dermal melanocytomas (blue nevi).21 Hepatic growth factor (HGF) gene is located on chromosome 7q21.11. HGF and its transmembrane tyrosine kinase receptor Met may play a role in the survival and proliferation of these dermal melanocytes. HGF also modifies the expression of E-cadherin, a transmembrane glycoprotein that facilitates the adhesion between keratinocytes and melanocytes in the epidermis.22 Basic fibroblast growth factor (bFGF) binds the tyrosine kinase FGF receptor-1 that is expressed on melanocytes. bFGF is a potent melanocyte mitogen.23 Melanocytes also express the β1 integrin receptor and plexin C1 receptor. By binding β1 integrin receptor, semaphorin 7A induces melanocyte dendrite formation, but by binding plexin C1 receptor, semaphorin inhibits melanocyte spreading and dendricity.24 Nerve growth factor (NGF) and neurotrophin 3 may play a role in the melanocyte survival by increasing the level of antiapoptotic bcl2 protein.25,26

ULTRASTRUCTURE OF MELANOCYTES It has been hypothesized that there are three populations of melanocytes: melanocyte stem cells, cutaneous melanocytes, and hair follicle melanocytes.27 A melanocyte resembles a nerve cell in morphology. Mature melanocytes have round cell bodies, out of which are protruding long, irregular dendritic processes that ramify between the neighboring keratinocytes of the basal and spinous layer (Fig. 44.2).21 Under the microscope, they appear to originate from the sides of melanocytes, but not from the portion embedded in the basement membrane. Dendritic processes end up in dents on the cellular surface of these layers. Melanocytes have numerous small mitochondria, a well-developed Golgi complex, short cisternae of the rough endoplasmic reticulum, and intermediate filaments around 10  nm in diameter.21 Melanocytes are not connected to the neighboring keratinocytes by desmosomes, but they adhere to neighboring keratinocytes by cadherins and to the basal lamina using hemidesmosomes.28 Their survival is not

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Fig. 44.2: Melanocyte morphology.

possible if they detach from the basal membrane and fall through in the dermis or epidermis. Keratinocytes are joined together by numerous desmosomes in the epidermis. In the basal layer, keratinocytes are going through an intense mitotic division, but not melanocytes. Melanocytes are aligned in a cyclic, regular arrangement on the basal membrane. There is approximately one melanocyte per nine or ten basal keratinocytes.21 Dean et al. reported that the ratio of melanocytes to keratinocytes in the human nipple areola complex (NAC) is far greater than the surrounding breast tissue 1:9.7 versus 1:14.7.29 While in modern society, the NAC is not exposed to significant amount of ultraviolet (UV) irradiation and the evolutionary advantage of pigment expression in the NAC remains unknown. Melanin functions vary from camouflage to the quenching of oxidative free radicals generated via exposure to UV irradiation.30 Melanocytes synthesize and transport melanin, a pigment polymer that is deposited within unique intracytoplasmic organelles called melanosomes. According to Hara et al., melanosomes migrate along microtubules from the cell body of melanocytes into dendrites in preparation for transfer to keratinocytes, hair matrices, and mucous membranes.31 Melanosome transfer has not been fully explained yet; for instance how keratinocytes, which are not in direct contact with melanocyte dendrites, contain melanosomes, and how pigmented melanomas show melanin restricted to the tumor cells, rather than transfer to stromal cells. Melanocyte dendrites are mobile, they extend before transfer and withdraw after melanosome transfer.32

The epidermal melanin unit describes a close association of single epidermal melanocyte with around 36 epidermal keratinocytes via their dendritic processes.33,34 Density of epidermal melanocytes per square millimeter ranges from approximately 550 to >1,200 with the highest concentrations found in the genitalia and face.20 Melanocyte density/mm2 is the same in individuals of different racial backgrounds. Although the number of active melanin units varies considerably in the different regions of the body, the number of keratinocytes supplied by each melanocyte remains constant.35 The oral cavity is lined by ectoderm-derived squamous epithelium and therefore it has also numerous melanocytes, similar to that of the skin. This is in comparison to the pharynx, which is derived from the endoderm and has only few melanocytes. Melanocytes also populate the vaginal canal and the cervix. The anal canal is lined by ectoderm-stratified squamous epithelium and is deeply pigmented in most individuals. Melanosomes are most closely related to the lysosome, while both organelles provide protection for the remainder of the cell, and can endocytose receptors that are targeted for degradation. Both organelles have lysosome-associated membrane proteins that participate in autophagy and regulation of intravesicular pH, as well as acid phosphatase, a marker enzyme for lysosomes.36,37 Melanosomes protect against melanin precursors (e.g., phenols, quinines) that can oxidize lipid membranes. Melanosomes contain (1) fibrillar matrix proteins (e.g., Pmel17, MART-1/Melan

Chapter 44: Introduction to the Biology of the Pigmentary System A) which form scaffolding upon which the melanin is deposited, (2) melanogenic enzymes (e.g., tyrosinase, TRP1, TRP2) that regulate the biosynthesis of melanin, (3) melanosome-associated receptors (e.g., OA1, Rab27), and (4) transport proteins [e.g., adaptor protein 3 (AP-3), P-protein, SLC24A5].38,39 Premelanosome protein Pmel17 is a key protein in melanosome maturation. It is included in formation of physiological amyloid fibrils upon which melanin is deposited in the lumen within melanosomes, as well as in sequestration of toxic melanin biosynthesis intermediates in later stage melanosomes.40,41 Tyrosinase and TRP1 in the melanin biosynthetic pathway are glycoproteins that require glycosylation and processing in the endoplasmic reticulum (ER) and the Golgi apparatus. They are then are packaged in vesicles (endosomes) and are combined with the matrix proteins to initiate melanogenesis. TRP2 follows similar maturation steps. Melanosomes originate in the ER as stage I, apart from the endosomes. After its synthesis, Pmel17 is transported to stage I melanosomes to form their ellipsoid shape and to promote melanin polymerization. Melanosomes then mature to stage II melanosomes and fuse with endosomes which contain melanogenic enzymes, in a process directed by the AP-3. Melanosomes lacking Pmel17 cannot transit to stage II and have no active melanogenesis. MART-1/Melan A is structural protein which is present in stage I and II melanosomes which forms a complex with Pmel17. MART-1 affects the expression, stability, trafficking, and processing of Pmel17 within the melanosomes. To date, there are no known hypopigmentary disorders in humans associated with mutations of neither Pmel17 nor MART-1.42 In patients with oculocutaneous albinism type 1 (OCA1) and OCA3, the melanogenic enzymes tyrosinase and TRP1 remain within the lumen of the ER for too long. Therefore they are destroyed by proteasomes and melanogenesis is interrupted.43 Patients with OCA1 type A have a total absence of melanin in their skin, hair, and eyes due to complete loss of tyrosinase activity. Patients with OCA1 type B have decreased tyrosinase activity and pheomelanin is produced, especially in the hair. Pheomelanin requires less tyrosinase activity than does the synthesis of eumelanin. Patients with OCA3 have total absence of TRP1 which is required to stabilize tyrosinase. The OCA2-HERC2 gene within the region of chromosome 15q12-q13.1 is related to OCA2. It encodes a P-protein that is a melanosomal membrane transporter determining the skin, hair, and eye color. P-protein regulates processing and transportation of tyrosinase into melanosomes.44 It stabilizes the tyrosinase–TRP1–TRP2 complex

and it is also required for maintaining an acidic environment within the melanosomes.45 The study confirmed an association of two single nucleotide polymorphisms (SNPs). The SNP alleles of OCA2 are associated with an elevated risk of melanoma and with gray–blue pigmentation of the irises.46 The sorting and positioning of specific melanosomal proteins to the correct organelle is an extremely complicated process directed by AP-3. AP-3 facilitate tyrosinase transport from endosomes to melanosomes.47 In AP-3deficient melanocytes, tyrosinase accumulates inappropriately in vacuolar and multivesicular endosomes. Mutations in the gene that encodes the 3βA subunit of AP-3 are responsible for a subset of patients with Hermansky– Pudlak syndrome 2 subtype (HPS2). HPS2 is an autosomal recessive disorder of oculocutaneous albinism, platelet dysfunction, and pulmonary disease.48 Depending on the type of melanin synthesized, there are three types of melanosomes: eumelanosomes, pheomelanosomes, and neuromelanosomes. When observing their morphology, eumelanosomes and pheomelanosomes differ. Eumelanosomes are larger (0.9 × 0.3  μm), elliptical in shape, and contain highly structured fibrillar glycoprotein matrix required for eumelanin synthesis. Pheomelanosomes are smaller (0.7  μm in diameter), spherical in shape, and their glycoprotein matrix appears disorganized and loose. Both eumelanosomes and pheomelanosomes may be present within a single melanocyte.49 Neuromelanosomes vary in size (0.5–2.5 μm) and appear as aggregates of electron-dense pigment granules combined with electron lucent lipid bodies and heterogeneous granular material.50 Melanosomes display four major stages of maturation (Table 44.2). Stage I melanosomes or premelanosomes likely develop from the ER. They have an amorphous matrix and display internal vesicles that form as a result of membrane invagination.51 Premelanosomes are spherical in shape. Although their glycoprotein matrix appears disorganized, they already contain the glycoprotein Pmel17, but there is no melanin deposition. Stage II melanosomes are oval in shape and have an organized, structured fibrillar matrix. Although they already contain tyrosinase, there is minimal deposition of melanin. In stage II, pheomelanosome melanogenesis takes place. Stage III and IV eumelanosomes are oval in shape. Moderate deposition of melanin on the fibrillar matrix due to high tyrosinase activity is found in stage III eumelanosomes, while stage IV eumelanosomes are fully melanized and minimal tyrosinase activity is found.39 As melanin is deposited within melanosomes, they migrate along microtubules

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III IV

Characteristics • Development from ER • Amorphous matrix • Spherical shape • Organization of fibrillary matrix • High tyrosinase activity • Formation of: eumelanosomes—oval, structured matrix, large (≈0.9 × 0.3 µm)—and pheomelanosomes—spherical, loose matrix, small (≈0.7 µm) • Melanin synthesis in pheomelanosomes • Deposition of melanin—partial melanization • High tyrosinase activity • Completed melanization • Minimal tyrosinase activity

(ER: endoplasmic reticulum)

from the cell body into dendrites in preparation for transfer to keratinocytes. Kinesin and dynein serve as molecular motors for microtubule-associated anterograde and retrograde melanosomal transport, respectively. Both motor proteins connect the melanosomes to the microtubules.31 Specialized protein myosin Va, which is linked to the melanosomal RAB27A GTPase by melanophilin, captures mature melanosomes when they reach the cell periphery and attaches them to the actin cytoskeleton.31 Griscelli syndrome (GS) is a rare autosomal recessive disorder caused by mutations in either the myosin Va (GS1), RAB27A (GS2), or melanophilin (GS3) genes. All three GS subtypes are commonly characterized by pigment dilution of the skin and hair, due to defects involving melanosome transport in melanocytes.52,53 Because myosin Va is also expressed in the brain, mutations of this gene may also cause severe neurological abnormalities, with developmental delay and intellectual disability. RAB27A also plays a role in immune-regulation and patients with mutations of this gene display potentially lethal immune defects and a hemophagocytic syndrome. Mutations of melanophilin result only in distinctive hypopigmentation.54 In lightly pigmented skin, melanosomes primarily contain stage II and III melanosomes. They are smaller (0.3–0.5  µm in diameter) and are clustered in groups of 2–10 within the lysosomes of keratinocytes. They are quickly degraded. In lightly pigmented skin, there are 200 melanosomes per melanocyte. Multiple genes have been implicated in normal pigment variation in humans, including SLC24A5 and ASIP. The presence of a variant allele of SLC24A5, whose protein product is a putative cation exchanger in the melanosomal membrane, correlates with lighter skin color. A haplotype with several polymorphisms in ASIP has been associated with red or blonde hair, freckling, and a tendency to burn, while variants that lead to destabilized ASIP mRNA have been associated with dark skin, brown eyes, and dark hair.55 Once melanosomes reach dendrite tips of melanocytes, they are transferred into the neighboring keratinocytes. In the absence of myosin Va, melanosomes do not collect in the dendrite tips.56 Several hypotheses of melanosome transfer to keratinocytes have been proposed: (1) release of packages containing melanosomes from melanocytes and their import into keratinocytes via cytokine excretion, (2) partial cytophagocytosis of melanocyte dendrite tips with melanosomes by keratinocytes, (3) fusion of keratinocyte and melanocyte plasma membrane which creates a space through which melanosomes are transferred, and (4) exocytosis of the melanin core of melanocytes into extracellular space and its subsequent endocytosis by keratinocytes.57,58 At present, the phagocytosis of melanocyte dendrite tips with melanosomes by keratinocytes is considered as the most probable hypothesis.59 Melanocyte dendricity and contact with keratinocytes is likely to be essential for transfer of melanin-containing melanosomes. Keratinocyte-derived factors such as ET1, NGF, α-MSH, ACTH, and prostaglandins are likely to play a role in melanocyte dendricity. Cytoskeletal reorganization, including reconstruction of actin fibers and microtubules, is essential for dendrite formation. In contrast with melanogenesis, for which numerous mutations in pigment-producing genes have been identified, a genetic defect resulting in impaired dendrite formation has not yet been found. A Group of proteins, the Rho family of small guanosine triphosphate (GTP)-binding proteins, act as master regulators of dendrite formation and actin cytoskeletal reorganization, particularly Rac and Rho. It appears that when Rho is activated by binding GTP, dendrites retract, while when Rac is activated, dendrites form.60 It has been shown that by increasing cAMP levels,

Chapter 44: Introduction to the Biology of the Pigmentary System α-MSH inhibits Rho, enhancing melanocyte dendricity. Ito et al. have shown that methylophiopogonanone B acts via the Rho signaling pathway, and it may directly or indirectly activate Rho. This results in actin cytoskeletal reorganization, including dendrite retraction and stress fiber formation. It also induces microtubule destabilization and tubulin depolymerization which causes morphological changes in melanocyte dendrites.61 A recent study showed that activation of the protease-activated receptor-2 (PAR-2), a G-protein-coupled receptor expressed only on keratinocytes, modulates melanosome transfer in epidermal keratinocytes.62 It is activated by cleavage of its extracellular portion by serine proteases. Scott et al. have shown that PAR-2 expression in skin pigmentation is upregulated by UV irradiation. UV irradiation is a potent stimulus for melanosome transfer through increased phagocytosis of melanosomes by keratinocytes, enhanced by increased PAR-2 expression on keratinocytes.63 Keratinocyte growth factor receptor has also been implicated in enhancing phagocytosis of melanosomes.64 As keratinocytes proliferate and migrate toward the stratum corneum, they carry their melanosome content. The melanosomal proteins are degraded, and only the melanin polymer remains to be desquamated from the stratum corneum. There are no enzymes known that degrade the melanin polymer, and the excretion of the melanin polymer back into ­environment by desquamation seems appropriate.21 Hair follicle melanocytes are similar in many aspects to cutaneous melanocytes. Melanin is synthesized and transported to keratinocytes only during the anagen active growing stage of the hair follicle cycle. Melanocytes proliferate, migrate, and undergo maturation during early-to mid anagen.65 The melanosomes of the hair cortex are larger on average than those in cutaneous melanocytes. It is not clear what happens to the follicular melanocytes during the catagen phase of the hair cycle. The bulge region of the hair follicle is a major reservoir for melanocytic stem cells. They express transcription factors SOX10 and PAX3. They also express TRP1 and TRP2, but lack tyrosinase, so they do not produce melanin. Melanocytic stem cells can leave the bulge region and migrate/differentiate in the epidermis or the hair follicle.66 Suspicions that melanocytic stem cells are present not only in bulge region, but also in extrafollicular localization, strongly suggest the existence of a reservoir of melanocytes in the more protective dermal layer of the skin. Therefore, it may be possible to induce differentiation of human

skin stem cells into functional epidermal melanocytes and develop future cell-based therapy for vitiligo.67

MELANIN BIOSYNTHESIS Melanins are the indole derivatives of 3,4-dihidroxyphenylalanine (DOPA), and they are formed in melanosomes through a series of complex oxidative steps. The main types of melanins include eumelanin, pheomelanin, and neuromelanin.68 The most common is eumelanin, of which there are two types—brown eumelanin and black eumelanin. Pheomelanin is a cysteine-containing red polymer of benzothiazine units, largely responsible for red hair, among other pigmentation. Eumelanin is dark, brown-black, and insoluble in most solvents, whereas pheomelanin is photolabile, red-yellow, sulfurcontaining, and alkali soluble. Melanins are not stable indefinitely. They may undergo more or less profound structural degradation upon chemical treatment with acids, alkali, oxygen, and hydrogen peroxide, even during their biosynthesis. They may also undergo alteration with physical agents such as UV light, as well as with aging.69 Melanosomal pH affects the activity of the melanogenic enzymes and influences melanin polymerization. Melanin biosynthesis initiates with the nonessential amino acid l-tyrosine (i.e., not required in a normal diet) which is then hydroxylated to DOPA. This is obligatory step for the synthesis of both eumelanin and pheomelanin.70 This chemical reaction is catalyzed by transmembrane enzyme tyrosinase located within the melanosome. This is found to be the critical rate-limiting step in melanogenesis, as inhibition of this reaction blocks melanin biosynthesis. DOPA is then oxidized into DOPAquinone by the same enzyme, a chemical reaction common to both eu- and pheomelanogenic pathways.68 DOPA is a cofactor and also a substrate for tyrosinase. DOPAquinone is further converted to DOPAchrome and 5,6-dihydroxyindole (DHI) by a series of oxidoreduction reactions. DOPAchrome can be converted into 5,6dihydroxyindole-2-carboxylic acid (DHICA) by the enzyme TRP1.71 The function of TRP1 has to be confirmed. It has been suggested that TRP1 functions to stabilize tyrosinase. The oxidation of DHI to indole 5,6-quinone is also catalyzed by tyrosinase which leads to the polymerization to form black eumelanin in melanosomes. This could explain why eumelanogenesis is especially dependent on tyrosinase in comparison to pheomelanogenesis.68 Alternatively, through incorporation of glutathione or cysteine, DOPAquinone can form cysteinyl DOPA, which

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Section 14: Pigmentation Disorders then become red/yellow pheomelanin. The switch determining the predominant pigment in each cell remains unidentified. Hydroquinone and l-phenylalanine are competitive inhibitors of tyrosinase activity and are used to treat disorders of hyperpigmentation. Phenylketonuria (PKU), an autosomal recessive disorder, results from a deficiency of the enzyme phenylalanine hydroxylase. The hydroxylation of phenylalanine is required step in synthesis of tyrosine. The characteristic blonde hair of PKU can undergo darkening when the patient is on a low-phenylalanine diet.72 Several metal ions, such as copper (tyrosinase is copper-containing enzyme), zinc, and iron, are found in high concentrations in pigmented tissues. It appears that copper, cobalt, nickel, zinc, and to a lesser extent iron, manganese, and calcium, all catalyze the rearrangement of DOPAchrome to form DHICA rather than DHI. Copper deficiency may lead to diffuse skin pigmentary dilution. In patients with Menkes disease, where a transmembrane Cu2+-transporting ATPase that delivers copper to melanosomes is dysfunctional, the resulting kinky hair is hypopigmented.73 By contrast, less is known concerning neuromelanin synthesis. Neuromelanin is brown/black macropolymer pigment, insoluble in organic solvents, produced within specific populations of catecholaminergic neurons in the brain by the oxidation of dopamine and other catecholamine precursors. It chelates metals and interacts with several inorganic and organic compounds. It has been proposed that neuromelanin and eumelanin have the same biochemical pathway, a claim denied by others who observe that patients with albinism who lack tyrosinase have normal neuromelanin within the substantia nigra.74–76 The precursors and biochemical pathways involved in neuromelanin synthesis need to be identified to further elucidate the normal cellular role of this pigment.

MELANOCYTE FUNCTION AND INFLUENCE OF UV IRRADIATION ON MELANOCYTE FUNCTION As the largest organ in the human body, skin provides important protection against a large number of external and internal harmful factors. The majority of the basement membrane is composed of melanocytes. Owing to their location, melanocytes are vulnerable to be attacked by reactive oxygen species (ROS). UV irradiation makes up only 10% of the entire electromagnetic spectrum (200–400  nm). It is biologically the most potent part of

the sunlight spectrum. UV light affects almost all epidermal and dermal cells: keratinocytes, Langerhans cells, endothelium, melanocytes, neutrophils, mastocytes, T-lymphocytes, fibroblasts, and macrophages. The interplay of the various photobiologic pathways is far from being completely understood. Melanosomes frequently accumulate in cytoplasm of keratinocytes over the apical pole of nucleus, thereby protecting the nuclear DNA like a supranuclear cap during keratinocyte division from the harmful effects of UV irradiation.77 An increase in skin cancer incidence on the depigmented skin of vitiligo patients has not been observed, which does not support current opinions that the melanin in keratinocytes protects the nuclear DNA from UV irradiation and subsequent skin cancer development. It has not yet been elucidated why non-sun-exposed areas of the body, such as the mouth, genitalia, vaginal tract, and anal canal, contain a great number of melanocytes per mm2. Likewise, in hair, melanin does not appear to have protective role, since UV irradiation does not reach the hair follicle. Melanocyte survival, proliferation, and function are greatly influenced by UV irradiation. UVB irradiation enhances transcription of the tyrosinase gene (via MITF) and upregulates expression of proopiomelanocortin and its derivative peptides within keratinocytes, melanocytes, and other cutaneous cells. UV light releases diacylglycerol from the plasma membrane, which activates protein kinase C (PKC) to stimulate melanogenesis by activating tyrosinase. UVB irradiation increases production of keratinocyte-derived cytokines and growth factors [e.g., ET-1, c-Kit].78 ET-1 is a small peptide produced by keratinocytes which can incite an increase in tyrosinase activity, followed by an increase in eumelanin production. ET-1 thus displays photo-protective effects, enhancing thymine dimer repair and increasing the level of antiapoptotic proteins in melanocytes. ET-1 also promotes dendrite formation.79 Similarly, steel factor is induced by UV irradiation. By functioning synergistically with other cytokines such as interleukin-3 (IL-3), IL-6, IL-7, IL-9, and granulocyte-macrophage colony-stimulating factor, steel factor regulates UV-induced melanogenesis and contributes to melanocyte survival after UV irradiation.80 In addition, increased activity of Rac1 (involved in dendrite formation), increased kinesin to dynein ratio, and upregulated expression of PAR-2 (involved in melanosome transfer) stimulate melanocyte dendricity and melanosome transport to keratinocytes. UV irradiation results in augmented anterograde transport by increased kinesin and decreased dynein activity.31 Like other

Chapter 44: Introduction to the Biology of the Pigmentary System keratinocyte-derived cytokines, bFGF is upregulated in response to UV irradiation. Keratinocyte growth factor, a member of the FGF family of proteins, has been shown to promote melanosome transfer from melanocytes to keratinocytes.23 Although pheomelanogenesis and eumelanogenesis are increased in response to UV irradiation, it is the concentrations of eumelanin that correlate better with the degree of tan. Therefore, eumelanin is believed to make a greater contribution in the tanning response. Melanogenesis is also stimulated by photochemotherapy. The process involves the photoconjugation of psoralens to DNA in melanocytes followed by mitosis and subsequent proliferation of melanocytes. This leads to repopulation of the epidermis, increased formation and melanization of melanosomes, enhanced transfer of melanosomes to keratinocytes, and increased synthesis of tyrosinase via stimulation of cAMP activity.81 In order to avoid apoptosis, melanocytes decrease expression of Fas ligand, increase expression of bcl2, and serve as scavengers of oxidative free radicals generated via exposure to UV irradiation. Melanocytes may also act as regulators of the skin’s immune responses by producing a wide variety of cytokines, IL-1, IL-3, IL-6, tumor-necrosis factor α (TNF-α), and nitric oxide (NO). Potential targets of these secretory products are keratinocytes, lymphocytes, fibroblasts, mast cells, and endothelial cells. It is significant that several of the substances produced by melanocytes have inflammatory properties. This therefore raises question as to whether melanocytes may contribute to UV-induced erythema.34 The production of NO could be related to a phagocytic property, which suggests that melanocytes may have a role in the skin’s immune system. NO increases tyrosinase activity via cGMP-dependent pathway and it is thus an autocrine as well as paracrine molecule (NO synthesis in keratinocytes is induced by UV light) that affects melanocyte function. There is also a possibility that the NO produced by melanocytes serves as a second messenger in regulating their differentiation, analogous to the situation in neuronal cells. In the latter, the induction of nitric oxide synthase by NGF causes growth arrest and differentiation.34 Melanocyte function in the epidermis is controlled by α-MSH. The main site of α-MSH production is the pars intermedia of the pituitary gland. Binding of melanocortin peptide α-MSH to melanocortin-1 receptor (MC1-R) on melanocytes regulates melanin production. The MC1R gene has been detected on chromosome 16q24.3. It encodes the melanocortin receptor, which is a melanogenesis regulator and secondary vitiligo autoantigen. It

is associated with red/light hair and fair, sun-sensitive skin. Some loss-of function mutations in MC1R gene confer a risk for developing melanoma, independent of pigmentary phenotype.54 UV irradiation elevates not only the level of α-MSH in the skin but it also upregulates the expression of the MC1-R on melanocytes, increasing the binding of α-MSH to melanocytes. On its binding to the MC1-R, α-MSH activates adenylate cyclase, leading to an increase in cAMP, resulting in the activation, de novo synthesis, and increased expression of tyrosinase via protein kinase A.81 α-MSH regulates the pattern of melanogenesis by preferentially stimulating the synthesis of eumelanin at the expense of pheomelanin. If the MC1-R is dysfunctional, then pheomelanogenesis is favored. The function of α-MSH is not only confined to melanogenesis; evidence is emerging that α-MSH affects several aspects of melanocyte behavior. Melanocytes, like nerve cells, are able to produce a wide variety of similar substances, including melanocortin peptides (α-MSH, ACTH), catecholamines (dopamine, epinephrine, norepinephrine), enzymes important for catabolism of neurotransmitters [monoamine oxidase (MAO) and Catechol-O-methyltransferase (COMT)], serotonin, β-endorphin, and eicosanoids in response to stimuli (stress, ACTH, α-MSH). Slominski et al. have suggested that melanocytes could function as important local regulators of a range of skin cells involved in maintaining epidermal homeostasis,1 while MC1-R is present on a variety of cells (keratinocytes, lymphocytes, fibroblasts, mast cells, and endothelial cells).34 Therefore, α-MSH could act as an endocrine, paracrine, and autocrine factor in the regulation of melanocyte function. Melanocyte’s ability to produce neuropeptides and neurotransmitters suggest a role as a neuroendocrine cell. Melanocortins may also regulate the release of cytokines, catecholamines, serotonin, and NO production from melanocytes. α-MSH may have some role in the modulation of the immune system. α-MSH has potent anti-inflammatory and immunomodulatory properties through its ability to antagonize the actions of proinflammatory cytokines. Neuromelanin is found in the leptomeninges, in the dopaminergic neurons of the substantia nigra, and the noradrenergic neurons of the locus coeruleus of the brain where UV irradiation cannot elicit any harmful roles to the host.82 One hypothesis suggests that neuromelanin could play a protective role by removing oxidative free radicals and using them to oxidize the amino acid tyrosinase to form neuromelanin or neurotransmitters; there exists a similarity in biochemical pathway and chemical

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Section 14: Pigmentation Disorders structure between melanin, thyroxine and dopamine, and noradrenaline. The precursors and biochemical pathways involved in neuromelanin synthesis need to be identified to further elucidate the normal cellular role of this pigment. Melanocytes in the brain are considered relevant in sleeping regulation and in the synthesis and release of central chemosensor(s) generating the respiratory rhythm.5 The same signaling molecules that have a role in the central and peripheral nervous tissue also have a role in cutaneous melanocytes. Signaling pathways, including PKC- and p53/p73-dependent pathways, are also common to melanocytes and neurons. Melanocytes share a common embryologic origin, signaling molecules, receptors, and signaling pathways with cells of the nervous system. Melanocytes, like other neural-derived tissues, have a low mitotic rate in comparison to keratinocytes. The similarity between melanocytes and neurons makes the melanocyte an attractive model system in which to study disorders that affect the nervous system.6 Further studies are needed to investigate if melanocytes are able to generate and conduct some kind of action potential within skin. Other major populations of extracutaneous melanocytes can be found within the posterior choroid and ciliary body of the uveal tract and the stria vascularis within the scala media of the cochlea.70 Melanin of the pigment epithelium and uveal tract prevents photodynamic damage in the very highly perfused choriocapillaris of the uveal tract and improves visual acuity by absorbing stray light. Melanin is not transferred from the cytoplasm of uveal melanocytes into other cells. In the choroid, the protective effect of melanin is thought to occur through the reduction of ROS rather than by direct UV protection as the choroid is not exposed to much direct environmental UV light.83 In contrast, in the iris, melanin is thought to confer UV photo-protection.84 Retinal pigment epithelium is formed by a distinct type of melanocyte, specifically present as a single layer of cells behind the retina. These melanocytes are involved in the metabolism of retinoids and of rod outer segments, with major implications in vision. Age-related macular degeneration (AMD) occurs significantly more often in lightly pigmented races compared to darkly pigmented races.85 In addition, a lightly colored iris is associated with a higher occurrence of AMD.86 Melanocytes within the inner ear play a critical role in the maintenance of the endocochlear potential, essential for hearing, by regulating potassium transport into the endolymph. The presence of hypoacusis

due to alteration of melanocytes may be present in patients affected by piebaldism.87 Cardiac melanocytes are localized to atria, mitral/ tricuspid valves, interventricular septum, and pulmonary veins.88 Their presence within these specific cardiac regions is significant; these anatomic regions are known for triggering clinical atrial arrhythmias. Levin et al. have proposed that dysfunction of cardiac melanocytes in the atrium and pulmonary veins may contribute to atrial fibrillation, the most common clinical cardiac arrhythmia. Dermal and cardiac melanocytes express many melanocytes markers such as tyrosinase, TRP1, TRP2, SOX10, and MITF, but do not express those of cardiomyocytes. TRP2expressing cells are involved in intracellular calcium regulation and the quenching of oxidative free radicals. They also express similar voltage-gated ion channels under conditions of increased oxidative stress that result in cellular excitability (Box 44.1).88 Eumelanin binds calcium with an affinity similar to calmodulin. This buffering capacity, as applied to calcium, would imply a role for eumelanin in cell function, since calcium is a critical second messenger. Cardiac melanocytes are excitable and are electrically coupled to neighboring cardiomyocytes (connexin 45) which support their role in arrhythmogenesis.88 It is possible that TRP2 activity, required in melanin biosynthesis, is downregulated by vagal output just before the onset of atrial fibrillation. This downregulation may then result in higher oxidative stress that could modulate voltage-gated

Box 44.1: Expression of selected ion channels in cardiac melanocytes. Calcium channel, voltage-dependent, L-type, α1C subunit ATPase, Ca++ transporting, plasma membrane 1 Ryanodine receptor 2, cardiac Gap junction protein, γ1 ATPase, Ca++ transporting, cardiac muscle 2 Chloride intracellular channel 4 Voltage-dependent anion channel 2 Caveolin 3 Potassium channel tetramerization domain ATPase, Na+/K+ transporting, α1 polypeptide Potassium channel modulatory factor 1 Chloride intracellular channel 4 Sodium channel, voltage-gated, type V, α Potassium channel, subfamily K, member 3 Potassium inwardly rectifying channel, subfamily J, member 1

Chapter 44: Introduction to the Biology of the Pigmentary System ion channels and calcium homeostasis, thereby increasing cell excitability, triggering pathological, ectopic electrical activity.88 The major difference between dermal and cardiac melanocytes is melanin transfer. There is an absence of melanin transfer in the heart due to decreased PAR-2 gene expression. Although growing evidence supports the similarities between dermal and cardiac melanocytes, further electron microscopy experiments would be required to investigate their similarities.

AGING OF MELANOCYTES Epidermal melanocyte aging is affected by both genetic and environmental factors. With aging, there is a decrease in the density of epidermal melanocytes by approximately 10% per decade.89 It seems that cutaneous and follicular melanocytes begin senescence in the fourth decade of life (40–49 years).90 DOPA-positivity of individual melanocytes is consistently greater in chronically-exposed skin than in non-exposed skin and does not vary with age.89 Hair begins to turn gray in the fourth and fifth decades of life.67,90 Nishimura et al. have suggested that hair graying is caused by the gradual disappearance of stem cells, which provide a constant supply of new melanocytes. According to them, it may be possible that changes occur in the survival, proliferation, or differentiation signals in the melanocytic stem cells and the limited number of cell divisions (intrinsically determined lifespan), which are related with human aging.67 Serous macular atrophy, a common cause of poor visual acuity in the elderly, begins in the fifth and sixth decades and is associated with a loss of retinal pigment cells in the foveal region. The reason for the disappearance of melanocytes throughout the body is unknown. If melanocytes play an important role as scavengers of oxidative free radicals generated via exposure to UV irradiation, their loss might explain in part the higher number of skin cancers observed in the elderly. In contrast to epidermal melanin, neuromelanin levels in the locus ceruleus increase with age and are comparable to the amounts found in the substantia nigra of the same individuals (2.5 μg/mg wet tissue at 61 years).91 Intraneuronal neuromelanin could prevent the toxic accumulation of cytosolic catechol derivatives. However, following the neuronal damage of dopaminergic neurons in Parkinson disease, extraneuronal neuromelanin might induce microglial activation, with production of neurotoxic molecules such as TNF-α, IL-6, and NO. These molecules may lead to chronic neuroinflammation and neurodegeneration.91 Therefore, melanocytes have become an attractive model system in which to study the

most common incurable and progressive neurodegenerative disorders.

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Section 14: Pigmentation Disorders 19. Spritz RA. Piebaldism, Waardenburg syndrome, and related disorders of melanocyte development. Semin Cutan Med Surg 1997;16:15–23. 20. Holbrook KA, Underwood RA, Vogel M. The appearance, density and distribution of melanocytes in human embryonic and fetal skin revealed by the antimelanoma monoclonal antibody, HMB-45. Anat Embryol 1989;180:443–55. 21. Bolognia JE, Orlow SJ. Melanocyte biology. In: Bolognia JL, Jorizzo JL, Schaffer JV, editors. Dermatology. 3rd ed. Edinburgh: Mosby; 2012. p. 1024. 22. Hirobe T, Osawa M, Nishikawa S. Hepatocyte growth factor controls the proliferation of cultured epidermal melanoblasts and melanocytes from newborn mice. Pigment Cell Res 2004;17:51–61. 23. Halaban R. The regulation of normal melanocyte proliferation. Pigment Cell Res 2000;13:4–14. 24. Scott GA, McClelland LA, Fricke AF. Semaphorin 7a promotes spreading and dendricity in human melanocytes through beta1-integrins. J Invest Dermatol 2008;128:151–61. 25. Stefanato CM, Yaar M, Bhawan J. Modulations of nerve growth factor and Bcl-2 in ultraviolet-irradiated human epidermis. J Cutan Pathol 2003;30:351–7. 26. Botchkarev VA, Yaar M, Peters EM. Neurotrophins in skin biology and pathology. J Invest Dermatol 2006;126:1719–27. 27. Tobin DJ, Bystryn JC. Different populations of melanocytes are present in hair follicles and epidermis. Pigment Cell Res 1996;9:304–10. 28. Jouneau A, Yu YQ, Pasdar M, Larue L. Plasticity of cadherin-catenin expression in the melanocyte lineage. Pigment Cell Res 2000;13:260–72. 29. Dean N, Haynes J, Brennan J, et al. Nipple-areolar pigmentation: histology and potential for reconstitution in breast reconstruction. Br J Plast Surg 2005;58:202–8. 30. Płonka PM, Picardo M, Slominski AT. Does melanin matter in the dark? Exp Dermatol 2017;26(7):595–7. 31. Hara M, Yaar M, Byers HR, et al. Kinesin participates in melanosomal movement along melanocyte dendrites. J Invest Dermatol 2000;114:438–43. 32. Rosdahl I, Bagge U. Vital microscopy of epidermal melanocytes. Acta Derm Venereol 1981;61(1):55–8. 33. Fitzpatrick TB, Breathnach AS. The epidermal melanin unit system. Dermatol Wochenschr 1963;147:481–9. 34. Tsatmali M, Ancans J, Thody AJ. Melanocyte function and its control by melanocortin peptides. J Histochem Cytochem 2002;50:125–33. 35. Frenk E, Schellhorn JP. Morphology of the epidermal melanin unit. Dermatologica 1969;139:271–7. 36. Orlow SJ. Melanosomes are specialized members of the lysosomal lineage of organelles. J Invest Dermatol 1995;105:3–7. 37. Marks MS, Heijnen HF, Raposo G. Lysosome-related organelles: unusual compartments become mainstream. Curr Opin Cell Biol 2013;25:495–505. 38. Theos AC, Truschel ST, Raposo G, Marks MS. The silver locus product Pmel17/gp100/Silv/ME20: controversial in name and in function. Pigment Cell Res 2005;18:322–36. 39. Falletta P, Bagnato P, Bono M, et al. Melanosomeautonomous regulation of size and number: the OA1

receptor sustains Pmel expression. Pigment Cell Melanoma Res 2014;27:565–79. 40. McGlinchey RP, Shewmaker F, McPhie P, et al. The repeat domain of the melanosome fibril protein Pmel17 forms the amyloid core promoting melanin synthesis. Proc Natl Acad Sci USA 2009;106:13731–6. 41. Watt B, Tenza D, Lemmon MA, et al. Mutations in or near the transmembrane domain alter PMEL amyloid formation from functional to pathogenic. PLoS Genet 2011;7:e1002286. 42. Hoashi TL, Watabe H, Muller J, et al. MART-1 is required for the function of the melanosomal matrix protein PMEL17/ GP100 and the maturation of melanosomes. J Biol Chem 2005;280:14006–16. 43. Wang N, Hebert DN. Tyrosinase maturation through the mammalian secretory pathway: bringing color to life. Pigment Cell Res 2006;19:3–18. 44. Brilliant MH. The mouse p (pink-eyed dilution) and human P genes, oculocutaneous albinism type 2 (OCA2), and melanosomal pH. Pigment Cell Res 2001;14:86–93. 45. Ni-Komatsu L, Orlow SJ. Heterologous expression of tyrosinase recapitulates the misprocessing and mistrafficking in oculocutaneous albinism type 2: effects of altering intracellular pH and pink-eyed dilution gene expression. Exp Eye Res 2006;82:519–28. 46. Amos CI, Wang LE, Lee JE, et al. Genome-wide association study identifies novel loci predisposing to cutaneous melanoma. Hum Mol Genet 2011;20:5012–23. 47. Theos AC, Tenza D, Martina JA, et al. Functions of adaptor protein (AP)-3 and AP-1 in tyrosinase sorting from endosomes to melanosomes. Mol Biol Cell 2005;16:5356–72. 48. Wei ML. Hermansky-Pudlak syndrome: a disease of protein trafficking and organelle function. Pigment Cell Res 2006;19:19–42. 49. Liu-Smith F, Poe C, Farmer PJ, Meyskens Jr FL. Amyloids, melanins and oxidative stress in melanomagenesis. Exp Dermatol 2015;24:171–4. 50. Fedorow H, Tribl F, Halliday G, et al. Neuromelanin in human dopamine neurons: comparison with peripheral melanins and relevance to Parkinson’s disease. Prog Neurobiol 2005;75:109–24. 51. Slominski A, Tobin DJ, Shibahara S, et al. Melanin pigmentation in mammalian skin and its hormonal regulation. Physiol Rev 2004;84:1155–228. 52. Ménasché G, Ho CH, Sanal O, et al. Griscelli syndrome restricted to hypopigmentation results from a melanophilin defect (GS3) or a MYO5AF-exon deletion (GS1). J Clin Invest 2003;112:450–6. 53. Pastural E, Barrat FJ, Dufourcq-Lagelouse R, et al. Griscelli disease maps to chromosome 15q21 and is associated with mutations in the Myosin-Va gene. Nat Genet 1997;16:289–92. 54. Dessinioti C, Antoniou C, Katsambas A, et al. Melanocortin 1 receptor variants: functional role and pigmentary associations. Photochem Photobiol 2011;87:978–87. 55. Sturm RA. Molecular genetics of human pigmentation diversity. Hum Mol Genet 2009;18(R1):R9–17.

Chapter 44: Introduction to the Biology of the Pigmentary System 56. Van Gele M, Dynoodt P, Lambert J. Griscelli syndrome: a model system to study vesicular trafficking. Pigment Cell Melanoma Res 2009;22:268–82. 57. Makino-Okamura C, Niki Y, Takeuchi S, et al. Heparin inhibits melanosome uptake and inflammatory response coupled with phagocytosis through blocking PI3k/Akt and MEK/ERK signaling pathways in human epidermal keratinocytes. Pigment Cell Melanoma Res 2014;27:1063–74. 58. Van Den Bossche K, Naeyaert JM, et al. The quest for the mechanism of melanin transfer. Traffic 2006;7:769–78. 59. Ando H, Niki Y, Yoshida M, et al. Involvement of pigment globules containing multiple melanosomes in the transfer of melanosomes from melanocytes to keratinocytes. Cell Logist 2011;1(1):12–20. 60. Scott G. Rac and rho: the story behind melanocyte dendrite formation. Pigment Cell Res 2002;15:322–30. 61. Ito Y, Kanamaru A, Tada A. A novel agent, methylophiopogonanone B, promotes Rho activation and tubulin depolymerization. Mol Cell Biochem 2007;297:121–9. 62. Seiberg M, Paine C, Sharlow E, et al. The protease-activated receptor 2 regulates pigmentation via keratinocyte– melanocyte interactions. Exp Cell Res 2000;254:25–32. 63. Scott G, Deng A, Rodriguez-Burford C, et al. Proteaseactivated receptor 2, a receptor involved in melanosome transfer, is upregulated in human skin by ultraviolet irradiation. J Invest Dermatol 2001;117:1412–20. 64. Cardinali G. Keratinocyte growth factor promotes melanosome transfer to keratinocytes. J Invest Dermatol 2005;125:1190–9. 65. Sato S, Kukita A, Jimbow K. Electron microscopic studies of dendritic cells in the human gray and white hair matrix during anagen. Pigment Cell 1973;1:20. 66. Steingrimsson E, Copeland NG, Jenkins NA. Melanocyte stem cell maintenance and hair graying. Cell 2005;121:9–12. 67. Gola M, Czajkowski R, Bajek A, et al. Melanocyte stem cells: biology and current aspects. Med Sci Monit 2012;18:RA155–9. 68. Prota G. The chemistry of melanins and melanogenesis. Fortschr Chem Org Naturst 1995;64:93–148. 69. d’Ischia M, Wakamatsu K, Cicoira F, et al. Melanins and melanogenesis: from pigment cells to human health and technological applications. Pigment Cell Melanoma Res 2015;28:520–44. 70. Tolleson WH. Human melanocyte biology, toxicology, and pathology. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 2005;23:105–61. 71. Jiménez-Cervantes C, Solano F, Kobayashi T, et al. A new enzymatic function in the melanogenic pathway. The 5,6-dihydroxyindole-2-carboxylic acid oxidase activity of tyrosinase-related protein-1 (TRP1). J Biol Chem 1994;269:17993–8000. 72. Al Hafid N, Christodoulou J. Phenylketonuria: a review of current and future treatments. Transl Pediatr 2015;44:304-17. 73. Ojha R, Prasad AN. Menkes disease: what a multidisciplinary approach can do. J Multidiscip Healthc 2016;9:371–85.

74. Xu Y. Tyrosinase mRNA is expressed in human substantia nigra. Brain Res Mol Brain Res 1997;45:159–62. 75. Tief K. New evidence for presence of tyrosinase in substantia nigra, forebrain and midbrain. Brain Res Mol Brain Res 1998;53:307–10. 76. Ikemoto K. Does tyrosinase exist in neuromelanin-pigmented neurons in the human substantia nigra?. Neurosci Lett 1998;253:198–200. 77. Minvalla L. Keratinocytes play a role in regulating distribution patterns of recipient melanosomes in vitro. J Invest Dermatol 2001;117:341. 78. Richard EG, Hönigsmann H. Phototherapy, psoriasis, and the age of biologics. Photodermatol Photoimmunol Photomed 2014;30:3–7. 79. Kadekaro AL, Kavanagh R, Kanto H. alpha-Melanocortin and endothelin-1 activate antiapoptotic pathways and reduce DNA damage in human melanocytes. Cancer Res 2005;65:4292–9. 80. Imokawa G, Kobayasi T, Miyagishi M. Intracellular signaling mechanisms leading to synergistic effects of endothelin-1 and stem cell factor on proliferation of cultured human melanocytes. Cross-talk via transactivation of the tyrosine kinase c-kit receptor. J Biol Chem 2000;275:33321–8. 81. Bolognia J, Murray M, Pawelek J. UVB-induced melanogenesis may be mediated through the MSH-receptor system. J Invest Dermatol. 1989;92(5):651–6. 82. Graham DG. On the origin and significance of neuromelanin. Arch Pathol Lab Med 1979;103(7):359–62. 83. Peters S, Lamah T, Kokkinou D, et al. Melanin protects choroidal blood vessels against light toxicity. Z Naturforsch C 2006;61:427–33. 84. Hu DN, Simon JD, Sarna T. Role of ocular melanin in ophthalmic physiology and pathology. Photochem Photobiol 2008;84:639–44. 85. Friedman DS, Katz J, Bressler NM, et al. Racial differences in the prevalence of age-related macular degeneration: the Baltimore Eye Survey. Ophthalmology 1999;106:1049–55. 86. Frank RN, Puklin JE, Stock C, et al. Race, iris color, and age-related macular degeneration. Trans Am Ophthalmol Soc 2000;98:109–15; discussion 115–7. 87. Conlee JW, Parks TN, Schwartz IR, et al. Comparative anatomy of melanin pigment in the stria vascularis. Acta Otolaryngol (Stockh) 1989;107:48–58. 88. Levin MD, Min Lu M, Petrenko NB, et al. Melanocyte-like cells in the heart and pulmonary veins contribute to atrial arrhythmia triggers. J Clin Invest 2009;119:3420–36. 89. Gilchrest BA, Blog FB, Szabo G. Effects of aging and chronic sun exposure on melanocytes in human skin. J Invest Dermatol 1979;73:141–3. 90. Sarin KY, Artandi SE. Aging, graying and loss of melanocyte stem cells. Stem Cell Rev 2007;3:212–7. 91. Zecca L, Zucca FA, Wilms H, et al. Neuromelanin of the substantia nigra: a neuronal black hole with protective and toxic characteristics. Trends Neurosci 2003;26:578–80.

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45

Disturbances of Melanin Pigmentation

Miroslava Kadurina, Kristina Semkova, Šitum Mirna, Kovacevic Maja, Kolić Maja, Guleva Dimitrina, Lotti Torello

DISORDERS OF HYPERPIGMENTATION Hereditary or Genetic Linear and Whorled Nevoid Hypermelanosis Linear and whorled nevoid hypermelanosis (LWNH) is a benign sporadic pigmentary disorder characterized by development during infancy of macular hyperpigmented streaks that follow the lines of Blaschko on the trunk and extremities without preceding inflammation. The lesions may be extensive or unilateral with a sharp midline cutoff. The soles, palms, face, and mucous membranes are spared. Progression with age is observed, but there are no other associated systemic findings. Rare cases are familial, and there is no gender predilection. Histopathological examination shows increase in the basal melanin and slight elongation of the rete ridges with a normal number of melanocytes and no melanophages. Progressive cribriform and zosteriform hyperpigmentation shows the same clinical and histological features and is believed to represent a localized form of LWNH.1

occasionally increase in melanocyte density in patients with NF1 as compared with patients with sporadic lesions.

Café-au-lait Macules

Reticulate Hyperpigmentary Disorders

Café-au-lait macules (CALMs) are hyperpigmented macular lesions with smooth or slightly irregular borders, light to dark brown in color, and variable in size and number. They can develop early in infancy but become prominent after the age of 2. CALMs are either sporadic or syndromic. They can be found in 95% of patients with neurofibromatosis type 1 (NF1) and are the earliest presenting sign of this disorder. They are seen also in patients with NF2, McCune–Albright syndrome, tuberous sclerosis, Fanconi anemia, Ataxia telangiectasia, Bloom syndrome, Basal cell nevus syndrome, Gaucher disease, and some other rare syndromes (Fig. 45.1). The underlying pathogenic mechanism is increase in melanin, often within giant melanosomes, or

Reticulate acropigmentation of Kitamura

Fig. 45.1: Café-au-lait-macule. Hyperpigmented macular lesion with irregular borders present on the lateral abdomen of a young child. Courtesy: Dr. Babar K. Rao, MD, New York, USA.

Reticulate acropigmentation of Kitamura (RAPK) is a rare genodermatosis described first in 1943 by Kitamura and Akamatsu.2 It results from mutations in ADAM10.3 The majority of reported cases are in Japanese patients. It usually develops during childhood or in the first and second decades of life. Affected skin sites are the dorsal aspect of the hands and feet, but proximal spread can also be seen with time. The early lesions are atrophic macules which darken progressively to the typical lentiginous hyperpigmented macules in a reticular pattern. Sunlight may exacerbate the condition. Palmoplantar pitting and dermatoglyphic disruption may be additional features. Histopathological examination reveals epidermal atrophy

Chapter 45: Disturbances of Melanin Pigmentation with slight hyperkeratosis without parakeratosis, associated with club-like elongation of rete ridges and increased melanin deposition in the basal cell layer.4

Dowling–Degos disease Dowling–Degos disease (DDD) was first described by Dowling in 19385 and Degos in 1954.6 It is an autosomal dominant disease due to mutation of KRT57 and recently described mutations in POFUT1 (encoding protein O-fucosyltransferase 1)8 and POGLUT1.9 However, sporadic cases have also been reported. The onset of the disease is usually in the third or fourth decade of life. Clinically, it is characterized by reticular hyperpigmentation of the flexures (neck, axillae, antecubital fossas, submammary areas, and groin).10 Dark comedo-like lesions as well as pitted perioral acneiform scars on the face and neck may be present. Pruritus in the flexural regions is also a feature, albeit not constant. The histological presentation is similar to RAPK with prominent involvement of hair follicles but acanthosis of the epidermis, tight digitiform rete ridges with prominent hyperpigmentation at the tips, pigmentary incontinence and small cornified cysts are also observed.4 The general health of patients with DDD is unaffected; however, the condition may be associated with hidradenitis suppurativa, squamous cell carcinoma, keratoacanthoma, and seborrheic keratoses. Therapy: There are no effective treatments for these conditions. Topical treatment with retinoids and adapalene is often unsuccessful or offers temporary improvement.11,12 Azelaic acid (AA) 20% is shown to be a potential option.13 Erbium-doped yttrium aluminum garnet (Er:YAG), an ablative laser that emits light at 2,940 nanometers for skin resurfacing and pigmentary disorders, is another therapeutic option.14

Reticulate acropigmentation of Dohi Reticulate acropigmentation of Dohi (RAD) is an autosomal dominant disease first described in 1924 by Komaya15 but as well-established condition in 1982 by Doha.16 Rarely, the disorder may occur as an autosomal recessive trait.17 RAD is commonly described in Japanese individuals. Clinically, it is characterized by hyper- and hypopigmented macules mixed in a reticulate pattern on the dorsal extremities extending slowly proximally over time to affect the neck, supraclavicular region, and face.18 Lesions usually start in infancy or childhood although later presentation has also been reported. Skin biopsy in RAD reveals a reduced density of DOPA-positive melanocytes in the depigmented macules.19 Treatment is challenging. Topical

steroids and Psoralen and Ultraviolet light A (PUVA) have no efficacy on the hypopigmented areas.19 Split-skin grafting has been effective but is not a treatment of choice due to its morbidity.19 The most appropriate approach for good cosmetic results is the use of camouflage creams.

Familial Progressive Hyperpigmentation Familial progressive hyperpigmentation (FPH) is a rare inherited genodermatosis first described by Chernovski et al in 1971.20 It is autosomal dominant20–22 or recessive mosaic germ-line mutation.23 The disease has been described mostly in African, Asian, and Hispanic individuals. Both sexes are affected equally.23 Clinically, FPH presents with hyperpigmented macules on the skin and mucous membrane initially affecting the face or groin with progressive increase in number and size. The lesions are commonly present at birth or in early infancy.24 The condition can progress to cover the entire body. Palms and soles, lips, oral mucous membrane, and conjunctiva are also commonly affected. The pattern of pigmentation may vary. The most common is the segmental pattern, followed by diffuse hyperpigmentation.20,23 In adulthood, FPH may disappear gradually or result in a bronze skin color or mottled diffuse skin pigmentation. Mottled appearance is observed in the oral mucous membranes.23,25 Systemic involvement is not a feature.26 Histological examination reveals a significant increase in melanin deposition in the epithelium, mostly in the basal cell layer.23,27 The differential diagnoses include melasma (chloasma), Addison’s disease, Cushing’s disease, Carbon Baby syndrome, Peutz–Jeghers syndrome, exposure to chemicals (bleomycin and mercury poisoning), smoker’s melanosis, and hemochromatosis. Prognosis is unclear due to the rarity of the condition. However, complications have not been described. Specific therapy is not available, but periodic follow-up may be advisable.

Acromelanosis Progressiva Acromelanosis progressiva (AP) is a rare disorder of pigmentation prevalent in darker phototypes and resulting from a sporadic mutation or with an autosomal recessive inheritance.28–30 Clinically, AP presents in the neonatal period or during the first years of life with brownish pigmentation of periungual areas. It can be localized only on the back of the fingers and toes but in some cases extends to the proximal extremities and even the trunk to affect large areas

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Section 14: Pigmentation Disorders of the skin surface. Rare sites of involvement include the ocular mucosa,30 genitals,29,31 and umbilicus.29 Although AP usually occurs in healthy children, association with intellectual disability and epilepsy,28 lactose intolerance and vitamin B12 deficiency30 and Wilms tumor32 have been reported. Whether this association is true or coincidental, remains unknown. The histological picture is non-specific and the diagnosis should be based on the clinical history and presentation. The prognosis is not clear and effective treatments are not available. It is, hence, recommended that follow-up be considered for these patients.

Melasma is a common benign acquired condition which is characterized by bilateral symmetrical hyperpigmented macules on sun-exposed skin. The name comes from the Greek word for black—“melas.” Chloasma is a synonymous term that may be used to describe the occurrence of melasma during pregnancy.

and endothelin 1.33,34 These substances stimulate melanin production by intraepidermal melanocytes which, in melasma, are not increased but are enlarged and more dendritic. This specific state of the melanocytes results in increased localized hyperpigmentation as opposed to diffuse pigmentation. Female sex hormones (estrogens and progesterones) have been linked to the development of melasma as evidenced by the association of this condition with pregnancy, oral contraceptive use, preferential development in women, and during the reproductive age. Estrogen receptor expression is up-regulated in affected skin.35 Estrogens stimulate melanogenesis by inducing synthesis of melanogenic enzymes such as tyrosinase, tyrosinase-related protein (TRP)-1, TRP-2, and MITF.36 Additional factors include the fibroblasts in the dermis which overexpress the tyrosine kinase receptor c-kit and other stem cell factors which induce melanogenesis.37 In the setting of pregnancy, melasma is considered a physiological change and a result of a tendency for generalized pigmentary changes. Estrogen, progesterone, and MSH levels are normally increased during the third trimester of pregnancy, and this is the time when melasma usually develops.38

Epidemiology

Clinical presentation

Melasma is very common and can affect both women and men of any race but is more prevalent in women with light brown skin types, of Latin American or Asian descent in particular. Ninety percent of all the cases occur in women. The frequency of melasma in pregnancy is reported to be as high as 56%. Eleven to 46% of patients on oral contraceptives can develop melasma as well.33 Any age can be affected, but melasma rarely occurs before puberty.

Melasma is classified according to the distribution pattern as centrofacial, malar, and mandibular39 or according to the location of the pigment as epidermal, dermal, or mixed.40 It presents with bilateral, usually symmetrical tan to brown pigmented macules. Dermal melasma can present with blue to black tint due to the Tyndall effect. In the centrofacial type, the lesions affect the upper lip, forehead, cheeks, nose, and chin; in malar—the nose and the cheeks; and in mandibular—the ramus of the mandible. Forearms may be affected in women on progesterone treatment or in Native Americans. Strong association with sun exposure is noticed by the patients. The clinical severity of melasma may be assessed by the Melasma Area and Severity Index with area of involvement and darkness being the most predictive factors.41

Acquired Melasma Definition

Pathophysiology The pathophysiology of melasma is not fully elucidated, but it is a known multifactorial disorder with exposure to ultraviolet (UV) light and hormonal milieu being the most significant triggering factors. Specific genetic polymorphisms have not been identified but epidemiological studies suggest strong correlation with family history (in about 30%).33 Sporadic and familial cases do not differ in clinical and histological presentation. UV radiation, including UVA, UVB, and visible light, is a well know trigger that induces hyperpigmentation via increased production of α-melanocyte–stimulating hormone (MSH), corticotropin, interleukin (IL)-1,

Differential diagnosis Melasma is an easy clinical diagnosis and differentiation from other conditions is only rarely needed. These should include postinflammatory hyperpigmentation, Riehl melanosis, ochronosis, nevus of Ota and nevus of Ito, poikiloderma of Civatte, actinic lichen planus, phytophotodermatitis.

Chapter 45: Disturbances of Melanin Pigmentation

Investigations Laboratory investigations are not necessary. Wood light examination may be used to differentiate between epidermal and dermal melanin deposition in lighter skin types. Epidermal pigment is enhanced during examination, whilst the dermal pigment remains the same. Histological examination reveals increase in melanin in the epidermal keratinocytes or melanin deposition in melanophages in the dermis. Biopsy is however not routinely recommended.

Management and prognosis Melasma, the dermal subtype in particular, is commonly refractory to treatment. Protection from sun exposure in combination with various depigmenting agents is the mainstay of treatment. Triple therapy of hydroquinone (HQ), retinoid, and corticosteroid is the most efficacious modality. The original Kligman formula (5% HQ, 0.1% tretinoin, and 0.1% dexamethasone) has now been replaced by milder but equally effective regimens (e.g., fluocinolone acetonide 0.01%, HQ 4%, tretinoin 0.05%.42 This combination is safe and effective when used continuously for up to 24 weeks.43 HQ in concentrations 2%–4% inhibits the conversion of dopa to melanin by blocking tyrosinase action and inhibits the formation, melanization, and degradation of melanosomes. HQ is one of the most effective treatments for melasma, both as a monotherapy or as a part of a combination regimen. Visible reduction of pigmentation is evident after 5–7 weeks, and the treatment should continue for 3 months and up to 1 year.44 The common side effects include erythema and burning. Ochronosis and confettilike depigmentation are rare but disfiguring. Topical retinoids can also be used as monotherapy or in combination. They stimulate keratinocyte turnover, decrease melanocyte activity, and enhance the penetration of other therapies. The main side effects include skin irritation, photosensitivity, and paradoxical hyperpigmentation. Tretinoin is the most commonly used agent, but adapalene shows similar effectiveness with better tolerance.45 Improvement is noticed after about 6 months. AA, as a 20% cream or 15% gel, may be as effective as 4% HQ and superior to 2% HQ in the treatment of melasma.44 AA inhibits tyrosinase but has a selective cytotoxic effect towards hyperactive melanocytes sparing the normally pigmented skin. The main side effect is initial and transient skin irritation. AA should be applied twice daily for up to 8 months. Decrease in pigmentation is usually not seen before 1–2 months of treatment.

Other agents have been studied for the treatment of melasma, including kojic acid, ascorbic acid, dioic acid, rucinol, oral tranexamic acid, and so on. More studies are needed to define their efficacy and safety. Second line treatments include destructive modalities such as chemical peels and lasers, but the results are difficult to predict and the potential for side effects (epidermal necrosis, scarring, and postinflammatory hyperpigmentation) is higher in comparison to topical formulations. Amongst the superficial skin peels, glycolic or salicylic acid are most commonly used. They can be applied on monthly and then weekly basis, usually in conjunction with topical agents. Skin dyspigmentation is a well-established side effect in darker skin types. Lasers (low-fluence Q-switched Nd:YAG 1,064 nm in particular) may be used in refractory cases, but their use is usually associated with low levels of efficacy and significant cosmetic side effects. Fractional resurfacing is another second line option with lower risk of postinflammatory dyspigmentation.

Prognosis Melasma is particularly refractory to treatment and sun exposure usually results in recurrence. Pregnancy or oral contraception related melasma usually fades away after discontinuation of the drug or after delivery, albeit it may not disappear completely in all patients.

Poikiloderma of Civatte (Erythromelanosis Interfollicularis Colli) Poikiloderma of Civatte presents with asymptomatic dyspigmentation, telangiectasia, and atrophy affecting symmetrically the face, neck, and upper chest. It results from repeated and prolonged sun exposure with additional influence of genetics, low estrogen, and phototoxic or photoallergic reactions to chemicals in fragrances or cosmetics. It is most common in fair-skinned female patients and presents at 30–50 years of age. Histological examination reveals atrophy of the epidermis, vacuolar degeneration of the basal layer and melanophages and dilated capillaries in the superficial dermis. Poikiloderma of Civatte is slowly progressive and irreversible. Treatment is unsatisfactory. High sun protection factor (SPF) photoprotection and avoidance of sun exposure, and cosmetic allergens is the mainstay of prophylaxis. Laser therapy (intense pulsed light (IPL), non-ablative

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Section 14: Pigmentation Disorders fractionated laser skin resurfacing, or tunable dye laser) may improve the ­cosmetic appearance.46

Riehl Melanosis (Pigmented Contact Dermatitis, Melanodermatitis Toxica, Photocontact Facial Melanosis) Pigmented contact dermatitis is a facial pigmentary disorder that results from frequent and repeated contact with minute amounts of sensitizing allergens in cosmetic and textile materials. It was postulated that the reaction may be phototoxic or lichenoid contact dermatitis with secondary pigment incontinence. Whether the cases described by Riehl in 191747 are the same or a result of a nutritional deficiency is still a matter of debate. Pigmented contact dermatitis is most common in middle-aged women and presents with a rapidly developing brown-gray pigmentation on the face with marked involvement of the temples and the forehead. The chest, neck, scalp, and the upper extremities may be affected occasionally. Subtle preceding mild erythema, edema, and pruritus may be present. Desquamation and follicular plugging are an additional feature. Histological examination reveals vacuolar degeneration of the basal layer of the epidermis, band-like, or lichenoid lymphocytic infiltrate and pigment incontinence. Dermoscopy and confocal microscopy show pseudonetworks, gray dots/granules, basal layer liquefaction, and pigment incontinence.48 The differential diagnosis includes melasma, ochronosis, erythromelanosis follicularis faciei, Hori nevus, poikiloderma of Civatte, drug induced hyperpigmentation, lichen planus pigmentosus, Berloque dermatitis, thiazide leukomelanoderma. Avoidance of the suspected allergen is the mainstay of treatment and improvement is usually seen gradually over several months. Topical depigmenting agents, chemical peels, and IPL may be used as well.

Erythromelanosis Follicularis Faciei Et Colli Erythromelanosis follicularis faciei et colli (EFFC) is a rare autosomal recessive condition of unknown etiology.49 It presents with asymptomatic, well-demarcated erythema (with or without telangiectasia), brownish pigmentation, and fine follicular papules predominantly on the preauricular cheeks and only occasionally on the neck. Onset is usually during childhood/early adolescence, and the

condition affects predominantly male patients. All races are affected with higher frequency in Asians. Keratosis pilaris is a common associated feature. EFFC is persistent and refractory to treatment, but the lesions heal without scarring or atrophy. The histological features are non-specific. There is compact hyperkeratosis, increased basal layer pigmentation, superficial telangiectasia, and dilated hair follicles with hypertrophic sebaceous glands.50 The differential diagnosis includes keratosis pilaris, poikiloderma of Civatte, melasma, actinic telangiectasia, and steroid rosacea. Treatment is usually unsatisfactory and recurrences are common. Topical tretinoin, keratolytics, tacalcitol, metronidazol, HQ, and ammonium lactate cream can be used as monotherapy or in combination.49 Oral isotretinoin can be tried in severe cases. Dual-wavelength laser system (585-nm pulsed dye laser and 1,064-nm Nd:YAG laser) therapy may reduce the erythema.51

Postinflammatory Hypermelanosis Postinflammatory hypermelanosis (PIH) is a macular pigmentation developing secondary to prior skin inflammation. It is common in deeply pigmented skin, in particular, can affect any age, and shows no sexual predilection. PIH presents with slate-brown macules that develop on sites of inflammatory lesions or following trauma (Figs. 45.2A and B). They are characterized by disruption of the basal layer. PIH can also result from increase in the production and transfer of melanin to surrounding keratinocytes stimulated by various inflammatory mediators [such as leukotrienes, prostaglandins, tromboxane-2, IL-1, IL-6, tumor necrosis factor-α, epidermal growth factor, and reactive oxygen species].52 Albeit rarely, preceding lesions may not be noticed by the patient and the hyperpigmentation may be the initial presenting sign. The clinical pattern may show the characteristics of the culprit dermatosis. Histological examination shows pigmentary incontinence with melanophages within the upper dermis. Colloid bodies may be seen at the dermo-epidermal junction as an evidence of a burnt out lichenoid reaction. The first line treatment includes management of the underlying cause and sun protection. Topical treatments such as those used for melasma may be tried as well as skin peels and lasers (see Treatment for melasma). The

Chapter 45: Disturbances of Melanin Pigmentation

A

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Figs. 45.3A and B: Erythema dischromicum perstans. Grey blue hyperpigmented macules on the face and neck.

B Figs. 45.2A and B: Postinflammatory hypermelanosis. Brown macules present at the sites of inflammatory acne in this adolescent male, on the upper back (A) and right shoulder (B). Courtesy: Dr. Babar K Rao, MD, New York, USA.

pigmentation usually lightens and resolves spontaneously for 6–12 months and rarely over several years.

Erythema Dischromicum Perstans (Ashy Dermatosis, Dermatosis Cenicienta, Erythema Chronicum Figuratum Melanodermicum, Idiopathic Eruptive Macular Pigmentation) Erythema dyschromicum perstans (EDP) is an asymptomatic idiopathic progressive gray-blue macular hyperpigmentation. It was first described in 1957 by Ramirez 53 in Salvadorans and is most common in young adults from Latin American or Asian origin. There is a slight female

preponderance. Prepubertal children can be affected as well but, unlike adult patients, children with EDP are usually Caucasians.54 It is proposed that the term EDP be used for lesions with inflammatory borders and ashy dermatoses for those without. The etiology of EDP is unknown, although some authors regard it as a variant of lichen planus actinicus. Association with endocrinopathies, ingestion of ammonium nitrate, treatment with dithiazide iodide, an X-ray contrast exposure, vitiligo, human immunodeficiency virus infection, and chronic hepatitis C have been reported. Genetic susceptibility related to HLA-DR4 subtype *0407 can play a role in Mexican Mestizos and the Amerindians.55 EDP presents with a slow onset of asymptomatic variably sized, oval or polygonal, gray-blue hyperpigmented macules symmetrically involving the trunk, proximal extremities, face, and neck (Figs. 45.3A and B). Early lesions have an erythematous and slightly elevated border which disappears within several months. The lesions progress slowly to extend peripherally and become confluent. The palms, soles, scalp, nails, and mucous membranes are usually spared. Rare patients may experience pruritus. Histopathological examination reveals prominent pigmentary incontinence with abundant melanophages and perivascular lymphohistiocytic infiltrate. The inflammatory border shows in addition interface changes with vacuolization of the basal cells, occasional colloid bodies, and more prominent lymphocytic infiltrate. Ultrastructural studies show immature, small melanosomes in melanocytes, and peripheral localization of melanosomes in keratinocytes.56

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Section 14: Pigmentation Disorders Treatment is largely unsatisfactory. Clofazimine 100  mg/day for 3 months and then reduced to 400  mg/ week is a first line management. Second line treatments include dapsone 100 mg/day for 3 months, oral or topical corticosteroids, or narrow-band UVB. Slow but irreversible progression is the regular course of the disease. Spontaneous resolution is unlikely in adult patients, but in prepubertal children, the lesions are most likely to resolve within 2–3 years.

Drug-induced Hypermelanosis Drug-induced pigmentary changes may be classified into three groups: hyperpigmentation/hypermelanosis, hypopigmentation/leukoderma, and dyspigmentation or unusual skin color. A large number of drugs can induce generalized or localized hyperpigmentation, and drugs are the cause of 10%–20% of all cases of acquired hyperpigmentation.57 The underlying pathogenic mechanisms include increased melanin synthesis, increased lipofuscin synthesis, deposition of specific drug-related material or hemosiderin and PIH. Specific clinical features to suggest drug-related etiology are not present. Pigmentation may develop several weeks to months after treatment and is usually reversible.

Amiodarone Amiodarone is used for the treatment of cardiac arrhythmias. Slate-gray or purple discoloration is seen in 6 months. The sun-exposed areas, in particular the face, nose, and ears are most commonly affected. Corneal pigmentation may occur earlier. The risk is higher with type 1 skin, dosages >800  mg/day, and the onset of an early photosensitivity on light-exposed areas.58 The supposed mechanism is accumulation of amiodarone and lipofuscin in the dermal macrophages. Slow but complete reversal of the pigmentation over several months or years is seen after drug discontinuation.

Antimalarials About 25% of patients on one of the most commonly used antimalarials [chloroquine, hydroxychloroquine, mepacrine (quinacrine), and mefloquine] for ≥4 months develop a blueish gray to dark purple pigmentation. The lesions affect mainly the anterior aspect of the lower legs (similar to minocycline) but may also involve the nail bed (diffuse pigmentation or transversal bands), the head and the oral

mucosa, especially the hard palate, cartilage, trachea, or joints. Clinically, there are macules that coalesce progressively into larger patches or diffuse pigmentation on the sunexposed areas with prolonged treatment. Lemon-yellow pigmentation is specific to mepacrine and may extend to involve the mucous membranes simulating jaundice. Hypopigmentation of hair can develop and, in combination with skin hyperpigmentation, is a clue to the diagnosis. Histological examination reveals increase of melanin and deposition of hemosiderin in the epidermis and dermis. The pigmentation usually fades away after treatment discontinuation, but the process may take several months.

Cancer chemotherapeutic agents Numerous cytotoxic and other therapies for cancer may induce cutaneous and mucosal hyperpigmentation of various patterns. The underlying pathogenetic mechanisms are generally unknown. Please refer to Table 45.1 for more specific information about selected agents.

Tetracyclines Tetracyclines, minocycline in particular, are associated with hyperpigmentation as a common adverse effect. Minocycline causes hyperpigmentation with long-term use in about 3%–5% of all patients. The changes become apparent after months of treatment, and the risk increases with excessive sun exposure and higher cumulative doses. Four types of pigmentation are recognized: (1) blue-black pigmentation of scars and sites of inflammation due to hemosiderin and/or iron chelate dermal deposition; (2) blue-gray pigmentation of normal skin on the extremities (anterior shins most commonly) due to deposition of melanin and iron-containing granules in the dermis and subcutis; (3) generalized brownish hyperpigmentation with more pronounced pigmentation on sun-exposed areas due to increased basal layer melanin; (4) hyperpigmentation of the vermilion area of the lower lip.57 Minocycline may cause pigmentation of other tissues including cartilage, bones, sclera, conjunctiva, tympanic membrane, pinna, lung, breast, thyroid, aorta, and lymph nodes.57 Tetracyclines are associated with brown pigmentation of the teeth in children. Hence, they should not be used before the age of 9. Discontinuation of treatment usually results in gradual fading of the pigmentation, although in some cases, usually in types 3 and 4 pigmentation, it may become

Chapter 45: Disturbances of Melanin Pigmentation Table 45.1: Chemotherapeutic agents that cause dyspigmentation. Drug Clinical features • Generalized hyperpigmentation Bleomycin59 • Flagellate hyperpigmentation after minor trauma • Transverse melanonychia • Hyperpigmentation over pressure points, joints or in scars Busulfan • Generalized hyperpigmentation Capecitabine, tegafur60 • Acral pigmentation (diffuse, along the crease lines, or macular over the palms and soles, tongue) Cisplatin, • Localized or patchy hyperpigmentation over the carboplatin60,61 dorsal surfaces of the hands and feet, elbows and knees, and operative incisions • Hair, nails, and oral mucosa hyperpigmentation Cyclophosphamide60,62 • Generalized hyperpigmentation of skin and mucosa • Localized hyperpigmentation of nails, palms and soles, teeth, and gingiva Cytarabine63 • Reticulate and/or linear hyperpigmented streaks • Generalized cutaneous hyperpigmentation Daunorubicin64 • Hyperpigmentation on sun-exposed areas • Transverse melanonychia Doxorubicin65 • Diffuse blue-gray skin pigmentation • Pigmentation of the oral mucosa and tongue • Transverse melanonychia Eltrombopag66 • Gray pigmentation on the face, arms, and legs • Generalized skin pigmentation Hydroxyurea57,67 • Localized pigmentation over pressure points • Transverse melanonychia Ifosfamide60 • Hyperpigmentation in the flexural areas, on the hands, feet, and scrotum, and under occlusive dressings • Diffuse hyperpigmentation Imatinib68,69 (Figs. 45.4A and B)

Paclitaxel63 Pemetrexed70 5-Fluorouracil60

• Hard palate pigmentation • Melasma-like pigmentation of face and forearms • Diffuse hyperpigmentation • Hair and nail pigmentation • Reticulate and/or linear hyperpigmented streaks • Hyperpigmentation of palms and soles • Serpentine supravenous hyperpigmentation from hand to shoulder • Widespread reticulate hyperpigmentation • Serpentine streaks in the back and buttocks • Acral pigmentation • Diffuse melanonychia, transverse bands

Outcome Develops 24 h to 6 months after treatment Usually complete resolution within 6 months to a year after treatment discontinuation

Usually complete resolution after treatment discontinuation Complete resolution after treatment discontinuation Develops in 70% of patients This risk increases with subsequent courses

Complete resolution 6–12 months after treatment discontinuation

Complete resolution after treatment discontinuation Complete resolution within weeks to months after treatment discontinuation Stable during the treatment

Can occur after a single course or many months of therapy Unpredictable outcome—may fade during treatment continuation or persist after treatment discontinuation Persistent

Partial or complete resolution after treatment discontinuation. Complete resolution with treatment discontinuation Can develop after sun exposure or after several days of therapy May fade gradually over time, and may not recur in subsequent courses

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persistent. Q-switched lasers such as the Q-switched ruby, alexandrite, and Nd–YAG are helpful in cases when treatment is needed.

95%75 of patients with Addison’s disease and results from increased levels of MSH due to the interruption of the feedback inhibition of the hypothalamus and the anterior pituitary gland. Hyperpigmentation is a hallmark, but not universal, sign of Addison’s disease and often helps with the diagnosis. It is typically diffuse with accentuation over the sun-exposed areas and affects the skin and mucous membranes. Darkening of the naturally pigmented areas (such as nipples, axillae and genitalia) is also seen. Increased pigmentation over the palm creases may be the initial presenting sign.76,77 Longitudinal melanonychia is a rare presenting sign.78 Other dermatological signs of Addison’s disease include vitiligo and loss of pubic and axillary hair in women.75 Detailed evaluation of the adrenal function is warranted in patients with diffuse and unexplained hypermelanosis. Management should be instituted accordingly. Replacement therapy with glucocorticoids and mineralocorticoids results in reversal of the hyperpigmentation.77

Miscellaneous

Others

Clofazimine: This synthetic riminophenazine dye, used for the treatment of leprosy and atypical mycobacterial infections, causes initial red-blue and then violet brown to blue-gray discoloration of the skin at the sites of inflammation. Reversible hair darkening can be seen with high doses.71 The main mechanism is drug accumulation in melanophages and the subcutis. Topical prostaglandin analogues (latanoprost, bimatoprost, and travoprost), used for the treatment of open-angle glaucoma and more recently for lashes enlargement, may cause perioral and/or conjunctival pigmentation on about 1% of patients.72,73 Complete resolution is seen 3–12 months after treatment discontinuation. Other drugs reported to cause hyperpigmentation of various patterns include antipsychotics, rifampicin, dapsone, isoniazid, hydantoin, barbiturates, adalimumab.74

Addisonian pattern of hyperpigmentation may also be seen in patients with acromegaly, Cushing syndrome, hyperthyroidism, and in patients on adrenocorticotropic hormone (ACTH) therapy.

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Figs. 45.4A and B: Melasma-like pigmentation of the face (A) and forearms (B) secondary to treatment with Gleevec (imatinib mesylate). Courtesy: Dr. Babar K Rao, MD, New York, USA.

Hyperpigmentation in Systemic Diseases Endocrine Addison’s disease Adrenal insufficiency was first described by Addison. The main insult is non-specific autoimmune destruction in developed countries or infection in the developing countries. Hyperpigmentation is seen in about

Neoplastic Increased pigmentation may be an associated, albeit inconstant, feature of various malignancies. It may be diffuse or localized and epidermal or dermal. The mechanism is unknown, but there may be an increase in the circulating MSH from physiological or paraneoplastic origin. Oat-cell carcinoma of the bronchus may release MSHlike or ACTH-like peptides resulting in ectopic ACTH syndrome. Clinically, the hyperpigmentation can be either diffuse or of the acanthosis nigricans type. Mucous membranes are commonly involved. Diffuse melanosis cutis (DMC) or diffuse dermal melanosis is a rare presentation of metastatic melanoma characterized by a progressive blue-gray pigmentation of the skin and mucous membranes.79 It is a poor prognostic factor and the mean time to death following the onset of DMC is about 4 months. Melanuria may be an associated finding. Free melanin, melanin precursors, and melanosomes are released into the circulation following cytolytic breakdown of melanoma metastases. Melanin is deposited

Chapter 45: Disturbances of Melanin Pigmentation in the dermis as perivascular deposits and in interstitial melanophages. Other neoplastic processes that may be associated with hyperpigmentation include cutaneous T-cell lymphoma, CD30+ lymphoproliferative disorders, carcinoid syndrome, and pheochromocytoma.

Connective Tissue Diseases Various patterns of hyperpigmentation can be seen in systemic sclerosis (SSc) including diffuse generalized hyperpigmentation of Addisonian type without involvement of the mucous membranes, focal depigmentation with perifollicular hyperpigmentation resembling vitiligo, localized hyperpigmentation in sclerotic areas, streaky hyperpigmentation over blood vessels, and reticulated hyperpigmentation.80 Keratinocyte derived endothelin-1 production and local expression and systemic release of stem cell factors might play a role in the development of diffuse hyperpigmentation in patients with severe SSc.80,81 Diffuse pigmentation can be seen in dermatomyositis and lupus erythematosus (LE). Localized hyperpigmentation may be the only presenting sign of dermatomyositis.82 Oral pigmentation83 or longitudinal melanonychia84 may be an additional feature of LE. Cutaneous hyperpigmentation is also seen as a side effect of hydroxychloroquine treatment in about 10%–25% of patients.85

Nutritional Deficiencies Nutritional deficiencies may cause either a diffuse, Addisonian type, hyperpigmentation or localized welldefined patchy pigmentation predominantly involving the face, neck, and trunk. Vitamin B12 deficiency: Patients with vitamin B12 deficiency develop skin changes in about 40%, with about 20% developing hyperpigmentation.86 It is usually generalized with accentuation on the dorsal surfaces of the palms and soles, in flexural areas, and the oral cavity. Areas of pressure may show more intense pigmentation as well.86 Nails and white hair can be affected.87 Replacement therapy reverses the hyperpigmentation over several months. The underlying mechanism for pigmentation is not fully understood. Histological examination shows increased melanin in the basal layer of the epidermis. Electron microscopy studies show an increased number of melanosomes in both melanocytes and surrounding keratinocytes suggesting an underlying increased melanin

synthesis.88 Cobalamin also decreases the level of the tyrosinase inhibitor reduced-type glutathione.89 Other nutritional deficiencies that may present with hyperpigmentation include pellagra, Vitamin A deficiency, and folate deficiency. Kwashiorkor can lead to hair pigmentation.90 Brown pigmentation over the bony prominences can be seen in marasmus and indicates poor prognosis.91

Metabolic Disease Hemochromatosis Hemochromatosis is a hereditary disease characterized by excessive iron absorption and deposition in the parenchymal cells of various tissues. The commonest mode of transmission is autosomal recessive and is due to mutations in the HFE gene. Clinical symptoms usually develop in the fifth decade of life or later and include hepatic cirrhosis, diabetes, cardiac abnormalities, arthritis, and diffuse hyperpigmentation. The hyperpigmentation is bronze or bluishgray and initially involves the sun-exposed areas. Mucous membranes and conjunctivae are affected in up to 20% of all patients. Other dermatological manifestations include alopecia, pruritus, localized ichthyosis, and koilonychia.92 Cutaneous hyperpigmentation develops via two mechanisms: (1) hemosiderin deposition and (2) increased production of melanin in the epidermis.92 Treatment with phlebotomy or iron chelators usually improves the hyperpigmentation.

Others Several neurological diseases can show diffuse hyperpigmentation including Wilson disease, ependymomas and adrenoleukodystrophy. Hyperpigmentation with intensification on sunexposed skin and diffuse hyperpigmentation of mucosal surfaces is usually seen in patients with end stage renal disease. The frequency increases with the duration of dialysis. These patients have reduced renal clearance and, hence, increased serum levels of MSH. Urochrome pigments and carotenoids deposition in the epidermis may also play a role.93

Exogenous Pigment Deposits in the Skin Ochronosis Ochronosis is blue-black pigmentation of tissues, including the ear cartilage, the skin, and the eye, seen

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Section 14: Pigmentation Disorders in alkaptonuria or after exposure to various substances such as phenols, trinitrophenol, resorcinol, mercury, picric acid, benzene, HQ, and other antimalarials. The inherited form (alkaptonuria) is a rare autosomal recessive disorder (1 in 250,000 to 1 million) of the tyrosine and phenylalanine metabolism, mainly due to homogentisic acid oxidase enzyme deficiency.94 Ochronotic pigment is deposited on sun-exposed areas such as the face and dorsal aspects of hands, cartilaginous regions (helices of the ears, nose), areas rich in sweat glands (armpits and groin), and nails. In the exogenous form, the pigment deposition corresponds to the area of exposure. Systemic involvement has been reported in alkaptonuria, including ochronotic arthropathy (axial and peripheral joints) and cardiovascular changes (stenosis and calcification of the aorta and mitral valves).95,96 Homogentisic acid levels may be estimated in the urine and blood by the gas–liquid chromatography method.97 Early detection is possible as dark urine can be seen in the diapers, or there may be blue-black staining of clothes from perspiration during adolescence.97 Skin biopsy taken from a lesion shows yellowish brown ochronotic pigment in globules with a characteristic “banana shape” in the dermis or within the vessel wall endothelium, eccrine sweat glands, or in the macrophages. Alkaptonuria progresses slowly, and there is no effective treatment. High doses vitamin C and E may be used in combination with a low-protein diet poor in tyrosine and phenylalanine.95,96 Early diagnosis and follow-up are essential to prevent cardiovascular involvement and ochronotic arthropathy.

The pigmentation is reversible and fades within about 2 months of treatment discontinuation.

DISORDERS OF HYPOPIGMENTATION Hereditary or Genetic Oculocutaneous Albinism Albinism (albus meaning white in Latin) comprises a group of rare Mendelian disorders characterized by generalized dilution of pigmentation due to defects in the melanin biosynthesis within melanocytes of the skin, hair follicles, and eyes with an onset at birth.100 The number and structure of epidermal, ocular, and follicular melanocytes are normal. The two main categories of albinism are oculocutaneous albinism (OCA) and ocular albinism (OA). Seven distinct forms of OCA are now recognized, all inherited in autosomal recessive pattern and caused by mutations in seven different genes. OCA types 1–7 affect the skin, hair follicles, and eyes (Table 45.2).101 OA primarily affects the retinal pigment epithelium, while skin and hair may appear similar or slightly lighter than that of other family members. The amount of reduction in melanin pigment can vary depending on the type of albinism.

Epidemiology OCA is the most common inherited disorder that leads to diffuse hypomelanosis. Albinism occurs in all racial and ethnic groups throughout the world. The global frequency is 1:20,000 people; however, in some African tribes, it is as high as 1:1,500 people.102,103 OCA types 1 (40% of patients) and 2 (50% of patients) are the most common types of OCA.104 Most children with albinism are born to parents who have normal hair and eye color for their ethnic background.

Carotenoderma β-carotene and vitamin A cause localized or generalized orange or deep yellow pigmentation of skin (carotenoderma). Palms, soles, nose, and nasolabial folds are particularly affected. β-Carotene is found in food products and in various medications. High β-carotene intake or hyperlipidemia in patients with diabetes mellitus and hypothyroidism or impaired conversion of carotene to vitamin A in patients with hypothyroidism or liver disease may lead to carotenemia with resultant carotenoderma. Drugs associated with carotenoderma development include trastuzumab, sorafenib, and sunitinib.98 Familial carotenoderma resulting from inborn error of metabolism can occur as well, albeit very rarely.99

Table 45.2: Types of OCA and the affected genes and their chromosomes. Types of OCA Gene Chromosome OCA1A TYR 11q14.3 OCA1B TYR 11q14.3 OCA2 OCA2 15q12–q13.1 OCA3 TRP1 9p23 OCA4 SCL45A2 5p13.2 OCA5 n.d. 4q24 OCA6 SLC24A5 15q21.1 OCA7 C10orf11 10q22.2–q22.3 (n.d.: not defined)

Chapter 45: Disturbances of Melanin Pigmentation

Pathogenesis and clinical features OCA type 1: Patients with OCA1 have an autosomal recessive inheritance pattern. In patients with OCA1, the melanogenic enzyme tyrosinase retains too long within the lumen of the ER within melanocytes; therefore, tyrosinase is destroyed by proteasomes, and melanin biosynthesis is stopped.105 There are two clinical subtypes of OCA1, based upon whether tyrosinase activity is reduced (OCA1B) or absent (OCA1A). OCA1A is the most severe form. It is characterized by complete absence of tyrosinase activity due to a mutation of its encoding gene (TYR), which has been mapped at chromosome 11q14–21. Due to a completely inactive tyrosinase in OCA1A, the melanocytes of the skin, hair, and eyes synthesize neither eumelanin nor pheomelanin throughout life. The skin, hair, eyelashes, and eyebrows are white, irides are completely translucent.106 OCA1A characteristic phenotype includes white hair, pinkish skin, and red pupils at birth. OCA1A phenotype provides an example of the role of eumelanin in protection against UV radiation. These patients have an extreme cutaneous and ocular sensitivity to trivial amounts of UV radiation. The skin does not have ability to tan. Amelanotic nevi may be present. With age, the hair may develop a slight yellow tint due to denaturing of hair keratins. Reduced visual acuity (≤1/10 with intense photophobia) is most severe in OCA1A, and some patients are legally blind.107 In patients with OCA1B, tyrosinase activity is greatly decreased but not completely absent. Therefore, some pigment formation (pheomelanin) is produced in OCA1B as pheomelanin is less dependent on tyrosinase activity than eumelanin. One of the characteristic OCA1B phenotypes is called “yellow albinism” because of yellow hair pigment in the first few years of life. These patients progressively accumulate cutaneous, ocular, and follicular pigment throughout life. Other clinical types of OCA1B have been referred to as “minimal pigment OCA,” “platinum OCA,” and “temperature-sensitive OCA.”107 All of these patients have little or no pigment at birth, but they develop some pigmentation of the hair and skin during the first and second decades of life. The majority burn without tanning after sun exposure, and some degree of iris translucency is often present. Amelanotic or pigmented melanocytic nevi can develop. In the temperature-sensitive OCA1B phenotype, patients have white hair and skin and blue eyes at birth. At puberty, scalp and axillary hairs (warmer areas of the body) remain white, whilst hairs at extremities turn progressively dark brown. A missense mutation in the

tyrosinase gene of these patients causes one amino acid replacement which makes the enzyme temperature-sensitive, losing its activity above 35°C. As a result, melanin synthesis does not occur in warmer areas of the body skin.107 OCA type 2: OCA2 is due to mutations in the OCA2 gene within the region of chromosome 15q12–q13.1. It encodes a P protein that is a melanosomal membrane transporter with roles in vacuolar accumulation of glutathione and regulation of melanosomal pH; dysfunction of the P protein can also lead to abnormal processing and trafficking of tyrosinase within melanocyte. Amos et al. have confirmed an association of two single-nucleotide polymorphisms (SNPs). The SNP alleles of OCA2 are associated with an elevated risk of melanoma and with gray/blue pigmentation of eyes’ irides.105 The OCA2 phenotype corresponds to the classic “tyrosinase-positive” OCA. The phenotypes of OCA2 are variable ranging from minimal to moderate pigmentary dilution of the hair, skin, and iris, with little to no ability to tan. The vast majority of individuals of African descent who have “tyrosinase-positive” OCA have OCA2.108 Hair color is usually not completely white, and there can be some pigment present in the skin, but skin color is usually lighter than in unaffected relatives. With time, pigmented melanocytic nevi and lentigines may develop in individuals with extensive sun exposure. This does not occur with other types of OCA. Another phenotype called “brown OCA” has only been reported in individuals with African ancestry. In these individuals, the hair and skin are light brown, the irides are gray at birth, and sunburns are unusual. Visual acuity is better than in OCA1 and can reach 3/10.107 OCA type 3: OCA3 results from mutations in the TRP1 gene located at chromosome 9p23. Patients with OCA3 have total absence of the melanogenic enzyme TRP1 which is required to stabilize tyrosinase.105 The phenotype of individuals with OCA3 is classified as “rufous” (vast majority of OCA3 patients) and “brown” (more often seen in OCA2). Rufous OCA has been identified in individuals with phototypes III–V. Among Africans, OCA3 affected patients have red to reddish-brown skin, ginger or reddish hair, and hazel or brown irides. Rufous OCA is associated with mutations in the TRP1 gene. A patient with the brown OCA phenotype due to mutations in both copies of the TRP1 gene has also been described: an African-American child with light brown skin, light brown hair, and blue-gray irides. Both hair and skin pigmentation increases with age. Vision problems are not as severe as OCA1 or OCA2. Nystagmus and photophobia may not be present.107

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Section 14: Pigmentation Disorders OCA type 4: A fourth type of OCA (OCA4) was identified more recently. The gene involved solute carrier family 45 member 2 (SLC45A2), encodes a transmembrane transporter protein with roles in tyrosinase processing, and intracellular trafficking of melanosomal proteins. The clinical phenotype of OCA4 is very similar to that of OCA2 patients. OCA4 was initially identified in an individual of Turkish origin and has been found in Asian populations including Japanese (25% of patients) and Korean individuals. PCA4 albinism is rare in Caucasian patients. The phenotype of OCA4 displays a highly variable phenotype regarding pigmentation, from just similar to OCA1A to near normal, among Japanese patients.109,110 Hair color of affected individuals can range from yellow to brown, and patients may or may not develop increased pigmentation of the skin and hair over time.

Ocular albinism OA is genetically heterogeneous. The most common form of OA is an X-linked recessive disorder—OA1 caused by mutations in the G protein-coupled receptor 143 (GPR143) gene, which encodes a pigment cell-specific intracellular G protein-coupled receptor that regulates melanosome formation and transport within melanocytes and cells of the retinal pigment epithelium. Mutations in GPR143 that lead to OA can result in retention of the aberrant protein within the endoplasmic reticulum. OA1 is characterized by a substantially reduced visual acuity, hypopigmentation of the retina, and the presence of macromelanosomes in the eyes. Affected boys have nystagmus, photophobia, and foveal hypoplasia. Their skin is usually clinically normal without notable pigmentary dilution, although hypopigmented macules have been described in affected individuals who have darkly pigmented skin. Macromelanosomes are evident on histologic examination of the skin. Autosomal recessive OA actually represent OCA1B or OCA2 but with subtle cutaneous findings.111 OCA types 5–7: OA5–7 were recognized in humans in 2012 and 2013 with mutations on three additional causative genes. Recently, Kausar et al. have identified OCA phenotype linked to a gene on human chromosome 4q24 that represents a genetic cause of OCA5. The underlying gene causing OCA5 has not yet been identified. Candidate genes within the linkage interval included members of the solute carrier protein family (i.e., SLC9B1, SLC9B2, and SLC39A8) and proteins known to be associated with lysosomes (i.e. MANBA), among other putative candidates.112 OCA5 patients have golden-colored hair, white skin, and visual disturbances including nystagmus, photophobia,

foveal hypoplasia, and impaired visual acuity, regardless of their sex and age. In addition, two new genes have been identified as causing OCA when mutated: SLC24A5 and C10orf11, and hence designated as OCA6 and OCA7, respectively.111 Currently, OCA6 is one of the rarest forms of OCA generally characterized by light hair color at birth that darkens with age, white skin, iris transillumination, photophobia, fovea hypoplasia, reduced visual acuity, and nystagmus. Wei et al. have found that mutations in SLC24A5, encoding a cation exchanger on melanosomal membranes required for the homeostasis of melanosomes, are associated with a new form of OCA, defined as OCA6.113,114 SLC24A5 mutations have been detected in patients of diverse ethnic origins.115 The lack of SLC24A5 may impair or disrupt normal melanin biosynthesis.116 In 2013, Grønskov et al. identified C10orf11 gene in a consanguineous Faroese family. The precise function of C10orf11 gene has not been elucidated till date. However, there is some evidence that it may play some role in melanocyte differentiation.116 Affected individuals present lighter skin pigmentation than their relatives, but ocular manifestations are predominant with nystagmus due to chiasmal misrouting of the optical pathways, iris transillumination, and reduced visual acuity ranging from 6/9 to 3/60. Hair color varies from light blond to dark brown. This new type of OCA has been termed OCA7.116

Ocular manifestations The many ocular manifestations of OA and OCA reflect a reduction in melanin within eye structures or misrouting of optic nerve fibers during development. A reduction in melanin within eye structures leads to reduced iris pigment with iris translucency that transmits light upon globe transillumination, as well as reduced retinal pigment and foveal hypoplasia that are associated with photophobia and substantial reduction in visual acuity. The severity of these findings correlates with the amount of melanin present in the eye.117 Vision acuity is usually better in those individuals with greater amounts of pigment. OCA1A patients have the most severe form of retinal damage including choroid blood vessel obstruction and shortening of the rod outer segments. The characteristic strabismus, horizontal and rotatory nystagmus, and reduced stereoscopic vision are caused by partial misrouting of the optic nerve fiber radiations at the chiasm during embryogenesis. This defect is not due directly to the absence of tyrosinase but is a consequence of a lack of l-DOPA, an intermediate early metabolite of the synthesis of melanin (or one of its derivatives), that is the only requirement to allow the retinal and visual development to proceed normally.118

Chapter 45: Disturbances of Melanin Pigmentation l-DOPA was subsequently described to be the ligand for the GPR143 receptor, which is associated with OA1.119 The involvement of tyrosinase, which catalyzes conversion of tyrosine to l-DOPA and to DOPAquinone in neuromelanin synthesis, has been proposed by some authors but denied by others.120–122 Albinos that lack tyrosinase, however, have a normally pigmented substantia nigra. The precursors and biochemical pathways involved in neuromelanin synthesis need to be identified to further elucidate the normal cellular role of this pigment.

UV-induced Skin Cancers OCA patients are highly susceptible to UV-induced skin cancer. It was suggested that OCA1A patients will have a lower risk factor of developing skin cancer as compared to other OCA types.123 OCA1 patients lack tyrosinase which is an obligatory enzyme for biosynthesis of both types of melanin—eumelanin and pheomelanin. Patients with partial loss of tyrosinase function do have an ability to produce pheomelanin. Pheomelanin promotes the production of oxidative free radicals with a well-known damaging effect on DNA that leads to skin cancer. Since OCA1A patients do not synthesize pheomelanin, the risk to produce UV-induced oxidative free radicals is lower.125 Another argument that OCA1A patients may be less vulnerable to skin carcinoma comes from the comparison with vitiligo. A negative correlation between vitiligo and skin cancer has been reported.125

Diagnosis The diagnosis of OCA1 is established by clinical findings of profound depigmentation of the skin and hair and characteristic ocular findings, but clinical phenotype of different types of OCA is not always distinguishable, making molecular diagnosis a useful tool and essential for genetic counseling.100 Molecular genetic testing of TYR (encoding tyrosinase) is used infrequently in diagnosis, except to distinguish between types 1A and 1B, as the phenotypes may be nearly identical in the first year of life. A substantial fraction of patients with albinism (approximately 20% of patients investigated) routinely remain molecularly unresolved, because only one mutation is found, or no mutations are found in any of the known genes.110 Histological examination reveals reduction in the deposited melanin in the epidermis with a normal number of melanocytes.

Differential diagnosis The majority of disorders associated with cutaneous, ocular, and follicular hypopigmentation have their onset at

birth or during infancy. The differential diagnosis includes several rare genodermatoses, such as Angelman, Prader– Willi, Chédiak–Higashi syndrome (CHS) and Hermansky– Pudlak syndrome (HPS). Approximately 1% of the patients with Angelman syndrome (AS) or port-wein stain (PWS) also have OCA2, which occurs when deletion of one copy of the P gene is accompanied by a mutation in the second copy. Unlike albinism, Angelman and Prader–Willi syndromes are characterized by intellectual disability. Patients with clinical presentation of OCA with additional systemic manifestations such as bleeding diathesis as well as interstitial pulmonary fibrosis and granulomatous colitis would suggest HPS, whereas bleeding diathesis, progressive neurologic dysfunction, and severe immunodeficiency would point to the CHS.126 There are several inherited disorders of amino acid metabolism with related hypopigmentation of skin, hair, and eyes with an onset at birth or during infancy such as phenylketonuria, histidinemia, and homocystinuria. In contrast to these disorders, patients with albinism have neither intellectual disability nor CNS abnormalities. Occasionally, patients with total body vitiligo and piebaldism may be thought to have OCA, but their epidermis lacks melanocytes. By comparison, patients with albinism have normal epidermal melanocyte number.126

Treatment There is no specific treatment available for albinism. Photoprotection and sun avoidance are mandatory in patients with OCA in order to avoid cutaneous photocarcinogenesis, in particular the development of squamous cell carcinomas.104 The latter are a significant cause of morbidity and mortality, especially in tropical regions. All patients should undergo ophthalmologic evaluation early in life, with longitudinal care as required. People with albinism are at risk of social isolation because the condition is often misunderstood. Social stigmatization can occur, especially within communities of color, where the race or paternity of a person with albinism may be questioned.127 Patients with OCA have normal lifespan, development, intelligence, and fertility.100

Vogt–Koyanagi–Harada Disease Vogt–Koyanagi–Harada disease (VKHD) is rare granulomatous systemic autoimmune disease which affects melanocyte-rich structures located in the eye, inner ear, meninges, skin, and hair.128 It was first described in 1906 by Alfred Vogt in a patient with premature whitening of eyelashes and bilateral subacute iridocyclitis and followed by report of a case series with bilateral serous

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Section 14: Pigmentation Disorders retinal detachment in association with cerebrospinal fluid (CSF) pleocytosis by Harada, while Koyanagi published a review article associating unequivocally the posterior eye involvement with auditory and integumentary manifestations.129 It has been more commonly reported in patients with pigmented skin such as Asians, Middle Easterners, Hispanics, and Native Americans. The disease is more frequent in females (female-to-male ratio is 2:1) in the second to fifth decades of life. It can frequently be unrecognized in children.130 Although its pathogenesis still remains uncertain, the mostly accepted theory is for a T-cell-mediated autoimmune reaction against antigens associated with uveal, dermal, and meningeal melanocytes in genetically susceptible individuals.128 Possible melanocyte antigens include tyrosinase- or tyrosinase-related proteins, an unidentified 75-kD protein obtained from cultured human melanoma cells (G-361), and S-100 protein.1321,132 Th1 and Th17 subsets of helper T cells together with the IL-7, IL-17, and IL-23 are most probably involved in the initiation and maintenance of the inflammatory process.133 Autoimmune pathogenesis of the disease is supported by the several HLA associations found in patients with VKHD, including HLA-DR4, HLA-DR53, and HLA-DQ4 and also with its association with other autoimmune disorders such as Hashimoto thyreoiditis, diabetes mellitus, psoriasis.134–136 Histopathological features of VKHD vary according to the stage of disease and affected organ. Histologic findings in the skin include subcellular abnormalities of melanocytes and cellular infiltrate composed of CD4+ T cells and melanophages.137,138 The disease is divided into four stages: (1) prodromal (dominance of neurologic signs and symptoms such as headache, confusion, neck stiffness, convulsions, paresis, aphasia, cranial nerve palsies, hemiparesis, optic neuritis, tinnitus, vertigo, hearing loss, and lymphocytosis in CSF), (2) acute uveitic (dominance of opthalmological, auditory symptoms, and meningeal involvement such as decreased visual acuity, anterior, and posterior uveitis with detachment of the retina, acute bilateral granulomatous iridocyclitis), (3) convalescent (skin and choroid depigmentation), and (4) chronic/recurrent (presence of ocular complications such as cataract, glaucoma, choroidal neovascularization, and retinal/choroidal fibrosis).128 Cutaneous clinical findings include vitiligo predominantly in sacral region, poliosis of the lashes, eyebrows, and scalp hair loss.139,140 Sugiura sign (perilimbal vitiligo) is the earliest depigmentation which occurs 1 month after the uveitic stage.141 Differential diagnoses include various infectious and non-infectious as well as inflammatory and non-inflammatory opthalmological disorders, other

inflammatory disorders such as sarcoidosis, lupus choroidopathy, leukemias, and lymphomas. Treatment of VKHD is focused on the ophthalmologic symptoms and is based on prescription of anti-inflammatory drugs such as corticosteroids antimetabolites, and biologics.

Alezzandrini Syndrome Alezzandrini syndrome is a rare disorder with features similar to Vogt–Koyanagi–Harada syndrome, first described by Alezzandrini and Casala in 1959.142 It is characterized by unilateral tapetoretinal degeneration with the ipsilateral appearance of facial vitiligo and poliosis, developing between 12 and 30 years of age. Hypoacusis is also described. Its etiopathogenesis still remains unclear; however, several theories involving viral or autoimmune factors have been suggested. Since melanocytes originate in the neural crest and then migrate to the skin, leptomeninges, retina, uvea, cochleae, and vestibular labyrinths, any disorder that destroys the melanocytes in the skin also affects other organs where melanocytes can be localized. Only six patients have been described in the English literature.143 Treatment options are limited to topical corticosteroids, intravitreal bevacizumab, and infliximab.144,145

Chediak–Higashi Syndrome Chediak–Higashi Syndrome (CHS) is a very rare autosomal recessive primary immunodeficiency disease, first described in 1943. Since then, around 200 cases have been reported worldwide, but mainly in Japan.146,147 The condition is due to mutations in the CHS1/LYST gene, located on chromosome 1q42–43, encoding the lysosomal trafficking regulator protein for the synthesis, transport, and fusion of cytoplasmic vesicles.148 Mutations of this gene result in the presence of enlarged and nonfunctional lysosomal granules mostly in granulocytes and monocytes, but also in fibroblasts, melanocytes, astrocytes, Schwann cells, and hematopoietic cells.149 These giant coalesced azurophilic granules are specific to CHS, and their presence in granulocytes from peripheral blood and bone marrow is essential for the diagnosis. 150 Skin is affected as there is impaired intracellular transportation of melanin and presence of giant melanosomes in the melanocytes which leads to partial OCA, fair skin, and silver hair. 151 Other clinical features include severe recurrent bacterial infections, hepatosplenomegaly, presence of large lysosomal-like organelles in most granule-containing cells, bleeding diathesis, horizontal and rotatory nystagmus, and late onset neurological

Chapter 45: Disturbances of Melanin Pigmentation manifestations (central and peripheral neuropathies, sensory loss, muscle weakness, parkinsonism, cerebellar ataxia, and cognitive impairment).146 Accelerated phase of the disease, characterized by pancytopenia, hemophagocytosis, and marked infiltration of organs by lymphocytes, is seen in 50%–85% cases, and it leads to multiorgan dysfunction.152 Early bone marrow transplantation is the treatment of choice before the accelerated phase.

Waardenburg Syndrome Waardenburg syndrome (WS) is a rare genetic disorder characterized by piebaldism and sensorineural deafness due to absence of neural-crest-derived melanocytes from the stria vascularis of the cochlea or due to failure of melanoblasts to migrate or survive.153 It was defined in 1951 by six main features: lateral displacement of the medial canthi combined with dystopia of the lacrimal puncta and blepharophimosis, prominent broad nasal root, hypertrichosis of the medial part of the eyebrows, white forelock, heterochromia iridis, and deafness.154 Mode of inheritance of WS is autosomal dominant for most patients with types 1, 2, or 3; type 4 is autosomal recessive with variable penetrance.155 The disease is classified into four types based on clinical and genetic criteria (Table 45.3). The estimated incidence in the general population is 1:42,000, and 1%–2% patients are congenitally deaf.156 Histological examination reveals absence of melanocytes in the inner ear and in hypopigmented patches; melanocytes with short dendrites with abnormal melanosomes can sometimes be found in unaffected skin.157 Several theories have been proposed to describe all clinical findings in WS, but none of them is complete: the association of WS and congenital

aganglionic megacolon supports the “deficient neural crest” theory, suggesting a developmental abnormality of the neural crest as a cause of the disease.158 Skin changes develop as a result of impaired melanoblast migration from the neural crest to the skin. Pigmentary abnormalities of skin can present as (1) achromic spots with sharply defined irregular borders and with hyperpigmented islands, and (2) hyperpigmented macules on normally pigmented skin that have been described as a “patchy skin” and give the cases of “dappled appearance.”159 The most common pigmentation abnormality present in WS1 is poliosis; other abnormalities include depigmented skin patches and pigmentary abnormalities of the iris, such as total heterochromia iridis, partial heterochromia iridis (variations of color within an iris), and hypoplastic blue irides106 (Fig. 45.5). Poliosis (white forelock) might be present at birth or develop later: it might persist throughout life or vanish in the first years of life and reappear in later age. It is localized at the forehead and medial eyebrows, but it can also be present posteriorly to the vertex or other part of the scalp. Pigmentary disturbances of the hair can also manifest as premature graying of scalp hair and of the eyebrows, cilia, or body hair.159 Irregularities associated with melanocytes characterize type 2: poliosis, depigmented white patches, heterochromia iridis, and congenital sensorineural deafness are common clinical findings. Patients with WS have normal life expectancy; morbidity is related to deafness and to defects of neural crest-derived tissues.

Menkes Kinky Hair Syndrome Menkes kinky hair syndrome is an X-linked recessive multisystem lethal disorder of copper metabolism caused

Table 45.3: Clinical and genetic criteria of different types of WS. Mode of Type inheritance Gene Dermatological findings 1 Waardenburg AD PAX3 Congenital piebald-like white patches in skin and hair AD, AR MITF, SLUG, Congenital piebald-like white 2 Waardenburg SOX10 patches in skin and hair (All above WS 1 features, except dystopia canthorum) 3 (Klein– AD, AR PAX3 WS1 findings Waardenburg) 4 (Shah– AD EDNRB EDN3 Congenital piebald-like white Waardenburg) patches in skin and hair Source: Adapted from Reference 106.

Other clinical findings Dystopia canthorum, heterochromia iridis, congenital deafness No dystopia canthorum, heterochromia iridis, frequent congenital deafness

WS1 findings + musculoskeletal abnormalities Congenital aganglionic megacolon (Hirschsprung disease)

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Section 14: Pigmentation Disorders Box 45.1: Dermatological findings in Menkes kinky hair syndrome.

Fig. 45.5: Waardenburg syndrome, presenting with partial, sectoral blue heterochromia iridis on the right, and complete blue heterochromia iridis on the left. Courtesy: Amer A Almohssen, MD, Detroid, Michigan, USA.

by mutations in the copper-transporting p-type ATPase (ATP7A) gene. This syndrome was first described by Menkes et al. in 1962 but was not before 1972 that the association with copper metabolism was established.160,161 ATP7A incorporates copper into copper-dependent enzymes, and it maintains intracellular copper levels by removing excess copper from the cytosol.162 Impaired intestinal copper transport is related to low serum copper and ceruloplasmin levels which lead to deficiency in copper-dependent enzyme activity such as tyrosinase (pigmentation of skin and hair), lysyl oxidase (elastin and collagen cross-linking), ascorbate oxidase (skeletal development), monoamine oxidase (possibly responsible for pili torti), superoxide dismutase (free-radical detoxification), dopamine β-hydroxylase (catecholamine production), peptidyl-glycine α-amidating mono-oxygenase (bioactivation of peptide hormones), and cytochrome c oxidase (electron transport and possibly responsible for hypothermia).163 The majority of patients are male with carrier or heterozygous mothers. Rarely, female patients may also be affected.164 It occurs in 1 in 100,000–250,000 births with higher incidence in Australia (1:50,000–100,000).165,166 The clinical presentations range from a severe clinical course leading to death in early childhood to a milder form (occipital horn syndrome) with connective tissue abnormalities and longer survival.164 Hypotonia, failure to thrive, and seizures usually present after birth. Clinical findings include dermatological (presented in Box 45.1), musculoskeletal deformities, cardiovascular findings, genitourinary findings, and central

Hair disorders (manifested soon after birth) • Pili torti (flattened hair shaft with clusters of narrow twists at irregular intervals) • Trichoclasis (“greenstick” fracture of the hair shaft, a transverse fracture splinted by an intact cuticle) • Trichoptilosis (longitudinal splitting of the distal end of the hair) • Trichorrhexis nodosa (formation of nodes along the hair shaft through which breakage occurs) • Shorter hair, thinner on sides, and occipitally • Hypopigmentation: white, silver, gray • Sparse, short, brittle, kinky, steel wool-like • Thin eyelashes • Thin, broken, horizontal eyebrows Skin findings • Sagging cheeks • Mottled (cutis marmorata pattern), hypopigmented, cutis laxa • Cupid’s bow upper lip

nervous system findings. On histology, there is decrease in the diameter of dermal collagen fibrils intermixed with amorphous elastin fibers. Trichogram shows twisting of hair along the longitudinal axis. This disorder usually has fatal course with death mostly occurring between 6 months and 3 years of age; patients with less severe disease have a better survival rate with copper supplementation which is effective in those cases where the mutated protein retains the ability to transport copper across the blood–brain barrier.164

Tuberous Sclerosis Tuberous sclerosis complex (TSC) is a genetic neurocutaneous disorder affecting cellular differentiation and proliferation, characterized by hamartoma formation in many organs (mostly in skin, brain, eye, kidney, heart).167 It was first described by Von Recklinghausen in 1862, and in 1908, Vogt proposed a triad typical for TS diagnosis consisting of epilepsy, intellectual disability, and “adenoma sebaceum” on the face.168 However, the full triad is seen in only 29% of patients; 6% of them lack all three of them.169 Mode of inheritance is autosomal dominant, although sporadic mutations occur in two thirds of the patients. One in 10,000 people in the general population and one in 6,800 in the pediatric age group are affected.169 The disease develops due to mutations in two tumor suppressor genes: TSC1 (located on 9q34, coding a protein named hamartin) or TSC2 (located on 16p13, coding a protein named tuberin).170 Hamartin and tuberin

Chapter 45: Disturbances of Melanin Pigmentation are responsible for the formation of a heterodimer, which suppresses cell growth and proliferation, named mammalian target of rapamycin (mTOR). Disorganized cellular overgrowth, abnormal cell differentiation, and the formation of tumors appear as a result of increased activation of mTOR kinase.171 In 1998, Tuberous Sclerosis Complex Consensus Conference established diagnostic criteria of the disease, presented in Box 45.2.172 Two or more different types of lesions, instead of multiple lesions of the same type in the same organ system, are required for the diagnosis of TSC. Dermatological manifestations of the disease are present in 70%–80% of the cases and are very important because some of these might even be present in the neonatal period, therefore providing early the diagnosis. The most characteristic skin lesions are angiofibromas, skin-colored telangiectatic papules, previously known by a misnomer, adenoma sebaceum. They are located on the face (nasolabial folds, cheeks, chin, forehead), scalp, and in and around nails (ungual fibromas). Bilateral facial papulonodular angiofibromas are considered as a primary or pathognomonic feature.173 These usually appear during or before puberty and should be differentiated from acne vulgaris, verruca Box 45.2: Diagnostic criteria for tuberous sclerosis complex.172 Major diagnostic criteria • Facial angiofibromas or forehead plaque • Non-traumatic ungual or periungual fibroma (≥2) • Hypomelanotic macules (≥3, ≥5 mm in diameter) • Shagreen patch (connective tissue nevus) • Multiple retinal nodular hamartomas • Cortical tuber • Subependymal nodule • Subependymal giant cell astrocytoma • Cardiac rhabdomyoma (single or multiple) • Lymphangioleiomyomatosis • Angiomyolipomas (≥2) Minor diagnostic criteria • Multiple, randomly distributed pits in dental enamel (>3) • Hamartomatous rectal polyps • Bone cysts • Cerebral white matter radial migration lines • Gingival fibromas (at least two) • Nonrenal hamartomas • Retinal achromic patch • “Confetti” skin lesions • Multiple renal cysts Definite diagnosis: two major features or one major feature with two or more minor features Possible diagnosis: either one major feature or two or more minor features

plana, syringomas, other benign appendageal tumors, and sarcoidosis. Forehead fibrous plaques are histologically classified as angiofibroma, although clinically they have fibrous appearance.174 These present in the neonatal period and represent the first skin lesion of TSC. Hypomelanotic macules, although found in 90%–98% of patients with TSC, are not a specific clinical feature.175 They are presented as ovoid, hypopigmented, ash leaf-shaped macules on the trunks or limbs. On histology, there is a reduction in the number, diameter, and melanization of melanosomes in melanocytes.176 Hypopigmented macules can also be seen on the extremities as “confetti lesions” and are one of the minor criteria. Shagreen patches are skin-colored soft plaques mostly found in the lumbosacral area with characteristic cobblestone surface with prominent follicular openings. Usually, they appear between the age of 5 and 14 years in 21%–80% of patients.177 Other dermatological signs include guttate leukoderma, CALMs, and poliosis. Due to the wide variety of clinical expressions, multidisciplinary approach is crucial for the treatment of these patients. The prognosis depends on the extent of involvement of internal organs.

Piebaldism Piebaldism is a disorder of melanoblast migration or its proliferation during embryonic development. Therefore, the clinical findings are related to the ventral part of the body. Piebaldism is due to mutations of the KIT protooncogene which encodes the cell surface transmembrane tyrosine kinase receptor for KIT ligand (mast-cell growth factor, stem-cell factor, steel factor); therefore, KITdependent signaling plays key roles in melanogenesis, gametogenesis, and early stages of hematopoiesis.178 Also, mutations in a zinc-finger neural crest transcription factor have been noticed in patients that lack mutations in the c-kit gene.179 The clinical findings are variable and depend on the site of the mutation within the KIT gene. Recently, two novel cases of piebaldism were described with a novel Val620Ala mutation in the KIT gene. These findings are in accordance with the hypothesis that progressive piebaldism might result from digenic inheritance of the KIT (V620A) mutation that causes piebaldism and a second unknown locus that causes progressive depigmentation.178 Disorders which might be present with piebaldism include Hirschsprung disease or aganglionic megacolon, NF1, congenital dyserythropoietic anemia type 2, DiamondBlackfan anemia, or transient acantholytic disease.180 On histology, there is decreased or absent melanin and/or

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Section 14: Pigmentation Disorders melanocytes in the hair bulbs of the affected hair follicles; the epidermal melanocytes are usually unaffected.181 Most of the patients are healthy with normal life expectancy. Due to comorbid diseases and the fact that piebaldism is one of the manifestations of WS, congenital leukoderma suggests the need for evaluation of ocular, auditory, and/or neurologic abnormalities.182 Dermabrasion and split-skin grafting, autologous punch grafting (in stable lesions), or autologous cell suspension transplantation are therapeutic options for management of skin lesions.183,184

Acquired Nevus Depigmentosus Nevus depigmentosus (nevus achromicus) is a congenital hypopigmented macule, stable in size and distribution, first described by Lesser in 1884.185 It is usually present at birth or detected in the first years of life. In most of the cases, this condition is limited to the skin, but rarely it might also be associated with unilateral limb hypertrophy, atopic dermatitis, seizures, intellectual disability, and abnormal systemic features.186 All races and genders can be affected. It is considered as form of cutaneous mosaicism, caused by the functional defects of melanocytes and the morphologic abnormalities of melanosomes.187 Clinically, nevus depigmentosus presents as a solitary hypopigmented macule with well-defined irregular borders that do not cross the midline, following the body growth and remaining stable thorough life. Usually it is localized on the trunk, neck, face, and proximal part of the extremities. Three types have been described: localized, segmental (following Blaschko lines), linear/whorled/ systematized (overlaps with hypomelanosis of Ito). The diagnosis can be made according to criteria proposed by Coup: (1) leukoderma present at birth/or early in life, (2) no alteration in texture or change in sensation in the lesions, (3) no alteration in localization of the lesion, and (4) no hyperpigmented border around the affected skin. Off-white accentuation without fluorescence is present under Wood’s lamp examination, in contrast to the chalkywhite accentuation with obvious bluish white fluores­ 188 cence observed in vitiligo patients. Histologic findings show either a normal or a decreased number of melanocytes, large reduction in the number of melanosomes and aggregated melanosomes of variable morphology, and normal size and degree of melanization of the melanosomes.188 Treatment is not necessary.

Hypomelanosis of Ito Hypomelanosis of Ito (HI) was first described by Ito in 1952.189 It is considered a neurocutaneous disease corresponding to a wide variety of trisomy mosaicisms.190 The incidence and prevalence of HI are reportedly one in 7,540 births and one in 82,000 individuals, respectively; it is 1.5– 2.5 times more common in women than in men.191 HI presents at birth with hypopigmentation along Blaschko lines, with pattern of streaks and whorls mostly on trunk and extremities.192 Skin lesions can be associated with abnormalities of CNS (epilepsy, intellectual disability, and psychomotor retardation), eyes or musculoskeletal system.193 Ocular anomalies include strabismus, epicanthal folds, and myopia. The musculoskeletal system is also frequently involved with a myriad of developmental defects. In addition, diffuse alopecia and nail and dental abnormalities have also been recorded. Histologically, skin lesions consist of decreased numbers of melanocytes, melanocytes exhibit shorter dendritic extensions and the number and size of melanosomes is decreased.194 The prognosis of the disease depends on the associated abnormalities.

Vitiligo Vitiligo is an acquired pigmentary disorder characterized by the appearance of progressively increasing circumscribed depigmented macules and patches due to a substantial loss of functioning epidermal and/or follicular melanocytes.195 It is the most common depigmenting disorder affecting 0.5%–1% of the world’s population, although it might be up to 8.8% in India.196,197 The disease is not age or sex related. Although the underlying mechanism of the disease is not completely elucidated, various pathogenetic theories have been introduced with emphasis on mutual effect of non-Mendelian, multifactorial, polygenic inheritance with alterations of cellular, and humoral immunity. The importance of autoimmunity in the etiology of vitiligo is backed by recently identified susceptibility genes which include melanocytic genes and genes involved in immune regulation and/or associated with other autoimmune disorders. The most frequently reported concomitant autoimmune diseases include thyroid disease (most frequently hyperthyroid), rheumatoid arthritis, psoriasis, adult-onset diabetes mellitus, Addison disease, pernicious anemia, alopecia areata, systemic LE, and atopic background.198 Also, the role of reactive oxygen species as inducers of inflammatory cascade has been proposed due to differences between melanocyte susceptibility to the oxidative stress

Chapter 45: Disturbances of Melanin Pigmentation

Fig. 45.6: Depigmented patches of segmental vitiligo on the trunk of a young child. Courtesy: Dr. Babar K Rao, MD, New York, USA.

between patients and unaffected individuals.199 Based on the distribution, vitiligo is classified as localized comprising unilateral depigmented macules following segmental (dermatomal) or focal (quasi dermatomal) pattern; generalized comprising acrofacial pattern involving face and distal extremities, and vitiligo vulgaris with widespread, usually symmetrically distributed lesions; universal vitiligo with complete or nearly complete depigmentation; and mucosal vitiligo presenting with typical depigmented macules exclusively on mucosal surfaces.200 Unilateral and segmental or band-shaped distribution, early involvement of the follicular melanocyte reservoir, early age of onset, and rapid stabilization characterize segmental vitiligo lesions (Fig. 45.6), while non-segmental vitiligo lesions are typically bilaterally distributed in an acrofacial pattern, or scattered symmetrically over the entire body, evolving over time.198 Diagnosis can be made clinically with visualization under

A

B

C

D

Figs. 45.7A to D: Vitiligo on a fair-skinned individual before (A) and after Wood lamp examination of the face (B and C) and elbows (D). Courtesy: Dr. Babar K Rao, MD, New York, USA.

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Section 14: Pigmentation Disorders Wood light or with biopsy (Figs. 45.7A to D). Histologically, the epidermal melanocytes are absent, and in the early inflammatory stages, there is a superficial band-like lymphocytic infiltrate.198 Various therapeutic options as topical corticosteroids, topical calcineurin inhibitors, topical vitamin D3 analogues, phototherapy (NB-UVB and PUVA), oral corticosteroids, antioxidants, laser and surgical therapy are currently used in vitiligo treatment.201 Unfortunately, most of these are off-label use (the only FDA-approved treatment for vitiligo is monobenzone) and without complete satisfactory therapeutic outcome. Targeted combination therapies in vitiligo are remarkably more effective than single treatments and mainly include topical and photo/laser ­therapy.202 Novel therapeutic approaches such as statins and Janus kinase inhibitor (based on inhibition of components of Th1 inflammatory response) as well as topical prostaglandin F 2aα and E2 analogues have been recently introduced

Box 45.3: Chemicals which cause development of leukoderma. • MBH • Hydroquinone • PTBC • PTBP • PTAP • MMH • MEH • p-Phenylphenol • p-Octylphenol • p-Cresol • Cysteamine • Sulfanilic acid • Cystamine dihydrochloride • Mercurials • Tretinoin • Arsenic • Benzoyl peroxide • Cinnamic aldehyde • Ammoniated mercury • PPD • Azelaic acid • Corticosteroids • Fluorouracil • Chloroquine • Brilliant lake red R • Soymilk and derived protein Thiotepa (MBH: monobenzyl ether of hydroquinone; MEH: monoethyl ether of hydroquinone; MMH: monomethyl ether of hydroquinone; PTAP: p-tert-amylphenol; PTBC: p-tert-butylcatechol; PTBP: p-tert-butylphenol) Source: Adapted from reference 209.

but their efficacy and safety still need to be confirmed with further studies.203–207

Chemical Leukoderma Chemical leukoderma (contact/occupational leukoderma) refers to acquired hypopigmentation caused by repeated exposure to specific chemical compounds simulating clinically idiopathic vitiligo.208 The first described culprit agent was monobenzylether of HQ by Oliver et al. in 1939 in a leather manufacturing company in workers who used “acid-cured” rubber gloves.209 Since then, different offending agents were described (Box 45.3). Etiological agents that cause chemical leukoderma are present ubiquitously: in cosmetic products (hair dye, deodorant and spray perfume, eyeliner, lip liner, lipstick, toothpaste), detergents and cleansers, black socks and shoes, rubber condoms, fur toys, insecticides, rubber footwear.210 Chemical leukoderma develops due to selective toxicity of certain environmental chemicals to melanocytes in genetically susceptible individuals.211 Although there are no histopathological criteria for differentiation between chemical leukoderma and vitiligo, the diagnosis is made clinically by a history of repeated exposure to a known or suspected depigmenting agent at the primary site, distribution of macules corresponding to chemical exposure, and the presence of numerous acquired confetti or pea-sized macules. Since chemical leukoderma develops not only at the site of chemical contact, but also remotely, it should be considered in the differential diagnosis of vitiligo.

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Section 14: Pigmentation Disorders 120. Xu Y. Tyrosinase mRNA is expressed in human substantia nigra. Brain Res Mol Brain Res 1997;45:159-62. 121. Tief K. New evidence for presence of tyrosinase in substantia nigra, forebrain and midbrain. Brain Res Mol Brain Res 1998;53:307–10. 122. Ikemoto K. Does tyrosinase exist in neuromelanin pigmented neurons in the human substantia nigra?. Neurosci Lett 1998;253:198–200. 123. de Vijlder HC, de Vijlder JJM, Neumann, HAM. Oculocutaneous albinism and skin cancer risk. J Eur Acad Dermatol Venereol 2013;27:e433–4. 124. Ress JL. The genetics of sun sensitivity in humans. Am J Hum Genet 2004;75:739–51. 125. Feily A, Pazyar N. Why vitiligo is associated with fewer risk of skin cancer? Providing a molecular mechanism. Arch Dermatol Res 2011;303:623–4. 126. Bolognia JL. A clinical approach to leukoderma. Int J Dermatol 1999;38:568–72. 127. Maia M, Volpini BM, dos Santos GA, et al. Quality of life in patients with oculocutaneous albinism. An Bras Dermatol 2015;90:513–7. 128. Lavezzo MM, Sakata VM, Morita C, et al. Vogt–Koyanagi– Harada disease: review of a rare autoimmune disease targeting antigens of melanocytes. Orphanet J Rare Dis 2016;11:29. 129. Lavezzo MM, Sakata VM, Morita C, et al. Vogt–Koyanagi– Harada disease: review of a rare autoimmune disease targeting antigens of melanocytes. Orphanet J Rare Dis 2016;11:29. 130. Berker N, Ozdamar Y, Soykan E, et al. Vogt–Koyanagi– Harada syndrome in children: report of a case and review of the literature. Ocul Immunol Inflamm 2007;15:351–7. 131. Yamaki K, Gocho K, Hayakawa K, et al. Tyrosinase family proteins are antigens specific to Vogt–Koyanagi–Harada disease. J Immunol 2000;165:7323–9. 132. Gloddek B, Lassmann S, Gloddek J, et al. Role of S-100beta as potential autoantigen in an autoimmune disease of the inner ear. J Neuroimmunol 1999;101:39–46. 133. Chi W, Yang P, Li B, et al. IL-23 promotes CD4+ T cells to produce IL-17 in Vogt–Koyanagi–Harada disease. J Allergy Clin Immunol 2007;119:1218–24. 134. Andreoli CM, Foster CS. Vogt–Koyanagi–Harada disease. Int Ophthalmol Clin 2006;46:111–22. 135. Kluger N, Mura F, Guillot B, et al. Vogt–Koyanagi–Harada syndrome associated with psoriasis and autoimmune thyroid disease. Acta Derm Venereol 2008;88:397–8. 136. Al Hemidan AI, Tabbara KF, Althomali T. Vogt–Koyanagi– Harada associated with diabetes mellitus and celiac d ­ isease in a 3-year-old girl. Eur J Ophthalmol 2006;16:173–7. 137. Rao NA. Pathology of Vogt–Koyanagi–Harada disease. Int Ophthalmol 2007;27:81–5. 138. Morohashi M, Hashimoto K, Goodman TF, et al. Ultra­ structural studies of vitiligo, Vogt– Koyanagi syndrome, and incontinentia pigmenti achromians. Arch Dermatol 1977;113:755–66. 139. Barnes L. Vitiligo and the Vogt–Koyanagi–Harada syn drome. Dermatol Clin 1988;6:229–39.

140. Haque WM, Mir MR, Hsu S. Vogt–Koyanagi–Harada syndrome: association with alopecia areata. Dermatol Online J 2009;15:10. 141. Friedman AH, Deutsch-Sokol RH. Sugiura’s sign. Perilimbal vitiligo in the Vogt–Koyanagi–Harada syndrome. Ophthalmology 1981;88:1159–65. 142. Alezzandrini AA. Unilateral manifestations of tapeto-retinal degeneration, vitiligo, poliosis, grey hair and hypoacousia. Ophthalmologica 1964;147:409–19. 143. Andrade A, Pithon M. Alezzandrini syndrome: report of a sixth clinical case. Dermatology 2011;222:8–9. 144. Raffa L, Bawazeer A. Intravitreal bevacizumab injection in a 14-year-old Vogt–Koyanagi–Harada patient with choroidal neovascular membrane. Can J Ophthalmol 2009;44:615–6. 145. Khalifa YM, Bailony MR, Acharya NR. Treatment of pediatric Vogt–Koyanagi–Harada syndrome with infliximab. Ocul Immunol Inflamm 2010;18:218–22. 146. Maaloul I, Telmoudi J, Chabchoub I, et al. Chediak–Higashi syndrome presenting in accelerated phase: a case report and literature review. Hematol Oncol Stem Cell Ther 2016; 9:71–5. 147. Nagai K, Ochi F, Terui K, et al. Clinical characteristics and outcomes of Chediak–Higashi syndrome: a nationwide survey of Japan. Pediatr Blood Cancer 2013;60:1582–6. 148. Barrat FJ, Auloge L, Pastural E, et al. Genetic and physical mapping of the Chediak–Higashi syndrome on chromosome 1q42–43. Am J Hum Genet 1996;59:625–32. 149. Olkkonen VM, Ikonen E. Genetic defects of intracellu lar-membrane transport. N Engl J Med 2000;343:1095–104. 150. De Azambuja AP, do Nascimento B, Comar SR, et al. Four cases of Chediak–Higashi syndrome. Rev Bras Hematol Hemoter 2011;33:315–22. 151. Sood S, Biswajit Biswas, Vijay Kaushal, et al. Chediak– Higashi syndrome in accelerated phase: a rare case report with review of literature. Indian J Hematol Blood Transfus 2014; 30(Suppl 1):195–8. 152. Bharti S, Bhatia P, Bansal D, et al. The accelerated phase of Chediak–Higashi syndrome: the importance of hematological evaluation. Turk J Hematol 2013; 30:85–7. 153. Spritz RA, Chiang PW, Oiso N, et al. Human and mouse disorders of pigmentation. Curr Opin Genet Dev 2003; 13:284–9. 154. Waardenburg PJ. A new syndrome combining devel opmental anomalies of the eyelids, eyebrows and nose root with pigmentary defects of the iris and head hair and with congenital deafness. Am J Hum Genet 1951; 3:195–253. 155. Jung HJ, Jin SA, Choi SJ, et al. A de novo SOX10 mutation in a patient with Waardenburg syndrome type IV. J Am Acad Dermatol 2013;68:e177–8. 156. Nayak CS, Isaacson G. World-wide distribution of Waardenburg syndrome. Ann Otol Rhinol Laryngol 2003;112:7–20. 157. Kaplan P, de Chaderevian JP. Piebaldism–Waardenburg syndrome: histopathologic evidence for a neural crest syndrome. Am J Med Genet 1988;31:679–88.

Chapter 45: Disturbances of Melanin Pigmentation 158. Fisch L. Deafness as part of a hereditary syndrome. J  Laryngol Otol 1959;73:353-62. 159. Dourmishev AL, Dourmishev LA, Schwartz RA, et al. Waardenburg syndrome. Int J Dermatol 1999; 38:656–63. 160. Menkes JH, Alter M, Steigleder GK, et al. A sex-linked recessive disorder with retardation of growth, peculiar hair, and focal cerebral and cerebellar degeneration. Pediatrics 1962;29:764–79. 161. Danks DM, Campbell PE, Stevens BJ, et al. Menkes kinky hair syndrome. An inherited defect in copper absorption with widespread effects. Pediatrics 1972;50:188–201. 162. Bertini I, Rosato A. Menkes disease. Cell Mol Life Sci 2008;65:89–91. 163. Imaeda S. Dermatologic manifestations of Menkes kinky hair syndrome. [Online] Oct 27, 2016. 164. Ojha R, Prasad AN. Menkes disease: what a multidisciplinary approach can do. J Multidiscip Healthc 2016;9:371–85. 165. Tønnesen T, Kleijer WJ, Horn N. Incidence of Menkes ­disease. Hum Genet 1991;86:408–10. 166. Tümer Z, Møller LB. Menkes disease. Eur J Hum Genet 2010;18:511–8. 167. Józ´ wiak S, Schwartz RA, Janniger CK, et al. Skin lesions in children with tuberous sclerosis complex: their prevalence, natural course, and diagnostic significance. Int J Dermatol 1998;37:911–7. 168. Borkowska J, Schwartz RA, Kotulska K, et al. Tuberous sclerosis complex: tumors and tumorigenesis. Int J Dermatol 2011;50:13–20. 169. Schwartz RA, Fernández G, Kotulska K, et al. Tuberous sclerosis complex: advances in diagnosis, genetics and management. J Am Acad Dermatol 2007;57:189–202. 170. Dabora SL, Jozwiak S, Franz DN. Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs. Am J Hum Genet 2001;68:64–80. 171. Jozwiak J, Jozwiak S, Wlodarski P. Possible mechanisms of disease development in tuberous sclerosis. Lancet Oncol 2008;9:73–9. 172. Roach ES, Gomez MR, Northrup H. Sclerosis consensus conference: revised clinical diagnostic criteria. J Child Neurol 1998;13:624–8. 173. Roach ES, Smith M, Huttenlocher P. Diagnostic crite ria: tuberous sclerosis complex. J Child Neurol 1992; 7:221–4. 174. Gomez MR. Criteria for diagnosis. In: Gomez MR, editor. Tuberous sclerosis. New York: Raven Press; 1988. p. 9–19. 175. Norio R, Oksanen T, Rantanen J. Hypopigmented skin alterations resembling tuberous sclerosis in normal skin. J Med Genet 1996;33:184–6. 176. Schwartz RA, Janniger CK. Vitiligo. Cutis 1997;60:239–44. 177. Webb DW, Clarke A, Fryer A, et al. The cutaneous features of tuberous sclerosis: a population study. Br J Dermatol 1996;135:1–5. 178. Spritz RA. Out, damned spot. J Invest Dermatol 2006;126: 949–51.

179. Sanchez-Martin M, Pérez-Losada J, Rodríguez-García A, et al. Deletion of the SLUG (SNAI2) gene results in human piebaldism. Am J Hum Genet 2003;122:125–32. 180. Janjua S, Khachemoune A, Guldbakke KK. Piebaldism: a case report and a concise review of the literature. Cutis 2007;80:411–4. 181. Sleiman R, Kurban M, Succaria F, et al. Poliosis circumscripta: overview and underlying causes. J Am Acad Dermatol 2013;69:625–33. 182. Grob A, Grekin S. Piebaldism in children. Cutis 2016; 97:90–2. 183. Garg T, Khaitan BK, Manchanda Y. Autologous punch grafting for repigmentation in piebaldism. J Dermatol 2003;30:849–50. 184. Komen L, Vrijman C, Tjin EP, et al. Autologous cell suspension transplantation using a cell extraction device in segmental vitiligo and piebaldism patients: a randomized controlled pilot study. J Am Acad Dermatol 2015;73: 170–2. 185. Deb S, Sarkar R, Samanta AB. A brief review of nevus depigmentosus. Pigment Int 2014;1:56–8. 186. Sarma N, Chakraborty S. Birthmarks of clinical signifi cance. In: Inamadar AC, Palit A, Sarkar R, editors. Advances in pediatric dermatology (Vol. 2). 1st ed. India: Jaypee Brothers Medical Publishers (P) Ltd; 2014. p. 198–9. 187. Lee HS, Chun YS, Hann SK. Nevus depigmentosus: clinical features and histopathologic characteristics in 67 patients. J Am Acad Dermatol 1999;40:21–6. 188. Hewedya ES, Hassan AM, Salah EF, et al. Clinical and ultrastructural study of nevus depigmentosus. J Microscopy and Ultrastructure 2013;1;22–9. 189. Ito M. Studies on melanin. Tohoku J Exp Med 1952;55:1–104. 190. Devillers C, et al. Hypomelanosis of Ito: pigmentary mosaicism with immature melanosome in keratinocytes. Int J Dermatol 2011;50:1234–9. 191. Ruggieri M, Pavone L. Hypomelanosis of Ito: clinical syndrome or just phenotype?. J Child Neurol 2000;15:635–44. 192. Molho-Pessach V, Schaffer JV. Blaschko lines and other patterns of cutaneous mosaicism. Clin Dermatol 2011;29: 205–25. 193. Pascual-Castroviejo I, Roche C, Martinez-Bermejo A, et al. Hypomelanosis of Ito. A study of 76 infantile cases. Brain Dev 1998;20:36–43. 194. Cellini A, Morroni M, Simonetti O, et al. Hypomelanosis of Ito: a case report with clinical and ultrastructural data. J Eur Acad Dermatol Venereol 1998;10:73–6. 195. Alikhan A, Felsten LM, Daly M, et al. Vitiligo: a comprehensive overview. J Am Acad Dermatol 2011;65:473–91. 196. Ezzedine K, Lim HW, Suzuki T, et al. Revised classifi cation/nomenclature of vitiligo and related issues: the Vitiligo Global Issues Consensus Conference. Pigment Cell Melanoma Res 2012;25:E1–13. 197. Sehgal VN, Srivastava G. Vitiligo: compendium of clinico-epidemiological features. Indian J Dermatol Venereol Leprol 2007;73:149–56. 198. Ezzedine K, Eleftheriadou V, Whitton M, et al. Vitiligo. Lancet 2015;386:74–84.

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Section 14: Pigmentation Disorders 199. Jimbow K, Chen H, Park JS, et al. Increased sensitivity of melanocytes to oxidative stress and abnormal expression of tyrosinase-related protein in vitiligo. Br J Dermatol 2001; 144:55–65. 200. Taieb A, Picardo M. Epidemiology, definitions and classification. In: Taieb A, Picardo M, editors. Vitiligo. Heidelberg: Springer Verlag; 2010. p. 13–24. 201. Felsten LM, Alikhan A, Petronic-Rosic V. Vitiligo: a comprehensive overview Part II: treatment options and approach to treatment. J Am Acad Dermatol 2011;65:493–514. 202. Lotti T, Buggiani G, Troiano M, et al. Targeted and combination treatments for vitiligo. Comparative evaluation of different current modalities in 458 subjects. Dermatol Ther 2008; 21 Suppl 1:S20–6. 203. Noël M, Gagné C, Bergeron J, et al. Positive pleiotropic effects of HMG-CoA reductase inhibitor on vitiligo. Lipids Health Dis 2004;10;3:7. 204. Harris JE, Rashighi M, Nguyen N, et al. Rapid skin repigmentation on oral ruxolitinib in a patient with coexistent vitiligo and alopecia areata (AA). J Am Acad Dermatol 2016;74:370–1.

205. Craiglow BG, King BA. Tofacitinib citrate for the treatment of vitiligo: a pathogenesis-directed therapy. J Am Acad Dermatol 2015;151:1110–2. 206. Anbar TS, El-Ammawi TS, Abdel-Rahman AT, et al. The effect of latanoprost on vitiligo: a preliminary comparative study. Int J Dermatol 2015;54:587–93. 207. Parsad D, Pandhi R, Dogra S, et al. Topical prostaglandin analog (PGE2) in vitiligo-a preliminary study. Int J Dermatol 2002;41:942–5. 208. Ghosh S. Chemical leukoderma: what’s new on etio pathological and clinical aspects?. Indian J Dermatol 2010;55:255–8. 209. Oliver EA, Schwartz L, Warren LH. Occupation leuko derma. J Am Med Assoc 1939;113:927–8. 210. Ghosh S, Mukhopadhyay S. Chemical leucoderma: a clinico-aetiological study of 864 cases in the perspective of a developing country. Br J Dermatol 2009;160:40–7. 211. Boissy RE, Manga P. On the etiology of contact/ occupational vitiligo. Pigment Cell Res 2004;17:208–14.

Section

15

Pediatric Dermatology

Chapter

46

Transient Benign Conditions of the Neonate and Infant Caitlin Gilman, Vikash S Oza

ERYTHEMA TOXICUM NEONATORUM Erythema toxicum neonatorum is a common eruption seen in up to 70% of full term neonates.1 Classic findings include 1–3 mm yellowish papules or pustules with a surrounding irregular flare of erythema. Erythema toxicum is often scattered with lesions involving the face, trunk, and extremities but sparing the palms and soles. Onset is usually between 24 and 48 hours of life and the lesions self-resolve by 7 days.2 A diagnosis of erythema toxicum is unlikely in premature and low birth weight neonates or if the eruption presents 1 week after birth. There is no gender or racial predilection. Diagnosis is made on clinical findings, though microscopic evaluation can be performed with Wright or Giemsa stain and will show numerous eosinophils with scattered neutrophils. Other pustular disorders, such as infantile acropustulosis, herpes simplex virus, staphylococcal impetigo, congenital candidiasis, transient neonatal pustular melanosis, and miliaria rubra can be considered in the differential diagnosis. Since this is a self-limited condition, no treatment is warranted.

TRANSIENT NEONATAL PUSTULAR MELANOSIS Originally termed “lentigines neonatorum,” transient neonatal pustular melanosis (TNPM) is most commonly seen in full-term African American neonates, though it has been described in all races.3 TNPM has three distinct types of lesions, which all may be present at the same time. Fragile, superficial pustules on a non-erythematous base, ranging in size from 2 to 10 mm are first seen and present at birth. As pustules rupture easily, a fine collarette is seen at the site of resolving pustules. Finally, these pustules resolve with postinflammatory hyperpigmented macules that can last for weeks to months.4 Diagnosis is based on clinical appearance. Microscopic evaluation with Wright or Giemsa stain will

reveal numerous neutrophils and rare eosinophils (in contrast to erythema toxicum neonatorum). No treatment is necessary.

MILIARIA Miliaria is the obstruction of eccrine ducts by sweat. It is usually caused by environmental factors, such as natural climate, warmed incubators, clothing, or blankets, but may also be seen in febrile infants. It is therefore rarely present at birth and develops within the first week of life. Miliaria crystallina, the most superficial form, is seen in the immediate neonatal period. It involves ductal obstruction within the stratum corneum and is characterized by 1–2 mm clear vesicles without surrounding erythema. Vesicles are widely spread and may be coalescent, most commonly found on the head, neck, and upper trunk. Miliaria rubra or “heat rash” is the result of sweat leakage into the deeper dermis, causing a localized inflammatory response. This results in 1–3 mm erythematous papules and pustules, which are non-follicular. It is most commonly seen on the head, neck, face, and scalp. In contrast with miliaria crystallina, miliaria rubra can cause itching or stinging exacerbated by sweating. Miliaria profunda is uncommon in neonates and represents a deeper obstruction of the eccrine duct. This variant of miliaria presents with skin colored to white, 1–3 mm papule on the trunk and proximal extremities that are frequently asymptomatic and resolve within 1–2 hours of onset. Miliaria profunda often occurs as the result of recurrent episodes of miliaria rubra. While the mechanism of miliaria formation is not entirely clear, it is proposed that the extracellular polysaccharide substance produced by Staphylococcus epidermidis causes ductal blockage.5 Differential diagnosis includes neonatal acne and neonatal infections such as herpes simplex virus, candida, or bacterial folliculitis. Diagnosis is made clinically,

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Section 15: Pediatric Dermatology especially in the neonate with history of sweating or elevated temperature. Skin biopsy will show eccrine obstruction and Wright stained smear of vesicular contents will show occasional squamous cells and lymphocytes. Treatment is not required, as lesions usually resolve with removal of heat source.

NEONATAL CEPHALIC PUSTULOSIS (ACNE) Neonatal cephalic pustulosis is one of the most common self-limited eruptions in neonates. It characterized by non-comedonal, inflammatory papules, and pustules usually limited to the face and occasionally the scalp. Though often termed neonatal acne, neonatal cephalic pustulosis is not a type of acne vulgaris. Once thought to be secondary to exposure to maternal and endogenous androgens, current proposed mechanisms include an inflammatory response secondary to skin colonization by Malassezia sp.6 There may be an overlap with atopic and seborrheic dermatitis given the often scaly quality of lesions on the scalp and eyebrows. Diagnosis is made based on clinical appearance, though pustules bear some resemblance to miliaria rubra, and differentiation may be difficult. Neonatal acne typically develops within the first 2–3 weeks of life and resolves by 4 months of age. Treatments are typically not employed but a topical imidazole or a low-potency corticosteroid such as hydrocortisone 1% can be used to hasten resolution in severe cases.7

ORAL MUCOSAL CYSTS (EPSTEIN PEARL AND BOHN NODULE) Epstein’s pearls and Bohn’s nodules are small (4 cm overlying the midline. Lumbosacral dimples that are deep, >0.5  cm, or located above the gluteal crease raise suspicion for spinal defects and should have imaging studies and surgical evaluation. The imaging modality of choice is MRI. High resolution ultrasound can be used in children less than 3 months but the sensitivity is lower than MRI in detecting signs of spinal dysraphism.

Developmental Anomalies of the Umbilicus (Anomalies of the Urachus and Omphalomesenteric Cyst) The umbilicus is the structure that remains after the umbilical cord stump separates from the newborn, which usually occurs by 1–2 weeks of life and may take up to 8 weeks. Drainage, a mass or signs of infection may indicate an anomaly of the underlying structures. The three most common anomalies of the umbilicus are the umbilical granuloma, the omphalomesenteric duct cyst, and urachal cyst. The umbilical granuloma is the most common and presents as a friable, red, small papule at the umbilicus. It

Chapter 46: Transient Benign Conditions of the Neonate and Infant represents incomplete re-epithelialization of the umbilicus after the stump falls off. Small granulomas can be managed with topical silver nitrate. The omphalomesenteric duct cyst typically presents with a bright red, glistening umbilical polyp. The cyst represents a failure of closure of the omphalomesenteric tract connecting the umbilical cord to the developing intestinal system. A complete lack of closure may result in a fistula between the ileum and umbilicus.26 The urachal duct cyst represents failed closure of the urachus, a connection between the fetal bladder and umbilicus. The cyst may present as a suprapubic mass if this duct remains partially patent. If the duct remains completely patent, urine may persistently drain from the umbilicus and a polyp can occasionally be seen at this site. An ultrasound can be useful in characterizing the extent of a urachal and omphalomesenteric duct cyst. Surgical excision is the management of choice for both.

INFLAMMATORY DISORDERS OF THE NEWBORN PERIOD Neonatal Lupus Neonatal lupus is the result of placental transmission of maternal IgG antibodies, anti-Ro (SSA), anti-La (SSB), and/or anti-U1RNP. Mothers typically have an underlying autoimmune disease, such as systemic lupus erythematosus or Sjogren’s syndrome. The most characteristic cutaneous feature is annular erythema involving the scalp, forehead, and periorbital area giving the appearance of “raccoon eyes.” Discoid lesions with scaling, atrophy, and telangiectasia have also been described. The eruption is noted in the first weeks of life and may be precipitated by ultraviolet exposure. Important extracutaneous manifestations include complete congenital heart block, transient liver disease manifesting as hepatomegaly and cholestatic transaminitis, and thrombocytopenia. The diagnostic work up should include an electrocardiogram, liver function tests, complete blood count and maternal and infant autoantibodies (anti-Ro, antiLa, and anti-U1RNP). The presence of positive antibodies and characteristic clinical findings is typically sufficient to make the diagnosis and skin biopsies are infrequently needed. Histologically, epidermal atrophy, vacuolization of the basal layer with a sparse lymphohistiocytic infiltrate at the dermoepidermal junction with a periappendageal distribution, characteristics of lupus erythematosus, are present. Ninety-five per cent of the affected children are

positive for anti-Ro.27 Importantly, mothers can have positive antibodies but be asymptomatic at the time of delivery, therefore the absence of an established autoimmune disorder in the mother does not rule out neonatal lupus erythematosus. The differential diagnosis includes seborrheic dermatitis, tinea corporis, congenital syphilis, and annular erythema of infancy. The skin lesions are transient as the maternal antibodies pass through the system. Management of the cutaneous features of neonatal lupus includes UV protection and topical corticosteroids. Heart block, however, is permanent and often requires pacemaker placement.

INFECTIOUS DISEASES Blueberry Muffin Lesions (Dermal Erythropoiesis) A purpuric eruption described as “blueberry muffin” is often indicative of extramedullary hematopoiesis within the dermis. The eruption presents as firm, infiltrative purpuric papules in a generalized distribution and measuring less than 1 cm in size. Petechiae and non-palpable purpura may also coexist. Histologically, there are poorly circumscribed collections of nucleated and non-nucleated red blood cells within the reticular dermis and subcutaneous tissue. Neonates with blueberry muffin lesions require a thorough investigation to elucidate the underlying cause. Neonatal extramedullary hematopoiesis can be secondary to congenital infections (rubella, cytomegalovirus, parvovirus B19, and toxoplasmosis) or hematologic dyscrasias (hereditary spherocytosis, ABO incompatibility, hematologic disease of the newborn, or twin–twin transfusion). In addition, neonatal malignancy, such as neuroblastoma, leukemia, and Langerhans histiocytosis, can disseminate to the skin and also result in the blueberry muffin presentation. The underlying cause needs to be addressed for resolution of these lesions.

Neonatal Herpes Simplex Virus Infection Herpes simplex virus (HSV) infection is one of the most serious infections in the neonatal period with high rates of morbidity and mortality. Fortunately, neonatal HSV is relatively uncommon with estimates of 10 cases per 100,000 births.28 Most cases of neonatal HSV occur in the perinatal period through exposure to viral shedding from

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Section 15: Pediatric Dermatology the genital tract at the time of delivery. Both HSV1 and HSV2 infections are responsible for genital infection and hence neonatal HSV. The risk of transmission is much greater for mothers who develop a primary HSV infection during the third trimester as opposed to HSV reactivation. The risk of transmission for mothers with a primary infection is estimated at 57% compared to 2% for mothers with HSV reactivation during the last trimester.28 Additional risk factors include vaginal as opposed to caesarean delivery, prolonged rupture of membranes, and use of fetal scalp electrode or other invasive instrumentation. Postnatal transmission of HSV through exposure to HSV from family members or healthcare workers is also possible but occurs less frequently.29 Classically, neonatal HSV has been divided into three categories: skin, eyes, or mouth (SEM disease); central nervous system (CNS) infection; and disseminated disease. SEM accounts for approximately 45% of cases, CNS disease 30%, and disseminated disease for the remaining 25% of cases.30 Importantly, vesicles are a presenting feature of all three categories. On average, SEM and disseminated disease presents 9–11 days after birth and CNS disease at 16–17 days.31 The cutaneous presentation consists of herpetiform clusters of vesicles on an erythematous base that may evolve into a pustule, small ulcer, and eschar. Vesicles are often seen at the presenting body part or at sites of local trauma, such as fetal scalp electrode site. Skin biopsy, which is rarely needed, shows intraepidermal vesiculation associated with ballooning degeneration of keratinocytes. Every neonate with skin or mucosal HSV infection requires an investigation for disseminated and CNS disease. HSV culture remains the most accurate means of diagnosis from cutaneous lesions. Additional testing that can provide more rapid results include Tzanck smear (stain for multinucleated giant cells), HSV PCR, or direct fluorescence antibody (DFA) testing. When neonatal HSV is suspected, swabs for culture should be obtained from the mouth, nasopharynx, conjunctiva, and anus in addition to the base of an unroofed vesicle. Viral cultures should also be obtained from the blood and spinal fluid. Intravenous acyclovir is the treatment of choice for neonatal HSV and should be initiated pending the results of HSV studies. SEM disease should be treated for 14 days and a minimum of 21 days is needed for CNS or disseminated disease. The differential diagnosis includes perinatal varicella, candidiasis, bacterial sepsis, epidermolysis bullosa,

epidermolytic hyperkeratosis, and incontinentia pigmenti where the vesicles follow the lines of Blaschko.

Congenital Herpes Simplex Virus Infection Congenital or intrauterine HSV is rare a condition (1 in 250,000 births) due to HSV infection in utero. The degree of disease in the neonate depends on the time and mode of exposure. Most congenital HSV infections are believed to result in fetal demise. Neonates with congenital HSV frequently present with active vesicles, approximately 70% of cases. These lesions may represent either persistence of infection from the fetal period or latent viral reactivation. Ulceration and scar formation can also be seen with the development of aplasia-cutis like skin findings. Congenital HSV infection is strongly associated with CNS damage and cases are frequently complicated by microcephaly and/or chorioretinitis.

Neonatal Varicella Zoster Virus Infection Neonatal varicella zoster virus (VZV) infection occurs when a mother is infected with the virus in the immediate pre- or postnatal period. Skin manifestations include the development of pink macules that progresses into a papulovesicular eruption. Lesions typically appear in infants within 1–2 weeks of the maternal rash. Infection may be localized to the skin or may become disseminated. The risk of disseminated VZV is related to the timing of maternal infection, with the primary risk being in the preceding 5 days prior to delivery and 2 days after delivery.32 In disseminated infections, infants may suffer from pneumonitis, respiratory compromise, hepatitis or encephalitis. The differential diagnosis is similar to that of neonatal HSV. The diagnosis of neonatal varicella can be made with VZV culture or VZV PCR evaluation from the base of vesicles, tissue, or CSF. Both direct fluorescent antibody testing and Tzanck smears can also aid in the diagnosis. Histologic findings are similar to HSV skin lesions. Varicella zoster immune globulin (VZIG) should be given as soon as possible to neonates whose mothers contracted primary varicella between 5 days prior and 2 days after delivery. Infants who show signs of varicella infection should also be treated with intravenous acyclovir. Moth­ers and infants may need to be isolated from

Chapter 46: Transient Benign Conditions of the Neonate and Infant each other and/or other individuals depending on clinical scenario.

Congenital/Neonatal Candidiasis Congenital candida results from an ascending fungal infection acquired in utero or during delivery. Risk factors include a maternal history of vaginal candidiasis, prolonged rupture of membranes, and vaginal or uterine foreign body. Isolated cutaneous candida presents most often on the first day of life with a generalized erythematous morbilliform eruption that evolves over time into pustules, vesicles, or bullae. It typically involves the oral mucosa, palms, and soles.33 Diagnosis can be made by the presence of budding yeast or pseudohyphae on KOH or growth of Candida sp. on fungal culture. Congenital infection can also occur in premature infants where cutaneous manifestation can include widespread erythema and erosions that can mimic staphylococcal scalded skin syndrome.34 Term infants can be treated with topical antifungal agents and lesions will resolve with fine desquamation within the first week of life. Premature and very low birth weight neonates in the neonatal intensive care unit are also at risk for non-congenital acquisition of candida and subsequent disseminated disease termed neonatal invasive candidiasis. Risk factors include gestational age 2.5 cm from Infantile hemangioma, anal verge 50% of all cutaneous lymphomas, and usually affects middle-aged adults. There is striking variability in clinical presentations of MF in addition to the classic Alibert-Bazin type with evolution of persistent pink, hyper or hypopigmented scaly patches, plaques, and tumors, with predilection for the buttocks and sun-protected sites (Fig. 102.4). Much historical outdated nomenclature is used by some instead of the more accurate term mycosis fungoides. This adds to confusion, and should be avoided if possible (Box 102.1). Within the WHO-EORTC classification system there are only three subtypes officially recognized due to their distinct clinical behavior. These are: Folliculotropic MF, pagetoid reticulosis, and Granulomatous slack skin.

Small-plaque Parapsoriasis It is worth briefly mentioning that the term “smallplaque parapsoriasis” (SPP) or “digitate dermatosis” is ripe with controversy and experts in the field disagree with the relationship between small-plaque parapsoriasis and mycosis fungoides. Importantly, the lesions

Fig. 102.4: Classic “Alibert-Bazin” mycosis fungoides with scaly, fixed large nummular scaly patches.

Box 102.1: Some historical terms used for mycosis fungoides. Parakeratosis variegata Parapsoriasis en plaques Parapsoriasis lichenoides Parapsoriasis variegata Retiform parapsoriasis Poikiloderma vasculare atrophicans Clinical/pathological versions of mycosis fungoides with behavior similar to “classic” Alibert-Bazin Type (not recognized as distinct variants by WHO/EORTC) Bullous mycosis fungoides Granulomatous mycosis fungoides Hyperpigmented mycosis fungoides Hypopigmented mycosis fungoides Lichenoid mycosis fungoides Mucinous mycosis fungoides Palmoplantar mycosis fungoides Papular mycosis fungoides Papuloerythroderma of Ofuji Pigmented purpuric mycosis fungoides Pustular mycosis fungoides Spongiotic mycosis fungoides Syringotropic mycosis fungoides Verrucous mycosis fungoides

described in SPP are patches, not plaques, (the term is French where plaque equates to patch in English). SPP may be applied to patients who present with small 3–6 cm × 1–2 cm ovoid finger-like patches without atrophy or poikiloderma, usually on the lateral trunk and upper extremities. Some contend these entities are the same, and others do not. These patients rarely go on to develop

Chapter 102: Cutaneous T-cell Lymphomas classic clinical and histologic features of MF. As such the term SPP is still utilized because it serves to separate these patients from those who have a definitive, potentially life-threatening lymphoma, and spares them from inappropriately aggressive therapy. Conversely, the term “large plaque parapsoriasis’’  is now regarded as mycosis fungoides.26

cysts and comedones within the plaques, resembling a nevus comedonicus, often affecting the head, neck, and extremities (Fig. 102.7). This subset may require more aggressive or systemic therapy, as it can portend a worse prognosis.27

Folliculotropic Mycosis Fungoides

Sarcoidal granulomas are a histologic feature in approximately 2% of all cutaneous lymphomas, and granulomatous slack skin (GSS) is a specific subtype of MF with characteristic clinical and microscopic features. Patients typically have poikilodermatous patches and plaques in body folds with associated skin laxity and an indolent progressive course over many years (Figs. 102.8). A lichenoid or diffuse infiltrate of lymphocytes is present

This variant of MF is characterized clinically by perifollicular papules and plaques often with associated alopecia (Figs. 102.5A to C). Histologic features include mucin and lymphocytes within hair follicles termed folliculotropism, or pilotropism (Fig. 102.6). In patients with marked follicular involvement, there can be associated

Granulomatous Slack Skin

B

A

C

Figs. 102.5A to C: Folliculotropic mycosis fungoides. There is often a 'keratosis pilaris like' papular accentuation around follicular ostia. Plaques frequently have alopecia and can be impetigenized or have comedonal plugging of follicles resembling a nevus comedonicus.

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Fig. 102.6: Folliculotropic malignant lymphocytes extending into deep dermis around adnexae.

Fig. 102.7: Granulomatous slack skin histology: atypical CD4+ T-lymphocytes with naked granulomas.

plaque of psoriasis or eczema. Classic histology demonstrates large, atypical epidermotropic haloed lymphocytes. Accurate diagnosis and management is needed to prevent local cutaneous morbidity in the affected site, most commonly infection and pain. A preferred treatment is localized radiation therapy usually 20–25Gy delivered in 1–1.5Gy fractions. The “generalized form” of Woringer–Kolopp referred to as Ketron–Goodman disease is no longer recognized, as most of these patients likely have primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma.29

Sézary Syndrome Fig. 102.8: Granulomatous slack skin with skin laxity and poikiloderma affecting body folds.

throughout the dermis with naked granulomas and giant cells. Epidermotropism is rarely seen. TCR for clonality is positive in most cases. Secondary lymphomas develop in approximately 20% of cases, most commonly Hodgkin lymphoma. The interval between GSS and another lymphoma may be years or decades, and these patients should be monitored accordingly.28

Pagetoid Reticulosis Woringer–Kolopp disease is synonymous with pagetoid reticulosis. This is a very rare localized variant of mycosis fungoides typically presenting as an acral, solitary plaque with slow growth. It is often misdiagnosed as an isolated

This condition was first described in 1892 by Besnier and Hallopeau, and in 1938 Sézary and Bouvrain associated patients with the clinical findings of erythroderma, pruritus, and lymphadenopathy with abnormal hyperchromatic mononuclear cells in both skin and blood (Fig. 102.9). In the early 1970s it was known that this condition was a malignancy of T-cell origin, but it was not until 2010 that Kupper et al. clearly demonstrated that MF and SS arose from distinct T-cell subsets, which helped to explain their different behaviors.13 As such, a patient classified as having Sézary syndrome should be one who presents with characteristic leukemic T-cells in the peripheral blood without preexisting MF. Patients suffering from SS often have intense pruritus which poses a severe, debilitating impact on their quality of life. Involvement of the proximal nail folds with erythema and scale can lead to trachyonychia and extensive

Chapter 102: Cutaneous T-cell Lymphomas

Fig. 102.9: Erythroderma/Sézary syndrome.

Table 102.3: Algorithm for diagnosis of early mycosis fungoides. Clinical 2 points (basic + 2 additional) Basic Persistent and/or progressive patches/thin plaques Additional 1 point (basic + 1 additional) Non-sun exposed location Size/Shape variation Poikiloderma Histopathologic 2 points (basic + 2 additional) Basic Superficial lymphoid infiltrate 1 point (basic + 1 additional) Additional Epidermotropism without spongiosis Lymphoid atypia (cells with enlarged hyperchromatic nuclei and irregular or cerebriform contours) Molecular Clonal T-cell receptor gene 1 point (clonality present) rearrangement Immunophenotypic 1 point (1 or more 80% BSA, but there is no distinction for subclassifying based on amount of erythema, induration, or scale. If a patient has presence of both tumors and erythroderma, the highest is used for staging, but both should be recorded (for e­ xample, T4(3)) to track variables that would otherwise be lost in the staging canon.32

Node

A

Nodal staging currently defines clinically abnormal nodes as those 1.5 cm in size in the longest transverse diameter or nodes which are firm, irregular, clustered, or fixed, regardless of size. Clinically enlarged nodes should be corroborated by imaging studies prior to biopsy, such as: ultrasound, computed tomography (CT), positron emission tomography (PET), or magnetic resonance imaging (MRI). Once a node is regarded as clinically abnormal, histologic examination should be performed, and the preferred method is excisional biopsy of the node, as staging necessitates assessment of the nodal architecture. The Dutch System and the NCI-VA systems are the two main histopathologic grading systems for lymph nodes in use today. The absence of clinically abnormal nodes is denoted as N0, and Nx is used for notation of abnormal nodes which have not been histologically confirmed. In the Dutch system, N1 designation is used when histology only demonstrates dermatopathic lymphadenopathy, N2 is early involvement by MF with presence of cerebriform cells, and N3 shows either complete or partial effacement of nodal architecture with malignant cells. A subscript of a or b is used for each of the N1, N2, and N3 stages to denote absence or presence of clonal cells, respectively.32

Metastases B Figs. 102.11A and B: Disease-specific survival according to (A) clinical stage and (B) T-classification.33

Visceral involvement (M1 disease, stage IVB) in MF/SS necessitates involvement of only one organ outside of the blood, skin, or lymph nodes. The liver and spleen are the most common organs involved and may be diagnosed by imaging criteria. Splenomegaly documented

Chapter 102: Cutaneous T-cell Lymphomas Table 102.4: ISCL/EORTC TNMB staging classification for mycosis fungoides and Sézary syndrome. SKIN Limited patches, papules, or plaques covering 80% BSA T4 NODE No clinically abnormal nodes N0 Clinically abnormal peripheral nodes, no histologic examination Nx Clinically abnormal peripheral nodes, dermatopathic lymphadenopathy, clone (–) N1a Clinically abnormal peripheral nodes, dermatopathic lymphadenopathy, clone (+) N1b Clinically abnormal peripheral nodes, early involvement with cerebriform cells, clone (–) N2a Clinically abnormal peripheral nodes, early involvement with cerebriform cells, clone (+) N2b Clinically abnormal peripheral nodes, effacement of nodal architecture with atypical cerebriform cells N3 VISCERA M0 M1 BLOOD B0a B0b B1a B1b B2

No visceral organ involvement Visceral involvement (liver and spleen by imaging criteria, any other by pathologic confirmation, specify organ) Absence or 50% BSA, phototherapy, or systemic medications. Because almost all patients relapse after TSEB at any dose, the lower dose regimens are becoming more widely used, due to the opportunity for repeat treatments given the lower toxicity, improved tolerability, and shorter treatment course.43

Oral and Topical Retinoids and Rexinoids Retinoids are vitamin A derivatives that bind to retinoicacid and retinoid X receptors. They alter gene transcription regulating cell division, differentiation, and immune responses. Retinoid X receptors can homodimerize with retinoic acid, thyroid, cholecalciferoal and peroxisomeproliferator-activated receptors, with diverse downstream effects.44 Etretinate was one of the earliest and

most widely studied retinoids in MF/SS but was withdrawn from the market in the US and Canada. There are minimal studies on the effectiveness of acitretin for treatment, although it is widely used by many centers in combination with phototherapy. Studies of isotretinoin showed overall response rates of 40–80%.45 Due to the minimal amount of evidence supporting the use of retinoids in MF/SS, the EORTC does not recommend their use as monotherapy. Bexarotene, a rexinoid which binds retinoid X receptors, has shown similar efficacy to IFN-α, with clinical response of 54% in patients taking 300 mg/m2 per day. Response rates were similar from stages IB-IVB, and the average time for response was 2 months, but can take up to 4 months in some patients. Common dose-dependent side effects include hyperlipidemia, leukopenias, and central-hypothyroidism.46 Some recommend starting at a lower dose and escalating over time, which slows clinical response, but allows for better control of side effects.

Topical Toll-like Receptor Agonists Toll-like receptors (TLRs) are a group of proteins found widely in plants and animals. There are 10 TLRs identified in humans. TLRs work as pattern-recognition receptors which recognize molecular patterns of microbial products and activate the innate immune system, and are located on dendritic cells, neutrophils, lymphocytes, NK cells, and B-cells. When bound, TLRs activate local IFN-α, IL-1α, TNF-α, IL-6, and IL-12 production.47 Imiquimod is a commercially available imidazoquinolone which triggers its action through toll-like-receptor (TLR) 7. It is approved for treatment of condyloma acuminata, actinic keratoses, and superficial basal cell carcinoma. While it is not an FDA-approved treatment for MF, it has been studied in its treatment and demonstrates clinical response in 50% of patients.48 Resiquimod, also an imidazoquinolone which binds TLR-7 and TLR-8, is not yet commercially available. However, it has also been studied in treatment of MF, and demonstrated marked clinical improvement in 75% of treated patients, with loss of the malignant clone and restoration of T-cell diversity by HTS.49

Phototherapy Ultraviolet B phototherapy (UVB) 290–320 nm was the first form of light therapy used in treatment of MF, and it

Chapter 102: Cutaneous T-cell Lymphomas halts T-cell proliferation via DNA-damage. The form most commonly used is narrowband UVB (NB-UVB) with a sharp emission peak at 311–313 nm. For early patch and plaque-stage MF, CR is seen in approximately 74% of patients after 5 months, and duration of remission is over 4 years in many patients on maintenance treatment. The most common side effects are UV-burn, pruritus, and photosensitivity. It can induce p53 mutations, and while there is concern of increased risk for skin cancer, several studies find no increased skin cancer risk in in patients treated with UVB phototherapy.50,51 Oral psoralen (usually, 8-methoxypsoralen, or 8–MOP) with ultraviolet A irradiation (PUVA) in the 320–400 nm wavelengths has been utilized since the 1970s in treatment of MF. Activation of psoralen by UV causes DNA-crosslinks in cellular DNA, inducing apoptosis of malignant lymphocytes and reducing antigen-presentation by Langerhans cells. CR is 85% for stage IA, and 65% for stage IB, and 23% for stage IIB. In general, phototherapy is initiated on a thriceweekly schedule until clearance is achieved. The goal dose depends upon the Fitzpatrick skin-type of the patient undergoing treatment. Once the maximum therapeutic dose and clinical response is achieved, a stepwise decrease in frequency to twice weekly, then to once weekly is undertaken every 4–8 weeks, with careful monitoring for worsening in disease status with each successive decrease in frequency. The maximum interval possible with UVB is approximately 12–14 days, and with PUVA, maintenance therapy can be as infrequent as every 3–4 weeks.52

Extracorporeal Photopheresis Extracorporeal photochemotherapy (ECP) was introduced in 1987 as a treatment for patients with advanced erythrodermic MF/SS, and is FDA-approved for its treatment. In this treatment, mononuclear cells are collected from peripheral blood, 8-MOP is added to the cell mixture, the mixture is then irradiated with a controlled dose of UVA, and it is then infused back into the patient.53 The mechanism of ECP is elusive, although it is likely due in part to DNA damage of malignant lymphocytes leading to apoptosis, which condition the healthy immune system to eliminate the malignant clone via activation of CD8+ T-cells by increased expression of MHC-1 and induction of TNF-α by monocytes. Clinical response occurs after an average of 10 months for most patients, and response rates are around 50%. Response depends on the severity and disease burden of the patient. 53,54

Interferons Interferons are naturally occurring cytokines produced in response to a variety of stimuli including infections and malignancies. There are three major types of injectable IFN which are commercially available: IFN-α, IFN-β, and IFN-γ. Efficacy of IFNs in treatment of MF/SS was first demonstrated in the 1980s. IFN-α2a is most commonly used to treat MF/SS, and it demonstrates efficacy rates ranging from 35–75% in most cases. The main acute side effects of IFN tend to dissipate over time and are flulike: arthralgias, myalgias, fever, and chills; these can be minimized by bedtime administration and NSAID pretreatment. Chronic side effects include hypothyroidism, depression, weight loss, transaminitis, cardiac toxicity, leukopenia, neutropenia, and thrombocytopenia. The nadir for hematologic side effects is usually during the first month of treatment. The dosing schedule varies in clinical trials from daily to three times weekly, with the maximum tolerated dose for most patients is 9 Mµ administered daily, with ranges of 1.5–18 Mµ in many cases. Starting doses are usually 3Mµ three times weekly, with dose escalation after 3 months of therapy if response is insufficient. After 6 months of therapy, doses can be increased if response is still inadequate, or a second agent may be added if the patient is at their maximum tolerated dose. The therapeutic dose that achieves clinical response should likewise be maintained for 3 months prior to attempts at tapering the dose or frequency of administration, which is usually undertaken over a period of 12 months. If a patient has thick plaques or tumors, the medication may be administered intralesionally which is reported to improve these lesions more dramatically.55

Histone Deacetylase Inhibitors Histones are proteins that organize DNA into nucleosomes, similar to thread around a spool. When histones are acetylated, this allows the DNA to unravel, allowing for gene transcription. When histones are deacetylated, chromatin remains condensed and transcription is suppressed. There are many downstream effects of inhibition of histone acetylation, including suppression of tumor gene transcription, induction of the cell-cycle inhibitor p21, increased pro-apoptotic proteins, and accumulation of reactive-oxygen species preferentially within tumor cells.56 Commercially available histone deacetylase inhibitors (HDACI) include romidepsin and vorinostat, which

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Section 30: Tumors of the Lymphoreticular System are metabolized primarily through CYP3A4. Romidepsin is usually administered at a dose of 14 mg/m2 on days 1, 8, and 15 of a 28-day cycle, and Vorinostat is dosed orally at 400 mg/day. Adverse effects include pancytopenias, QT prolongation, hypocalcemia, and hypomagnesemia, as well as common side effects such as headache, nausea, and diarrhea. Overall response rates for HDCAI are 34–40% in patients with advanced disease who have failed at least one other systemic therapy. While there are reports of HDACI use in combination with other agents such as retinoids, toxins and cytotoxic agents, the data are sparse and require further investigation.57

Pralatrexate Pralatrexate is a folate analog similar to methotrexate, but has a high affinity for folate-carrier-1 oncoprotein which is preferentially expressed in tumor cells. It is approved for relapsed/refractory peripheral T-cell lymphoma. It is used in treatment of MF/SS for patients with relapsed or refractory disease to first-line systemic agents, and has been used in combination with oral bexarotene.58 Usual doses range from 15–30 mg/m2 per week with intramuscular B12 and oral folate supplementation to prevent mucositis and anemias. Overall response rates are around 45%, usually with partial response of a 6–12 month duration on therapy.59

Allogeneic Stem-cell Transplant Data for allogeneic stem-cell transplant (Allo-SCT) in the treatment of MF/SS are predominantly case-series and retrospective. Allo-SCT has demonstrated long-term remissions in many patients with advanced disease, who might otherwise have died from their disease. Comparison of myeloablative vs. non-myeloablative conditioning regimens shows that the reduced-intensity regimens are equally as effective in terms of engraftment and remission rates, but with lower overall toxicity. There is strong evidence for a graft-vs-tumor effect in these patients with donor lymphocyte infusions often reinduce remission in patients who relapse after transplant. At present, the optimal timing and conditioning regimen for patients with advanced MF/SS is unknown.60 For advanced-stage MF/ SS, disease-free survival rates extend are greater than three years in over half of patients, and overall survival of 80% at five years following allo-SCT. The side effects and risks of allo-SCT are extensive and include graft-vs-host disease, infections, and death. Due to these risks, patient selection is critical. In particular, allo-SCT should be considered

given its superiority for durable remission over other systemic chemotherapies in patients younger than 60 with advanced or aggressive disease, who relapse after treatment with one or two systemic agents.61

ADULT T-CELL LEUKEMIA/LYMPHOMA Adult T-cell leukemia/lymphoma (ATLL) is caused by the retrovirus human T-cell lymphotropic virus type I which is more common in Central Africa, the Caribbean islands, southwestern Japan, and South America. Brazil has the highest seroprevalence with 1.8% of the population affected. The majority of seropositive individuals are asymptomatic carriers, but approximately 5% develop sequelae including leukemia, cutaneous lymphoma, acute infective dermatitis, and tropical spastic paraparesis. ATLL is a T-cell malignancy with an aggressive course, affecting the skin in approximately 40–70% of cases.62 There are four main clinical subtypes of ATL including acute, chronic, lymphoma and smoldering. Cutaneous lesions are usually a manifestation of more extensive systemic disease in which patients often present with leukemia, lymphadenopathy, organomegaly, and hypercalcemia, 50% have cutaneous lesions most often generalized plaques, papules, nodules, or tumors. The less common “smoldering” variant manifests as slowly progressive skin-limited disease, clinically resembling lesions of mycosis fungoides.12

PRIMARY CUTANEOUS CD30+ LYMPHOPROLIFERATIVE DISORDERS Overview The second most frequently occurring cutaneous T-cell lymphoma is comprised of the primary cutaneous CD30+ lymphoproliferative disorders. This group includes primary cutaneous anaplastic large cell lymphoma and lymphomatoid papulosis. In general, this group portends a good prognosis and are indolent in behavior. There are no established staging guidelines are established specifically for this group of disorders, and it is recommended that clinicians use the TNM classification system for cutaneous lymphomas other than MF/SS defined by the ISCL/EORTC.63 At initial presentation, these two entities can be difficult to distinguish, and definitive categorization can only be achieved once the patient is followed over time to determine the clinical behavior of the lesions.

Chapter 102: Cutaneous T-cell Lymphomas

Primary Cutaneous Anaplastic Large Cell Lymphoma Primary cutaneous anaplastic large call lymphoma (PCALCL) generally presents with individual or grouped, rapidly growing, often ulcerating plaques or tumors (Fig.  102.14). In rare circumstances the lesions may be multifocal and can spontaneously regress in about 40% of patients. The prognosis for PCALCL is quite good with a 75–95% overall survival rate at 5-years. The histology of PCALCL typically shows a dense dermal infiltrate of immunoblastic cells with abundant pale cytoplasm and nuclear atypia, at least 75% of which should demonstrate CD30+, and most cases also express either CD4 or CD8. Epithelial membrane antigen (EMA) is generally not expressed by PCALCL and cutaneous lymphocyte antigen is expressed by the neoplastic cells, both of which provide a contradistinction from nodal ALCL. Additionally, anaplastic lymphoma kinase (ALK-1) and t(2;5) translocations are seen in systemic processes and are not typical for PCALCL. If they are seen, it may signify cutaneous spread of an underlying systemic process. Upon diagnosis, patients with PCALCL should have thorough work-up with imaging studies, such as CT-scan with contrast, or positron emission tomography. Biopsy should be performed if there is suggestion of nodal involvement on imaging. Bone-marrow biopsy is generally of low-yield and is not indicated unless a patient has multifocal disease at initial presentation or significant unexplained hematologic abnormalities. First-line treatment for PCALCL is usually either surgical excision or radiotherapy, with clinical resolution in 95–100% of patients with either approach, and relapse in

about 40% of patients within 5 years. Conversely, multiagent chemotherapy demonstrates CR in only about 90% of patients and has relapse rates in about 60% of patients. Other single-agent treatments such as retinoids, topical or systemic chemotherapies have been reported, but data are insufficient to draw conclusions regarding efficacy of each treatment.64

Lymphomatoid Papulosis Lymphomatoid papulosis (LYP) typically has a chronic course of waxing and waning, bright pink to reddish brown, usually firm, papulonodules (Figs. 102.15A and B). Lesions spontaneously regress over weeks to months and may demonstrate central necrosis. While patients with LYP alone do not differ in survival from age-matched peers, between 5–20% may develop a second cutaneous lymphoid malignancy such as MF, ALCL, or Hodgkin lymphoma, either before or during the course of their disease. Currently, there are five different histologic subtypes of this disease most of which will demonstrate CD30+ atypical T-cells, which are outlined in Table 102.6. The most common histologic subtype (75%) of LYP is Type A, with large CD30+ atypical cells with convoluted nuclei and prominent nucleoli, resembling Reed–Sternberg cells. Figure 102.16 is characterized by large (25–40 µm) CD30+ atypical cells intermingled with a prominent inflammatory infiltrate. The large tumor cells have polymorphic convoluted nuclei with a minimum of one prominent nucleolus, resembling Reed–Sternberg cells when binucleate, as is seen in HD. Type A lymphomatoid papulosis is the most common histologic variant and accounts for 75% of all lymphomatoid papulosis specimens. Clinicalpathologic correlation is absolutely essential because CD30 antigen is merely a marker of reactive T- or B-cells

A Fig. 102.14: Primary cutaneous anaplastic large cell lymphoma.

B

Figs. 102.15A and B: Lymphomatoid papulosis with detail showing lesions close-up. Papules frequently evolve with central crust/necrosis resembling folliculitis or arthropod bite reactions.

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Section 30: Tumors of the Lymphoreticular System Table 102.6: Histologic subtypes of lymphomatoid papulosis. Type A

Type B Type C

Type D

Type E

Most common. Wedge-shaped infiltrate of CD30+ tumor cells admixed with neutrophils, eosinophils, histiocytes, and small lymphocytes Similar to MF with epidermotropic small CD30+ or CD30- cerebriform lymphocytes Sheets of CD30+ large atypical lymphocytes with scant admixed inflammatory cells resembles ALCL histologically Resembles primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma with epidermotropic small/medium atypical CD30+/ CD8+ lymphocytes. Angioinvasive type. Small-to-medium CD30+/CD8+ atypical lymphocytes with angiodestruction.

Fig. 102.17: Lymphomatoid papulosis type E, clinical appearance can mimick more aggressive lymphomas such as γ/δ T-cell lymphoma or aggressive epidermotropic cytotoxic CD8+ T-cell lymphoma.

of 97%, with approximately 60% of patients demonstrating relapse of disease after discontinuation of treatment after months or years. Other treatment modalities such as antibiotics, topical chemotherapy, oral bexarotene, and systemic interferons have been utilized with some success. However, the numbers reported are insufficient to extrapolate meaningful data on relapse and response rates to these treatments.64

SUBCUTANEOUS PANNICULITIS-LIKE T-CELL LYMPHOMA Fig. 102.16: Classic lymphomatoid papulosis with a wedge-shaped infiltrate of large CD30+ lymphocytes with convoluted nuclei and prominent nucleoli with background eosinophils and neutrophils.

and can be seen in a variety of infections and inflammatory disorders. Certain subtypes of LYP, particularly Type E, can clinically and histologically mimic more aggressive lymphomas (Fig. 102.17). Thorough physical examination with evaluation for lesions resembling MF should be performed with laboratory studies including blood count with differential, chemistries, and lactate dehydrogenase. If patients report no systemic symptoms and physical exam and laboratory findings do not suggest a concomitant second lymphoma, advanced imaging studies and/or bone marrow biopsies are not necessary. The best-documented treatments for LYP include topical steroids, phototherapy, and low-dose methotrexate (MTX). Clinical response rates to MTX are on the order

Subcutaneous panniculitis-like T-cell lymphoma (SPTL) is a rare entity mimicking panniculitis and limited to α/β cytotoxic T-cells predominantly expressing a CD3+, CD8+, and CD4-. It usually carries a CD56- phenotype, which also may express the cytotoxic proteins granzyme B, TIA-1, and perforin. Staining for betaF1 is always p ­ ositive, which confirms the α/β phenotype. Patients typically present with isolated or multiple nodular skin lesions or deep plaques most commonly involving the legs, arms, or trunk, respectively (Fig. 102.18). B-symptoms are reported in half of patients, and approximately 20% may have coexisting autoimmune diseases such as lupus, rheumatoid arthritis, diabetes, and multiple sclerosis. The most serious complication reported is hemophagocytic syndrome (HPS) which may occur in about 15% of cases.65 Histologically, lesions demonstrate a subcutaneous pleomorphic small to medium lymphoid infiltrate with irregular and hyperchromatic nuclei with tropism for fat lobules, usually sparing septae. Fat necrosis is always present to variable degrees (Fig. 102.19). Malignant

Chapter 102: Cutaneous T-cell Lymphomas auto-SCT in patients with SPTL, but complete remission was achieved in a few reported cases, although none had HPS. Information currently available suggests that conservative treatments should be considered first for this group of patients and more aggressive therapies such as CHOP or SCT should be reserved for patients not responding or progressing, despite more conservative efforts.65–67

EXTRANODAL NK/T-CELL LYMPHOMA (NASAL TYPE)

Fig. 102.18: Subcutaneous panniculitis-like T-cell lymphoma. Violaceous subcutaneous nodule, which can mimick other panniculitides.

Fig. 102.19: Subcutaneous panniculitis-like T-cell lymphoma. Malignant lymphocytes line up along fat cells. Courtesy: Scott C Wickless.

lymphocytes can extend into the reticular dermis and concentrate around adnexae. In-situ hybridization for EBV is always negative, which helps to distinguish SPTL from extranodal NKT-cell lymphoma involving the subcutis.66 Thorough history, physical examination and laboratory evaluation for HPS, coexisting autoimmune disease and whole body PET-CT for extent of disease is usually undertaken in these patients. Radiation can be utilized for localized disease, and for patients with coexisting lupus or other autoimmune disease, systemic steroids are the preferred mode of treatment. Aggressive multi-agent chemotherapy such as CHOP is reported as effective in many patients. Limited data does not demonstrate superiority of this treatment to other less-aggressive treatments. Very ­little information exists on either allo- or

In general, lymphomas expressing natural-killer (NK) cell phenotype are exceedingly rare in Western countries. Extranodal NKT-cell lymphoma, nasal type (ENKT) is an aggressive disease with poor prognosis. It most commonly occurs in mucosal or cutaneous epithelia of skin, nasal mucosa, or gastrointestinal tract. Males older than 50 are more commonly affected, and at least 7 out of 10 cases occur in East Asians. Survival is the same regardless of the gender or ethnicity of the patient.68 Patients typically present with facial nodules or ulcerations mimicking invasive fungal infections, leishmaniasis, or inflammatory conditions such as granulomatosis with polyangiitis. Histology demonstrates diffuse mixed inflammatory cells with small to medium pleomorphic lymphocytes with irregular nuclei and prominent angioinvasion and destruction. Malignant cells are CD3-, CD3ε+, CD56+, TIA-1+, Granzyme B+, and perforin +. In situ hybridization for EBV is positive in these cases and aids in diagnosis. Many of these tumors express P-glycoprotein which mediates resistance to many chemotherapeutic agents.69 Limited data suggest simultaneous radiochemotherapy of >50Gy with concurrent l-asparaginase or gemcitabine chemotherapy may result in better outcomes for localized disease, and autologous SCT has been used in high-risk patients. Disease rarity is a challenging aspect of ENKT and makes choice of optimal therapy difficult in more advanced patients.70–71

Hydroa Vacciniforme-like Lymphoma This rare cutaneous T-cell lymphoma is usually seen in Hispanic or Asian children. Hydroa vacinniformelike lymphoma (HVL) is associated with chronic latent Epstein–Barr virus. Affected patients often present with a deep-seated inflammatory plaques and nodules that may mimic cellulitis or arthropod bite reactions. However, it often presents with concomitant epidermal lesions that resemble hydroa-vacinniforme with edema, blisters, ulcers and scarring, usually on the head and upper

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Section 30: Tumors of the Lymphoreticular System extremities. Systemic symptoms of fever, lymphadenopathy, and hepatosplenomegaly are often present.72 Histologically, a dense, polymorphic lymphocytic infiltrate concentrated around adnexae and vessels throughout the mid-to-deep dermis, and occasionally extending to the subcutis, is present. The phenotype expressed is usually CD8+, or CD56+, with rare cases that are CD4+, suggesting either a T-cell or NK-cell progenitor. Cases with an NK-phenotype tend to present with clinical and histologic lesions resembling a panniculitis. All cases express cytotoxic markers such as granzyme B, TIA-1, and occasionally have CD30 expression. All cases are positive for Epstein–Barr early RNA (EBER).72–74 The clinical course of these patients is variable with some patients having a rapid, fatal, treatment-resistant course, and others marked by periods of remission and exacerbation. Progression appears to be more likely in patients expressing a T-cell phenotype and presenting clinically with severe facial swelling, systemic symptoms, and abnormal titers to EBV indicating chronic active infection. Treatment with radiation and chemotherapy tend to have little benefit or worse prognosis. Immunomodulatory treatments such as IFN-α, cyclosporine, chloroquine, and thalidomide often have symptom improvement or temporary remission.74

ANGIOIMMUNOBLASTIC T-CELL LYMPHOMA First described in 1974, but later found to be a T-cell lymphoma, angioimmunoblastic T-cell lymphoma (AITL) is a CD4+, CD8- process with dysregulation of endothelial and B-cells. Lymphadenopathy, B-symptoms, and hepato­ splenomegaly occur in about half of patients. Diagnosis is usually made upon lymph node biopsy, demonstrating effaced architecture with proliferation of follicle center dendritic cells and a polymorphous infiltrate of neoplastic T-cells, admixed with histiocytes, plasma cells, and eosinophils. Patients with cutaneous involvement often have pale to deep pink macules and papules, often with intense pruritus (Fig. 102.20). Histology often demonstrates a clonal T-cell population and a majority of cases also demonstrate B-cells with clonal IgH gene re-arrangements. B-cells and follicular dendritic cells are often EBV-positive. It is thought that the interactions of EBV infected cells chronically stimulates T-helper cells leading to malignant transformation. HHV-6 has also been isolated in many cases. Treatment usually consists of anthracycline-based chemotherapies, antiangiogenic agents such as lenalidomide might also be effective, future development of CD21

Fig. 102.20: Angioimmunoblastic T-cell lymphoma.

antagonists which block EBV entry may have application in treatment of this disease.75

PRIMARY CUTANEOUS PERIPHERAL T-CELL LYMPHOMA (UNSPECIFIED) This group of entities consists of T-cell lymphomas that do not fit into any of the other subtypes of cutaneous T-cell lymphoma. They are heterogeneous and account for 15 cm and ≤ 30 cm diameter T2c Large All encompassing > 30 cm diameter T3 Generalized T3a 2 non-contiguous body regions T3b ≥ 3 non-contiguous body regions

For PCMZL and PCFCL with solitary or limited disease, first-line treatment is radiation therapy or surgery, with fewer recurrences reported with radiation treatment (RT), perhaps due to the ability to treat a wider margin of uninvolved skin, particularly in lesions >5 cm in size at diagnosis. While the optimal dose for single lesions of PCFCL has not been established, the ISCL/EORTC recommends a dose of at least 30Gy with a treatment margin of 1 to 1.5 cm. Surgically excised lesions should have at least a 5 mm margin of clinically uninvolved tissue. Other treatments include intralesional steroid injections, topical high-potency steroids, imiquimod, and topical nitrogen mustard with varying efficacy. In cases of widespread or recurrent disease, a variety of treatment approaches have been used, including topical imiquimod, intralesional steroid injections, radiotherapy, and systemic rituximab, an anti-CD20 monoclonal antibody. If patients have disseminated disease, or very large tumors which impair function, they may rarely require chemotherapy if firstline options are not viable or ineffective. In these cases, the usual choice is cyclophosphamide, doxorubicin, oncovin/ vincristine, and prednisone (CHOP) with or without rituximab (R-CHOP).40 The diagnosis of PC-DLBCL is generally a harbinger of a more aggressive course of disease with close to a 50% 5-year mortality rate. Prognosis is worse in patients with leg lesions or multifocal disease at diagnosis. A slightly better overall survival rate was seen in patients with isolated non-leg lesions at diagnosis. Given this clinical scenario, PC-DLBCL is usually managed with anthracycline-based chemotherapy plus radiation. The standard protocol consists of R-CHOP in combination with local RT.

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Section 30: Tumors of the Lymphoreticular System Other systemic treatments currently under study for relapsed or refractory disease include lenalidomide which targets CD80 and CD40. Aurora kinase inhibitors which mediate effects via BCL-6, as well as Lumiliximab which targets CD23 may have application for treatment of PC-DLBCL.40 In summary, the cutaneous B-cell lymphomas represent a small, but diverse group of entities each with distinct clinical, histological, and immunophenotypic characteristics (Box 103.2). Every attempt to specifically categorize the patient’s disease should be made and correlated with clinical or histologic features that might suggest a secondary cutaneous spread of a primary lymphoma. Therapeutic approaches vary based on the extent and type of disease. Clinicians and pathologists must work in a collaborative manner to establish a clear-cut diagnosis, as there are times when histologic findings can be identical in both benign and malignant processes, and the disease can only be classified by molecular diagnostic or immunophenotypic data. An exacting approach informs the field of cutaneous lymphoma research and generates the body of knowledge, allowing for new therapeutic strategies in the future.

REFERENCES 1. Kupper TS, Fuhlbrigge RC. Immune surveillance in the skin: mechanisms and clinical consequences. Nat Rev Immunol 2004;4(3):211–22. 2. Egbuniwe IU, Karagiannis SN, Nestle FO, et al. Revisiting the role of B cells in skin immune surveillance. Trends Immunol 2015;36:102–11. 3. Pieper K, Grimbacher B, Eibel H. B-cell biology and development. J Aller Clin Immunol 2013;131:959–71. 4. LeBien TW, Tedder TF. B lymphocytes: how they develop and function. Blood 2008;112(5):1570–80. 5. Niiro H, Clark EA. Regulation of B-cell fate by antigenreceptor signals. Nat Rev Immunol 2002;2(12):945–56. 6. Melchers F. Checkpoints that control B cell development. J Clin Invest 2015;125(6):2203–10. 7. Picker LJ, EC Butcher. Physiological and molecular mechanisms of lymphocyte homing. Annu Rev Immunol 1992;10:561–91. 8. Shimizu Y, Newman W, Tanaka Y, et al. Lymphocyte interactions with endothelial cells. Immunol Today 1992;13: 106–12. 9. Okada T, Ngo VN, Ekland EH, et.al. Chemokine requirements for B cell entry to lymph nodes and Peyer’s patches. J Exp Med 2002; 196:65–75. 10. Ebisuno Y, Tanaka T, Kanemitsu N, et al. Cutting edge: the B cell chemokine CXC chemokine ligand 13/B lymphocyte chemoattractant is expressed in the high endothelial

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venules of lymph nodes and Peyer’s patches and affects B cell trafficking across high endothelial venules. J Immunol 2003;171:1642–6. Stein JV, Nombela-Arrieta, C. Chemokine control of lymphocyte trafficking: a general overview. Immunol 2005;116:1–12. Nihal M, Mikkola D, Wood GS. Detection of clonally restricted immunoglobulin heavy chain gene rearrangements in normal and lesional skin: analysis of the B cell component of the skin-associated lymphoid tissue and implications for the molecular diagnosis of cutaneous B cell lymphomas. J Mol Diagn 2000;2:5–10. Lukowsky A, Marchwat M, Sterry W, et al. Evaluation of B-cell clonality in archival skin biopsy samples of cutaneous B-cell lymphoma by immunoglobulin heavy chain gene polymerase chain reaction. Leuk Lymphoma 2006;47(3):487–93. Morales AV, Arber DA, Seo K, et al. Evaluation of B-cell clonality using the BIOMED-2 PCR method effectively distinguishes cutaneous B-cell lymphoma from benign lymphoid infiltrates. Am J Dermatopathol 2008;30(5):425–30. Blombery PA, Dicinson M, Westerman DA. Molecular lesions in B-cell lymphoproliferative disorders: recent contributions from studies utilizing high-throughput sequencing techniques. Leuk Lymphoma 2014;55(1):19–30. Goyal A, Moore JB, Gimbel D, et al. PD-1, S-100 and CD1a expression in pseudolymphomatous folliculitis, primary cutaneous marginal zone B-cell lymphoma (MALT lymphoma) and cutaneous lymphoid hyperplasia. J Cutan Pathol 2015;42:6–15. Bergman R, Khamaysi K, Khamaysi Z, et al. A study of histologic and immunophenotypical staining patterns in cutaneous lymphoid hyperplasia. J Am Acad Dermatol 2011;65:112–4. Bergman R, Khamaysi Z, Sahar D, et al. Cutaneous lymphoid hyperplasia presenting as a solitary facial nodule: clinical histopathologic, immunophenotypical, and molecular studies. Arch Dermatol 2006;142:1561–6. Willemze R, Jaffe ES, Berg G, et al. WHO-EORTC classification for cutaneous lymphomas. Blood 2005;105:3768–85. Slater DN. The new World Health Organization-European Organization for research and treatment of cancer classification for cutaneous lymphomas: a practical marriage of two giants. Br J Dermatol 2005;153:874–80. Swerdlow SH, Campo E, Harris NL, et al. eds. WHO Classification of Tumours of Hematopoietic and Lymphoid Tissues. Lyon: IARC Press, 2008. Riou-Gotta MO, Fournier E, Mermet I, et al. Primary cutaneous lymphomas: a population-based descriptive study of 71 consecutive cases diagnosed between 1980 and 2003. Leuk Lymphoma 2008;49:1537–44. Bradford PT, Devesa SS, Anderson WF, et al. Cutaneous lymphoma incidence patterns in the United States: a population-based study of 3884 cases. Blood 2009;113:5064–73. Vermeer MH, Willemze R. Recent advances in primary cutaneous B-cell lymphomas. Curr Opin Oncol 2014;26: 230–6.

Chapter 103: Cutaneous B-cell Lymphoma 25. Zinzani PL, Quaglino P, Pimpinelli N, et al. Prognostic factors in primary cutaneous B-cell lymphoma: the Italian study group for cutaneous lymphomas. J Clin Oncol 2006;24:1376–82. 26. Suarez AL, Pulitzer M, Horwitz S, et al. Primary cutaneous B-cell lymphomas: Part I. Clinical features, diagnosis, and classification. J Am Acad Dermatol 2013;69:329.e1–13. 27. Kim BK, Surti U, Pandya A, et al. Clinicopathologic, immunophenotypic, and molecular cytogenetic fluorescence in situ hybridization analysis of primary and secondary cutaneous follicular lymphomas. Am J Surg Pathol 2005;29:69–82. 28. Senff NJ, Hoefnagel JJ, Jansen PM, et al. Reclassification of 300 primary cutaneous B-cell lymphomas according to the new WHO-EORTC classification for cutaneous lymphomas: comparison with previous classifications and identification of prognostic markers. J Clin Oncol 2007; 25:1581–7. 29. Berti E, Alessi E, Caputo R, et al. Reticulohistiocytoma of the dorsum. J Am Acad Dermatol 1988;19:259–72. 30. Hoefnagel JJ, Vermeer MH, Jansen PM, et al. Bcl-2, Bcl-6 and CD10 expression in cutaneous B-cell lymphoma: further support for a follicle centre cell origin and differential diagnostic significance. Br J Dermatol 2003;149:1183–91. 31. Child FJ, Russell-Jones R, Woolford AJ, et al. Absence of the t(14;18) chromosomal translocation in primary cutaneous B-cell lymphoma. Br J Dermatol 2001;144:735–44. 32. Ghatalia P, Porter J, Wroblewski D, et al. Primary cutaneous marginal zone lymphoma associated with juxta-­ articular fibrotic nodules in a teenager. J Cutan Pathol 2013;40:477–84.

33. Goodlad JR, Davidson MM, Hollowood K, et al. Primary cutaneous B-cell lymphoma and Borrelia burgdorferi infection in patients from the highlands of Scotland. Am J Surg Pathol 2000;24:1279–85. 34. Cerroni L, Zöchling N, Pütz B, et al. Infection by Borrelia burgdorferi and cutaneous B-cell lymphoma. J Cutan Pathol 1997;24:457–61. 35. Hristov AC. Primary cutaneous diffuse large B-cell lymphoma, leg type: diagnostic considerations. Arch Pathol Lab Med 2012;136:876–81. 36. Senff NJ, Zoutman WH, Vermeer MH, et al. Fine-mapping chromosomal loss at 9p21: correlation with prognosis in primary cutaneous diffuse large B-cell lymphoma, leg type. J Invest Dermatol 2009;129:1149–55. 37. Wick MR, Mills SE, Scheithauer BW, et al. Reassessment of malignant “angioendotheliomatosis”. Evidence in favor of its reclassification as “intravascular
lymphomatosis”. Am J Surg Pathol 1986;10:112–23. 38. Shimada K, Kinoshita T, Naoe T, et al. Presentation and management of intravascular large B-cell lymphoma. Lancet Oncol 2009;10(9):895–902. 39. Golling P, Cozzio A, Dummer R, et al. Primary cutaneous B-cell lymphomas—clinicopathological, prognostic and therapeutic characterisation of 54 cases according to the WHO-EORTC classification and the ISCL/EORTC TNM classification system for primary cutaneous lymphomas other than mycosis fungoides and Sézary syndrome. Leuk Lymphoma 2008 Jun; 49(6): 1094-103. 40. Suarez AL, Querfeld C, Horwitz S, et al. Primary cutaneous B-cell lymphomas: Part II. Therapy and future directions. J Am Acad Dermatol 2013;69:343.e1–11.

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31

Dermatologic Surgery

Chapter

104

Dermatologic Surgery Eric Millican, Rachel Redenius, William G Stebbins

INTRODUCTION Dermatologic surgery encompasses a wide range of procedures from shave biopsies to complex facial reconstruction. Surgical dermatology is a required component of all residencies approved by the Accreditation Council for Graduate Medical Education, emphasizing the importance of knowledge of anatomy, proper preoperative care, surgical technique and postoperative management. These fundamentals will help dermatologists comfortably and safely perform procedures and adequately treat their patients.

ANATOMY Thorough knowledge of relevant surgical anatomy is essential for any invasive procedure.1,2 The danger zones for motor nerve transection deserve emphasis given their importance in minimizing complications.

Danger Zones Cutaneous sensory nerves are transected during skin surgery, but the resulting anesthesia is typically temporary and limited. In most cases, motor nerves are protected by overlying muscles and spared from inadvertent damage. There are exceptions, however, where motor nerves lie close to the surface with limited protection. Surgeons must remain vigilant about these “danger zones” to avoid permanent impairment. 1. The temple: As the temporal branch of the facial nerve crosses the zygoma, it is protected by a thin layer of subcutaneous fat and the temporoparietal fascia, also known as the superficial musculoaponeurotic system. The danger zone is the space between a line connecting the earlobe with the lateral tail of the eyebrow and a line connecting the tragus to just above the highest forehead crease. 2. The zygomatic cheek: The zygomatic branch of the facial nerve lies superficial to the masseter after it emerges from the parotid.

3. The mandible: The danger zone for the mandibular branch of the facial nerve occurs where the facial artery is palpable as it crosses the mandible. With age and increasing skin laxity, the nerve can sink into the submandibular neck. 4. The posterior triangle of the neck: The danger zone for the spinal accessory nerve is defined by a triangle bound by the midpoint of the posterior edge of the sternocleidomastoid, a superior point two thirds of the height of the posterior edge of the sternocleidomas-toid and a point one third of the height of the anterior edge of the trapezius.3

SURGICAL EQUIPMENT Dermatologic surgeons require various instruments including scalpels, scissors, curettes, skin hooks, hemostats, needle drivers and forceps. In addition, a standard surgical tray often contains a marking pen, ruler, towels, gauze, cottontipped applicators and suture material (Fig. 104.1). Scalpels consist of a handle and blade. Handles can be flat or round, and the most commonly used in dermatologic surgery are the Bard-Parker #3 and Beaver handles (Fig. 104.2). The Bard–Parker #3 can be used with #10, #11, #15 or #15c blades depending on the procedure and anatomic location. Scissors are an essential component of any surgical tray and come in many shapes and sizes (Figs. 104.3 to 104.5). Longer handles provide better access when working in a deeper plane, but shorter handles allow for better control. Blunt tips are used for undermining while sharp tips are used for dissection. Hemostats are used to clamp bleeding vessels and can be straight or curved. The Halsted Mosquito hemostat is commonly used in cutaneous surgery (Fig. 104.6B). Needle drivers come with small or large handles and smooth or serrated jaws (Figs. 104.6A and C). They grasp needles when suturing. Forceps may have tips that are smooth, serrated or toothed, but toothed most effectively grasp tissue while minimizing trauma (Figs. 104.7A to C).

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Section 31: Dermatologic Surgery

Fig. 104.1: (A) Needle driver; (B) Needle driver with scissors; (C) Suture scissors; (D) Curved Iris scissors; (E) Adson forceps; (F) Bishop-Harmon tissue forceps; (G) Round-handled scalpel.

Fig. 104.3: Top row left to right: tissue scissors, Gradle scissors, suture removal scissors. Bottom row left to right: curved Metzen­ baum scissors, curved Mayo scissors, curved Ragnell scissors. Courtesy: George-Tiemann & Co.

A

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Fig. 104.2: (A) Siegel No. 3 round scalpel handle with knurled handle and etched ruler; (B) Bard-Parker No. 3 handle with etched ruler. Courtesy: George-Tiemann & Co.

Single or double pronged skin hooks can evert and manipulate the skin with even less trauma than toothed forceps. Other instruments include eye shields, chalazion clamps in lip or eyelid procedures, Allis clamps to grab fibrous tissue, towel clamps to hold sterile drapes in place, nail splitters to cut the nail plate and nail elevators to separate the nail plate from the nail bed and nail folds. The surgeon should be familiar with their advantages and disadvantages of each instrument to optimize performance and ensure durability.4–6

Fig. 104.4: From left to right: black handle indicating one serrated scissor blade, gold handle indicating tungsten carbide inserts at the tip, plain handle. Courtesy: George-Tiemann & Co.

PREOPERATIVE CONSIDERATIONS General Overview A thorough preoperative evaluation lays the foundation for a successful surgery. It allows a meaningful discussion regarding the risks, benefits and alternatives to the planned procedure. It also identifies factors that may lead to adverse outcomes and allows the surgeon to avoid or minimize complications. Physicians should perform a focused physical examination assessing the overall health of the patient and

Chapter 104: Dermatologic Surgery

A

B

C Fig. 104.5: Castroviejo spring-loaded locking needle holder (top). Westcott spring-loaded scissors (bottom). Courtesy: George-Tiemann & Co.

Figs. 104.7A to C: (A) Suture removal forceps; (B) Bishop-Harmon toothed forceps; (C) Adson toothed forceps. Courtesy: George-Tiemann & Co.

A

diagnosis, description of the planned procedure, associated risks and benefits and alternatives including the consequences of treatment refusal. During this process, it is important to invite the patient to participate in shared decision-making and to explore the patient’s wishes and values. Informed consent laws vary by state, and surgeons should understand their state’s requirements.

B

Past Medical History

C Figs. 104.6A to C: (A) Tungsten carbide tipped needle driver; (B) Straight 3.5” and curved 5” mosquito hemostats; (C) Cross-hatch needle driver serrations (left) vs horizontal hemostat serrations (right). Courtesy: George-Tiemann & Co.

identifying the lesion of interest. When the site is identified, the patient and/or caregiver should confirm the location. Photographs taken at the time of the biopsy are ideal for clarifying the location, as a well-healed biopsy site can be challenging to identify.7

Informed Consent Once all parties agree on the correct site, the physician should thoroughly explain the planned procedure. The  informed consent should include discussion of the

Patients with certain comorbidities are at greater risk for complications and deserve special attention. Hyperten­ sion may increase bleeding, which could predispose to hematoma, wound dehiscence, flap or graft necrosis and infection.8 Diabetes increases the risk of wound infection but does not apparently increase the risk of other complications.9 Patients with a history of cardiovascular disease may take anticoagulants, have an implantable cardiac device or have an increased risk of infective endocarditis (Box 104.1). The presence of a bleeding disorder should be elicited in the preoperative evaluation so meticulous hemostasis, close follow-up and possibly consultation with hematology can be planned. The patient’s medical history should specifically include blood-borne infections such as HIV, hepatitis B and hepatitis C as personnel may wish to take additional precautions such as double gloving, which reduces the risk of glove perforation.10 Smoke evacuators can also be used to prevent inhalation of viral particles that may be present in surgical smoke.11

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Section 31: Dermatologic Surgery

Implantable Cardiac Devices Implantable cardiac devices include pacemakers and de­fibrillators. Any electromagnetic interference can po­­ tentially impair the sensor and cause inappropriate firing of the device, but modern devices now include insulated coatings and bipolar leads that greatly reduce the risk of interference from electrosurgery.12 Additionally, no signi­ ficant morbidity or mortality has been reported even when electromagnetic interference has occurred.13 Surgeons may take the following precautions to further reduce risk of interference: use of electrocautery, use of bipolar devices, moving the grounding pad to the side opposite the implanted device, using monopolar devices at least 15 cm from the implanted cardiac device, limiting bursts to 5 seconds or less and using the lowest possible power setting.12–14

Anticoagulation Approximately 25–38% of patients take at least one antithrombotic medication, most often aspirin or warfarin.15 Surgeons previously discontinued these medications due to the presumed risk of hemorrhagic complications. This risk is quite low, however, and thrombotic events from stopping anticoagulants can be fatal.16–18 Guidelines now unanimously recommend continuing these medications during dermatologic surgery.

Antibiotic Prophylaxis Cutaneous surgery has a very low incidence of infection ranging from 1% to 3%. The majority of dermatologic surgeries do not require preoperative antibiotics, though they may be considered for procedures that breach the oral mucosa or infected skin, procedures on the lower legs or groin, wedge excisions of the lip or ear, flaps on the nose, skin grafts or procedures in patients with extensive inflammatory skin disease.19,20 Certain narrowly defined circumstances may also require prophylactic antibiotics to reduce bacteremia.21 The American Heart Association guidelines specify cardiac conditions at high risk for infective endocarditis (Box 104.1),22 while the American Academy of Orthopedic Surgeons and the American Dental Association identify a higher risk for prosthetic joint infections in patients with hip or knee replacement less than two years prior to surgery (Box 104.2).19,20,23 In each case the guidelines recommend prophylaxis for these patients only for particularly

Box 104.1: High-risk cardiac conditions necessitating antibiotic prophylaxis. • History of previous endocarditis • Congenital heart disease limited to: (a) Unrepaired cyanotic congenital heart disease (b) Repaired congenital heart disease in the first 6 months following surgery (c) Repaired congenital heart disease with residual defects • Prosthetic heart valve • Cardiac transplant patient with valve dysfunction

Box 104.2: Patients at increased risk of prosthetic joint infection. • History of previous prosthetic joint infection • Joint replacement in the 2 years prior to the procedure • Patients with the following medical conditions: (a) Type I diabetes (b) Hemophilia (c) HIV infection (d) Malignancy (e) Malnourishment (f) Inflammatory arthropathies • Immunocompromised or immunosuppressed patients

high risk surgeries, such as procedures involving infected skin. Skin flora, particularly Staphylococcus and Strepto­ coccus species, cause most surgical site infections. Cephalexin 2 g PO given 15–60 minutes prior to the procedure provides adequate coverage for most cases, while amoxicillin is preferred for procedures involving the oral mucosa.24,25 Patients with penicillin allergy may take clindamycin, azithromycin, levofloxacin or trimethoprimsulfamethoxazole (Table 104.1).

Anesthesia Local anesthetics prevent nerve depolarization by inhibiting sodium channels. Small unmyelinated C-fibers, which transmit pain and temperature, are affected more than the larger myelinated A-fibers, which transmit touch, pressure and motor function. Most cutaneous surgeons use lidocaine due to its rapid onset of action and intermediate duration.26 Epinephrine is a vasoconstrictor often premixed with lidocaine at a concentration of 1:100,000 or 1:200,000. It decreases bleeding and diffusion of the local anesthetic.

Chapter 104: Dermatologic Surgery Table 104.1: Antibiotic prophylaxis. Surgical site Oral (1) Patient unable to take PO (2) Penicillin allergy Non-oral (1) Patient unable to take PO (2) Penicillin allergy

Antibiotics Amoxicillin Cefazolin/ceftriaxone Ampicillin Azithromycin Clindamycin Cephalexin Dicloxacillin Cefazolin/ceftriaxone Azithromycin Clindamycin Levofloxacin Trimethoprim-sulfamethoxazole

Reducing diffusion allows safe use of higher concentrations of lidocaine (4.5 mg/kg without epinephrine; 7.0 mg/ kg with epinephrine), though some patients may develop tachycardia or palpitations from the epinephrine. Sodium bicarbonate may be added to lidocaine in a 1:10 ratio to decrease its acidity and therefore the pain associated with infiltration. The most common technique for administering anesthesia in dermatologic surgery is local infiltration. Intradermal injection provides faster onset but may be more painful than subcutaneous administration. Many techniques may be used to improve patient comfort (Box  104.3).26 To anesthetize large areas and reduce the need for multiple injections, the surgeon may use a regional nerve block (see chapter 110).

Antisepsis For minor procedures, many dermatologists clean the skin with alcohol swabs. For more extensive procedures, chlorhexidine is most commonly used due to its broad-­ spectrum activity against gram positive and negative bacteria.27 It may cause ototoxicity or corneal toxicity when in direct contact with the eye or tympanic membrane and should be avoided in these areas. Iodine-containing preparations, such as povidone-iodine (Betadine), also have broad-spectrum activity but can stain the skin and are inactivated by blood. Both chlorhexidine and povidoneiodine can cause skin irritation. Preoperative depilation by shaving, clipping or use of chemicals, is sometimes used to keep hair from entering the incision site. If hair removal is necessary, clipping the hair to 1 mm in length may result in fewer surgical site infections than shaving.28

Dosage 2 g PO 1 g IV/IM 2 g IV/IM 500 mg PO 600 mg PO 2 g PO 2 g PO 1 g IV/IM 500 mg PO 600 mg PO 500 mg PO 160 mg/800 mg PO

Box 104.3: Minimizing pain with injection of local anesthetic. • Use small diameter needles (30 gauge) • Pinch adjacent skin to distract patient • Add sodium bicarbonate to anesthetic • Inject anesthetic slowly • For large areas, minimize the number of skin punctures as much as possible and inject into previously anesthetized areas • Consider topical anesthetic in children

There is no difference in the incidence of infection when shaving or clipping are performed on the day of surgery compared to the day prior to surgery.29

PROCEDURES Cryosurgery Cryosurgery is a method of destroying tissue through the use of freezing temperatures. It is a safe, simple, inexpensive procedure with minimal downtime and generally acceptable cosmetic outcomes. While side effects are usually mild, it can induce pain, dyspigmentation, bullae, paresthesia and alopecia.30,31 Large case series suggest it is effective for a range of lesions; however, treatment protocols vary, and high-quality randomized controlled trials are lacking. Effective cryotherapy involves one or more cycles of rapid freeze, greater than 100°C per minute, to a temperature of at least −40°C for malignant tissue, or −20°C for benign lesions (Table 104.2). A slow, complete thaw less than 10°C per minute follows, with slower thaw times

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Section 31: Dermatologic Surgery Table 104.2: Target temperatures for destruction with cryotherapy. Target Target temperature Melanocytes −4 to −7°CC Keratinocytes −25°CC BCC/SCC/Lentigo Maligna −50 to −60°C (BCC: basal cell carcinoma; SCC: squamous cell carcinoma)

creating more tissue destruction. The mechanism of tissue destruction is complex but involves intracellular ice crystal formation and apoptosis as well as ischemic cell death from microvascular failure during thawing.32 Liquid nitrogen, with a melting point of −195.6°C, is the most common agent used. Most commonly surgeons achieve this freeze-thaw cycle using a spray-tip on a hand-held canister. The tip is held perpendicular to the treated lesion at a distance of 1–2 cm. The depth of freezing is approximately equal to the lateral spread of the ice ball though this does not indicate the depth of any specific isotherm. By one estimate a 5-mm lateral spread formed within 90 seconds corresponds to −50°C at a depth of 3 mm.33 The “halo thaw time” is the time for the peripheral tissue around the lesion to thaw, and a longer halo thaw time indicates a deeper ice ball. A thermocouplepyrometer inserted into the lesion gives a more precise measurement of temperature and depth of freeze. For a more confined treatment the surgeon can place a plastic cone or otoscope tip over the target lesion.33 Alternative approaches include dipping a cotton-tipped applicator into liquid nitrogen then quickly applying it to the skin surface. This avoids the noise and expense of a spray canister, but at a cost of a smaller temperature differential as the cotton applicator warms before contacting the skin. Cryotherapy is commonly used to remove benign lesions such as seborrheic keratoses, condylomata and verrucae. Because melanocytes are more sensitive than keratinocytes, cryotherapy can also minimize the appearance of solar lentigines and ephelides.32 However, few high-quality randomized trials document the efficacy of cryotherapy in these conditions. A meta-analysis of cryotherapy for verruca vulgaris, for example, noted poor methodology of the studies and found a non-significant reduction compared with placebo.34 Cryotherapy remains the first-line treatment for isolated actinic keratosis. Retrospective studies suggested a cure rate greater than 98% using a total thaw time of 20–45   seconds.35 More recent randomized controlled

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C

D

Figs. 104.8A to D: (A) Initial curettage performed in all directions; (B) Lesion after surface curettage; (C) Electrodessication of lesion surface; (D) Additional curettage of crusted lesion performed after first and second passes. Crust is left intact after third pass.

trials have shown cure rates at 3 months ranging from 68% for a single freeze-thaw cycle36 to 88% for two cycles.37 Treatment of malignant tumors with cryotherapy has largely been supplanted by electrodessication and curettage (Figs. 104.8A to D), excisions, and Mohs micrographic surgery (MMS). It remains a viable alternative for appropriately selected patients who are unable or unwilling to tolerate surgery. A systematic review of basal cell carcinomas found a recurrence rate ranging from 0 to 8.2%, though protocols varied from 25 to 60 seconds of freezing.38 Curettage prior to cryotherapy may improve the clearance rate significantly.39 Some expert practitioners advocate cryosurgery for lentigo maligna.40 This should be approached cautiously, however, as cryotherapy is inadequate for any occult invasive melanoma. It can also induce atypia in treated nevi, making the diagnosis of any later recurrence problematic.41 Benign lesions treated with light cryotherapy can develop crusting, bullae and pigment alterations but heal without scarring. Malignant tumors treated with deeper freezes often ulcerate and heal by second intention. The scarring is less impressive than expected, however, because the fibroblasts and connective tissue matrix are relatively resistant to damage from freezing. This

Chapter 104: Dermatologic Surgery residual scaffolding may encourage cosmetically favorable healing.32

Biopsy Biopsy skills are essential for all dermatologists. The choice of biopsy technique varies with the differential diagnosis and cosmetic importance of the targeted area. Shave b ­iopsies adequately sample small, superficial lesions while punch, incisional or excisional biopsies are necessary for deep dermal or subcutaneous processes. Deeper scoop-shave biopsies provide middle ground for broad pigmented lesions, allowing full removal of the breadth of the lesion while adequately assessing tumor depth. This technique, however, creates a more prominent depressed scar. Biopsies on the central face present a cosmetic dilemma. A small, superficial shave biopsy creates minimal scarring, but a slightly deeper shave risks an unsightly depressed scar. A punch biopsy invariably creates a scar, but with meticulous suturing, the resultant linear scar can be preferable. Regardless of biopsy type, the target lesion should be marked clearly. Photographs including nearby anatomic landmarks facilitate identification of the site if it requires additional treatment.7 The biopsy area is then cleansed with alcohol wipes and anesthetized. Superficial dermal anesthesia placement and injection of relatively large volumes of anesthesia ensures coverage of the superficial nerves and elevates the lesion away from underlying structures.42 A shave biopsy can be obtained with a scalpel, a disposable flexible razor blade or a flexible razor blade with plastic side grips. The scalpel is held nearly parallel with the skin and the under surface of the lesion excised with smooth, even strokes. Lateral pressure on a razor blade creates a curvature of the cutting surface, which is then angled slightly downward into the skin and advanced. As the blade is advanced, the downward angle is decreased until, at the midpoint of the biopsy, the blade is parallel with the skin surface. The blade is then angled gradually upward until it exits at the far side of the lesion nearly tangential to the skin surface (Figs. 104.9A to D). Topical aluminum chloride solution or light electrocautery provides hemostasis. Daily application of petrolatum and a simple bandage provide adequate wound care. For a punch biopsy, an appropriately sized punch should be selected to completely remove the lesion or to

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Figs. 104.9A to D: (A) Skin made taught and blade placed tangential to the skin at the wound edge; (B) Blade angled slightly downward while advancing into the lesion; (C) Blade brought parallel to the skin surface at the base of the lesion; (D) Blade angled slightly upward through the distal portion of the lesion.

provide an adequate sample of a larger tumor or eruption. In general a 3 mm or larger punch is required.43 The skin around the biopsy site should be stretched perpendicular to the relaxed skin tension lines with the thumb and index finger of the non-dominant hand. The punch is centered on the target and pressed downward while rotating in one direction. After adequate depth is obtained the punch is removed. The tissue is grasped gently with toothed forceps and the base is cut with scissors. Two to three interrupted sutures reapproximate the epidermis and ensure hemostasis (Figs. 104.10A to F). Alternatively, some practitioners let the area heal by second intention with a pressure bandage. Punch biopsies 8 mm or larger may also require deep absorbable sutures and removal of standing cones.

Excision Excisions aim for complete removal of a lesion for diag­ nosis or definitive treatment. When the intent is treatment, the periphery of the lesion is marked and an additional margin of normal appearing skin is included in all directions. The size of this margin is based on histologic studies demonstrating the amount required to clear at least 95% of tumors of a given type (Table 104.3). Incisional biopsies

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Figs. 104.10A to F: (A) Biopsy site marked and anesthetized; (B) Punch centered over the lesion; (C) Punch inserted with twisting motion to desired depth; (D) Tissue gently grasped and cut at the base; (E) Resulting defect sutured with simple interrupted or figure of 8 suture; (F) Biopsy site following closure.

Table 104.3: Surgical margins. Benign Atypical nevus Basal cell carcinoma Squamous cell carcinoma Melanoma in situ Melanoma: • Breslow ≤ 1 mm • Breslow > 1 mm but ≤ 2 mm • Breslow > 2 mm

the direction. First, it should follow the natural relaxed skin tension lines. These lie perpendicular to the contractile direction of the underlying muscles and can be visualized by maximally contracting the muscles in the area, e.g., smiling for the cheeks or squinting for the temples. Notably, areas such as the neck and forehead have muscles acting in multiple directions, and closures in these locations can vary more freely. Second, the excision should respect the boundaries of cosmetic units. The face can be divided into multiple cosmetic units and subunits, defined by natural concavities and by relatively uniform skin thickness and composition. Excisions that cross boundaries between subunits will be more apparent, as will excisions in the center rather than the boundaries of a subunit. If a tumor occupies the majority of a subunit, total resection and replacement of the subunit may provide a more pleasing result.44 This must be balanced with the preservation of healthy tissue, however.45

Procedure 0–1 mm 2 mm 4 mm1 4–6 mm2 5 mm3 1 cm 1–2 cm 2 cm3

encompass a representative portion of the lesion. Proper preoperative planning is essential to ensure cosmetically acceptable outcomes.

Orientation To create a smooth scar, excisions are designed as fusiform shapes comprising a central circular lesion with two triangles at each pole. The orientation of these triangles can dramatically alter the final appearance. Most importantly, excisions must be designed to avoid tension on free margins including eyelids, nares and lips. Even a small excision parallel to these margins can generate unidirectional tension and noticeable distortion. Around the eyelids this can result in ectropion. After ensuring the orientation runs perpendicularly to adjacent free margins, the excision is designed to lie within the most cosmetically subtle lines. Two principles guide

Once the best orientation has been decided, the excised area is marked along with the desired margin and planned line of closure. The excision site and surrounding area are cleansed with the appropriate antiseptic. A sterile field is created with sterile towels or a plastic drape. A diamond or fusiform outline is drawn encompassing the lesion, the margins and the expected tissue redundancies at each pole. To minimize standing cutaneous deformities or “dog ears,” an apical angle of approximately 30 degrees is needed. This necessitates a length-width ratio of 3–4:1. The straight lines and sharp angles of the diamond excision can be rounded, but this may require a longer length to width ratio.46 Additionally, on a convex surface such as the arm, an S-shaped excision can be planned with the center of the excision following relaxed skin tension lines while the poles deviate away in opposite directions. This minimizes persistent dog ears at the poles (Figs. 104.11A to C).47 After the shape is outlined, the surgeon makes a full thickness excision into the superficial subcutaneous fat. The scalpel should be perpendicular to the skin throughout the incision. One single, smooth pass with the scalpel is preferable to multiple partial cuts, since a series of cuts can cause a stair-step beveled edge. It can be beneficial to lightly score the excision outline in the beginning since a smooth incision is difficult after half of the excision line has been released. Once the subcutaneous fat is reached, the excision specimen is gently grasped with toothed forceps and lifted. The base of the tissue is freed in a level

Chapter 104: Dermatologic Surgery

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Figs. 104.11A to C: (A) Design of S-plasty with attention to relaxed skin tension lines; (B) Immediately after wound closure; (C) 4-week follow-up.

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hemostasis is ensured. The ideal closure direction is then determined by drawing the wound together using manual pressure or a skin hook on each side. The closure orientation is then set by a single interrupted suture across the center of the wound. This temporary closure highlights the standing tissue cones at each pole. These are excised by grasping the center of the cone with forceps and incising the skin at one side of the cone until the incision connects with the primary wound edge. The cone is then undermined, the redundant skin is draped over the skin of the opposite edge and the base of this triangle is incised in a line that extends from the primary wound edge. The process is repeated at the other pole, ultimately creating a fusiform excision where the size and orientation of the triangular poles are dictated by the actual, rather than theoretical amount of redundant tissue. A layered closure of the wound is performed as discussed below.

Nail Procedures The nail unit presents particular challenges yet diagnostic and therapeutic procedures of this area are frequently indicated. The details of nail unit anatomy and a complete discussion of nail procedures are covered in Chapter 61 and several recent reviews.49,50

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Figs. 104.12A to F: (A) Excision design with 5 mm margins around a basal cell carcinoma; (B) Ellipse excised; (C) Excision taken evenly to subcutaneous fat; (D) Skin edges undermined with gentle grasping with Adson forcep; (E) Dermis and subcutaneous fat approximated with buried vertical mattress sutures; (F) Epidermis approximated with running suture.

plane using smooth, full width cuts with a #15 blade scalpel or scissors. The specimen can be tagged with a suture at the superior apex to clarify areas of concern if the excision margins are positive. Once the tissue is removed and placed in formalin, the surgeon undermines the wound edges, obtains hemostasis and performs a layered closure as detailed below (Figs. 104.12A to F). Preplanned ellipses are convenient and help ensure tissue redundancies are adequately removed. Unfortunately, they are often larger than necessary for a smooth closure.48 They also lack flexibility. If an M-plasty or S-curve would create a better closure, this must be determined prior to any incisions. An alternative approach starts by excising the target tumor plus the appropriate margin. This excision specimen can be tagged with a 12 o’clock suture as well. The edges of the wound are then undermined and

Anesthesia The entire nail apparatus can be well anesthetized with a digital block at the base of the finger supplemented by a wing block at the nail folds.51 Despite previous concern about the use of epinephrine in the fingertip, its safety has been well-established.52 Caution may still be warranted in patients with Raynaud’s or peripheral vascular disease.53–55

Avulsion Nail avulsion may be partial or total, therapeutic or diagnostic, and it may be the primary procedure or the initial step in biopsy or excision of a subungual lesion. The site is anesthetized and a tourniquet or rolled glove finger is placed to provide hemostasis. The nail plate is separated from the bed with a Freer elevator then divided as needed with a nail splitter. The nail is removed, hemostasis is obtained, long acting local anesthetics are added if desired and a dressing is placed that allows adequate blood flow to the fingertip. Patients should keep the treated limb e­ levated for 1–2 days to minimize throbbing and bleeding.

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Biopsy and Excision Biopsies of the nail unit can include punch biopsies, shave biopsies or excisional biopsies. For a punch biopsy of the nail bed, a 3–4 mm punch can be performed through the nail plate followed by a 3 mm or smaller punch biopsy of the nail bed. Both the plate and the nail bed specimens should be sent for pathology, as the nail bed epidermis often adheres to the nail plate specimen. All other nail unit biopsies require an initial full or partial nail avulsion. If a shave or a matrix excision is required, the distal matrix should be targeted where possible and the long axis of the wound should be directed horizontally for optimal healing.56 Even with immaculate technique, biopsy of the nail matrix will cause thinning of the nail plate distal to the biopsy, and permanent nail dystrophy is possible. Dressings and wound care are the same for nail unit biopsies and nail avulsions.57

Mohs Micrographic Surgery In the 1930s, Dr Frederic Mohs at the University of Wisconsin developed a surgical technique that allowed for complete removal of skin cancers while sparing normal tissue.58,59 This technique, referred to as chemosurgery, used zinc chloride paste to chemically fix the tissue followed by excision 24 hours later with microscopic examination of horizontal sections. These horizontal sections allowed visualization of 100% of the deep and peripheral margins unlike standard bread loafed vertical sections that sample less than 1% of the margins.16 Areas containing tumor were mapped in relation to body landmarks, and the procedure was repeated daily until no tumor remained. While cure rates were high, several disadvantages with the fixed tissue technique were noted. The 24-hour fixation time resulted in lengthy procedures, significant discomfort and limited options for reconstruction. These limitations led to the development of the fresh tissue technique that is used today. Dr. Mohs first used this technique in 1953 for eyelid tumors, but when Dr Theodore Tromovitch presented his data in 1970 at the annual meeting of the American College of Chemosurgery its safety and effectiveness were confirmed and its popularity began.60,61 Using the fresh tissue technique increased the speed of the procedure, allowing surgeons to remove several layers in a single day. It also substituted the pain of fixation for the limited pain of local anesthesia and allowed for a wide variety of reconstructive options. The procedure became known as Mohs micrographic surgery (MMS) in 1985 and this name continues in use today.58

In current practice, the patient is prepped, positioned and anesthetized with 1% lidocaine with 1:100,000 epinephrine buffered with sodium bicarbonate. Some surgeons debulk the tissue sharply with a curette or scalpel to better delineate the tumor margins and assist with processing. A thin margin around the clinically evident tumor is then incised circumferentially with a 45-degree bevel using a #15 blade. Prior to removal from the patient, the specimen is oriented with partial thickness hash marks. The hash marks are extended to the surrounding skin, providing reference points if additional tissue removal is required. The layer is removed, inked with 2–4 colors to maintain orientation and documented on a two-dimensional map (Figs. 104.13A to F). Hemostasis is obtained, and the patient is bandaged while the specimen is processed. In processing the tissue, the bowl-shaped specimen is flattened and the epidermal edges are brought down into the same horizontal plane as the deep margin. Creating relaxing incisions or bisecting the specimen is often required. The specimen is then frozen, cut on a cryostat into thin horizontal sections, and stained with hematoxylin and eosin or toluidine blue. For subtle tumors such as lentigo maligna, there are rapid protocols that allow the use of immunohistochemical stains.62 The Mohs surgeon reads the slides and marks any remaining tumor on the map. Additional tissue is removed only from these positive areas, and the process is repeated until all sections are

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Figs. 104.13A to F: (A) Surgical site is identified and 2 mm margin marked around the tumor; (B) Tumor is curetted to debulk and accurately define the borders; (C) Excision is performed at a 45 degree angle to create a beveled edge; (D) Beveled edge allows epidermis to be laid down on all sides; (E) Tissue is inked for evaluation; (F) Histologic appearance of Mohs layer with inked margins aligning with representation in E.

Chapter 104: Dermatologic Surgery Table 104.4: Summary of the appropriate use criteria for Mohs micrographic surgery. Area H (central face, eyelids, eyebrows, nose, lips, chin, ear, periauricular skin, temple, genitalia including perineal and perianal skin, nipples/areola, hands, feet, nail units and ankles) • Primary or recurrent BCC, SCC, lentigo maligna and melanoma in situ Area M (cheeks, forehead, scalp, neck, jawline, pretibial surface) • BCC –– Primary or recurrent: aggressive*, nodular, superficial in immunocompromised patient or size ≥ 0.6 cm • SCC –– Primary or recurrent: all histological subtypes • Lentigo maligna/melanoma in situ –– Primary or recurrent Area L (trunk and extremities – excluding pretibial surface, hands, feet, nail units and ankles) • BCC –– Primary: Aggressive* ≥ 0.6 cm, nodular > 2 cm, nodular in immunocompromised patient > 1.1 cm –– Recurrent: Aggressive*, nodular • SCC –– Primary: All histological subtypes > 2 cm or ≥ 1.1 cm in immunocompromised patients, KA-type ≥ 1.1 cm in immunocompetent patients and ≥ 0.6 cm in immunocompromised patients –– Recurrent: All histological subtypes except in situ/Bowen’s disease • Lentigo maligna/melanoma in situ –– Recurrent tumors (BCC: basal cell carcinoma; SCC: squamous cell carcinoma; KA: keratoacanthoma) *Aggressive BCC includes perineural invasion and the morpheaform/sclerosing, infiltrative, metatypical and micronodular histological subtypes.

tumor free. This technique provides the highest cure rates for skin cancers while maximally conserving normal tissue, making it the standard of care for large, aggressive, recurrent tumors and those in functionally or cosmetically sensitive areas.63–68 It is a safe and cost-effective treatment that can be performed as an outpatient procedure with limited complications.69–71 The tissue sparing benefits of Mohs are not required for all tumors, however, and a diverse expert panel released Appropriate Use Criteria specifying when Mohs surgery is appropriate, uncertain or inappropriate (Table 104.4).72

Reconstruction When the site is clear of tumor, the surgeon designs a repair that best preserves function and cosmetic appearance. The surgeon may repair the wound by linear closure, local or regional flap, graft or second intention healing.44,73 This is based on certainty of clear margins, patient factors, location of the wound, local tissue movement, presence of free margins, vascular supply and cosmesis. For a full ­discussion of reconstructive options (see Chapter 111). In the appropriate setting, second intention healing can be optimal (Figs. 104.14A to C). It is best for superficial wounds on concave surfaces away from free margins, such as the conchal bowl, medial canthus, and nasal alar groove, and for partial thickness defects on the lip. The

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Figs. 104.14A to C: (A) Surgical defect involving vermilion and cutaneous lower lip; (B) 2-week follow-up; (C) 4-week follow-up with complete healing.

resulting circular scar may be more visible than a wellexecuted closure, though the esthetic outcome is often outstanding. Where second intention healing is not ideal, most wounds are readily repaired with a layered closure involving buried interrupted vertical mattress dermal sutures with epidermal sutures, staples, adhesive glue or steristrips to approximate the skin edges (Figs. 104.15 and 104.16). This method is quick, simple and provides good cosmesis when it avoids tension on free margins, follows relaxed skin tension lines and respects the boundaries of cosmetic subunits. For large wounds or when side-to-side closure creates tissue distortion, the surgeon must recruit tissue laxity from other areas. Advancement (Figs. 104.17 and 104.18),

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Figs. 104.15A to E: (A) Simple interrupted sutures; (B) Simple running suture; (C) Running subcuticular suture; (D) Running horizontal mattress suture; (E) Vertical mattress suture. Courtesy: Matt Hand, MD

Figs. 104.17A to D: (A) Advancement flap design to cover cheek and portion of nasal sidewall; (B) Flap widely undermined in subcutaneous plane; (C) Flap advanced to cover majority of defect; (D) Burrow’s triangles (excised standing cones) used as full-thickness skin grafts to repair remainder of wound.

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Fig. 104.16A to F: Initial wound (A) symmetrically reapproximated by the rule of halves (B to C); The ensures even distribution of tissue along the wound during placement of deep (D and E) and epidermal (F) sutures; The use of a skin hook for retracting is also demonstrated (D).

rotation, transposition (Figs. 104.19 and 104.20), and axial flaps (Figs. 104.21A to F) slide or lift tissue into the defect to gain additional tissue mobility, reorient the tension vectors away from free margins and/or displace dog-ear deformities to cosmetically acceptable areas.74–81 It is important to consider both the primary movement (intended movement into the defect) and secondary movement (movement of the surrounding skin in response to the primary movement) when designing flaps. Knowledge of anatomy, tissue type and blood supply is also essential. Random pattern flaps do not include large, named arteries, and their

Figs. 104.18A to F: (A) Wound involving right upper lip with planned flap design; (B) Wound expanded to fill entire vertical height of upper lip (excluding apical triangle) and squared off to minimize pincushioning; (C) Central pedicle demonstrated; (D) Immediately after wound closure; (E) 1-week suture removal; (F) 6-week follow-up.

length to width ratio is limited.82 Axial pattern flaps include a named artery, which can support a much longer pedicle. In all cases, excessive manipulation, tension, inadequate pedicle size or vasoconstriction from smoking or

Chapter 104: Dermatologic Surgery

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Figs. 104.21A to F: (A) Full thickness helical defect involving cartilage; (B) Postauricular interpolation flap in place; (C) 1-week postop appearance; (D) Division and inset of flap at 2 weeks with granulating postauricular wound; (E) Restored helical contour at 4 weeks after division and inset; (F) Healing postauricular donor site at 4 weeks.

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Figs. 104.19A to D: (A) Flap design; (B) Incision of flap; (C) Depth and width of undermining demonstrated; (D) Closure of the wound with no tension on free margin (eyelid and brow).

grafts can repair the defect. Grafts can include partial or full thickness dermis and/or cartilage for added structural support. In all cases the graft survival is dependent on the blood supply of the recipient site (Figs. 104.22A to I).83–85

POSTOPERATIVE CONSIDERATIONS Dressings A

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Figs. 104.20A to F: (A) Bilobed flap design; (B) Flap undermined in submuscular plane; (C) Transposition of lobes into position with closure of tertiary defect; (D) Sutured wound; (E) Frontal view at 4-week follow-up; (F) Side view at 4-week follow-up.

diabetes can lead to flap ischemia. Flaps are not advisable until clear margins are obtained either by Mohs surgery or staged excision, as recurrence requires re-excision of a significant portion of the flap, and the subsequent repair is hindered by scar tissue and the loss of at least one nearby tissue reservoir. Where flaps are not a viable option, skin

Following repair, the surgeon must select an appropriate wound dressing. Modern wound care options are manifold and are covered in detail in chapter 61. A pressure dressing is typically applied for 24–48 hours to maintain hemostasis. This involves a thin layer of petrolatum covered with a non-adherent pad. A thick, absorbent layer is then created with cotton gauze, and tape is stretched over the dressing. Some sites, like the extremities, may benefit from additional covering with a stretchable wrap. For flaps with a tenuous blood supply, surgeons may forgo a pressure dressing and use the same approach with a looser layer of tape instead. The exposed edges of an interpolation flap pedicle are adequately managed with pinpoint hemostasis followed by a circumferentially wrapped Xeroform or oxidized cellulose gauze that can be sutured lightly in place. Skin grafts require adherence to the wound bed for their survival. To ensure the graft remains in close approximation to the wound bed, a bolster dressing can be sutured

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Section 31: Dermatologic Surgery preferentially used due to the risk of allergic contact dermatitis from antibiotic-containing emollients, particularly those with neomycin.86

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Figs. 104.22A to I: (A) Large defect of left ala and lateral nasal tip; (B) Nasal valve at risk for collapse without cartilage placement due to anticipated wound contraction; (C) Harvest sites for full-thickness skin graft (hairless preauricular cheek) and cartilage graft (antihelix); (D) Cartilage strut placed in left ala secured with basting sutures; (E) Fullthickness skin graft placed; (F) Nasal valve competency restored with cartilage strut; (G) Bolster of Xeroform gauze placed on both sides of repair; (H) 6-week follow-up, frontal view with patent nasal valve and symmetric result; (I) 6-week follow-up, lateral view.

Table 104.5: Suture removal times. Site Days before suture removal Scalp 10–14 Face 5–7 Neck 5–7 Trunk 10–14 Extremities 10–14

in place for the first week. Xeroform or Vaseline impregnated gauze covers the graft followed by a thick cotton gauze, eye pad or dental roll. Non-absorbable sutures are then sutured to skin surrounding the graft and tied together over the dressing, pulling it down firmly against the graft. After pressure dressings or bolsters are removed, the surgical sites can be washed gently with soap and water and/or dilute acetic acid solution. Daily dressings consist of petrolatum covered by a non-stick pad secured with tape. These dressings continue until sutures are removed (Table 104.5) or until a second intention wound has fully re-epithelialized. Plain petrolatum is

Postoperative pain following dermatologic procedures is usually mild, but the indications for more aggressive pain management are not well understood. Patients who are younger as well as those with obesity, a history of depression, regular opioid use or hyperalgesia syndromes are at higher risk for significant postoperative pain.87 Patient gender has been variably linked to increased use of pain medication.87,88 Flap repairs and procedures on highly innervated areas such as the scalp, ears and nose may also require additional pain control.88 Acetaminophen, 500 mg every 4–6 hours, is the first line treatment for postprocedure pain. It does not increase the risk of bleeding and has minimal side effects if the dose remains less than 3 g over 24 hours. For patients with severe liver disease or acetaminophen intolerance, ibuprofen 400 mg every 4–6 hours is reasonable. In fact, a combination of acetaminophen and NSAIDs likely provides better pain control than either medication alone or opioids.89 There is concern about bleeding with NSAIDs because they impair platelet aggregation, but it is unclear if this is clinically significant. One small case series found no increased postoperative bleeding due to NSAIDs.90 When these efforts are inadequate, narcotic pain medication may be used. Oxycodone or hydrocodone 5 mg combined with acetaminophen 325 mg or ibuprofen 400 mg is typically effective. Moderate to severe pain peaks in the first 1–2 days in most patients.88 Surgeons should prescribe a sufficient amount of medication to cover this period but not more. In one study 86% of patients who filled a prescription for opioids following dermatologic surgery had unused pills left over, and over half of them planned to keep them for future self-medication.91 A special note should be made about postoperative antibiotics. As noted above, there are certain narrow cases where a single preoperative antibiotic dose is indicated. Anecdotally, patients frequently receive variable lengths of postoperative antibiotics in addition to or in lieu of this. This is likely inappropriate. Guidelines from general surgery recommend antimicrobials once preoperatively with intraoperative redosing if the surgery lasts greater than two continuous hours. Postoperative antibiotics are not given or discontinued within 24 hours.25 Prolonged Mohs cases may warrant a second perioperative dose,

Chapter 104: Dermatologic Surgery though the benefit has not been demonstrated. Multi-day postoperative antibiotic courses have not been proven beneficial and carry the risks of adverse drug reactions and antibiotic resistance.92 As noted previously, certain situations have a higher risk of surgical site infection and patients may benefit from preoperative antibiotics in these cases, but published guidelines do not currently recommend postoperative antibiotics even in these instances.27,30

COMPLICATIONS

so abscesses can be drained and wound cultures can be obtained prior to initiating antibiotics. A first generation cephalosporin or doxycycline is a good first line therapy for all sites while awaiting culture results. Necrosis typically appears within the first 1–2 weeks, particularly at the leading edges of flaps or the center of high-tension closures. Flaps with pallor at the time of inset are at high risk of failure and should be immediately revised or, if revision is not possible, treated with gentle heat or possibly hyperbaric oxygen.95 If necrosis occurs, the area should be treated as a second intention wound and allowed to heal fully prior to revision. Wound dehiscence most often occurs at the time of suture removal barring earlier infections or hematomas. Dehisced wounds can be freshened and resutured or left to heal by second intention.

Complications in dermatologic surgery are uncommon.70,93,94 When they occur, they can be minor, or they can cause significant morbidity or, rarely, mortality. Anti­ cipation of avoidable complications and management of unavoidable ones optimize results. Bleeding is a relatively common complication that typically occurs within the first 24 hours. Most cases are quickly controlled with direct pressure, but when it persists it must be addressed to avoid hematoma formation with concomitant risk of dehiscence, flap necrosis and infection (Figs. 104.23A to F). An actively expanding hematoma in the orbit or neck constitutes a medical emergency. Infections typically declare themselves 4–8 days postoperatively when the wound becomes increasingly red, tender and indurated (Figs. 104.24A to F). The patient should be evaluated in person whenever possible

With careful planning, meticulous technique and excellent wound care, surgical scars can cause little to no cosmetic penalty. Patient factors and improper technique frequently prevent this ideal, however, and this risk should be discussed preoperatively. Patients who smoke carry an increased risk of postoperative necrosis and should be strongly encouraged to quit or at least decrease consumption in the weeks preceding and following surgery.96,97 Similarly, patients with uncontrolled diabetes or significant peripheral vascular disease may see delayed

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Figs. 104.23A to F: (A) Large, wound-threatening hematoma; (B) Wound opened revealing a large, congealed hematoma; (C) Wound cleaned and hemostasis achieved; (D) 1-week follow-up with improvement in bruising and resolved hematoma; (E) 8-week follow-up, lateral view; (F) 8-week follow-up, frontal view.

Suboptimal Scarring

Figs. 104.24A to F: (A) Wound infection with erythema, induration, tenderness, and purulent discharge; (B) Wound opened and rinsed; (C) Xeroform gauze placed for 7 days; (D) Wound allowed to heal by second intention, granulation at 4-week follow-up; (E) 7-week followup; (F) 12-week follow-up with complete wound contraction back to a linear scar.

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Section 31: Dermatologic Surgery wound healing with concomitant risk of dehiscence and excess scarring. Anatomic location of the surgery can also impact wound healing with lower extremity wounds subject to slow healing and dehiscence and upper torso wounds prone to developing hypertrophic scars. Surgeons may consider wider undermining and longerlasting dermal sutures in these areas to minimize the risk of spread scars.98 Finally, certain repair options carry inherent specific risks of poor healing, such as suture tracks from epidermal sutures and pincushioning from transposition flaps. Surgeons may minimize but not entirely eliminate these through careful technique.99 Suboptimal scarring will develop at some point in even the most expert hands. It is manageable using a number of techniques, but regular and open discussion with the patient about their perception of the scar is essential. Simple suboptimal results such as spitting sutures, prominent erythema or even persistent standing cutaneous deformities are readily addressed once the surgeon is aware of the issue. Other forms of poor healing present a greater challenge and may require multiple followup procedures. Contour deformities can be minimized with manual dermabrasion or ablative laser resurfacing (Figs. 104.25A to D).100 Keloid and hypertrophic scars

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Fig. 104.25A to D: (A) Scar with contour irregularity along the suture line; (B) Manual dermabrasion performed with diamond fraise; (C) 6 weeks later, fractional CO2 laser to scar for further contour; (D) 6 weeks after fractional CO2 laser with significantly improved contour.

present a particular challenge. Silicone sheets applied daily postoperatively may decrease their formation, though simple occlusion and hydration may be equally effective.101–103 Once a hypertrophic scar has developed, the first line treatment remains serial intralesional corticosteroids. These can decrease thickness and relieve symptoms, but they risk atrophy and hypopigmentation of the surrounding skin.104 Second line treatments include intralesional fluorouracil, ablative or non-ablative lasers, radiation or various combinations of these approaches. Surgeons should consider re-excision very cautiously as there is a high risk of creating a larger, more symptomatic scar.

REFERENCES 1. Salasche SJ, Bernstein G, Senkarik M. Surgical anatomy of the skin. Norwalk: Appleton & Lange; 1988. 2. Bennett RG. Fundamentals of cutaneous surgery. St Louis: Mosby; 1988. 3. Landers JT, Maino K. Clarifying Erb’s point as an anatomic landmark in the posterior cervical triangle. Dermatol Surg 2012;38:954–7. 4. Pinnella Z, Robbins K, Joseph AK. Surgical instruments. In: Avram MR, Avram MM, Ratner D, editors. Procedural dermatology. New York: McGraw-Hill; 2015. p. 82–8. 5. Weber LA. The surgical tray. Dermatol Clin 1998;16:17–24. 6. Neuburg M. Instrumentation in dermatologic surgery. Semin Dermatol 1994;13:10–9. 7. McGinness JL, Goldstein G. The value of preoperative biopsy-site photography for identifying cutaneous lesions. Dermatol Surg 2010;36:194–7. 8. Larson RJ, Aylward J. Evaluation and management of hypertension in the perioperative period of Mohs micrographic surgery: a review. Dermatol Surg 2014;40:603–9. 9. Dixon AJ, Dixon MP, Dixon JB. Prospective study of skin surgery in patients with and without known diabetes. Dermatol Surg 2009;35:1035–40. 10. Mischke C, Verbeek J, Saarto A, et al. Gloves, extra gloves, or special types of gloves for preventing percutaneous exposure injuries in healthcare personnel. Cochrane Database Syst Rev 2014;3:CD009573. 11. Oganesyan G, Eimpunth S, Kim SS, et  al. Surgical smoke in dermatologic surgery. Dermatol Surg 2014;40:1373–7. 12. Howe N, Cherpelis B. Obtaining rapid and effective hemostasis: part II. Electrosurgery in patients with implantable cardiac devices. J Am Acad Dermatol 2013;69:677 e1–9. 13. Matzke TJ, Christenson LJ, Christenson SD, et al. Pacemakers and implantable cardiac defibrillators in dermatologic surgery. Dermatol Surg 2006;32:1155–62; discussion 62. 14. Riordan AT, Gamache C, Fosko SW. Electrosurgery and cardiac devices. J Am Acad Dermatol 1997;37:250–5. 15. Callahan S, Goldsberry A, Kim G, et al. The management of antithrombotic medication in skin surgery. Dermatol Surg 2012;38:1417–26.

Chapter 104: Dermatologic Surgery 16. Cook-Norris RH, Michaels JD, Weaver AL, et al. Complications of cutaneous surgery in patients  taking clopidogrel-containing anticoagulation. J Am Acad Dermatol 2011;65:584–91. 17. Bordeaux JS, Martires KJ, Goldberg D, et al. Prospective evaluation of dermatologic surgery complications including patients on multiple antiplatelet and anticoagulant medications. J Am Acad Dermatol 2011;65:576–83. 18. Kovich O, Otley CC. Thrombotic complications related to discontinuation of warfarin and aspirin therapy perioperatively for cutaneous operation. J Am Acad Dermatol 2003;48:233–7. 19. Wright TI, Baddour LM, Berbari EF, et al. Antibiotic prophylaxis in dermatologic surgery: advisory statement 2008. J Am Acad Dermatol 2008;59:464–73. 20. Bae-Harboe YS, Liang CA. Perioperative antibiotic use of dermatologic surgeons in 2012. Dermatol Surg 2013;39:1592–601. 21. Shurman DL, Benedetto AV. Antimicrobials in dermatologic surgery: facts and controversies. Clin Dermatol 2010;28:505–10. 22. Wilson W, Taubert KA, Gewitz M, et al. Prevention of infective endocarditis: guidelines from the American Heart Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation 2007;116:1736–54. 23. Watters W, 3rd, Rethman MP, Hanson NB, et al. Prevention of orthopaedic implant infection in patients undergoing dental procedures. J Am Acad Orthop Surg 2013;21: 180–9. 24. Classen DC, Evans RS, Pestotnik SL, et al. The timing of prophylactic administration of antibiotics and the risk of surgical-wound infection. N Engl J Med 1992;326:281–6. 25. Bratzler DW, Dellinger EP, Olsen KM, et al. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Am J Health Syst Pharm 2013;70:195–283. 26. Koay J, Orengo I. Application of local anesthetics in dermatologic surgery. Dermatol Surg 2002;28:143–8. 27. Sebben JE. Surgical antiseptics. J Am Acad Dermatol 1983;9:759–65. 28. Lefebvre A, Saliou P, Lucet JC, et al. Preoperative hair removal and surgical site infections: network metaanalysis of randomized controlled trials. J Hosp Infect 2015;91:100–8. 29. Tanner J, Norrie P, Melen K. Preoperative hair removal to reduce surgical site infection. Cochrane Database Syst Rev 2011;11:CD004122. 30. Nix TE, Jr. Liquid-nitrogen neuropathy. Arch Dermatol 1965;92:185–7. 31. Poziomczyk CS, Koche B, Dornelles Mde A, et al. Pain evaluation in the cryosurgery of actinic keratoses. An Bras Dermatol 2011;86:645–50. 32. Gage AA, Baust JM, Baust JG. Experimental cryosurgery investigations in vivo. Cryobiology 2009;59:229–43.

33. Torre D. Cryosurgical instrumentation and depth dose monitoring. Clin Dermatol 1990;8:48–60. 34. Kwok CS, Gibbs S, Bennett C, et al. Topical treatments for cutaneous warts. Cochrane Database Syst Rev 2012; 9:CD001781. 35. Lubritz RR, Smolewski SA. Cryosurgery cure rate of actinic keratoses. J Am Acad Dermatol 1982;7:631–2. 36. Freeman M, Vinciullo C, Francis D, et al. A comparison of photodynamic therapy using topical methyl aminolevulinate (Metvix) with single cycle cryotherapy in patients with actinic keratosis: a prospective, randomized study. J Dermatolog Treat 2003;14:99–106. 37. Kaufmann R, Spelman L, Weightman W, et al. Multicentre intraindividual randomized trial of topical methyl aminolaevulinate-photodynamic therapy vs. cryotherapy for multiple actinic keratoses on the extremities. Br J Dermatol 2008;158:994–9. 38. Kokoszka A, Scheinfeld N. Evidence-based review of the use of cryosurgery in treatment of basal cell carcinoma. Dermatol Surg 2003;29:566–71. 39. Lindemalm-Lundstam B, Dalenback J. Prospective follow-up after curettage-cryosurgery for scalp and face skin cancers. Br J Dermatol 2009;161:568–76. 40. Kuflik EG, Gage AA. Cryosurgery for lentigo maligna. J Am Acad Dermatol 1994;31:75–8. 41. Adeniran AJ, Prieto VG, Chon S, et al. Atypical histologic and immunohistochemical findings in melanocytic nevi after liquid nitrogen cryotherapy. J Am Acad Dermatol 2009;61:341–5. 42. Salasche SJ, Giancola JM, Trookman NS. Surgical pearl: hydroexpansion with local anesthesia. J Am Acad Dermatol 1995;33:510–2. 43. Todd P, Garioch JJ, Humphreys S, et al. Evaluation of the 2-mm punch biopsy in dermatological diagnosis. Clin Exp Dermatol 1996;21:11–3. 44. Summers BK, Siegle RJ. Facial cutaneous reconstructive surgery: general aesthetic principles. J Am Acad Dermatol 1993;29:669–81; quiz 82–3. 45. Rohrich RJ, Griffin JR, Ansari M, et al. Nasal reconstruction—beyond aesthetic subunits: a 15-year review of 1334 cases. Plast Reconstr Surg 2004;114:1405–16; discussion 17–9. 46. Moody BR, McCarthy JE, Sengelmann RD. The apical angle: a mathematical analysis of the ellipse. Dermatol Surg 2001;27:61–3. 47. Zitelli JA. TIPS for a better ellipse. J Am Acad Dermatol 1990;22:101–3. 48. Lee TS, Murakami CS, Suryadevara AC. Tissue conservation using circular defect with dog-ear deformities excision technique. Laryngoscope 2011;121:2299–304. 49. Fleckman P, Allan C. Surgical anatomy of the nail unit. Dermatol Surg 2001;27:257–60. 50. Haneke E. Surgical anatomy of the nail apparatus. Dermatol Clin 2006;24:291–6. 51. Jellinek NJ, Velez NF. Nail surgery: best way to obtain effective anesthesia. Dermatol Clin 2015;33:265–71. 52. Firoz B, Davis N, Goldberg LH. Local anesthesia using buffered 0.5% lidocaine with 1:200,000 epinephrine for tumors

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53.

54.

55.

56.

57. 58.

59. 60.

61. 62.

63.

64.

65.

66.

67.

68.

69.

70.

of the digits treated with Mohs micrographic surgery. J Am Acad Dermatol 2009;61:639–43. Krunic AL, Wang LC, Soltani K, et al. Digital anesthesia with epinephrine: an old myth revisited. J Am Acad Dermatol 2004;51:755–9. Thomson CJ, Lalonde DH, Denkler KA, et al. A critical look at the evidence for and against elective epinephrine use in the finger. Plast Reconstr Surg 2007;119:260–6. Lalonde D, Bell M, Benoit P, et al. A multicenter prospective study of 3,110 consecutive cases of elective epinephrine use in the fingers and hand: the Dalhousie Project clinical phase. J Hand Surg Am 2005;30:1061–7. Jellinek N. Nail matrix biopsy of longitudinal melanonychia: diagnostic algorithm including the matrix shave biopsy. J Am Acad Dermatol 2007;56:803–10. Haneke E. Nail surgery. Clin Dermatol 2013;31:516–25. Brodland DG, Amonette R, Hanke CW, et al. The history and evolution of Mohs micrographic surgery. Dermatol Surg 2000;26:303–7. Mohs FE. Chemosurgery: a microscopically controlled method of cancer excision. Arch Surg 1941;42:279–95. Mohs FE. Chemosurgery for skin cancer: fixed tissue and fresh tissue techniques. Arch Dermatol 1976;112: 211–5. Tromovitch TA, Stegeman SJ. Microscopically controlled excision of skin tumors. Arch Dermatol 1974;110:231–2. El Tal AK, Abrou AE, Stiff MA, et al. Immunostaining in Mohs micrographic surgery: a review. Dermatol Surg 2010;36:275–90. Leibovitch I, Huilgol SC, Selva D, et al. Cutaneous squamous cell carcinoma treated with Mohs micrographic surgery in Australia I. Experience over 10 years. J Am Acad Dermatol 2005;53:253–60. Pugliano-Mauro M, Goldman G. Mohs surgery is effective for high-risk cutaneous squamous cell carcinoma. Dermatol Surg 2010;36:1544–53. Leibovitch I, Huilgol SC, Selva D, et al. Microcystic adnexal carcinoma: treatment with Mohs micrographic surgery. J Am Acad Dermatol 2005;52:295–300. Leibovitch I, Huilgol SC, Selva D, et al. Basal cell carcinoma treated with Mohs surgery in Australia I. Experience over 10 years. J Am Acad Dermatol 2005;53:445–51. Ratner D, Thomas CO, Johnson TM, et al. Mohs micrographic surgery for the treatment of dermatofibrosarcoma protuberans. Results of a multi-institutional series with an analysis of the extent of microscopic spread. J Am Acad Dermatol 1997;37:600–13. Zitelli JA, Brown C, Hanusa BH. Mohs micrographic surgery for the treatment of primary cutaneous melanoma. J Am Acad Dermatol 1997;37:236–45. Merritt BG, Lee NY, Brodland DG, et al. The safety of Mohs surgery: a prospective multicenter cohort study. J Am Acad Dermatol 2012;67:1302–9. Alam M, Ibrahim O, Nodzenski M, et al. Adverse events associated with Mohs micrographic surgery: multicenter prospective cohort study of 20,821 cases at 23 centers. JAMA Dermatol 2013;149:1378–85.

71. Cook J, Zitelli JA. Mohs micrographic surgery: a cost analysis. J Am Acad Dermatol 1998;39:698–703. 72. Ad Hoc Task F, Connolly SM, Baker DR, et al. AAD/ACMS/ ASDSA/ASMS 2012 appropriate use criteria for Mohs micrographic surgery: a report of the American Academy of Dermatology, American College of Mohs Surgery, American Society for Dermatologic Surgery Association, and the American Society for Mohs Surgery. J Am Acad Dermatol 2012;67:531–50. 73. Zelac DE, Swanson N, Simpson M, et al. The history of dermatologic surgical reconstruction. Dermatol Surg 2000;26:983–90. 74. Krishnan R, Garman M, Nunez-Gussman J, et al. Advancement flaps: a basic theme with many variations. Dermatol Surg 2005;31:986–94. 75. Braun M, Jr., Cook J. The island pedicle flap. Dermatol Surg 2005;31:995–1005. 76. Goldman GD. Rotation flaps. Dermatol Surg 2005;31:1006–13. 77. Miller CJ. Design principles for transposition flaps: the rhombic (single-lobed), bilobed, and trilobed flaps. Dermatol Surg 2014;40 Suppl 9:S43–52. 78. Rohrer TE, Bhatia A. Transposition flaps in cutaneous ­surgery. Dermatol Surg 2005;31:1014–23. 79. Zitelli JA. The bilobed flap for nasal reconstruction. Arch Dermatol 1989;125:957–9. 80. Nguyen TH. Staged cheek-to-nose and auricular interpolation flaps. Dermatol Surg 2005;31:1034–45. 81. Brodland DG. Paramedian forehead flap reconstruction for nasal defects. Dermatol Surg 2005;31:1046–52. 82. Baker SR. Local flaps in facial reconstruction. Philadelphia: Elsevier Saunders; 2014. 83. Adams DC, Ramsey ML. Grafts in dermatologic surgery: review and update on full- and split-thickness skin grafts, free cartilage grafts, and composite grafts. Dermatol Surg 2005;31:1055–67. 84. Weisberg NK, Becker DS. Repair of nasal ala defects with conchal bowl composite grafts. Dermatol Surg 2000;26:1047–51. 85. Ibrahimi OA, Campbell T, Youker S, et al. Nonanatomic free cartilage batten grafting with second intention healing for defects on the distal nose. J Drugs Dermatol 2012;11:46–50. 86. Sheth VM, Weitzul S. Postoperative topical antimicrobial use. Dermatitis 2008;19:181–9. 87. Glass JS, Hardy CL, Meeks NM, et al. Acute pain management in dermatology: risk assessment and treatment. J Am Acad Dermatol 2015;73:543–60. 88. Firoz BF, Goldberg LH, Arnon O, et al. An analysis of pain and analgesia after Mohs micrographic surgery. J Am Acad Dermatol 2010;63:79–86. 89. Sniezek PJ, Brodland DG, Zitelli JA. A randomized controlled trial comparing acetaminophen, acetaminophen and ibuprofen, and acetaminophen and codeine for postoperative pain relief after Mohs surgery and cutaneous reconstruction. Dermatol Surg 2011;37:1007–13. 90. Lawrence C, Sakuntabhai A, Tiling-Grosse S. Effect of aspirin and nonsteroidal anti-inflammatory drug therapy on bleeding complications in dermatologic surgical patients. J Am Acad Dermatol 1994;31:988–92.

Chapter 104: Dermatologic Surgery 91. Harris K, Curtis J, Larsen B, et al. Opioid pain medication use after dermatologic surgery: a prospective observational study of 212 dermatologic surgery patients. JAMA Dermatol 2013;149:317–21. 92. Jobe BA, Grasley A, Deveney KE, et al. Clostridium difficile colitis: an increasing hospital-acquired illness. Am J Surg 1995;169:480–3. 93. Cook JL, Perone JB. A prospective evaluation of the incidence of complications associated with Mohs micrographic surgery. Arch Dermatol 2003;139:143–52. 94. Starling J, 3rd, Thosani MK, Coldiron BM. Determining the safety of office-based surgery: what 10 years of Florida data and 6 years of Alabama data reveal. Dermatol Surg 2012;38:171–7. 95. Pellitteri PK, Kennedy TL, Youn BA. The influence of intensive hyperbaric oxygen therapy on skin flap survival in a swine model. Arch Otolaryngol Head Neck Surg 1992;118:1050–4. 96. Goldminz D, Bennett RG. Cigarette smoking and flap and full-thickness graft necrosis. Arch Dermatol 1991;127:1012–5. 97. Gill JF, Yu SS, Neuhaus IM. Tobacco smoking and dermatologic surgery. J Am Acad Dermatol 2013;68:167–72.

98. McDonald M, Stasko T. Prevention of unsatisfactory scarring. In: Harahap M, editor. Surgical techniques for cutaneous scar revision. New York: Marcel Dekker; 2000. p. 53–80. 99. Kaufman AJ, Kiene KL, Moy RL. Role of tissue undermining in the trapdoor effect of transposition flaps. J Dermatol Surg Oncol 1993;19:128–32. 100. Harmon CB, Yarborough JM. Scar revision by derm abrasion. In: Roenigk RK, and Roenigk HHK, editors. Dermatologic surgery principles and practice. New York: Marcel Dekker; 1996. p. 911–21. 101. Berman B, Flores F. Comparison of a silicone gel-filled cushion and silicone gel sheeting for the treatment of hypertrophic or keloid scars. Dermatol Surg 1999;25:484–6. 102. Mustoe TA, Cooter RD, Gold MH, et al. International clinical recommendations on scar management. Plast Reconstr Surg 2002;110:560–71. 103. O’Brien L, Jones DJ. Silicone gel sheeting for preventing and treating hypertrophic and keloid scars. Cochrane Database Syst Rev 2013;9:CD003826. 104. Ketchum LD, Smith J, Robinson DW, et al. The treatment of hypertrophic scar, keloid and scar contracture by triamcinolone acetonide. Plast Reconstr Surg 1966;38:209–18.

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105

Surgical Instruments Collin Blattner, Cory Maughan, Benjamin Perry, William Lear

INTRODUCTION Dermatologists have numerous surgical instruments in their armamentarium that when used correctly can be of great benefit to both physician and patient. In order to understand instruments, we must first understand the history of surgical instruments and the materials that were used to construct them. Surgical instruments including primitive knives, blades, lancets and scalpels were first crafted out of human nail plates.1 During the Roman Era, instruments were made utilizing copper alloys. Various bones and ivory were used in 19th century Europe.1 Single use, thin ivory blades were sold in packs of 100 for vaccination and are the first known form of disposable surgical blades.1 As technology advanced throughout the 19th century, steel became the most commonly used material in the production of surgical instruments. After the introduction of stainless steel in the early twentieth century, instrument manufacturers and practitioners rapidly adopted it. In 1916, Mayer and Company made the first stainless steel surgical instruments for otolaryngologists.2 By 1938, more than half of all surgical instruments were made of stainless steel.3 This percentage has continued to increase and it is currently above 90%.3

MATERIALS Harry Brearly was working to improve rifle barrels when he first invented stainless steel in 1912.2 He accidently discovered that by adding chromium to low carbon steel it became increasingly “stain resistant” thus giving it the name stainless steel.2 The first stainless steel contained 13% chromium, 1% nickel and 0.2% carbon and would now be classified as a “low alloy” stainless steel.2 “Low alloy” steel typically has a carbon content that is less than 0.25% and is commonly used by welders. Modern stainless steel is important for a number of commercial applications and is commonly known as “high alloy” steel.

It is an alloy (a mixture or solid solution of two or more metals) that ­contains a minimum of 10.5% chromium by mass.2 It  must contain at least this amount of chromium to receive the designation of stainless steel. “Low alloy” steel has an inferior cutting edge, is not inert and corrodes when it comes into contact with fluid.2 “High alloy” stainless steel has a superior cutting edge, is inert within the body and does not corrode.2 Carbon steel and stainless steel blades are commonly used in surgery. Carbon steel blades retain their sharpness for a longer period throughout a procedure, but stainless steel blades are sharper at the beginning of the procedure. Carbon steel blades are also less expensive than stainless steel blades. Other metals commonly contained in stainless steel surgical blades and carbon steel surgical blades are summarized in Table 105.1. One of the most important advantages of stainless steel is that it does not rust or corrode as quickly as regular steel when exposed to the environment.4 The resistance to corrosion is secondary to the interaction between the environment and the alloying elements contained in stainless steel. The “rust resistant” process is known as passivation and occurs as long as the chromium content Table 105.1: Composition of stainless steel versus carbon steel surgical blades. Stainless steel surgical blades Carbon steel surgical blades Carbon 0.6–0.7% Carbon 1.20–1.30% Silicon Manganese Phosphorus Sulfur

0.5% max 1% max 0.03% max 0.025% max

Silicon Manganese Phosphorus Sulfur

0.10–0.035% 0.20–0.45% 0.035% max 0.025% max

Chromium Nickel

12–13.5% 0.5% max

Chromium Nickel

0.10–0.40% None

Information courtesy Cincinnati Steel, Cincinnati, Ohio, USA.

Chapter 105: Surgical Instruments is high and oxygen is present.4 By definition, stainless steel must contain enough chromium for passivation to occur and thereby forms an ultrathin invisible film of chromium oxide (Cr2O3).4 The chromium atoms and their oxides are similar in size, allowing them to pack together tightly on the metal surface to form a stable layer of thin film. The Cr2O3 blocks oxygen diffusion to the stainless steel surface and halts the detrimental effects of internal corrosion (Table 105.2). The layer of film is so thin (nanometers) that it is invisible to the naked eye and can only be seen microscopically. This film helps the metal remain smooth and maintains the lustrous appearance the naked eye associates with stainless steel.4 On the other hand, common steel reacts with oxygen from water to form a relatively unstable iron oxide/hydroxide film. The film will increase in thickness with time and repeated exposure to water and air. This film formed is rust and eventually the film will become thick enough to be visible to the naked eye. There are over 150 different grades of stainless steel that are available depending on each physician’s unique preferences. Different metals may be added to the alloy mixture to confer certain properties to the instruments. For example, increasing the amount of nickel (up to 13%) can be used to form a crystal structure that decreases the brittleness of stainless steel at low temperatures.5 The formation of a crystalline structure also makes the metal non-magnetic.5 Table 105.2: Problems associated with corrosion of metal. Problem Description Perforation “Free iron” deposits that have oxidized (pitting) in one or more areas. Area(s) corrodes quicker than others as corrosive environment only penetrates through the film in a small number of areas Decreased strength

Degradation of appearance Scale or rust can cause contamination

Mechanism not well defined. Likely secondary to decreased cross-sectional area of metal. Ten percent corrosion decreased the yield and ultimate strength by 4.5 and 3.3%.6 Yield stress is the stress at which the material permanently deforms. Ultimate tensile stress is the stress at which the material breaks Oxidation reactions convert ferrous hydroxide into rust (hydrated ferric oxide)7 Result of surface contamination, may be secondary to improper maintenance. Rust is formed by oxidation of steel in setting of moisture

Manganese is very similar to nickel and provides many of the same benefits. Manganese, which is traditionally less expensive than nickel, may be used as a low cost alternative to nickel. Stainless steel is strong and yet ductile, so it can absorb a significant amount of energy without breaking. It  also has a high temperature resistance that is expressed as “creep strength.” This is the ability of the material to resist distortion over the long term. There are five main types of stainless steel, of which three are commonly used in the manufacture of surgical instruments: Austenitic, Ferritic and Martensitic. Austenitic steel is the most common type of stainless steel. It accounts for about 70% of all stainless steel produced and can be formed and welded with ease. Austenitic steel typically contains between 16 and 25% chromium, which prevents oxidation and corrosion, and has the highest tensile strength.8 It exhibits a single-phase, the face-centered cubic structure that can be maintained over a wide range of temperatures.8 Nickel, which is more expensive than manganese, is often used to stabilize its structure. Austenitic steel Type 304 is probably the most common type of surgical stainless steel. Ferritic steel contains less than 0.10% carbon, ferrite, iron and chromium.8 It cannot be hardened with heat treatment and is less ductile (the ability for a solid material to deform under tensile strength) than austenitic steel. This property limits the use of ferritic steel.8 Martensitic steel contains more carbon than ferritic steel (up to 1%). It can be hardened and sharpened and is extremely useful when the strength of the steel is more important than its anticorrosive properties.8 Tungsten, also known as wolfram, is another chemical element used in surgical instruments. More specifically, tungsten carbide (WC) is a combination of equal parts tungsten (W) and carbon (C) atoms, often with cobalt or nickel used as a metal binder. WC is much harder and two times stiffer than stainless steel.9 Therefore, the jaws of needle holders with WC would be less prone to wear and tear from repeated use. However, tungsten is less ductile than stainless steel.10 This means that once it exits the elastic portion of its stress–strain curve, WC will not bend or give as much as stainless steel. Because of this, it may crack. Therefore, if a needle driver became bent and had a WC insert, one would risk breaking the insert by attempting to mold it back in place with pliers.10 Needle drivers with WC inserts, easily identifiable by their gold handles, can have their inserts replaced. This is not the case for most stainless steel needle drivers.10 These instruments are more expensive than traditional stainless steel but offer many advantages to the operator.11

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CURRENT BLADES AND BLADE HANDLES The most commonly used blades in Europe are disposable carbon steel while in North America the most commonly used blades are stainless steel.3 These blades are easily mass-produced, and although they will corrode over time, they are usually disposed of before any signs of rust appear. A fixed blade handle improves control, accuracy and efficiency during surgery. It also provides an extra safety mechanism for the user and patient. It is important to recognize that when not in use, the unprotected blade may be easily damaged or injure the user inadvertently. Consequently, the dermatologic surgeon must properly care for his instruments to protect the integrity of the instrument as well as investment.10 Often times the handle of choice for dermatologic surgeons is the Bard-Parker® surgical blade handle. It is reusable and made of stainless steel. The #3 scalpel blade handle is also commonly used and will accommodate any of the four standard surgical blades (#10, #11, #12, #15) (Figs. 105.1A and B). Other types of blade handles are pictured along with their respective description (Figs. 105.2A to G).

A

Folding Blades Folding blades were likely developed to assist in protecting blade points and permitting knives to be carried safely outside the operating suite. Historically, a folded blade requires less space, which was advantageous in terms of travel.1

Dismounting Blades The ability to dismount a blade from the handle in a timely and safe manner is important to the dermatologic surgeon. Replaceable blades allow for sterile and unsterile procedures to be performed efficiently and safely. Dermatologic surgeons often favor the Bard-Parker® surgical blade handle that is used in combination with conventional stainless steel blades for tissue separation and other surgical procedures that require the clinician to cut or puncture the skin.

Types of Blades Currently, there are numerous blades available to the dermatologist. These blades can be used for skin biopsies,

B Figs. 105.1A and B: (A) Scalpel blade #15; (B) Scalpel blade #10.

excisions and the harvesting of grafts. The most commonly used blade is the #15 blade. Other commonly used blades include the double-edged razor blade (Personna), dermablade (Personna), plastic scalpel handle #15 blade (Bard-Parker), #15 blade (Southmedic, Canada), #10 blade (Personna) and #15c blade (Personna).12–22 The blade chosen by a dermatologic surgeon is based on numerous factors including personal preference, type and site of lesion, and type of surgical procedure.12–22 There are also differences in blade shape and size that determine the blades inherent advantages and disadvantages.

Blade Sharpness One aspect of the blade that is critical to blade performance is sharpness.23 Different blades provide different advantages and disadvantages given their shape, size and sharpness. A recent study by Awadalla et al. aimed

Chapter 105: Surgical Instruments

A

B

C

D

E

F

Figs. 105.2A to F: (A) Scalpel handle #3; (B) Round knurled handle allows for control by twisting rather than rocking motion; (C) Scalpel handle #3, Round handle Siegal style, fits blades #10–15; (D) Scalpel handle #3, round handle, graduated CM’s, fits blades #10–15; (E) Scalpel handle #3 for blade sizes #10–15; (F) Scalpel handle #3 long for blade sizes #10–15.

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Fig. 105.2G: Scalpel handle #4 for blade sizes #20–25.

to define the blade sharpness. The Sharpness Tester was used to test the force in Newtons a blade requires to cut through a standard silicone cylinder. The sharpness of the tip, belly and flat part of the blade were tested and averaged. The double-edged razor blade was the sharpest (0.395 N) followed by the dermablade (0.46 N), plastic handled #15 (0.541 N), #15c (0.575 N), #10 (0.647 N) and the #15 blade (0.664 N).23 Interestingly, the #15 blade is likely the most commonly used blade in dermatologic surgical procedures, yet it is the least sharp of all the blades.23 Consequently, physician preference indicates that a less sharp blade should not always be viewed as inferior.23 For example, Bhatia noted that when making large cuts in thicker tissue using a slightly less sharp blade confers more depth control.24 This is especially vital when important underlying structures are nearby.24 Duller blades may in effect provide a somewhat built-in protective mechanism against inadvertent damage to underlying structures. Thicker tissue such as the skin of the back is not adversely affected by the reduction in sharpness of the blade.24 An experienced surgeon will be able to choose the right instrument for each unique procedure.

Blade Hardness Besides shape, size and sharpness, the hardness of the blade should also be considered because it contributes to the blade’s durability when engaged in extensive cutting. Blade hardness is usually measured as a number on the Rockwell C scale, which determines hardness by measuring the depth of penetration of an indenter on an object

Table 105.3: Detailed description of scissors available to the dermatologic surgeon. Type of scissors Description Iris (Figs. 105.3A Sharp tip, short blade, used for sharp to C) dissection and cutting on face Gradle (Fig. Curved and tapered blade; ideal for use 105.3D) in the periorbital area Westcott (Fig. Fine sharp point ideal for cutting near the 105.3E) eye; operates on a spring system O’Brien Blade is angled with fine point used for cutting suture in hard to reach areas Metzenbaum Blunted tips used in blunt dissection on (Fig. 105.3F) all areas of body, commonly used for undermining Spencer Curved blade with unilateral notch, (Littauer) (Figs. commonly used to cut or remove sutures 105.3G and H) Come in different sizes depending on removal of fine or large sutures Mayo dissecting Available as a straight or curved (Fig. 105.3I) instrument with standard beveled blade Curved instrument is generally used for dissecting or cutting deep tissue. Straight instrument is used to cut superficial tissue and suture Ragnell (Kilner) Ring handle instrument with flat blade scissors (Figs. and blunt tips commonly used for 105.3J and K) undermining/dissection. Scissors have long straight shanks and short curved jaws Information obtained and adapted from Sklar Surgical Instruments®, West Chester, PA, USA. Figures courtesy of Hayden Medical, Santa Clarita, CA, USA.

under a large load compared to the penetration made by a preload.25 Indentation hardness directly correlates with tensile strength.25 For greater hardness, more carbon can be added.

SCISSORS Scissors are another important instrument in the armamentarium of the dermatologic surgeon. Important uses of scissors include both fine and blunt dissection, suture placement and removal, and to shape bandages for wounds. Scissors should be held with the thumb and ring finger on the rings with the index finger on the fulcrum.9,10 Scissors operate on three forces: closing, shear and torque.9,10 Numerous types of scissors are available to the dermatologist. These scissor types are detailed in Table 105.3.

Chapter 105: Surgical Instruments

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F

Figs. 105.3A to F: (A) Iris scissors; (B) Iris scissors with tungsten insert; (C) Iris scissors super-cut; (D) Gradle eye suture scissors; (E) Westcott utility scissors; (F) Metzenbaum scissors.

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G

H

I

J

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Figs. 105.3G to K: (G) Spencer stitch scissors; (H) Littauer stitch scissors; (I) Mayo dissecting scissors; (J) Ragnell (Kilner) undermining scissors with tungsten; (K) Ragnell (Kilner) undermining scissors.

Chapter 105: Surgical Instruments

NEEDLE DRIVERS The needle driver is used to grasp circular needles to protect the operator from injury and help apply rotational force though both needle and tissue.10 There are four grips that may be employed when holding the needle driver: thumb/ring finger, thenar, palmed and pencil.26 The needle should be placed perpendicular to the driver jaws, being careful not to damage the tip or bend the needle. Different needle drivers have different advantages and disadvantages. For example, the Halsey needle driver has more delicate, longer jaws that are used to hold suture that is United States Pharmacopeia (USP) 5-0 or smaller. Similarly, the Webster needle holder is used to grasp sutures that are USP 6-0 or smaller (Figs. 105.4A and B). The Castroviejo needle holder is typically used for microsurgery using a USP 6-0 suture or finer (Fig. 105.4C). Needle drivers may also be serrated or flat. Serrated needle drivers deliver slightly more grip to the user but there is

A

C

the inherent risk of bending the needle or fraying suture. A smooth needle driver is less likely to damage the needle and provides more even pressure.

COMBINATION INSTRUMENT One instrument that deserves special note is the Olsen– Hegar needle holder (Fig. 105.5). It combines a traditional needle holder with a suture scissor. This combination instrument provides surgeons who operate independently with increased flexibility since one instrument can be used for multiple purposes. The Olsen–Hegar needle holder commonly has WC inserts with serrated jaws that have 2,600–16,000 teeth per square inch. WC jaws provide specific advantages to the user: (1) increased durability, (2) superior grip and (3) replaceable jaws. One disadvantage of the Olsen–Hegar needle holder is the possibility of accidentally cutting suturing when not intending to with the instrument. As previously mentioned, the presence of

B

Figs. 105.4A to C: (A) Baby Webster needle holder; (B) Webster needle holder; (C) Castroviejo needle holder.

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A Fig. 105.5: Olsen–Hegar needle holder with scissors.

gold handles helps to differentiate instruments with WC inserts.

FORCEPS Forceps are another commonly used surgical instrument. Forceps are used to handle and manipulate tissue. Numerous types are available and each dermatologist prefers different types of forceps depending on a physician’s individual practice style. The most important distinction is the presence or absence of teeth. Teeth are small, sharp protrusions at the distal tips of the forceps. They allow pressure to be directed in a very small area, as opposed to non-toothed forceps, which apply pressure to a larger surface area and can easily result in crush injuries to the tissue. As such, “tissue forceps” have teeth while “dressing forceps,” do not. In terms of distinctive styles of forceps, the Adson forceps is the most commonly used. Adson forceps have a broad handle that tapers down slowly to a long and narrow tip (Figs. 105.6A to C). The wider, flat handle allows for easy user operation. Other commonly used types of forceps are summarized in Table 105.4.

CURETTES Curettes are looped blades that are used for a variety of procedures (Figs. 105.7A to D). Most often, they are used for electrodessication and curettage (ED&C) of superficial and nodular basal cell carcinomas (BCCs) and squamous cell carcinoma (SCC) in-situ with good results. This is a commonly used method for the removal of primary BCCs.27 However, it is important to recognize that although

B

C Figs. 105.6A to C: (A) Adson tissue forceps; (B) Adson dressing forceps; (C) Adson tissue forceps with tying platform.

this is a quick method for the destruction of certain tumors, ED&C is not as accurate as surgical removal since margins cannot be visualized. It is also impossible for the surgeon

Chapter 105: Surgical Instruments

D

E

F

G

H

I

Figs. 105.6D to I: (D) Littauer Cilia forceps; (E) Swiss Cilia and suture forceps; (F) Castroviejo micro suturing forceps; (G) Splinter forceps; (H) Hartman mosquito forceps; (I) Halsted mosquito forceps.

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Section 31: Dermatologic Surgery Table 105.4: Detailed description of forceps available to the dermatologic surgeon. Type of forceps Description Bishop Harman Delicate tip with or without teeth, three holes present on each side to decrease weight Jewelers Very fine and sharp tip used primarily for suture removal Brown Adson Very similar to Adson but with 16 teeth Dressing Commonly used to hold dressing materials including gauze pads, change dressings and wound packing. The instrument is straight with serrated tips to allow for easy grasping Tissue Used for holding and manipulating tissue. Thumb tissue forceps more commonly have teeth to better hold tissue Littauer Cilia (see Fig. 105.6D) Used for grasping and holding eyelashes. Handle tapers to the base before flaring out to the tip that creates a 4-mm flat grasping surface with fine horizontal serrations Swiss Cilia and suture Thumb forceps used for grasping and holding eyelashes. Also used for removing (see Fig. 105.6E) foreign bodies and sutures around the eye and eyelid. Possess slanted, diagonal tips that are raised slightly from the rest of the body of the forceps Castroviejo micro suturing Used around the eye to hold tissue and remove suture. Small teeth are used to (see Fig. 105.6F) grasp suture Splinter (see Fig. 105.6G) Thumb forceps that taper down to fine tip used for removing foreign bodies, grasping tissue and holding bandages Hartman mosquito (see Fig. 105.6H) Both straight and curved available. Can be used as a hemostat and for fine dissection. Instrument has fine tips and short serrated jaws Halsted mosquito (see Fig. 105.6I) Both straight and curved available. Have fine tips with serrated jaws. Can be used as small vessel clamp for hemostasis as have ratcheted finger ring handle that provides locking grip. Toothed variation used for grasping tissue for skin grafting or performing biopsies Information obtained and adapted from Sklar Surgical Instruments®, West Chester, PA, USA. Figures courtesy of Hayden Medical, Santa Clarita, CA, USA.

to adequately assess the depth of the tumor, and there is a small chance of recurrence (10%).27 Curettes are designed specifically for surgeons to curettage and debride a lesion. Initially, a surgeon may use a larger curette to debulk a lesion before proceeding to use a smaller curette to remove smaller fragments.27 When performing an ED&C, it is important that the operator applies significant force to the tissue. It is believed that most recurrences are due to lack of aggressiveness on the part of the surgeon. Curettage should be avoided on cosmetically sensitive areas since it tends to leave an atrophic, hypo­ pigmented scar.28 It should also be avoided on hair bear­­­ing areas such as the scalp and face since a tumor may extend down the follicle, which prevents adequate removal.28

SKIN HOOKS Skin hooks are another commonly used instrument by dermatologic surgeons. They are handheld retractors that are used to grasp the edges of skin during procedures. The edges of skin hooks are sharp so it is important for the

operator to be mindful and not apply excessive force to the tissue. Both single and double skin hooks are commercially available (Figs. 105.8A to F).

SKIN BIOPSY PUNCHES Skin biopsy is one of the most commonly performed procedures by dermatologists with more than 2.2 million performed annually.29 Dermatologists perform five different types of biopsies: shave, punch, curettage, incisional and excisional. These procedures are generally performed under local anesthesia using lidocaine and epinephrine. Written and verbal consent should always be obtained prior to any procedure. Table 105.5 describes the types of biopsies along with the indications for each.

CHALAZION CLAMP A chalazion clamp is particularly helpful for surgical procedures on vascular areas such as the oral mucosa and alar surface (Fig. 105.10).30,31 They traditionally come

Chapter 105: Surgical Instruments

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C

D

Figs. 105.7A to D: (A) Williger curette; (B) Fox dermal curette; (C) Meyhoefer Chalazion curette; (D) Piffard dermal curette. Source: Information obtained and adapted from Sklar Surgical Instruments®, West Chester, PA, USA. Figures courtesy of Hayden Medical, Santa Clarita, CA, USA.

in sizes of small (ring size: 11 × 17 mm), medium (ring size: 12 × 23 mm) and large (ring size: 17 × 28  mm).30 Dermatologists may also use small chalazion clamps when performing a shave or punch biopsy in vascular areas. They may also be useful for patients on ­anticoagulants such as coumadin, clopidogrel or aspirin. Larger clamps may be used for lesions with increased surface area. Chalazion clamps can provide for hemostasis since the pressure exerted by the tightened clamp is usually sufficient to control bleeding. It also allows for better visualization of the surgical field, which can facilitate quick curettage and lesion removal. After removal of the lesion, the pressure from the clamp is released by unscrewing the dial on the clamp. While the clamp loosens, bleeding vessels that require cauterization can be identified. This identification of vessels allows surgeons to reduce the risk of charring tissue.30,31

A chalazion clamp can also be used on the oral mucosa. To properly position the instrument, the ring portion should face the mucosal surface. The other side of the clamp is flat and should be on the cutaneous surface. After proper placement, the clamp should be carefully tightened in order to avoid strangulation of tissue. A biopsy can then be taken and adequate hemostasis obtained before using an absorbable suture to close the defect. Typically, 3-0 plain or chromic catgut should be used.32 Temporary surgical suture may be used to hold tissue in place prior to beginning the procedure.33

SURGICAL STAPLES Surgical staples have become most common amongst emergency room physicians, orthopedist and general surgeons due to their ease of use and time saving advantage. They are placed as the stapler is held level and

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F

Figs. 105.8A to F: (A) Frazier Dura hook; (B) Guthrie (Iris) hook; (C) Cottle double hook; (D) Lahey skin hook; (E) Barsky nasal hook; (F) KleinertKutz hook.

Chapter 105: Surgical Instruments Table 105.5: Detailed description of biopsy procedures and indications. Biopsy type Procedure description Shave Area anesthetized with local anesthesia, then small scalpel blade, razor blade or DermaBlade® used to remove fragment of skin before applying proper hemostasis with aluminum chloride or electrocautery Punch (Figs. 105.9A and B) Size ranges from 1 mm to over 12 mm. Area anesthetized with local anesthesia. Circular blade is held like pencil and rotated circumferentially through epidermis, dermis and into subcutis. Fine-toothed forceps used to lift the specimen and scissors should be used to remove tissue. Hemostasis may be obtained with stitch or left to heal via secondary intention if smaller than 3 mm Curettage Traditionally done on surface of epidermal tumors using a curette

Incisional

A portion of a larger lesion is removed for histological examination. Often performed with a scalpel or punch biopsy

Excisional

The entire lesion is removed, often with a small margin of normal skin around it. This is usually performed with a scalpel, although smaller lesions could be excised with a large punch.

A

B

Figs. 105.9A and B: (A) Keyes dermal punch biopsy set; (B) Keyes dermal punch biopsy.

Indications Ideal for diagnosis of BCC, SCC and other conditions limited to the epidermis and dermis Ideal for infectious or inflammatory skin disorders

Can be used to diagnose some epidermal tumors. Dermatopathologist should be notified of curetted specimen Caution must be exercised in performing incisional biopsies, since there may be sampling error (e.g. falsely labeling a malignancy as benign) This is the method of choice for sampling pigmented lesions that may be suspicious for melanoma.

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Fig. 105.10: Desmarres Chalazion forceps.

perpendicular to the skin defect. Pulling the handle causes the mechanism of the stapler to push the sides of the staple toward the skin, bending it as in Figures 105.11A and B. Releasing the handle of the stapler disengages the staple onto the surface of the skin. Staple placement technique is often user dependent and varies with level of experience. Most staple devices used in dermatologic surgery come preloaded with 5–35 staples available in two widths: regular (4–6 mm) or wide (6.5–7.5 mm).10 Staple placement has been found to be 80% faster than traditional suture placement.34 Stapling is also a quicker and more cost-effective mechanism of wound closer. However, most dermatologic surgeons tend to favor sutures for their closures. Sutures may be less bothersome to the patient on cosmetically sensitive areas. To date, there has been no significant difference in superficial infection rates and secondary outcomes comparing sutures to staples.35 However, the rate of partial necrosis or slow healing in flap operations favors the use of sutures over surgical staples. This was demonstrated in a retrospective study where the complication rate in 45 skin flap operations was 20.6% for sutured flaps compared to 62.5% of stapled flaps.36 The authors proposed that crimping of the skin edges by the staples resulted in excess tension across the flap and subsequent decrease in blood supply.36 Absorbable surgical staples (INSORB®) are also available. They offer the cosmetic advantage of being entirely subcuticular and essentially invisible to the patient. They have the potential to reduce “tram-track scarring” that occurs with traditional metal skin staples. Absorbable staples also have also been reported to be more cost effective and decrease the rate of infection and inflammation when compared to traditional

Figs. 105.11A and B: Mechanism of surgical stapler operation. (A) There is a hook portion below the middle of the staple to support it. Activation of the mechanism pushes the sides of the staple down; (B) Staple in final position. Release of the handle of the stapler disengages the hook, releasing the staple from the stapler to rest in the skin.

surgical staples.37 Another advantage of absorbable skin staples is the elimination of staple removal. This thereby does away with any pain or anxiety associated with the staple removal procedure.

COMEDONE EXTRACTORS Comedone extraction is a simple technique that is performed in the office by most dermatologists (Figs. 105.12A to E). It is an adjunct to medical therapy. Manual pressure is applied to the skin with a comedone extractor. This pressure opens the clogged pilosebaceous unit and allows for the instrument to extract the contents (open and closed comedones). Most instruments have a small loop on one end and a larger loop on the opposite end.

NAIL INSTRUMENTS Nail instruments are used for a variety of nail surgeries performed by dermatologist. Nail nippers can be used to remove a portion of the finger or toenail plate (Fig.  105.13A). Special heavy-duty nail nippers are also available to cut through the thickened nails of patients suffering from onychomycosis (Fig. 105.13B). Ingrown toenail scissors may be used when cutting and removing painful ingrown toenails (Fig. 105.13C). The toenail scissors often have a smooth, flat underside that slides underneath the nail bed to allow for simple nail cutting.

STANDARD MOHS SURGICAL TRAY The standard Mohs surgical tray varies widely among surgeons (Fig. 105.14A). Surgeons may elect to have a sterile

Chapter 105: Surgical Instruments

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B

C

D

E

Figs. 105.12A to E: (A) Saalfield comedone extractor; (B and C) Schamberg comedone extractor; (D) Unna comedone extractor; (E) Walton comedone extractor.

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C or non-sterile setup for their Mohs layer tray. Standard equipment generally includes a scalpel handle and 15 blade or disposable equivalent, toothed forceps, location appropriate scissors and a supply of gauze. A battery powered cautery device or hyfrecator tip is also found on a standard tray. Some surgeons may also include a marking pen and ruler on the layer tray. The closure tray may differ to an even greater extent due to surgeon preference (Fig. 105.14B). These trays are generally set up in a sterile fashion. Typical closure instruments may include: scalpel, forceps, surgical and suture scissors, needle holders, sutures, skin hooks, sterile cautery and towel clamps. Sterile gauze, cotton tipped app­ licators and topical antiseptics are also commonly found on closure trays.

CARE OF INSTRUMENTS Cleaning and sterilization of instruments is of utmost importance to dermatologic surgeons. Proper technique

Figs. 105.13A to C: (A) Nail nipper; (B) Mycotic heavy duty nail nipper; (C) Ingrown toenail scissors.

of instrument cleaning not only reduces infection rate but also protects and preserves instruments. The first step in proper cleaning of instruments involves removing all debris and blood. Instruments that are dissimilar should not be grouped together and all instruments with locking mechanisms should be unlatched to avoid damaging or weakening the mechanism.10 Chlorine and phosphate solutions should be avoided as they may cause pitting or staining of instruments.10 Decontamination of the instruments using a commercial cleaning solution should follow.10 This reduces the risk of exposure to diseases including hepatitis B virus, hepatitis C virus, tuberculosis and HIV/AIDS. After decontamination, detergents should be applied to clean the instruments. Lubricant should also be applied to the instrument to prevent rust and corrosion. Finally, after thorough air drying and subsequent packing in appropriate trays or packages, all instruments should be autoclaved. Generally, this is achieved with high-pressure saturated steam at 121°C (249°F) for 15–20 minutes.38 Proper cleaning and sterilization will

Chapter 105: Surgical Instruments

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Figs. 105.14A and B: (A) Standard Mohs layer surgical tray in our practice; (B) Standard closure tray in our practice.

significantly reduce infection rates. It will also optimize instrument performance and hopefully extend its functional lifespan.

REFERENCES 1. Kirkup J. The history and evolution of surgical instruments. VI. The surgical blade: from finger nail to ultrasound. Ann R Coll Surg Engl 1995;77(5):380–8. 2. Raz Y. CIS Self-Study Lesson Plan. Purdue University. 2015. Available at: http://studylib.net/doc/18661610/cisself-study-lesson-plan [Accessed 25 June, 2016]. 3. Kirkup J. The evolution of surgical instruments: an illustrated history from ancient times to the twentieth century. Historyofscience.com. Novato, (CA): Norman Publishing; 2006. 4. Duarte MJ, Klemm J, Klemm SO, et al. Element-resolved corrosion analysis of stainless-type glass-forming steels. Science. 2013;341(6144):372–6. 5. Heiniger F, Bucher E, Muller J. Low temperature specific heat of transition metals and alloys. Physik der kondensierten Materie 1966; 5.4:243–84. 6. Andrade C, Alonso C, Garcia D, et al. Remaining lifetime of reinforced concrete structures: Effect of corrosion on the mechanical properties of the steel. 2nd Meeting, Life prediction of corrodible structures; Cambridge, in Life prediction of corrodible structures 1994;546–57. 7. Taha NA, Morsy M. Study of the behavior of corroded steel bar and convenient method of repairing. HBRC J 2016;12(2):107–13. 8. McGuire MF. Martensitic stainless steels. Stainless steels for design engineers. Novelty, OH, USA.: ASM International 2008;123–35. 9. Blau PJ. Wear of materials. Amsterdam: Elsevier; 2003. p. 1345. ISBN 978-0-08-044301-0.

10. Lear W. Instruments and materials. surgery of the skin: procedural dermatology, by William Lear, 3rd ed, Amsterdam: Elsevier/Saunders; 2015. pp. 63–72. 11. Reichert M, Young JH. Sterilization technology for the health care facility. Burlington, MA: Jones & Bartlett Learning; 1997. p. 30. ISBN  978-0-8342-0838-4. 12. Goldberg LH, Segal RJ. Surgical pearl: a flexible scalpel for shave excision of skin lesions. J Am Acad Dermatol 1996;35:452–3. 13. Bennett RC. Common procedures in cutaneous surgery. In: Fundamentals of cutaneous surgery. St. Louis: CV Mosby Co.; 1988. p. 528–9. 14. Grabski WJ, Salasche SJ, Mulvaney MJ. Razor-blade surgery. J Dermatol Surg Oncol 1990;16:1121–6. 15. Firoz BF, Goldberg LH, Katz T, et al. The use of the flexible scalpel for minimally invasive and minimally scarring surgery: a case series of four patients with large scalp tumors. J Drugs Dermatol 2010;9:1268–71. 16. Vujevich JJ, Goldberg LH, Kimyai-Asadi A. Mohs micrographic surgery using a flexible blade for tumors of the scalp. Dermatol Surg 2009;35:1130–3. 17. Gurgen J, Judy D, Witfill K, et al. An alternative approach for Mohs surgery using a combination of a flexible blade and the traditional scalpel. J Eur Acad Dermatol Venereol 2013;27:506–8. 18. Vergilis-Kalner IJ, Goldberg LH, Firoz B, et al. Horizontal excision of in situ epidermal tumors using a flexible blade. Dermatol Surg 2011;37:234–6. 19. Jaffe AT, Proper SA. An alternate approach for harvesting Mohs specimens with a flexible scalpel. Dermatol Surg 2001;27:851–3; discussion 854. 20. Grabski WJ, Salasche SJ. Razor blade excision of Mohs specimens for superficial basal cell carcinomas of the distal nose. J Dermatol Surg Oncol 1988;14:1290–2. 21. Kontos AP, Qian Z, Urato NS, et al. The use of a flexible razor blade in skin graft harvesting. Dermatol Surg 2009;35:120–3.

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Section 31: Dermatologic Surgery 22. Awadalla F, Hexsel C, Goldberg LH. The sharpness of blades used in dermatologic surgery. Dermatol Surg Materials Park, OH: 2016;42(1):105–7. 23. Bhatia AC. Commentary on the sharpness of blades used in dermatologic surgery. Dermatol Surg. 2016;42(1):108. 24. Tobolski EL, Fee A, Macroindentation hardness testing, ASM handbook, volume 8: mechanical testing and evaluation. Materials Park, OH: ASM International; 2000. p. 203–11. ISBN 0-87170-389-0. 25. Pavlina EJ, Van Tyne CJ. Correlation of yield strength and tensile strength with hardness for steels. J Mater Eng Perform 2008;17(6):888–93. 26. Romfh RR. Technique in the use of surgical tools. 2nd ed. New York: Prentice Hall; 1992.27. 27. Silverman MK, Kopf AW, Grin CM, et al. Recurrence rates of treated basal cell carcinomas. Part 2: curettage-electrodesiccation. J Dermatol Surg Oncol 1991;17(9):720–6. 28. Habif TP. Dermatologic surgical procedures. In: Clinical dermatology. 5th ed. St. Louis (MO): Mosby; 2010. p. 1002–10. 29. Stern RS. Dermatologists and office-based care of dermatologic disease in the 21st century. J Investig Dermatol Symp Proc 2004;9:126–30. 30. Amir I, Marmur ES, Kriegel DA. Bloodless nasal alar surgery: another innovative use of the chalazion clamp. Dermatol Surg 2009;35(5):843–4.

31. Jha AK, Ganguly S. Chalazion clamp in dermatology revisited. Indian J Dermatol Venereol Leprol 2015;81: ­ 280–1. 32. Savant SS. Basics of cutaneous surgery. In: Valia RG, Valia AR, editors. IADVL text book of dermatology. 3rd ed. Mumbai: Bhalani Publishing House; 2008. p. 1687–709. 33. Savant SS. Skin biopsy techniques. In: Savant SS, editor. Textbook of dermatosurgery and cosmetology. 2nd ed. Mumbai: ASCAD; 2005. p. 72–80. 34. Orlinsky M, Goldberg RM, Chan L, et al. Cost analysis of stapling versus suturing for skin closure. Am J Emerg Med 1995;13:77–81. 35. Krishnan R, MacNeil SD, Malvankar-Mehta MS. Comparing sutures versus staples for skin closure after orthopaedic surgery: systematic review and meta-analysis. BMJ Open 2016;6(1):e009257. 36. Coupland RM. Sutures versus staples in skin flap operations. Ann R Coll Surg Engl 1986;68(1):2–4. 37. Cross KJ, Teo EH, Wong SL, et al. The absorbable dermal staple device: a faster, more cost-effective method for ­ incisional closure. Plast Reconstr Surg 2009;124(1): 156–62. 38. Black JG. Microbiology. Upper Saddle River, NJ: Prentice Hall; 1993. p. 334.

Chapter

106

Wound Closure Dalee M Zhou, Anthony M Rossi, Erica H Lee

INTRODUCTION Dermatologic procedures generally involve some level of wound closure for defect repair. This is typically accomplished using sutures, which serve as a temporary means of approximating wound edges to provide tensile strength and facilitate wound healing. They are available in a wide variety of natural and synthetic material compositions with differing properties. Their selection and use are largely guided by these attributes and their advantages and disadvantages. Optimal functional and esthetic outcomes depend on both good suturing technique and use of appropriate suture material.

SUTURE PROPERTIES The properties of a suture that determine its use are: ease of handling, capillarity, configuration, elasticity, coefficient of friction, memory, plasticity, pliability, tensile strength, tissue reactivity, knot security, spitting potential (Table 106.1). Many of these material properties are interdependent. For example, ease of handling is related to the coefficient of friction and pliability, while knot security is directly proportional to the coefficient of friction and inversely proportional to memory. Furthermore, certain properties are also influenced by suture size and configuration. Among these properties, the most important are the basic tensile properties, which dictate suture behavior under stress and strain. In addition to the breaking force of sutures, tensile properties include failure stress, failure strain, failure elongation and modulus, which are derived from stress–strain curves.1 It should be noted that the knot represents the weakest point of any suture and affect its mechanical properties. Sutures are sized numerically by the United States Pharmacopeia (USP) as series of 0, 00(2-0), and 000000 (6-0), where the larger the number, the smaller the strand diameter and the weaker the tensile strength. Two configurations of sutures exist: monofilament and multifilament. The latter are further subdivided into braided

and twisted configurations. Monofilament sutures are ­composed of a single strand of material, which confers a low coefficient of friction and low capillarity, allowing for comparatively easy passage through tissue and low tissue reactivity.2 However, their construction also lends to high memory and increased stiffness, resulting in lower ease of handling and weaker knot security.2 They are also susceptible to nicking or developing weak spots leading to potential breakage if crushed or crimped during manipulation.3 Multifilament sutures, on the other hand, have greater tensile strength, pliability, and flexibility and low memory, which afford superior ease of handling and knot security.3 However, they also have higher comparative coefficients of friction, tissue reactivity and capillarity (greater in twisted vs braided), which can lead to tissue injury as well as increased risk of infection,4 although evidence surrounding the latter hazard is conflicting.5 Further, data from a recent study1 examining the tensile properties of commonly used sutures in dermatologic procedures suggest that monofilament sutures may actually outperform multifilament sutures, challenging dogma established by prior research. A number of multifilament sutures are also manufactured with coating, which serves to decrease the coefficient of friction, tissue reactivity and capillarity, thereby improving the ease of passage through tissue and risk of infection.6 Finally, selected sutures are also available with an antibiotic coating (usually triclosan) designed to prevent bacterial colonization and further decrease the risk of surgical site infection. In vitro and in vivo studies of these antibacterial sutures have dem­ onstrated efficacy in preventing colonization of methicillin-sensitive and methicillin-resistant Staphylococcus aureus, S. epidermidis, and other common surgical site pathogens, as well as minimal interference with normal wound healing.7,8 The ideal suture would be easy to handle, knot securely and reliably, and have high-tensile strength. It would also be biologically inert, absorbable and able to lose strength at the same rate that the healing tissue gains

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Section 31: Dermatologic Surgery Table 106.1: Suture properties. Property Description Capillarity Ability to absorb and transfer fluid; multifilament sutures have greater capillarity than monofilament; controversial whether increased capillarity increases potential for bacterial colonization Coefficient of Ability to slide through tissue; sutures with low friction coefficients slide easily through tissue and are friction particularly useful in subcuticular suturing, but also unravel easily, requiring extra knots for security; coating decreases coefficient of friction Configuration Monofilament or multifilament; multifilament sutures handle easily and have high knot security but also have high capillarity; monofilament sutures generally have low coefficients of friction but have low ease of handling and knot security. Elasticity Ability to stretch and rebound; good elasticity allows for stretch to accommodate tissue edema as well as recoil to original length as the wound retracts; excellent for use in exterior suturing Handling Ability to manage and work with the suture Knot security Likelihood that a knot will hold without slipping Memory Ability to maintain original configuration; sutures with high memory do not handle easily and have relatively low knot strength, requiring extra knots for security Plasticity Ability to stretch and maintain length and tensile strength; good plasticity allows for stretch to accommodate tissue edema without cutting into tissue Pliability Ease with which suture can be bent; greater pliability lends to greater knotting ease; braided sutures are more pliable than monofilament ones Spitting potential Likelihood that suture will be extruded from tissue; pertains to buried absorbable suture; large diameter and multifilament configuration are associated with higher spitting potential; polyglycolic acid in particular exhibits high-spitting potential Tensile strength Force required to break suture; dependent on suture diameter (greater strength with increased diameter); decreased 1,014% when knots are in place; synthetic sutures are generally stronger than natural sutures Tissue reactivity Likelihood that suture will evoke a foreign body inflammatory response; natural materials generally have higher tissue reactivity than do synthetic materials USP size Based on suture diameter and tensile strength and expressed as a series of 0, from 0 (largest) to 12-0 (smallest); very large sutures are ascribed numbers greater than 0 ascending with increasing suture diameter

strength. Unfortunately, the ideal suture material remains elusive, and thus the dermatologic surgeon must choose the most suitable material for any given surgical situation based on desired characteristics.

SUTURE TYPES Sutures are customarily classified as absorbable or nonabsorbable, depending on their degree of biodegradability. A suture is considered absorbable if it loses the majority of its tensile strength to hydrolytic or proteolytic degradation within 60 days. Non-absorbable sutures, too, despite their namesake, are absorbed in tissues to some extent, but at negligibly slow rates. In general, synthetic absorbable sutures are degraded more slowly than natural absorbable sutures, owing to differences in their degradation mechanisms (hydrolytic vs proteolytic, res­ pectively).3 The rate of absorption of suture is also influenced by environmental and patient factors, such as tissue pH or infection, where excess moisture (e.g. mucosal areas), non-neutral pH, high tension, irradiation, elevated

temperature (e.g. febrile illness), high bacterial or free radical loads and protein deficiency tend to accelerate degradation in vivo.9

Absorbable Sutures Absorbable suture is typically employed in deep sutures to minimize dead space, relieve tension and assist in wound edge approximation in the dermis or deeper subcutaneous space while eliminating the need for postprocedural removal. The most commonly used absorbable sutures and their properties are outlined in Table 106.2. The most commonly used absorbable sutures in dermatologic procedures are polyglactin 910 and poliglecaprone 25.10 The process of degradation and loss of tensile strength occurs over a period of one to eight weeks. During this time, a wound regains approximately 7–10% of its final tensile strength at two weeks and approximately 60% at five weeks, by which point the likelihood of dehiscence with normal activity is low.11 Full absorption can take more than six months, depending on the suture material.

Multifilament

Monofilament

Polyester (Velosorb)

Polydioxanone (PDS I, II)

Dyed and Poor undyed

Dyed and Good undyed

Very good

Multifilament (braided)

Fast-absorbing polyglactin 910 (Vicryl Rapide)

Undyed

Dyed and Good undyed

Multifilament (braided), monofilament

Polyglactin 910 (Vicryl, Polysorb)

Fair

Dyed and Good undyed

Undyed

Surgical gut (fast- Monofilament absorbing) Synthetic Polyglycolic acid Multifilament (Dexon) (braided)

Table 106.2: Commonly used absorbable sutures.* Ease of Suture Configuration Color handling Natural Surgical gut Monofilament Undyed Fair (plain) Surgical gut Monofilament Dyed Poor (chromic)

Coated

Coated

Uncoated

Low

Low

Low

Moderate to Fair high, 50% at 5 days, 0% at 14 days Moderate to Fair high, 45% at 5 days, 0% at 14 days Poor High; ≥3-0: 80% at 14 days, 60% at 42 days; 4-0: 60% at 14 days, 35% at 42 days

Coated

Low

Fair

High, 75% at 14 days, 50% at 21 days

Dexon S: uncoated; Dexon II coated

Uncoated

Low

Low

Uncoated

Uncoated

Coating

Good

Moderate, 20% at 21 days

Poor

Moderate, less than plain

Poor

Low, 50% at 3–5 days

Moderate

Poor

Low, lost in 7–10 days Low, lost in 10–21 days

Tissue reactivity

Knot security

Tensile strength

Nonantibacterial and antibacterialcoated (PDS Plus)

Nonantibacterial

Uses and considerations

182–238 days

(Contd...)

Subcutaneous closure (high-tension areas); longest absorption time

40–50 days Surface sutures (including mucosal)

Surface sutures (including mucosal)

60–90 days Subcutaneous closure, vessel ligation; high knot extrusion (spitting) 56–70 days Subcutaneous closure, vessel ligation; high memory

Rarely used in skin Skin grafts, mucosal surface sutures; unpredictable absorption rate 21–42 days, Skin grafts, variable surface sutures

60–70 days, variable 90 days, variable

Absorption rate

Nonantibacterial and antibacterialcoated (Vicryl Plus) Non42 days antibacterial

Nonantibacterial

Nonantibacterial

Nonantibacterial Nonantibacterial

Antibiotic coating

Chapter 106: Wound Closure 1555

Monofilament

Monofilament

Monofilament

Monofilament, barbed

Monofilament

Polytrimethylene carbonate (Maxon)

Polyglytone 6211 (Caprosyn)

Poliglecaprone 25 (Monocryl)

Polyglactone 72 (Monoderm)

Glycomer 631 (Biosyn)

Dyed and Good undyed

Dyed and Good undyed

Dyed and Good undyed

Dyed and Good undyed

Dyed and Fair undyed

Ease of Color handling Dyed and Poor undyed

*Information obtained from various manufacturers’ literature.

Configuration Monofilament, barbed

Suture Polydioxanone barbed (PDO)

(Contd...)

Good

High, 75% at 14 days, 40% at 21 days

Poor

Minimal

High, 62% at N/A, Low 7 days, 27% knotless at 14 days

Minimal

Low

Uncoated

Coated

Uncoated

Uncoated

Uncoated

Good

Low

Coating Uncoated

Knot Tissue security reactivity N/A, Low knotless

High, Good 50–60% at 7 days

Tensile strength High; ≥3-0: 80% at 14 days, 40% at 42 days; 4-0: 67% at 14 days, 50% at 28 days Very high, 81% at 14 days, 59% at 28 days High, 50–60% at 5 days

Nonantibacterial

Nonantibacterial and antibacterialcoated Nonantibacterial

Nonantibacterial

Nonantibacterial

Antibiotic coating Nonantibacterial

90–110 days

90–120 days

91–119 days

56 days

60–180 days

Absorption rate 120–180 days

Subcutaneous closure (hightension areas); rapid absorption Subcutaneous closure when minimal tissue reactivity is essential Surface sutures (including mucosal); virtually no knot extrusion (spitting) Subcutaneous closure; highest tensile strength among absorbable sutures

Subcutaneous closure (hightension areas)

Uses and considerations Subcutaneous closure; virtually no knot extrusion (spitting)

1556 Section 31: Dermatologic Surgery

Chapter 106: Wound Closure

Non-absorbable Sutures Non-absorbable suture is most commonly used in s­ urface sutures to finely approximate epidermal edges for optimal healing and cosmesis. The most commonly used nonabsorbable sutures and their properties are outlined in Table 106.3. Sutures are typically left in place for 5–14 days, de­­ pending on anatomic location.3 For facial repairs and mucosal sites, sutures are usually removed after 5–7 days. In select sites, such as the neck, ears, arm, hand and genital Table 106.3: Commonly used non-absorbable sutures* Ease of Tensile Suture Configuration Color handling strength Natural Silk Multifilament Dyed Gold Low, none (braided) standard in 365 days Synthetic Nylon Ethilon Monofilament Dyed Good to High, 20% and fair lost per undyed year Dermalon Monofilament Good to fair Surgilon Nurolon Polypro­ pylene (Prolene, Surgilene, Surgipro)

Multifilament (braided) Multifilament (braided) Monofilament

Polyester Multifilament (braided) (Dacron, Mersilene, Ethibond Excel) Polyester (Ethibond Excel) Polybut­ Monofilament ester (Novafil)

area, sutures may be removed after 7–10 days.3 Finally, in areas subject to higher tissue tension, such as the trunk, shoulder, lower extremity and scalp, sutures should be left in place for 10–14 days.3

Barbed Sutures Barbed suture, or knotless tissue-control devices, is a new class of suture material that has become available recently (Figs. 106.1A and B). It is primarily used in cosmetic plastic surgery12 but has also been used in orthopedic surgery13

Knot security

Tissue reactivity Coating

Good

High

Uncoated NonMucosal antibacterial surfaces

Poor

Low

Uncoated NonSkin surface antibacterial closure; high memory; may Coated tear through delicate tissue

Poor

Good

Fair

Coated

Good

Fair

Uncoated

Antibiotic coating

Uses and considerations

Dyed and undyed

Good to fair

Moderate, Poor extended

Minimal

Uncoated NonSkin surface antibacterial closure, including subcuticular closure

Dyed and undyed

Very good

Very high, Very good indefinite

Minimal

Uncoated NonMucosal antibacterial surfaces

Dyed and undyed

Good to fair

High, extended

*Information obtained from various manufacturers’ literature.

Good (coating decreases) Poor Low

Coated

Coated

NonConsider antibacterial when significant edema is anticipated (high elasticity)

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Section 31: Dermatologic Surgery

A

B

Figs. 106.1A and B: Barbed suture. (A) Bidirectional barbed suture with needles at either end and barbs switching directions at midpoint; (B) Magnified view of suture barbs.

as well as obstetric and gynecologic procedures.14 More recently, it has been introduced for use in cutaneous procedures with success.15 Barbed suture is available in nylon, polypropylene, polyglyconate, polydioxanone, poly­ glactone 72 and glycomer 631.3 Unlike traditional sutures, which possess a smooth and continuous surface, barbed sutures are nicked in symmetric or helical pattern, creating either unidirectional or bidirectional barbs that anchor tissue without the assistance of knots. Barbed suture offers a number of advantages over traditional suture.12,16 First, the lack of need for knots virtually eliminates the potential for knot-related complications, namely suture weakness and knot slippage. Second, suture tension is distributed evenly along the entire length of the closure rather than focally at fixed points (knots). Finally, barbed suture allows for easier and more rapid wound closure, increasing efficiency and convenience. In addition, the use of barbed suture may potentially lead to more natural scarring and improved cosmesis, thanks to the lack of knots and uniform tension distribution.12 Importantly, physicians should note that the functional tensile strength of barbed suture is reduced by the process of cutting barbs when compared to traditional smooth suture.14

SUTURE SELECTION The choice of suture material (s) should take into account the location of the wound, amount of static and dynamic tension on the wound, number of layers of closure, depth of suture placement, anticipated amount of edema and need for as well as anticipated timing of suture removal. To minimize tissue trauma and scar formation, the surgeon

should strive to use the smallest caliber suture that can provide adequate strength for closure. In areas of high tension, sutures with longer absorption rates should be used for subcutaneous closure. Likewise, in areas of high cosmetic importance, sutures with minimal tissue reactivity should be used. Although non-absorbable monofilament, thought to produce less scarring and better cosmesis due to its minimal inflammatory potential, has been the traditional suture of choice for superficial closure, absorbable suture is gaining acceptance in use for surface suturing.3 Studies examining the use of absorbable and non-absorbable suture in superficial closure have found no difference between the two materials in terms of cosmetic outcome, complications or patient satisfaction.17,18 Comparing poliglecaprone 25 and fast-absorbing polyglactin 910 for closure of facial skin wounds following skin cancer removal, Parell and Becker found no significant difference in inflammatory response or scar formation between the two materials.17 Similarly, Rosenzweig et al. evaluated the use of poliglecaprone 25 and polypropylene for superficial closures and found no significant difference in cosmetic results between the two materials and no reports of wound complications.18 Rather, the use of absorbable suture as the sole suture material for wound closure has been associated with significant time and cost savings.18

SUTURE NEEDLES The choice of needle size and shape must also be taken into consideration when selecting a suture material. Like suture strands, suture needles are sized by diameter using the

Chapter 106: Wound Closure

A

Fig. 106.3: Suture needle types. Cross-sectional shape of tapered (­circular) and cutting needles (triangular). The conventional cutting needle has its primary cutting edge on the inner curvature of the ­needle, facing the wound edge. Conversely, the reverse cutting needle has its primary cutting edge on the outer curvature of the needle, oriented away from the wound edge, decreasing the potential for tissue tearing. Non-cutting tapered needles are least likely to cause tissue tearing, making them especially useful in delicate tissues.

B Figs. 106.2 A and B: (A) Surgical needle anatomy; (B)The surgical needle is composed of the point, body and swage (shank/eye). The body represents the strongest part of the needle and the part that should be grasped by the needle holder, ideally one-quarter to one-half the distance from the swaged end.

USP sizing system and are available in a variety of sizes and shapes. The suture needle is typically composed of stainless steel and comprises three segments: the eye or swage/ shank (point of attachment to the suture), body and point (Figs. 106.2 A and B).3 Most sutures are swaged onto the eye or swage of the needle, allowing both needle and suture to pass through tissue atraumatically. The body of the needle spans the area between the point and the swage and determines the shape of the needle: straight; 1/4, 3/8, 1/2 or 5/8 circle; or compound curve.3 The 3/8 circle is most commonly used. The needle should be grasped by the needle holder one-quarter to one-half of the distance from the swaged end, as this segment represents the strongest part of the needle.3 The point of the needle is designated as tapered or cutting, depending on its cross-sectional shape: round or triangular, respectively (Fig. 106.3).3 The cutting

needle is most frequently used in dermatologic surgery and has two variations: the conventional cutting needle, where the apex of the triangle faces the inner curvature of the needle; and the reverse cutting needle, where the apex faces the outer curvature of the needle.3

SUTURING TECHNIQUES Suture placement technique greatly influences both the functional and cosmetic outcome of defect repair. The ideal wound closure technique reduces tension on wound edges, provides adequate hemostasis, achieves accurate approximation and eversion of wound edges, and leaves minimal if any lasting suture marks. The primary determinant of the best technique for closing a defect is the tension experienced across the wound when closure is attempted, which is largely dependent on the location of the defect and intrinsic characteristics of the skin in that area. As much tension as possible should be directed away from wound edges, as undue wound tension can result in dehiscence as well as scar widening. A combination of standard buried dermal or buried vertical mattress sutures and simple interrupted or simple running sutures are frequently used to close incisions, but a number of other suturing techniques may be considered to enhance

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Section 31: Dermatologic Surgery cosmesis in complicated closures.19 This chapter provides an overview of fundamental suturing techniques used in dermatologic surgery. The instrument tie is the knotting technique of choice in cutaneous surgery. Knots should be tied securely and laid flat against the wound surface. Suture should be knotted tightly enough to evert wound edges and promote hemostasis without strangulating the tissue. Further, surgeons should be mindful and take into account that the tissue around the wound will initially swell, causing sutures to become tighter, when knotting.

Simple Interrupted Suture—Epidermal Closure Uncomplicated and versatile, the simple interrupted suture is the most widely used suturing technique. This technique is commonly used alone to close biopsy sites, small lacerations and low-tension incisions, as well as in surface closure in layered closures. Simple interrupted sutures are also useful for making adjustment in wounds closed using other techniques. The simple interrupted stitch (Figs. 106.4A and B) begins with placement of the needle 1–4 mm from the wound edge (depending on skin thickness), importantly at a 90° angle to the skin to achieve good eversion and minimize the size of the entry wound. The needle is then directed through the epidermis, reangled away from

the wound edge and advanced through the dermis to the desired depth, and subsequently rotated through the ­tissue on the opposing wound edge in a mirror path by rolling the wrist along the arc defined by the curvature of the needle. Accurate alignment of wound edges is vital for good cosmesis when suturing with this or any other technique. Thus, great care should be taken to place the suture at the same depth on either side of the wound to avoid vertical misalignment or “step-off” deformities. Similarly, the same care should be taken to accurately approximate wound edges to avoid horizontal misalignment. The exit and entry points of the needle on the contralateral wound edge should be equidistant from the wound. Forceps can be used to facilitate needle entry by grasping the deep tissue with the forceps and passing the needle through skin, as well as needle exit by grasping the needle near (but not on) the tip and pulling the rest of the needle and suture through. For larger defects, larger amounts or “bites” of ­tissue are usually taken, and it may be necessary to reload the needle in the center of the wound before passing it through the opposing wound edge. Correctly placed, the simple interrupted stitch forms a flask- or pear-shaped loop with everted wound edges. Incorrect or inappropriate placement may provide excellent approximation of wound edges but may also result in wound inversion and a sunken scar at the suture line due to vertical contraction of the scar. In rare instances, wound inversion may be desired, e.g. in naturally concave areas, such as the alar crease, but specialized stitching techniques for producing wound inversion are recommended in these instances.19

Vertical Mattress Suture—Epidermal Closure

A

B

Figs. 106.4A and B: Simple interrupted suture. (A) (1) The needle enters the epidermis perpendicularly 1–4 mm from the wound edge and is directed through the dermis in a slightly oblique path away from the wound edge. (2) The needle crosses the wound near the base, including a wider bite of dermis (and underlying subcutaneous tissue) and (3) is redirected up through the dermis of the contralateral wound edge in a path that mirrors the first. (4) The needle exits the epidermis at the same distance from the wound edge as it entered, and the suture is tied; (B) Flask/pear-shaped appearance of the completed suture.

The vertical mattress stitch combines the advantages of deep dermal and superficial interrupted stitches and excels at relieving wound tension, providing good closure and eversion, as well as closing dead space. Vertical mattress stitches are placed in a “far-far-near-near” sequence, as will be described. The needle is introduced 5–10 mm from the wound edge (the far entry point) and directed down through a generous portion of the dermis and exited just above the base of the wound (Figs. 106.5A to C). The needle is then directed into the opposing wound edge near the base and advanced upwards through the dermis and epidermis (the far exit point). The far entry and exit points should be equidistant from the wound. The needle is then loaded in the needle driver in the reverse direction and reintroduced on the same side as the far exit point 1–3 mm

Chapter 106: Wound Closure from the wound edge (the near entry point) and exited in the same position on the starting side of the wound (the near exit point), taking a small bite of dermis and epidermis on both sides of the wound. The suture is then tied with sufficient tension to approximate defect edges but not too tightly, as undue tension can strangulate the dermal blood supply and lead to wound edge necrosis and surface scarring. For optimal results using this technique, all ­needle entry and exit points should lie along an imaginary line lying perpendicular to the incision. Due to their more time-consuming placement compared to simple interrupted stitches, vertical mattress stitches are less frequently used and likely underutilized despite their usefulness. This technique is particularly useful in areas where wound edges have a tendency to invert, such as the posterior neck. For wounds under significant tension, placement of bolsters made of cardboard, cotton, rubber or other compressible materials between ­extracutaneous loops of suture and the skin may help

prevent injury to the underlying epidermis, particularly after the onset of postoperative edema.20

Horizontal Mattress Suture—Epidermal Closure The horizontal mattress stitch is a suturing technique that is especially good at redistributing wound tension along wound edges while providing eversion and closing dead space (Figs. 106.6A and B). This suture is particularly well suited as an anchoring (holding) or retention suture in

A

B

A

C Figs. 106.5A to C: Vertical mattress suture. (A) (1) The needle is introduced 5–10 mm from the wound edge and placed deeply, ­ (2) entering the opposite side of the wound at the base before exiting the skin in the same position; (B) (3) The needle is reintroduced to the skin on the same side of the wound 2–4 mm from the wound edge and placed more superficially before exiting the skin on the starting side of the wound in the same position as the near entry point. (4) The suture is tied off gently, giving it its final appearance (C).

B Figs. 106.6A and B: Horizontal mattress suture. (A) The needle is introduced 4–10 mm from the wound edge and placed like a simple interrupted stitch. (1, 2) The needle is then reintroduced on the second side of the wound 3–5 mm down and parallel to the wound edge, and a second simple interrupted stitch is placed in the opposite direction to the first. (3, 4) Numbers indicate order of needle entry points. The suture is tied gently and carefully, giving it its final appearance (B).

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Section 31: Dermatologic Surgery high-tension wounds and larger wounds or flaps due to its ability to reduce tension and facilitate placement of subsequent sutures. In addition, its tension-relieving properties make it a good choice for closing more delicate tissues. The needle is introduced 4–10 mm from the wound edge and directed through the dermis or subcutaneous tissue and exited on the contralateral side of the wound at a distance from the wound edge equal to that between the entry point and the wound edge. The needle is then reintroduced to the skin 3–5 mm from the exit point parallel to the wound edge and directed back across the wound and exited on the same side and distance from the wound edge as the initial entry site. The suture is then tied gently and with care not to strangulate tissue. When tied, the extra cutaneous loops of the horizontal mattress stitch should run parallel to the wound edges. The main disadvantage of this technique is the heightened risk of strangulation of the dermal blood ­ supply. Thus, it is rarely used in areas with poor vascular supply or in suturing flaps. As for vertical mattress stitches, bolsters may be used to help prevent epidermal injury.21 Other disadvantages of this technique include difficulty achieving precise wound edge apposition, troublesome removal and risk of scarring. Early suture removal is especially important in cosmetically sensitive areas due to the risk of scarring. When used as an initial holding suture for epidermal closure, the horizontal mattress suture(s) may be removed first and the remaining sutures later (if suture removal is required). Because the suture incorporates a large amount of tissue within the passage of the suture, horizontal mattress stitches make for effective hemostatic sutures in highly vascular tissues, such as the scalp. A modified version of this suture called the locking horizontal mattress suture further enhances its hemostatic capabilities and is also helpful for wounds that require wound edge compression. Placement of the locking horizontal mattress suture begins with placement of a traditional horizontal mattress suture, but the extracutaneous loop formed on the contralateral side of the wound is left loose so that the needle and suture can be passed beneath it to lock the suture.22

closes dead space but poses a relatively low risk of tissue strangulation and suture scarring. The suture begins the same way as a traditional horizontal mattress stitch, but the needle is directed horizontally through the dermis of the opposing wound edge in a parallel plane to the epidermal surface. The needle then reenters the starting wound edge at the dermal level and is exited lateral to the initial needle entry point, and the suture is tied like a traditional horizontal mattress stitch. As mentioned earlier, this technique is frequently used to approximate and secure the angular tip of one or more flaps or M-plasty incisions. The buried portion of the tip stitch is embedded in the dermis of the flap tip (s), and the exposed suture loop is strategically placed on the contralateral wound edge such that an imaginary line bisecting the opposing flap tip forms a line of symmetry across the wound (Figs. 106.7A and B). Correct placement results in apposition of angled wound edges without having to suture the small and fragile flap tip (s), preserving more blood flow to the flap tip (s) as a result. When used in combination with other superficial sutures, the tip stitch should be placed first to guide the rest of the repair.

Running (Continuous) Techniques— Epidermal Closure

Running or continuous suture placement involves successive placement of individual stitches without interruption by knots. Running techniques offer significant savings in time compared to interrupted suture placement, but running sutures are not equivalent in strength to interrupted ones and so should be used judiciously as the sole means of defect closure. Running sutures should be used cautiously to close wounds under more than minimal tension, as they can strangulate the vascular supply to the skin. Nevertheless, running sutures are often an ­efficient and excellent means of epidermal closure and can produce superior cosmetic outcomes in the right wounds. Most epidermal sutures, including simple and mattress sutures, can be adapted for continuous placement. The most commonly used running simple stitch will be covered in detail. First, a simple interrupted stitch is Half-buried Horizontal Mattress placed and tied, but only the free end of the suture is cut (Tip) Suture (Fig. 106.8). The needle is then reintroduced through the A variation of the horizontal mattress stitch, the half-­ epidermis next to the initial stitch and directed through buried horizontal mattress stitch derives its name from the dermis diagonally across the defect to exit the skin the embedment of half of the suture in the dermis. This 3–5 mm from the wound edge on that side. Next, the neesuture is particularly useful for repairing defects with dle is reintroduced through the skin on the opposing side angular flap tips as a “tip stitch,” as it provides eversion and of the wound at the same 3–5 mm distance from the wound

Chapter 106: Wound Closure

A

B

Figs. 106.7A and B: Half-buried horizontal mattress (tip) stitch. (A) (1) The needle is introduced 4–10 mm from the apex of the V-shaped portion of the wound edge and passed horizontally through the dermis from (2) one side of the flap tip to the other. (3, 4) The needle is then directed back through the wound edge at the same position from the apex as the first entry point, and the suture is tied; (B) Final appearance of the completed tip stitch with subsequent placement of simple interrupted stitches.

Fig. 106.8: Running simple suture. Placement of this stitch begins with (1) a simple interrupted stitch, followed by multiple simple stitches in succession for rapid and efficient wound closure. Numbers denote order of needle entry points.

edge to form a loop that will lie perpendicular to the incision. Subsequent loops are then placed 3–7 mm apart by passing the needle transcutaneously from one side of the wound to the next by repeating the steps above until the entire wound is closed. Sufficient tension should be placed on the suture while suturing to maintain wound closure without causing strangulation. Once the entire wound is closed, the last loop is grasped by the needle driver and used to tie off the suture. A modified version of the running simple stitch that involves locking each loop of suture allows each loop of suture to act more independently in bearing tension and

can be useful in longer incisions or in wounds with a high risk of postoperative bleeding, such as the scalp. In this version, the needle is passed through the remaining suture loop with each stitch, connecting the loops of suture above the skin (Fig. 106.9). Surgeons should be aware that locking leads to loss of the equal tension distribution intrinsic to the basic running stitch and thus an increased risk of strangulation. Both vertical and horizontal mattress stitches can also be adapted for running placement. However, because their removal can be difficult, many recommend the placement of a simple running stitch after every two to three mattress sutures for easier removal.22,23

Running Subcuticular Suture—Epidermal Closure The running subcuticular suture involves minimal epidermal puncture points, allowing for prolonged suture support and better wound healing with minimal risk of suture-track scarring, and is thus favored by many ­surgeons for its excellent cosmetic results. Sutures with low friction coefficients should be used for this type of suture. Both absorbable and non-absorbable suture may be used, as overall wound cosmesis does not appear to vary based on absorbable vs non-absorbable material.18 The needle is introduced approximately 10 mm distal to one end of the wound and brought through the apex of the wound at the dermal level (Fig. 106.10). The free end of

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Section 31: Dermatologic Surgery of the defect until the other end of the wound is reached. After the last bite is taken, the needle is exited through the distal apex of the wound 10 mm from wound. The suture is then pulled until wound edges are well approximated and finally tied back on itself or secured using tape (if using non-absorbable suture). Excessive tension may cause the skin to bunch and should thus be avoided. Alternatively, the end of each side of suture can be buried, with an internal buried dermal knot, if an absorbable suture is used for this type of closure.

Fig. 106.9: Running locked suture. Placement of the running locked suture closely resembles placement of a running simple suture, but the needle is passed through each loop of suture to lock each successive stitch. This locking modification promotes hemostasis. Numbers denote order of needle entry points.

Fig. 106.10: Running subcuticular suture. The needle enters the skin ~10 mm from one end of the wound and passes through the proximal apex at the dermal level. Multiple horizontal dermal sutures are placed in succession on alternating sides of the wound in a zigzagging fashion until the wound is closed. The needle then exits through the apex on the other side of the wound ~10 mm from the end of the wound. This suture involves minimal epidermal entry points and produces epidermal and dermal closure without leaving suture marks. Numbers denote order of needle entry points.

the suture is then tied on itself or, if using non-absorbable suture can be secured with tape. Next, a horizontal bite of dermis is taken by introducing the needle through the dermis of one wound edge and directing it through the dermal plane to exit 10–15 mm down the wound at the same dermal level. The needle is then introduced to the contralateral wound edge at the same dermal plane 2–3 mm proximal to the preceding needle exit point, forming a zigzag pattern down the wound to achieve good dermal apposition and complete closure. Repeating these steps, horizontal bites of dermis are taken from alternating sides

Vertical Deep/Buried Dermal (Absorbable) Sutures Subcutaneous sutures are indispensable for the repair of deep defects, as they effectively redistribute wound tension to the dermis instead of the epidermis, close dead space and promote wound edge apposition. Deep or buried sutures offer prolonged support to healing wounds, greatly reducing the risk of dehiscence and thus improving cosmetic results. When used, deep sutures are almost always combined with surface sutures or another form of epidermal closure. Meticulous placement is extremely important for good results, as improper placement can result in suture migration and extrusion (“spitting”) if placed too high or “step-off” deformities if placed unevenly. Undermining of wound edges is frequently performed beforehand to facilitate placement of both buried and surface sutures. To place a traditional buried suture, the wound edge is everted using forceps or a skin hook, and the needle is introduced at the subcutaneous level, ideally through the undersurface of the skin flap, advanced upwards through the dermis and brought back out through the mid-dermis of the same wound edge, following the natural arc of the needle (Figs. 106.11A and B). The needle is then introduced to the opposing wound edge at the same dermal level as the preceding exit point and exited through the subcutaneous tissue at the same subcutaneous level as the initial point of entry. The suture is then tied deep at the subcutaneous level and the free ends cut on the knot, thereby removing as much excess suture as possible and minimizing tissue reaction. If greater eversion of wound edges is desired, the buried vertical mattress stitch can provide considerably more and longer-lasting eversion than the simple buried suture.24 To place a buried vertical mattress stitch, the needle is introduced through the subcutaneous tissue and directed through the dermis in an arc that first travels up through the superficial dermis and then back down to exit through the mid-dermis (Figs. 106.12A and B). Crossing the wound, the needle is then introduced to the other

Chapter 106: Wound Closure

A

B

Figs. 106.11A and B: Traditional buried suture. (A) (1) The needle enters at the subcutaneous level and (2) crosses the wound at the mid-dermal level before exiting on the opposing side of the wound at the same subcutaneous level as the initial entry point. The suture is tied deep at the subcutaneous level and produces mild eversion of wound edges; (B) Final appearance of the completed conventional buried suture.

wound edge through the mid-dermis and directed through the dermis in an arced course that follows a mirror image of the first side, up towards the superficial dermis and then back down to exit at the subcutaneous level. When tied, this suture will naturally evert the wound edges and may be used as the sole means of closure with elegant cosmetic results under the appropriate circumstances.25 A third type of dermal stitch, the buried butterfly suture, offers maximal wound eversion and removes tension from wound edges, promoting minimal scar ­ ­formation.26 Placement of this suture requires undermining of wound edges beforehand. To place this suture, the needle is introduced through the undersurface of the skin flap and directed up through the subcutaneous tissue and dermis and back down along the curvature of the needle and exited back through the undersurface of the flap near the base of the wound (Figs. 106.13A and B). The needle is then directed through the opposing wound edge in a similar manner, entering through the undersurface of the skin flap at the same distance from the wound base as the preceding exit point, traversing the dermis in a curved path away from the wound edge and exiting back out through the flap at a point lying farther from the wound base than the entry point. The suture is then tied, which will evert the epidermal edges and redistribute closure tension to the surrounding skin. This may initially cause temporary dimpling in the skin surrounding the wound and/or elevation or ridging along the incision line due to deliberate eversion of wound edges, but such changes will resolve as the skin stretches and the sutures degrade.

SUTURE COMPLICATIONS Potential suture-related complications include local inflammation and tissue reactivity, suture extrusion, and

A

B

Figs. 106.12A and B: Buried vertical mattress suture. (A) (1) The needle enters the undersurface of the skin flap and passes up and outward through the subcutaneous tissue and dermis in an arced path before exiting at the mid-dermal level. (2) The needle then crosses the wound and enters the mid-dermis of the opposing wound edge at the same vertical level and is directed through the dermis and out the subcutaneous tissue, where its course follows a mirror image of the starting side. The suture is tied, giving it its final appearance (B). Note the greater degree of wound eversion achieved by the buried vertical mattress suture compared to the conventional buried suture.

A

B

Figs. 106.13A and B: Buried butterfly suture. (A) (1) The needle enters the far undersurface of the undermined skin flap and is directed up through the subcutaneous tissue and dermis and back down in a curved path before exiting the undersurface near the wound base. The same process is repeated on the other skin flap but in the reverse order, (2) entering near the wound base and exiting at a farther distance from the wound edge; (B) Final appearance of the buried butterfly suture once tied. Note the large degree of wound eversion achieved by this technique.

infection, as well as abscess or fistula formation.27 Tissue strangulation can also occur if sutures are tied too tightly, or conversely, wound dehiscence, if they are tied too loosely to provide adequate tension for proper wound closure. Inflammatory tissue reactions are most commonly associated with natural materials, though granulomatous foreign body reactions have been observed with synthetic absorbable sutures, both monofilamentous and multifilamentous.27,28 Sterile pustules or suture abscesses can also develop around sutures, which may become s­ econdarily infected. In addition, formation of a sinus tract within the skin can also occur with suture extrusion (­spitting). In both cases, removal of the offending suture usually suffices for treatment. Antibiotics may be necessary in the case of secondary infection.27 As discussed earlier, it is controversial as to whether multifilament suture introduces an increased risk of

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Section 31: Dermatologic Surgery infection. A study published in 2001 demonstrated that local wound complications were primarily related to patient factors, wound characteristics and surgeon experience, rather than suture material or suturing technique.29 The  choice of suture material and suturing technique may be of greater practical consideration, however, especially if patient and wound factors cannot be changed.

NON-SUTURE ALTERNATIVES A number of alternative non-suture wound closure materials are also available to the dermatologic surgeon.

Staples Surgical stainless steel staples are an efficient means of wound closure and are most commonly used when closing long or high-tension wounds (e.g. on the scalp).19 Staples offer the highest tensile strength among all wound closure materials and have a lower risk of reactivity, infection and tissue strangulation compared to sutures.19,30 They also provide excellent wound eversion and have been shown to have equivalent cosmetic results in comparison to nylon sutures in epidermal closure in certain anatomical areas.19,31–34 In addition, the staple placement is less time-consuming than of suture placement, rendering it more cost-effective when factoring in time.35

Tissue Adhesives Tissue adhesives are a class of cyanoacrylate compounds that are utilized for their ability to bind to tissue and other surfaces via a rapid polymerization reaction that occurs on contact with water. The major advantages of using tissue adhesives include ease and speed of use, immediate wound closure, innate hemostatic properties, and good cosmesis and decreased potential for infection owing to the lack of puncture wounds. In addition, tissue adhesives eliminate the need for a secondary bandage or dressing, water avoidance after surgery and need for suture removal.36 They are most commonly used to close superficial lacerations, especially in pediatric patients, but are also used to repair small, superficial defects or in place of epidermal sutures after placement of subcutaneous sutures.19 A variety of formulations of cyanoacrylates that differ in alkoxycarbonyl (-COOR) side chain composition and physical property are commercially available. Two  major tissue adhesives are used in dermatologic ­surgery: n-butyl-2-cyanoacrylate and octyl cyanoacrylate (Table 106.4).

Tissue adhesives can be applied directly to a clean, dry wound in a drop-wise manner or using a brush, taking care to ensure wound edges are in direct apposition with no gaps or bleeding before application of the ­adhesive. Even  very small gaps can result in adhesive migration between the wound edges, inhibiting normal epithelialization and wound healing. In addition, postoperative bleeding or oozing may result in epithelial wound edge separation.19,36 Tissue adhesives are contraindicated in the presence of infection or ulceration, bleeding or ­oozing from the wound, edematous wound edges, wounds in high-tension areas, mucosal surfaces and mucocutaneous junctions, areas with high moisture or dense hair, and in patients with delayed wound healing or allergies to cyanoacrylates and its cross reactors.37 In terms of esthetic outcomes, numerous studies have demonstrated tissue adhesives to be cosmetically equivalent to epidermal sutures.37–40 However, dermatologic surgeons should be aware that sutures are superior to tissue adhesives in minimizing dehiscence39 and may produce better cosmesis in cosmetically sensitive areas and excisional surgeries attributable to their ability to evert wound edges.41 The use of buried stitches that promote wound edge ever­ sion, such as vertical mattress stitches (discussed in subsequent ­sections) may decrease the risk of wound dehiscence and postoperative scar widening.3 Of additional consideration, tissue adhesives can be costly, with single-use vials generally being more expensive than multiuse vials.19

Surgical Adhesive Tapes Surgical adhesive tapes or surgical strips are available in a variety of sizes and colors and are most commonly used to support sutured wounds or to repair very superficial lacerations. They can also be used in place of sutures for epidermal closure in low-tension wounds that have been closed with a layer buried dermal sutures.42 The main advantages of suture-less skin closure with adhesive tape include reduced local skin tension, speed of use, reduced overall cost, lack of requirement for in-office removal, as well as decreased risk of infection compared to superficial sutures43,44 and faster restoration of tensile strength.45 Wound cosmesis is quite good, and both patient and surgeon satisfaction is high. However, the use of surgical adhesive tape alone without other means of epidermal closure is not recommended in cosmetically sensitive areas or in areas with high tension, as wound inversion may result.36 To optimize adhesive strength and length of time, the surrounding skin should be degreased with alcohol, and a liquid adjuvant adhesive such as benzoin or Mastisol

Chapter 106: Wound Closure Table 106.4: Tissue adhesives.* Cyanoacrylate Manufacturer Indermil, Covidien; N-butyl-2GluStitch, Liquiband, cyanoacrylate (Indermil, GluStitch, GluStitch, Inc, Delta, Canada; Histoacryl, B. Liquiband, Braun Melsungen AG, Histoacryl) Germany Octyl cyanoacrylate, Ethicon n-2-cyanoacrylate (Dermabond)

Properties Faster polymerization, stronger bond formation and decreased tissue toxicity compared to short-chain cyanoacrylate predecessors; drying time approximately 30 seconds Equivalent strength to 5-0 nylon sutures or subcuticular absorbable suture, polymerizes in 2.5 minutes (first layer), good flexibility, less tissue toxicity compared to n-butyl-2cyanoacrylate; inhibits bacterial growth

Uses and considerations Only Indermil has approval by the Food and Drug Administration (FDA) for use in wound closure; Liquiband approved by FDA for use on unbroken skin as a skin protectant in USA; GluStitch available in multiuse vials Packaged in 0.5 mL single-use ampules; must be applied in three layers with complete drying between layers unless using newer advanced formulations requiring only one layer of application; polymerization generates heat, which may cause discomfort; high-viscosity formulation reduces risk of adhesive migration from wound and may improve wound cosmesis

*Information obtained from various manufacturers’ literature.

(Ferndale Laboratories, Inc., Ferndale, MI) may be applied around the wound edges (while avoiding the wound itself ) before placing the surgical strips. Application of surgical strips in a parallel, non-overlapping fashion after coating the entire application area with adhesive adjunct produces the best and longest-lasting adherence.46 Care should be taken to approximate wound edges accurately and without wound edge inversion. When applied with optimal technique, surgical strips can last 1–2 weeks.43,46 Surgical strips can also be used as a tissue-strengthening adjunct to sutures on thin skin, preventing sutures from tearing through the fragile tissue. Strips can be placed either perpendicular or parallel to the laceration line, followed by placement of simple interrupted or horizontal mattress sutures through the strips, based on the individual preferences of the surgeon.3,47,48 While no studies have compared the outcomes of perpendicular versus parallel strip placement in surgical-strip-suture combination repair, parallel strip placement may be more advan­ tageous, as the configuration provides even ten­­ sile strength along the entire length of the defect.3,47 Before placement patients should be asked about any allergy to adhesives or tape.

REFERENCES 1. Naleway SE, Lear W, Kruzic JJ, et al. Mechanical properties of suture materials in general and cutaneous surgery. J Biomed Mater Res B Appl Biomater 2015;103(4):735–42. 2. Im JN, Kim JK, Kim HK, et al. Characteristics of novel monofilament sutures prepared by conjugate spinning. J  Biomed Mater Res B Appl Biomater 2007;83:499–504.

3. Yag-Howard C. Sutures, needles, and tissue adhesives: a review for dermatologic surgery. Dermatol Surg 2014; 40(Suppl 9):S3–15. 4. Bucknall TE. Factors influencing wound complications: a clinical and experimental study. Ann R Coll Surg Engl 1983;65:71–7. 5. Edmiston CE, Jr., Krepel CJ, Marks RM, et al. Microbiology of explanted suture segments from infected and noninfected surgical patients. J Clin Microbiol 2013;51:417–21. 6. Stone JK, von Fraunhofer JA, Masterson BJ. Mechanical properties of coated absorbable multifilament suture materials. Obstet Gynecol 1986;67:737–40. 7. Rothenburger S, Spangler D, Bhende S, et al. In vitro antimicrobial evaluation of coated VICRYL* plus antibacterial suture (coated polyglactin 910 with triclosan) using zone of inhibition assays. Surg Infect (Larchmt) 2003;3(Suppl 1): S79–87. 8. Sajid MS, Craciunas L, Sains P, et al. Use of antibacterial sutures for skin closure in controlling surgical site infections: a systematic review of published randomized, ­controlled trials. Gastroenterol Rep (Oxf ) 2013;1:42–50. 9. Lin PH, Hirko MK, Von Fraunhofer JA, et al. Wound healing and inflammatory response to biomaterials. In: Chu  CC, Anthony von Fraunhofer J, Greisler HP, editors. Wound ­closure biomaterials and devices. 1st ed. Boca Raton (FL): CRC Press; 1996. p. 7–24. 10. Adams B, Levy R, Rademaker AE, et al. Frequency of use of suturing and repair techniques preferred by dermatologic surgeons. Dermatol Surg 2006;32:682–9. 11. Harris DR. Healing of the surgical wound. I. Basic considerations. J Am Acad Dermatol 1979;1:197–207. 12. Villa MT, White LE, Alam M, et al. Barbed sutures: a review of the literature. Plast Reconstr Surg 2008;121:102e–8e. 13. Levine BR, Ting N, Della Valle CJ. Use of a barbed suture in the closure of hip and knee arthroplasty wounds. Orthopedics 2011;34:e473–5.

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Section 31: Dermatologic Surgery 14. Greenberg JA, Goldman RH. Barbed suture: a review of the technology and clinical uses in obstetrics and gynecology. Rev Obstet Gynecol 2013;6:107–15. 15. Strasswimmer J, Latimer B, Speer H. Barbed absorbable suture closure for large Mohs surgery defect. JAMA dermatology 2013;149:853–4. 16. Goldstein LJ, Chary D, Brennan S. Knotless tissue control devices: an asset in plastic surgery. Plast Surg Nurs 2014;34:39–42. 17. Parell GJ, Becker GD. Comparison of absorbable with nonabsorbable sutures in closure of facial skin wounds. Arch Facial Plast Surg 2003;5:488–90. 18. Rosenzweig LB, Abdelmalek M, Ho J, et al. Equal cosmetic outcomes with 5-0 poliglecaprone-25 versus 6-0 polypropylene for superficial closures. Dermatol Surg 2010;36:1126–9. 19. Regula CG, Yag-Howard C. Suture products and techniques: what to use, where, and why. Dermatol Surg 2015; 41(Suppl 10):S187–200. 20. Zuber TJ. The mattress sutures: vertical, horizontal, and corner stitch. Am Fam Physician 2003;66(12):2231–6. 21. Coldiron B. Closure of wounds under tension. The horizontal mattress suture. Archives of dermatology 1989;125: 1189–90. 22. Hanasono MM, Hotchkiss RN. Locking horizontal mattress suture. Dermatol Surg 2005;31(5):572–3. 23. Chacon AH, Shiman MI, Strozier N, et al. Horizontal running mattress suture modified with intermittent simple loops. J Cutan Aesthet Surg 2013;6:54–6. 24. Zitelli JA, Moy RL. Buried vertical mattress suture. J Dermatol Surg Oncol 1989;15(1):17–9. 25. Hohenleutner U, Egner N, Hohenleutner S, et al. Intradermal buried vertical mattress suture as sole skin closure: evaluation of 149 cases. Acta Dermato-Venereol 2001;80(5):344–7. 26. Breuninger H, Keilbach J, Haaf U. Intracutaneous butterfly suture with absorbable synthetic suture material. Technique, tissue reactions, and results. J  Dermatol Surg Oncol 1993;19(7):607–10. 27. Hirko MK, Lin PH, Greisler HP, et al. Biological properties of suture materials. In: Chu CC, Anthony von Fraunhofer J, Greisler HP, editors. Wound closure biomaterials and devices. 1st ed. Boca Raton (FL): CRC Press; 1996. p. 237–88. 28. Holzheimer RG. Adverse events of sutures: possible interactions of biomaterials? Eur J Med Res 2005;10:521–6. 29. Gabrielli F, Potenza C, Puddu P, et al. Suture materials and other factors associated with tissue reactivity, infection, and wound dehiscence among plastic surgery outpatients. Plast Reconstr Surg 2001;107:38–45. 30. Bennett RG. Selection of wound closure materials. J Am Acad Dermatol 1988;18(4 Pt 1):619–37. 31. Grgic M, Ivkic M. Use of skin staplers in head and neck surgery: prospective clinical study. J Otolaryngol 2002;31(3):137–9. 32. Khan AN, Dayan PS, Miller S, et al. Cosmetic outcome of scalp wound closure with staples in the pediatric

emergency department: a prospective, randomized trial. Pediatr Emerg Care 2002;18(3):171–3. 33. dos Santos LR, Freitas CA, Hojaij FC, et al. Prospective study using skin staplers in head and neck surgery. AmJSurg 1995;170(5):451–2. 34. Meiring L, Cilliers K, Barry R, et al. A comparison of a disposable skin stapler and nylon sutures for wound closure. S Afr Med J 1982;62(11):371–2. 35. Orlinsky M, Goldberg RM, Chan L, et al. Cost analysis of stapling versus suturing for skin closure. Am J Emerg Med 1995;13(1):77–81. 36. Coulthard P, Worthington H, Esposito M, et al. Tissue adhesives for closure of surgical incisions. Cochrane Database Syst Rev 2004(2):Cd004287. 37. Kim J, Singh Maan H, Cool AJ, et al. Fast absorbing gut suture versus cyanoacrylate tissue adhesive in the epidermal closure of linear repairs following Mohs micrographic surgery. J Clin Aesthet Dermatol 2015;8(2):24–9. 38. Sniezek PJ, Walling HW, DeBloom JR, 3rd, et al. A randomized controlled trial of high-viscosity 2-octyl cyanoacrylate tissue adhesive versus sutures in repairing facial wounds following Mohs micrographic surgery. Dermatol Surg 2007;33(8):966–71. 39. Dumville JC, Coulthard P, Worthington HV, et al. Tissue adhesives for closure of surgical incisions. Cochrane Database Syst Rev 2014(11):Cd004287. 40. Farion K, Osmond MH, Hartling L, et al. Tissue adhesives for traumatic lacerations in children and adults. Cochrane Database Syst Rev 2002(3):Cd003326. 41. Bernard L, Doyle J, Friedlander SF, et al. A prospective c­omparison of octyl cyanoacrylate tissue adhesive (dermabond) and suture for the closure of excisional wounds in children and adolescents. Arch Dermatol 2001;137(9):1177–80. 42. Katz KH, Desciak EB, Maloney ME. The optimal application of surgical adhesive tape strips. Dermatol Surg 1999;25(9):686–8. 43. Al-Mubarak L, Al-Haddab M. Cutaneous wound closure materials: an overview and update. J Cutan Aesthet Surg 2013;6(4):178–88. 44. Conolly WB, Hunt TK, Zederfeldt B, et al. Clinical ­comparison of surgical wounds closed by suture and adhesive tapes. Am J Surg 1969;117(3):318–22. 45. Forrester JC, Zederfeldt BH, Hayes TL, et al. Tape-closed and sutured wounds: a comparison by tensiometry and scanning electron microscopy. Br J Surg 1970;57(10): 729–37. 46. Kolt JD. Use of adhesive surgical tape with the absorbable continuous subcuticular suture. ANZ J Surg 2003;73(8):626–9. 47. Lin M. Trick of the Trade: Steris-trip-suture combo for thin skin lacerations: academic life in emergency medicine,; 2011 [accessed 30.03. 2011]. 48. Davis M, Nakhdjevani A, Lidder S. Suture/steri-strip combination for the management of lacerations in thin-skinned individuals. J Emerg Med 2010;40(3):322–3.

Chapter

107

Electrosurgery Lilia Correa-Selm, Bahar F Firoz

INTRODUCTION Electrosurgery is defined as the passage of current through an electrode to the body tissues, where current is trans­ formed to heat which can be used for various surgical applications. There are four types based on the mecha­ nism of tissue damage. 1. Electrolysis uses direct current (DC) and a chemical reaction at the electrode tip to induce tissue damage. 2. Coblation uses high frequency alternating current (AC) to ionize a conductive medium like saline to transmit heat which causes superficial skin damage. 3. High frequency AC uses heat production to cause tissue damage, and is the method utilized in electro­ desiccation, electrofulguration, electrocoagulation and electrosection. 4. Electrocautery differs from electrosurgery in that a DC or high frequency AC heats up a metal probe which is then applied to the tissue to cause destruction.

Variations in the current, amperage, voltage and elec­ trodes used, define the various techniques including electrodesiccation, electrocoagulation, electrofulgura­ tion and electrosection. This chapter will focus on the latter two methods.

PRINCIPLES An electrosurgery device is comprised of two electrodes and one high frequency current generator. One elec­ trode is active while the other is dispersive in that it takes the current back to the generator to close the electrical circuit. The active electrode serves as a conductor to the current flowing from the generator to the patient’s body (Fig. 107.1). Once the current reaches the tissue, the cur­ rent turns to heat, which can be wielded surgically. This electrode may be cooler than the treated area as contact with the tissue is required to close the electrical circuit and convert electricity to heat; this is different than the

Fig. 107.1: Electrosurgery consists of the passage of current through an electrode to the patient body, where electricity from a high frequency AC is transformed to heat.

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Section 31: Dermatologic Surgery electrocautery tip which can generate heat independent of any bodily contact.1

Monopolar and Bipolar The active electrosurgery electrode can be composed of one or two tips. A monopolar electrode includes one active tip. A bipolar electrode consists of two tips, an active elec­ trode tip and a dispersive tip (Fig. 107.2). One example of a monopolar device is a pointed electrode, while electro­ surgical forceps would be considered a bipolar device. The bipolar electrode causes less damage to the tissue and has less risk of burns to the patient compared to monopolar because it is a more narrowly defined, closed circuit where the only active area is the tissue between the two tips.1–3

Monoterminal and Biterminal An electrosurgery device is monoterminal when it has an active electrode without a dispersive electrode because the return electrode is connected to earth (hence “earth-referenced”), usually through the power supply cable. A biterminal device, on the other hand, is one that has both an active electrode and a dispersive electrode (ground plate) which takes the energy back to the gen­ erator (Fig. 107.3). Monoterminal indicates that only one electrode delivers current to the patient, while a biterminal uses two electrodes. A monopolar device could be either monoterminal or biterminal depending on if the disper­ sive ground is connected back to the machine or earthreferenced. A bipolar device is biterminal as it is always

Fig. 107.2: Monopolar electrode has one tip in contact with the skin and bipolar electrode has two tips in contact with the skin.

Fig. 107.3: A monoterminal device has an active electrode without a dispersive electrode and a biterminal device is the one that has both an active electrode and a dispersive electrode.

Chapter 107: Electrosurgery grounded back to the generator. Electrodesiccation and electrofulguration are monoterminal procedures, while electrocoagulation and electrosection are biterminal pro­ cedures (Table 107.1).1–3

Damped vs. Undamped This refers to the form of the wave that the current pro­ duces. A damped waveform is composed of energy bursts that gradually return to zero, while an undamped wave­ form has a continuous flow in which the amplitude of the wave remains unchanged (Fig. 107.4). Electrodesiccation and electrofulguration are damped, while electrocoagu­ lation and electrosection can be moderately damped or undamped. The waveform can influence the rate and the depth of the heat produced in the tissue.1,3 Table 107.1: Modes of electrosurgery. Electrodesiccation Monopolar, monoterminal, damped High voltage, low amperage Electrofulguration Monopolar, monoterminal, damped High voltage, low amperage Electrocoagulation Bipolar/monopolar, biterminal, moderately damped Low voltage, high amperage Electrosection Monopolar, biterminal, slightly damped/undamped Low voltage, high amperage

Fig. 107.4: Types of electrosurgery waveforms.

ELECTROCAUTERY Electrocautery uses DC to heat a metal wire which is applied to the tissue, without any flow of current through the patient’s body. This is the safest form of hemostasis in patients with implantable electronic devices, although perhaps not the most effective (Fig. 107.5). The downside of this technique is that in addition to less than optimal hemostasis, the direct heat applied to the skin can cause third-degree burns, persistent pain, sensory and muscle dysfunction and an undesirable cosmetic result.1,3,4 Even though electrosurgical techniques have been shown to be relatively safe, this method is risk free for patients with pacemakers and implantable electronic devices because it uses heat and not electricity to exert action on the tis­ sues. The primary precaution in patients with implant­ able electronic devices is to avoid applying the probe directly over the device, which can cause direct heat damage.5 The applications of this procedure are mainly hemostasis when electrocoagulation cannot be used, and for the destruction of superficial skin lesions.

ELECTROSURGERY Electrodesiccation This type of electrosurgery dehydrates the tissue through accelerating water vaporization. It is a monopolar, monoterminal and damped device that works with uni­ form and rapid heating (Fig. 107.6).1,3 The effects it exerts on the tissue are mainly coagulation of small superficial

Fig. 107.5: Electrocautery uses DC to heat the electrode that comes in contact with the skin.

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Fig. 107.6: Electrodesiccation uses a monopolar device to treat superficial lesions.

vessels and superficial destruction, with minimal scarring. It can be used to treat epidermal lesions like actinic kera­ toses, flat warts, acrochordons, epidermal nevi, lentigines and seborrheic keratoses. The end point of the treatment is char and pinpoint bleeding. Following the treatment, the epidermis separates from the dermis and can be easily removed with a gauze.1,2

Electrofulguration Similar to electrodesiccation, this technique is a monopo­ lar, monoterminal, damped device which causes super­ ficial dehydration and carbonization of tissues without coming in direct contact with the skin.1 The electrode is held close, a few millimeters from the skin, and a spark arc is produced between the two surfaces (Fig. 107.7). Since high voltage and low amperage current is used in both electrodesiccation and electrofulguration, the destruction achieved with this technique is very superficial, hence the applications are the same as electrodesiccation.2,3 Curettage followed by electrodesiccation or electroful­ guration (ED&C) applied a series of two to three times are treatment modalities for very low risk basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Even though the cure rates after ED&C range from 88 to 99% depend­ ing on the location, size of the tumor and the technique used, the cure rates after excision or Mohs surgery are higher.1,6 These treatments are usually reserved for super­ ficial lesions, or in patients where excision or Mohs sur­ gery are not good options. Studies have shown that these modalities are highly operator and technique dependent,

and even in the hands of skilled clinicians, the cure rates are inferior to Mohs surgery. Some studies done on BCCs after ED&C have shown recurrence rates ranging from 1.6 to 7.7%,7,8 which vary extensively depending on the site and size of the tumor. In addition, studies that show low recurrence rates may not be directly comparable to other modalities because the modalities of treatment are not randomly assigned; the high-risk tumors are usually treated with surgical exci­ sion or Mohs surgery.6 In a 1991 review done of BCCs from 1955 to 1982, multivariate analysis showed patients’ age, sex and lesion duration did not affect recurrence rates, but the tumor site and pre-operative diameter were shown to be independent risk factors for high recurrence rates. Low-risk sites such as neck, trunk and extremities showed a 5-year recurrence rate of 3%, independent of the size. However, middle-risk sites (scalp, forehead, pre and postauricular, malar areas) showed a 5-year recurrence rate of 5% for tumors 3 mm, change in pigmentation, involvement of thumb and great toe, and Hutchinson’s sign (pigmentation appearing at the proximal nail fold or tissue surrounding the nail) should raise clinical suspicion for melanoma (Fig. 113.14). Once the diagnosis is certain after biopsy, the melanoma is removed via excision of the entire nail organ with histopathologic confirmation of clear margins. Melanoma >1 mm may require amputation of the digit or even metatarsal or metacarpal amputation. Referral to a general or hand surgeon is also appropriate.37,73–79

Bowen’s Disease and Squamous Cell Carcinoma Bowen’s disease and early squamous cell carcinoma may at times be very subtle or resemble verrucae, dermatitis and longitudinal melanonychia. Persistent verrucae of the nail unit have a high risk of transformation to squamous cell carcinoma. Often, non-healing lesions refractory to treatment and clinical suspicion can alert physicians to the presence of squamous cell carcinoma. Fortunately, squamous cell carcinoma of the nail unit rarely metastasizes. The tumor clinically presents as a warty plaque with occasionally overlying longitudinal melanonychia, particularly in dark skinned individuals. Longitudinal leukonychia signifies that the matrix is involved. Etiologies of SCC include human papilloma viruses, chronic radiation and arsenic exposure. Once the diagnosis is established, Mohs micrographic surgery offers the best cure rate while preserving the most normal tissue. Bowen’s disease of the nail bed can be treated with wide excision. Bony involvement of

Fig. 113.14: Hutchinson sign.

the tumor requires amputation, although metastasis rarely occurs. Repair can be performed with a bridge flap from the lateral distal phalanx if the defect is no wider than half of the nail, cross finger flaps for wider defects and full thickness skin grafts.1,53,80–85

EXOSTOSES The diagnosis of exostoses is usually very evident and is confirmed by X-rays. The surgical management involves the dissection of the overlying nail tissue (usually the nail bed), removal of the exostosis using a bone rongeur or nail clipper and closing the nail tissue. Recurrences require a repeat procedure. Enchondromas similarly require surgical removal.1,11

REFERENCES 1. Haneke E. Nail surgery. Clin Dermatol 2013;31(5):516–25. 2. Bolognia J, Jorrizo, JL, Schaffer, JV. Dermatology 2012; 753–60. 3. Andre J, Sass U, Richert B, et al. Nail pathology. Clin Dermatol 2013;31(5):526–39. 4. Haneke E. Anatomy of the nail unit and the nail biopsy. Semin Cutan Med Surg 2015;34(2):95–100. 5. Gupta AK, Tosti A. Nails and the clinician. Clin Dermatol 2013;31(5):507–8. 6. Fleckman P, Allan C. Surgical anatomy of the nail unit. Dermatol Surg 2001;27(3):257–60. 7. Becerro de Bengoa Vallejo R, Losa Iglesias ME, Alou Cervera L, et al. Efficacy of preoperative and intraoperative skin and nail surgical preparation of the foot in reducing bacterial load. Dermatol Surg 2010;36(8):1258–65. 8. Jellinek NJ. Nail surgery: practical tips and treatment options. Dermatol Ther 2007;20(1):68–74. 9. Jellinek NJ, Velez NF. Dermatologic Manifestations of the Lower Extremity: Nail Surgery. Clin Podiatr Med Surg 2016;33(3):319–36. 10. Shipkov H, Irthum C, Seguin P, et al. Evaluation of the risk of post-operative bleeding complications in skin cancer surgery without interruption of anticoagulant/­antithrombotic medication: a prospective cohort study. J Plast Surg Hand Surg 2015;49(4):242–6. 11. Robinson JK, Hanke CW, Siegel D, et al. Surgery of the skin: procedural dermatology. London: Elsevier/Saunders; 2015. 12. Richert B. Basic nail surgery. Dermatol Clin 2006;24(3): 313–22. 13. Abimelec P. Tips and tricks in nail surgery. Semin Cutan Med Surg 2009;28(1):55–60. 14. Jellinek NJ, Velez NF. Nail surgery: best way to obtain effective anesthesia. Dermatol Clin 2015;33(2):265–71. 15. Cordoba-Fernandez A, Rodriguez-Delgado FJ. Anaesthetic digital block with epinephrine vs. tourniquet in ingrown toenail surgery: a clinical trial on efficacy. J Eur Acad Dermatol Venereol. 2015;29(5):985–90.

Chapter 113: Surgery of the Nail 16. Findley A, Lee K, Jellinek NJ. Nail surgery among Mohs surgeons: prevalence, safety, and practice patterns. Dermatol Surg 2014;40(6):691–5. 17. Altinyazar HC, Demirel CB, Koca R, et al. Digital block with and without epinephrine during chemical matricectomy with phenol. Dermatol Surg 2010;36(10):1568–71. 18. Firoz B, Davis N, Goldberg LH. Local anesthesia using buffered 0.5% lidocaine with 1:200,000 epinephrine for tumors of the digits treated with Mohs micrographic surgery. J Am Acad Dermatol 2009;61(4):639–43. 19. Hogan ME, vanderVaart S, Perampaladas K, et al. Systematic review and meta-analysis of the effect of warming local anesthetics on injection pain. Ann Emerg Med 2011;58(1):86–98.e1. 20. Vinycomb TI, Sahhar LJ. Comparison of local anesthetics for digital nerve blocks: a systematic review. J Hand Surg 2014;39(4):744–51.e5. 21. Bibbo C, Patel DV, Gehrmann RM, et al. Chlorhexidine provides superior skin decontamination in foot and ankle surgery: a prospective randomized study. Clin Orthop Relat Res 2005;438:204–8. 22. Cummings AJ, Tisol WB, Meyer LE. Modified transthecal digital block versus traditional digital block for anesthesia of the finger. J Hand Surg 2004;29(1):44–8. 23. Yin ZG, Zhang JB, Kan SL, et al. A comparison of traditional digital blocks and single subcutaneous palmar injection blocks at the base of the finger and a meta-analysis of the digital block trials. J Hand Surg (Edinburgh, Scotland) 2006;31(5):547–55. 24. McIntosh CD, Thomson CE. Honey dressing versus paraffin tulle gras following toenail surgery. J Wound Care 2006;15(3):133–6. 25. Block SL. “Nailing” the management of the ingrown great toenail. Pediatr Ann 2014;43(11):434–9. 26. Pandhi D, Verma P. Nail avulsion: indications and methods (surgical nail avulsion). Indian J Dermatol Venereol Leprol 2012;78(3):299–308. 27. McGinness JL, Parlette HL, 3rd. Versatile sterile field for nail surgery using a sterile glove. Dermatol Online J 2005;11(3):10. 28. Joseph AK. Commentary: nail avulsion before nail surgery: is it always necessary? Dermatol Surg 2013;39(2):315–6. 29. Shepard GH. Treatment of nail bed avulsions with split-thickness nail bed grafts. J Hand Surg 1983;8(1):49–54. 30. Lai WY, Tang WY, Loo SK, et al. Clinical characteristics and treatment outcomes of patients undergoing nail avulsion surgery for dystrophic nails. Hong Kong Med J 2011;17(2):127–31. 31. Collins SC, Cordova K, Jellinek NJ. Alternatives to complete nail plate avulsion. J Am Acad Dermatol 2008;59(4):619–26. 32. Grover C, Chaturvedi UK, Reddy BS. Role of nail biopsy as a diagnostic tool. Indian J Dermatol Venereol Leprol 2012;78(3):290–8. 33. Rich P. Nail biopsy. Indications and methods. J Dermatol Surg Oncol 1992;18(8):673–82. 34. Stewart CL, Rubin AI. Update: nail unit dermatopathology. Dermatol Ther 2012;25(6):551–68.

35. Grover C, Khandpur S, Reddy BS, et al. Longitudinal nail biopsy: utility in 20-nail dystrophy. Dermatol Surg 2003;29(11):1125–9. 36. Dominguez-Cherit J, Gutierrez Mendoza D. Best way to perform a punch biopsy. Dermatol Clin 2015;33(2):273–6. 37. Mannava KA, Mannava S, Koman LA, et al. Longitudinal melanonychia: detection and management of nail melanoma. Hand Surg 2013;18(1):133–9. 38. Richert B, Caucanas M, Andre J. Diagnosis using nail matrix. Dermatol Clin 2015;33(2):243–55. 39. Bostanci S, Kocyigit P, Parlak N, et al. Chemical matricectomy with sodium hydroxide: long-term follow-up results. Dermatol Surg 2014;40(11):1221–4. 40. Ozan F, Dogar F, Altay T, et al. Partial matricectomy with curettage and electrocautery: a comparison of two surgical methods in the treatment of ingrown toenails. Dermatol Surg 2014;40(10):1132–9. 41. Fernandez Canedo I, Blazquez Sanchez N, De Troya Martin M. Chemical matricectomy with phenol. Actas Dermosifiliogr 2013;104(1):79–80. 42. Ceilley RI, Collison DW. Matricectomy. J Dermatol Surg Oncol 1992;18(8):728–34. 43. Byrne DS, Caldwell D. Phenol cauterization for ingrowing toenails: a review of five years’ experience. Br J Surg 1989;76(6):598–9. 44. Khunger N, Kandhari R. Ingrown toenails. Indian J Dermatol Venereol Leprol 2012;78(3):279–89. 45. DeBrule MB. Operative treatment of ingrown toenail by nail fold resection without matricectomy. J Am Podiatr Med Assoc 2015;105(4):295–301. 46. Misiak P, Terlecki A, Rzepkowska-Misiak B, et al. Comparison of effectiveness of electrocautery and phenol application in partial matricectomy after partial nail extraction in the treatment of ingrown nails. Pol Przegl Chir 2014;86(2):89–93. 47. Kucuktas M, Kutlubay Z, Yardimci G, et al. Comparison of effectiveness of electrocautery and cryotherapy in partial matrixectomy after partial nail extraction in the treatment of ingrown nails. Dermatol Surg 2013;39(2): 274–80. 48. Erdogan FG, Guven M, Erdogan BD, et al. Previous nail surgery is a risk factor for recurrence of ingrown nails. Dermatol Surg 2014;40(10):1152–4. 49. Di Chiacchio N, Di Chiacchio NG. Best way to treat an ingrown toenail. Dermatol Clin 2015;33(2):277–82. 50. Tassara G, Machado MA, Gouthier MA. Treatment of ingrown nail: comparison of recurrence rates between the nail matrix phenolization classical technique and phenolization associated with nail matrix curettage—is the association necessary? An Bras Dermatol 2011;86(5): 1046–8. 51. Lin YC, Su HY. A surgical approach to ingrown nail: partial matricectomy using CO2 laser. Dermatol Surg 2002;28(7):578–80. 52. Persichetti P, Simone P, Li Vecchi G, et al. Wedge excision of the nail fold in the treatment of ingrown toenail. Ann Plast Sur 2004;52(6):617–20.

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Section 31: Dermatologic Surgery 53. Lonsdale-Eccles AA, Langtry JA. Treatment of digital myxoid cysts with infrared coagulation: a retrospective case series. Br J Dermatol 2005;153(5):972–5. 54. Zook EG, Guy RJ, Russell RC. A study of nail bed injuries: causes, treatment, and prognosis. J Hand Surg 1984;9(2):247–52. 55. Ogo K. Split nails. Plast Reconstr Surg 1990;86(6):1190–3. 56. Miller MA, Brodell RT. The treatment of the splitting nail with phenol alcohol partial nail matricectomy. Dermatol Surg 1996;22(4):388–90. 57. Chang P, Meaux T. Onychogryphosis: a report of ten cases. Skinmed 2015;13(5):355–9. 58. Han XC, Zheng LQ, Zheng TG. Onychogryphosis in tuberous sclerosis complex: an unusual feature. An Bras Dermatol 2016;91(5 suppl 1):116–8. 59. Singh G, Haneef NS, Uday A. Nail changes and disorders among the elderly. Indian J Dermatol Venereol Leprol 2005;71(6):386–92. 60. Bartolomei FJ. Onychauxis. Surgical and nonsurgical treatment. Clin Podiatr Med Surg 1995;12(2):215–20. 61. Raza SI, Muhammad N, Khan S, et al. A novel missense mutation in the gene FZD6 underlies autosomal recessive nail dysplasia. Br J Dermatol 2013;168(2):422–5. 62. DeKlotz CMC, Schwartz ME, Milstone LM. Nail removal in pachyonychia congenita: patient-reported survey outcomes. J Am Acad Dermatol 2017;76(5):990–2. 63. Leggit JC. Acute and chronic paronychia. Am Fam Physician 2017;96(1):44–51. 64. Lomax A, Thornton J, Singh D. Toenail paronychia. Foot Ankle Surg 2016;22(4):219–23. 65. Herschthal J, McLeod MP, Zaiac M. Management of ungual warts. Dermatol Ther 2012;25(6):545–50. 66. Baran R, Richert B. Common nail tumors. Dermatol Clin 2006;24(3):297–311. 67. Wang PJ, Zhang Y, Zhao JJ. Treatment of subungual glomus tumors using the nail bed margin approach. Dermatol Surg 2013;39(11):1689–94. 68. Lee SH, Roh MR, Chung KY. Subungual glomus tumors: surgical approach and outcome based on tumor location. Dermatol Surg 2013;39(7):1017–22. 69. Rushing CJ, Ivankiv R, Bullock NM, et al. Onychomatricoma: a rare and potentially underreported tumor of the nail matrix. J Foot Ankle Surg 2017;56(5):1095–8. 70. Beirao P, Pereira P, Nunes A, et al. An unusually large ­onychomatricoma. BMJ Case Rep 2017. Published online. 71. Kim M, Sun EY, Jung HY, et al. Onychopapilloma: a report of three cases presenting with various longitudinal chromonychia. Ann Dermatol 2016;28(5):655–7.

72. Tosti A, Schneider SL, Ramirez-Quizon MN, et al. Clinical, dermoscopic, and pathologic features of onychopapilloma: a review of 47 cases. J Am Acad Dermatol 2016;74(3): 521–6. 73. Levit EK, Kagen MH, Scher RK, et al. The ABC rule for clinical detection of subungual melanoma. J Am Acad Dermatol 2000;42(2 Pt 1):269–74. 74. Di Chiacchio N, Hirata SH, Enokihara MY, et al. Dermatologists’ accuracy in early diagnosis of melanoma of the nail matrix. Arch Dermatol 2010;146(4):382–7. 75. Duarte AF, Correia O, Barros AM, et al. Nail matrix melanoma in situ: conservative surgical management. Dermatology (Basel, Switzerland). 2010;220(2):173–5. 76. Duarte AF, Correia O, Barros AM, et al. Nail melanoma in situ: clinical, dermoscopic, pathologic clues, and steps for minimally invasive treatment. Dermatol Surg 2015;41(1): 59–68. 77. Sureda N, Phan A, Poulalhon N, et al. Conservative surgical management of subungual (matrix derived) melanoma: report of seven cases and literature review. Br J Dermatol 2011;165(4):852–8. 78. Lee WJ, Lee JH, Won CH, et al. Nail apparatus melanoma: a comparative, clinicoprognostic study of the initial clinical and morphological characteristics of 49 patients. J Am Acad Dermatol 2015;73(2):213–20. 79. Carreno AM, Nakajima SR, Pennini SN, et al. Nail apparatus melanoma: a diagnostic opportunity. An Bras Dermatol 2013;88(2):268–71. 80. Nicholls A, Jacoby J, Hartley R, et al. Squamous cell carcinoma of the nail bed. BMJ (Clinical research ed). 2015;351: h4640. 81. Dika E, Fanti PA, Patrizi A, et al. Mohs surgery for squamous cell carcinoma of the nail unit: 10 years of experience. Dermatol Surg 2015;41(9):1015–9. 82. Ormerod E, de Berker D. Nail unit squamous cell carcinoma in people with immunosuppression. Br J Dermatol 2015;173(3):701–12. 83. Lecerf P, Richert B, Theunis A, et al. A retrospective study of squamous cell carcinoma of the nail unit diagnosed in a Belgian general hospital over a 15-year period. J Am Acad Dermatol 2013;69(2):253–61. 84. Valero J, Gallart J, Gonzalez D, et al. Subungual squamous cell carcinoma and exostosis in third toe—case report and literature review. J Eur Acad Dermatol Venereol. 2014; 28(10):1292–7. 85. Riddel C, Rashid R, Thomas V. Ungual and periungual human papillomavirus-associated squamous cell carcinoma: a review. J Am Acad Dermatol 2011;64(6):1147–53.

Chapter

114

Lip Reconstruction Janet Y Li, Jo Cooke-Barber, Vineet Mishra

INTRODUCTION The lips are complex structures essential for the beauty and function of the lower face. Reconstruction of the lips, oral mucosa and perioral region should aim to maintain oral mobility, aperture, sensation and appearance. Careful preoperative planning is essential to maintaining a patient’s ability to eat, speak, smile and frown. Repair of a lower lip defect that restores perfect appearance and yet leaves the patient drooling is a failure. An intimate knowledge of not only perioral anatomy, but also the patient’s goals and expectations, is required for optimal results.

ANATOMY The regions of the lip include the vermilion, the philtrum, the left and right cutaneous upper lip and the cutaneous lower lip (Fig. 114.1).1,2 The vermilion is divided into the dry region, which is the modified mucosal epithelial surface of the true lip, and the wet region, which is contiguous with the intraoral mucosa. The wet–dry border is located at the point of contact between the upper and lower lips when the mouth is closed. The labial mucosa is red in those with light skin and dark in those with dark

Fig. 114.1: Anatomic landmarks of the lip.

skin. The vermiliocutaneous junction is the well-defined line that separates the dry vermilion from the cutaneous lip. The white roll forms the raised junction between the cutaneous lip and the vermilion. The philtrum is composed of a midline sulcus and bilateral philtral ridges. Its inferior borders form the Cupid’s bow and lacks creases. The upper cutaneous lip is bordered superiorly by the bilateral alar creases and nasal sill and laterally by the melolabial fold. The inferior melolabial and mental creases form the lateral and inferior borders of the lower lip, respectively. Relaxed skin tension lines and perioral rhytides radiate circumferentially from the oral aperture. Sharp definition of the vermiliocutaneous junction, philtrum, Cupid’s bow, alar creases, nasal sill, melolabial fold and mental creases are important in achieving the esthetic goals of reconstruction. A plump lower lip and an overhanging upper lip that is full beneath the Cupid’s bow and tapers toward the oral commissures is considered esthetically beautiful in many cultures. The layers of the lip, from superficial to deep, consist of the epidermis, dermis, subcutaneous tissue, orbicularis oris, submucosal and mucosal layers (Fig. 114.2). Lip tissue is remarkably elastic and distensible. The orbicularis oris muscle encircles the lips, providing sphincter function

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Fig. 114.2: Histology of the lip in cross section.

Fig. 114.3: Innervation and vasculature of the lip.

and bulk (Fig. 114.3). The muscle fibers decussate at the modiolus, which is immediately lateral to the oral commissures. Muscles of facial expression originate along the outer margin of the orbicularis and radiate outwards. The melolabial fold and labiomandibular crease mark their points of attachment.

The buccal and marginal mandibular branches of the facial nerve provide motor innervation to the lip. These nerves generally lie deep to muscle. The infraorbital and mental branches of the trigeminal nerve provide sensory innervation to the upper and lower lips, respectively. The infraorbital and mental foramen are

Chapter 114: Lip Reconstruction both located in the midpupillary line and are useful for nerve blocks. The superior and inferior labial arteries arise from the facial artery lateral to the oral commissures and course medially deep to the orbicularis oris in the submucosa. In a minority of patients, the labial arteries run within the orbicularis oris muscle.3 As the arteries approach midline, they travel at the level of the vermiliocutaneous junction and into the vermilion lip. The venous pattern is less well defined.

PREOPERATIVE CONSIDERATIONS When planning reconstruction, careful consideration should be given to patient characteristics. The perioral tissue of elderly patients has more elasticity and redundancy to be able to accommodate large flaps. Flaps that cause microstomia are not preferred for patients who wear dentures, as they will not be able to insert them through a small oral aperture. Debilitated patients may not tolerate the restriction in nutrition with a soft or liquid diet required by staged interpolated flaps. Small shallow wounds of the cutaneous and ver­milion lips may be left to heal by second intention, oftentimes with remarkable cosmesis. The concavities of the apical lip and nasal sill may especially be suited for this option. The most elegant repair is the simplest repair, which may oftentimes be a primary linear closure. This technique is best employed for approximation of smaller defects up to 25% of the lip. For larger defects, flaps and grafts must be considered. On the lateral lip, local skin flaps are preferred over second intention healing or skin grafts due to a superior match of skin texture, thickness and color. Adjacent flap transfer should be carefully considered in males in hair-bearing areas. A flap from the non-hairbearing cheek may not be desirable for a defect of the upper lip in males. If the defect is less than one third of the entire width, closure with primary linear repair may be a more practical and ideal option. Another option would be a hair-bearing V-Y advancement flap. Careful planning is paramount to preserve anatomic landmarks. In order to preserve the integrity and symmetry of the vermiliocutaneous junction, its location may be marked with a skin pen or a scoring incision prior to anesthetic infiltration. The philtral ridges, mental crease and melolabial folds should also be marked. Scars should be oriented along relaxed skin tension lines and natural creases for better camouflage. For defects of the lower cutaneous lip, marionette lines and the mental crease

may help to conceal scars. For apical defects, suture lines can be hidden in the alar sulcus or melolabial crease. When there is a risk of blunting of the melolabial crease, periosteal sutures aid in better definition. Contraction of a linear scar crossing the vermilion may lead to notching of the vermilion border. When avoidable, incisions should not cross these landmarks, and an M-plasty may be performed to shorten the length of closure. When the orbicularis oris muscle is disrupted during tumor resection, careful reapproximation of its fibers is crucial to maintaining muscle function. Inaccurate approximation of the muscle may lead to dimpling and scarring. If restoration of the orbicularis is not possible, then the repair is directed toward restoring some degree of static oral competence. Absorbable sutures may be used to reapproximate muscle and subcutaneous tissue while braided non-absorbable sutures are used to reapproximate mucosa and vermilion. The skin should be closed with a slight eversion of the edges, which helps to create a narrow flat scar and decreases the chance of trap door deformity. Due to the abundant vascularity of the lip and the limited use of local lidocaine with epinephrine, ample bleeding may be expected. The use of suction and cautery will help to visualize the operative field.

ANESTHESIA Regional nerve blocks decrease the need for local anesthesia, which causes swelling and distortion of distensible lip tissue. To perform an infraorbital nerve block, the needle is inserted into the superior gingival sulcus between the first and second premolar and angled toward the infraorbital foramen. The needle is then advanced approximately 1 cm and 1–2 mL of anesthetic is injected. The mental nerve block is injected by inserting the needle into the inferior labial sulcus between the first and second premolar. The needle is advanced to the periosteum and 1–2 mL of anesthetic is injected. Once the nerve block achieves its effect, small amounts of anesthetic with epinephrine may be injected. The surgeon should wait at least 15 minutes prior to incising to allow the resulting distention to subside and the epinephrine to take effect.

SMALL-TO-MEDIUM PARTIALTHICKNESS LIP DEFECTS Small-to-medium partial-thickness lip defects encompassing up to one third of the width of the lip may be

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Section 31: Dermatologic Surgery reconstructed in a variety of ways. Secondary intention is an option for shallow defects of the vermilion and the apical triangles of the superior lip. In defects for which second intention would lead to unacceptable cosmetic results, several options exist for closure: primary fusiform repair, advancement and rotation flaps, island pedicle flaps, transposition flaps and full-thickness skin grafts.

Primary Fusiform Repair Fusiform excision and primary linear repair are the basic tools of reconstruction on the lip. When possible, it is the preferred method of repair. Primary closure on the cutaneous lip should be attempted generally on defects less than 1 cm2 to minimize distortion of the vermilion and decreased oral aperture.4 Linear repair may also be performed for philtrum defects that encompass less than half the philtrum width. This should not be attempted for larger philtrum defects due to risk of flattening of the upper lip and displacement of the free margin. The fusiform excision should not extend beyond anatomic boundaries such as the labiomental crease or the melolabial fold. When necessary, it may extend onto the vermilion, with care to prevent distortion of the border. M-plasty may be employed to shorten the length of the scar and avoid such anatomic boundaries (Figs. 114.4A and B).

Advancement and Rotation Flaps Various combinations of advancement and rotation flaps may be used to reconstruct defects of the cutaneous lip. Lateral defects typically require an arc in flap movement

A Figs. 114.4A and B: Linear repair and M-plasty.

whereas medial defects require flap linear advancement. These flaps should be elevated above the orbicularis oris and other facial musculature. For defects at the central cutaneous lip, A-to-T advancement flaps are preferred, with the risk of tension causing distortion of the oral commissure (Figs. 114.5A and B). The distortion usually corrects naturally over time with mouth movements. Standing cones may occur at the oral commissure, which can be removed. Extending the incision inferolaterally below the oral commissure and along the inferior melolabial crease will also decrease the chance of standing cones (Figs. 114.6A and B). Rotation flaps for lateral defects should be placed such that the superolateral border of the flap is in or parallel to the melolabial fold. If necessary, the flap may extend inferior to the oral commissure. A useful adjunct to the above flaps is the perialar crescentic advancement flap (Figs. 114.7A and B). When performed in solo, the flap may repair small lateral defects near the nasal sill and alar crease. It may also be combined with more extensive rotation and advancement flaps in repair of larger lateral and medial defects (Figs. 114.7C and D). A crescent of skin is excised adjacent to the alar crease and another Burow’s triangle is excised inferiorly. Wide undermining is performed in the superficial subcutaneous plane above the orbicularis oris and may extend into the cheeks for adequate mobilization of the flap. The flap is then advanced medially to cover the defect. The sutures lines are concealed within the alar crease, the nasal sill and relaxed skin tension lines. The advantages of the perialar crescentic advancement include well-concealed scars and the use of adjacent texture- and color-matched

B

Chapter 114: Lip Reconstruction

A

B

Figs. 114.5A and B: A-to -T flap.

A

B

Figs. 114.6A and B: Rotation flap.

tissue. This flap should not be attempted if the crescent were to extend the scar into the melolabial fold.

Island Pedicle (V-Y Advancement) Flaps Island pedicle or V-Y advancement flaps are robust and highly vascularized due to the deep subcutaneous or muscular pedicle. They are also highly mobile due to their freedom from dermal attachment. The borders of the resulting kite shape are best hidden in anatomic boundaries. In the lip region, the island pedicle flap may be used on the philtrum, the vermilion, the lateral cutaneous upper lip and the cutaneous lower lip. For defects of the philtrum which encompass up to 1.5 times the width of the philtrum and less than 50% of the philtral

ridge height.5 The flap is designed as a triangle immediately superior to the defect. Large defects of the lateral upper lip that are adjacent to the melolabial crease and nasal ala may also be repaired with an island pedicle flap (Figs. 114.8A and B). The blood supply of the island pedicle in this region is based on the perforators of the angular artery. The superior flap incision is placed within the melolabial fold and the leading edge of the flap is formed from the inferolateral border of the defect. When executing an island pedicle flap in the perioral region, tension on the pedicle must be minimized to prevent eclabium. The flap is excised and undermined at the superficial subcutaneous plane at a slight bevel. At the philtrum, the pedicle should be broad-based whereas it may be narrower at the melolabial fold. Adequate flap

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A

B

C

D

Figs. 114.7A to D: Perialar crescentic advancement.

A Figs. 114.8A and B: Island pedicle flap.

B

Chapter 114: Lip Reconstruction mobility may require undermining down to fascia and thinning of the superior and inferior attachments. If there is still risk of distorting the lip, the flap may be converted to a Burow’s graft. There is a risk of pin-cushioning or trapdoor deformity due to the bulk of the pedicle. Wide undermining and undersizing of the flap diminishes this risk.

Transposition Flaps The transposition flap is generally not an ideal repair opt­ion for lip defects. In select cases of small defects of the upper or lower cutaneous lip, a transposition flap may be designed from the lateral lip (Figs. 114.9A and B). Transposition flaps may be transferred from the submental crease to the lower lip. Melolabial transposition flaps may be used to repair lateral upper lip defects (Figs. 114.10A and B).

The flap is sized 1–2 mm wider than the defect to prevent eclabium, and designed such that the closure lies within the melolabial fold. Disadvantages include a possibility of trap door and blunting of the melolabial or submental creases, which may be ameliorated by wide undermining, flap thinning and use of a periosteal tacking sutures. In men, there is also disruption of upper lip hair growth.

Full Thickness Skin Graft For small to medium-sized defects of the apical lip, nasal sill or superior lip, a full thickness skin graft may be a viable option. Burow’s grafts provide a superior texture and color match for small defects. For larger defects, the graft may be harvested from the pre or postauricular skin. The disadvantages of skin grafts include their tendency to contract unevenly and pincushion, a difficulty in providing adequate color and texture match, and difficulty in matching facial hair in men.

SMALL-TO-MEDIUM FULL-THICKNESS DEFECTS A wedge repair may be used for full-thickness defects that encompass up to one third of the vermilion and cutaneous lip.6 In men, partial-thickness upper lip defects may be converted to full-thickness and repaired primarily in order to preserve the mustache. The lower lip is more forgiving and able to withstand larger defect reconstruction. On the A

B Figs. 114.9A and B: Transposition flap.

A

B

Figs. 114.10A and B: Melolabial transposition flap.

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Section 31: Dermatologic Surgery upper lip, tissue attachment at the pyriform aperture may lead to excessive tension and distortion of the vermilion. Also, wedge repair of larger defects on the upper lip may lead to loss of its normal overhang. Therefore, lip-switch flaps and other flap combinations are preferred for repair of larger upper lip defects. First, a V-shaped full-thickness defect is created. A W-plasty may be placed at the base of a lower lip wedge to prevent extension onto the chin and allow for repair of larger defects. Lines of closure should parallel the relaxed skin tension lines radiating from the oral aperture. Isolating and ligating the labial arteries prior to removal of the wedge is recommended. Closure should be oriented along the relaxed skin tension lines (e.g. vertical at the center of the lip and angled at the lateral lip) and should not extend beyond the mental crease inferiorly or the melolabial crease superiorly. All four layers of the lip must be approximated carefully: mucosa, muscle, subcutaneous tissue and epidermis. The vermiliocutaneous junction must be approximated to avoid distortion. The orbicularis oris must be reapproximated and the epithelium must be everted to prevent a depressed scar.

Lateral flap designs should be avoided due to potential distortion of the oral commissure. The flap is designed with the same vertical height as the defect but only 50% of its

A

MEDIUM-TO-LARGE FULL-THICKNESS DEFECTS For large defects between one third and two thirds of the total lip length, several options are available: (1) cross-lip flaps such as the Abbe or Estlander; (2) circumoral advancement rotation flaps such as the Karapandzic or Gilles; (3) the stair-step advancement flap.

B

Abbe and Estlander Flaps The Abbe flap is a two-staged lip-switch interpolation flap that utilizes a vascular pedicle based on the superior or inferior labial artery (Figs. 114.11A to C).7 It offers excellent restoration of lip function while preserving lip anatomy, and is best used for either full-thickness defects or partialthickness defects with a significant deficit of the orbicularis. For wounds of the upper lip, the lower lip serves as the donor site, and vice versa. The Abbe flap results in temporary narrowing of the oral aperture and so should not be considered for patients who cannot tolerate necessary change in eating patterns (e.g. restriction to liquid and soft foods or drinking through a straw). In males, hair growth on the flap will be opposite that of the recipient. The flap should be created at the midline or near midline position.

C Figs. 114.11A to C: Abbe flap.

Chapter 114: Lip Reconstruction width. Lip elasticity allows for a narrower flap, which enables a proportional decrease in the width of both lips. The pedicle may be derived from the ipsilateral or contralateral side. An ipsilateral flap is preferred to minimize pedicle twisting and allow for the widest possible oral opening for eating. Flaps on the lateral lip must be pedicled on the contralateral side, however. Prior to flap design, any remaining mucosa or muscle in the defect should be excised to full-thickness. To execute a subunit repair on the upper lip, which would hide suture lines within the melolabial fold, the defect should be extended to the superior border while avoiding the oral commissure.2 After the defect is templated, any remaining layers of skin, muscle or mucosa are excised. The free edge of the flap is then incised to the subcutaneous plane and the labial artery dissected bluntly. The labial artery may be ligated or preserved until the pedicle is developed. The incisions are then completed to full-thickness to liberate the flap. Alternatively, an initial full-thickness incision can be made through the free edge of the flap while compressing the labial artery laterally. Slow release of the labial artery will disclose its location for later pedicle development.8 The pedicle is then bluntly dissected and rotated 180° into the lower lip defect and sutured into place in a layered fashion. The first suture must approximate the vermiliocutaneous junction and white roll precisely, and the orbicularis muscle must also be aligned to retain sphincter function. After 3 weeks of vascular maturation, the pedicle is divided and the flap inset. There are several caveats to the Abbe flap. Although the orbicularis sphincter is reestablished, abnormal lip mobility may still occur. Pin-cushioning may occur, and may be minimized by completely excising all layers of the defect to ensure a good fit. The vein pattern of the lip is not well-defined and venous return is unpredictable. Venous congestion and flap ischemia are minimized with a posterior pedicle width of 1 cm. If the inferior labial artery is transected, the flap may still survive based on mucosal attachments and ascending labiomental artery perfusion.9,10 The cross-lip Estlander flap is a one-stage reconstruction designed to repair lateral lip defects (Figs. 114.12A to E). Like the Abbe flap, the donor site is constructed with the same height and half of the width of the defect. In order to better conceal the scar, the lateral border of the flap may be placed within the melolabial fold. The pedicle is medially based and the flap rotates around the oral commissure. Reconstruction of either

upper or lower lip defects may be made. Its major disadvantage is a blunting of the commissure and prolonged denervation.

Karapandzic and Gilles Flaps The Karapandzic flap utilizes a full-thickness composite rotation advancement flap that preserves most of its neural and vascular structures (Figs. 114.13A and B). It is most ideal for reconstruction of large central defects of the lower lip, since the two bilateral opposing flaps may be designed symmetrically. For lateral defects, the flaps may be designed with different lengths. Separate partial thickness incisions are made on the skin and deep mucosa in a radial fashion parallel to the lip margin. Incisions are placed along the mental crease, continue around the oral commissure and into the melolabial fold, and end at the nasal ala. Neurovascular bundles are bluntly dissected and transferred along with the flap as it is moved into position. The wound must be closed in a layered fashion with an attempt made to secure the muscles of facial expression to the orbicularis oris in their anatomic locations. Failure to perform a layered closure would result in a circumferential scar. Maintenance of consistent flap thickness and symmetry is crucial to prevent distortion. Although this technique creates microstomia and blunted commissures, sensation and mobility is preserved. The lips may stretch over time, either with manipulation by hand or with an assistive appliance. The Gilles fan flap rotates around the oral commissure like the opening of a handheld folding fan in order to transfer the remaining segment of the affected lip along with the lateral portion of the opposing lip (Figs. 114.14A and B). Although the Gilles flap may appear similar to the Karapandzic flap, the Gilles flap uses full-thickness incisions rather than partial-thickness incisions. The fullthickness incision begins along the inferior aspect of the defect, curves around the vermilion, extends into the melolabial fold and then turns toward the superior vermilion. The flap is then rotated and advanced toward the defect. Bilateral Gilles fan flaps may be used to reconstruct large central lower lip defects. Limitations of this technique include microstomia, blunting of the oral commissures and impairment of function and sensation.

The Stair-step Advancement Flap The stair-step advancement flap may repair defects of small to large size encompassing two thirds of the lower

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A

B

C

D

E lip (Figs. 114.15A and B).11 Small rectangles are excised in a stair-step fashion at 45° from the defect base following the border of the chin. Bilateral triangles are then

Figs. 114.12A to E: Estlander flap.

excised from the flap base. The flap is then advanced to cover the defect and each step is approximated. The advantage of this technique is the sparing of the mental

Chapter 114: Lip Reconstruction

A

B1

B2

B3

B4

Figs. 114.13A and B: Karapandzic flap.

crease and decreased contracture. However, the scar does not appear as natural as would one placed within the mental crease.

NEAR-TOTAL-TO-TOTAL FULLTHICKNESS DEFECTS Repair options for defects encompassing 80–100% of the lip include: (1) the Webster–Bernard flap, (2) the Fujimori “gate flap”, (3) distant flaps, (4) the radial forearm free flap. The Webster–Bernard flap will be discussed here.

Webster–Bernard Flap The Webster–Bernard flap advances cheek tissue to repair total or near-total lip defects, with scar lines hidden within the melolabial and mental creases (Figs. 114.16A and B).12 To reconstruct lower lip defects, four Burow’s triangles are excised: two on the superior cheek and two on the inferior cheek. The vermilion may be recreated with a mucosal advancement flap. The incisions should only be made to the subcutaneous plane in order to preserve underlying muscle integrity. This repair does not restore orbicularis

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Section 31: Dermatologic Surgery

A

B

Figs. 114.14A and B: Gilles flap.

A

B

Figs. 114.15A and B: Stair-step advancement flap.

A Figs. 114.16A and B: Webster–Bernard flap.

B

Chapter 114: Lip Reconstruction function and creates a taut and a dynamic lip, with unavoidable postoperative drooling.

VERMILION DEFECTS The vermilion is the most characteristic feature of the lip and consists of modified squamous epithelium. Small partial-thickness defects may be left to heal by second intention with remarkable results. However, there is a risk of wound contraction leading to distortion. Reconstruction options are numerous and include: primary closure, mucosal advancement flaps, mucosal V-Y advancement flaps,6 vermilion advancement flaps,13 cross-lip vermilion flaps,14 buccal mucosal flaps,15 facial artery musculomucosal flaps,16 and tongue flaps.6,17 Mucosal advancement flaps, mucosal V-Y advancement flaps and cross-lip vermilion flaps will be discussed below.

Mucosal Advancement Flaps Mucosal advancement flaps may be considered in the case of broad and shallow surgical wounds occupying the vermilion. The entire vermilion is removed with a vermillionectomy. Extension of the defect above the oral commissure and onto the lateral upper vermillion allows for

Fig. 114.17: Mucosal advancement flap.

superior concealment of scar and decreased risk of trough development.4 A mucosal flap is created by incising along the entire horizontal length of the border between the wet and dry vermilion (Fig. 114.17). The flap is undermined at the plane below the minor salivary glands and superficial to the posterior surface of the orbicularis oris. The undermining follows the curvature of the lip and may extend completely to the gingivolabial sulcus. The flap is then advanced to the vermiliocutaneous junction and secured with soft braided non-absorbable sutures. The mucosal advancement flap heals quickly due to its rich blood supply and scars are well hidden along the vermilion border. Vermilion width is better maintained with a mucosal advancement flap compared to primary closure.18 Although the flap provides an esthetic repair of either lip, several limitations exist. Flap contraction can cause flattening of the lip, which negates its natural pleasing fullness. This may be minimized with less undermining. The color of the mucosal advancement will also be darker than the nat­u­ral vermilion, which may have a feminizing effect. The chance of ischemia is low with small to medium diameter wounds due to a rich vascular supply, but larger diameter wounds carry a greater risk of ischemia due to increased wound tension. Metaplasia of the new lip skin can result in chronic peeling and there may be decreased mucosal sensation. Sensory

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Section 31: Dermatologic Surgery deficits in the reconstructed vermilion typically return after several months. However, in some cases, the return is inadequate. Some surgeons advocate for a selective spreading technique in order to preserve neurovascular structures and thereby sensation and function.6,19

A

Mucosal V-Y Advancement Flaps Alternatively, defects confined to the vermilion may be repaired by advancing mucosal skin anteriorly on a mucosal V-Y flap island pedicle flap (Figs. 114.18A to F).6,20

B

C

D

E C Figs. 114.18A to F: Mucosal V-Y flap.

F

Chapter 114: Lip Reconstruction The tip of the triangular flap is oriented toward the gingivolabial sulcus and the base located at the defect border. Incisions are made through the mucosa and submucosa to the superficial orbicularis oris. The flap is then advanced vertically on a broad-based pedicle, which utilizes the orbicularis oris and its accompanying blood supply for perfusion. Preservation of the labial artery is paramount to maintaining flap viability.

as a horizontal wedge that tapers toward the oral commissure, located on the wet mucosa immediately posterior to the wet-dry line. It is then elevated and rotated 180° and sutured into the defect. The donor site is closed primarily. Division of the pedicle and flap inset occurs 3 weeks later. Disadvantages of this technique include its temporary decrease in oral aperture and a two-stage surgery.

POSTOPERATIVE CARE AND CONSIDERATIONS

Interpolated Cross-lip Flap An interpolated cross-lip vermilion flap has been  des­ cribed for the reconstruction of upper lip defects (Figs. 114.19A to C). It transfers labial mucosa or vermilion and underlying soft tissue from one lip to the other.6,14 The flap may be constructed with a single pedicle for small defects or a bipedicle (“bucket handle”) for wider defects. The defect is prepared by incising to the superficial orbicularis oris. The flap is designed on the contralateral opposite lip

A

C

A strong adherent dressing may be constructed with antibiotic ointment, non-adhesive Telfa pad, gauze and Hypafix tape. Routine external wound care is conducted with petrolatum ointment and daily dressing changes. Intraoral wound care may include irrigation with saline or Peridex. Patients should limit excessive oral and facial movements, which may disrupt the sutures. Care should be taken to

B

Figs. 114.19A to C: Interpolated cross-lip vermillion flap

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Section 31: Dermatologic Surgery maintain adequate nutrition and hydration, but soft or liquid foods are preferred. Straws may be used, but with caution against excessive lip pursing. Patients should also be counseled against the consumption of very hot foods and beverages, especially immediately postprocedure while still anesthetized. Postsurgical edema and bruising is common and may be limited by the use of ice. Oral antibiotics, analgesics and antiemetics should be pres­cribed in a liquid formulation.

REFERENCES 1. Constantinidis J, Federspil P, Iro H. Functional and aesthetic objectives in the reconstruction of lip defects. Facial Plast Surg 1999;15(4):337–49. 2. Burget GC, Menick FJ. Aesthetic restoration of one-half the upper lip. Plast Reconstr Surg 1986;78(5):583–93. 3. Schulte DL, Sherris DA, Kasperbauer JL. The anatomical basis of the Abbe flap. Laryngoscope 2001;111(3):382–6. 4. Chapman JT, Mellette JR. Perioral reconstruction. In: Rohrer TE, Cook JL, Nguyen TH, editors. Flaps and grafts in dermatologic surgery. Philadelphia (PA): Elsevier; 2007. 5. Kaufman AJ, Grekin RC. Repair of central upper lip (philtral) surgical defects with island pedicle flaps. Dermatol Surg 1996;22(12):1003–7. 6. Renner GJ. Reconstruction of the lip. In: Baker SR, Swanson NA, editors. Local flaps in facial reconstruction. St. Louis: Mosby; 1995:xiii, 606 p. 7. Abbe RA. A new plastic operation for the relief of deformity due to double harelip. Medical Record 1898;53:477–8. 8. Nguyen TH. Staged interpolation flaps. In: Rohrer TE, Cook JL, Nguyen TH, editors. Flaps and grafts in dermatologic surgery. Philadelphia (PA): Elsevier; 2007. 9. Millard DR, Jr., McLaughlin CA. Abbe flap on mucosal pedicle. Ann Plast Surg 1979;3(6):544–8.

10. Wu D, Song T, Li H, et al. An innovative cross-lip flap with a musculomucosal pedicle based on the vascular network of the lower lip. Plast Reconstr Surg 2013;131(2): 265–9. 11. Johanson B, Aspelund E, Breine U, et al. Surgical treatment of non-traumatic lower lip lesions with special reference to the step technique. A follow-up on 149 patients. Scand J Plast Reconstr Surg 1974;8(3):232–40. 12. Webster RC, Coffey RJ, Kelleher RE. Total and partial reconstruction of the lower lip with innervated musclebearing flaps. Plast Reconstr Surg Transplant Bull 1960;25:360–71. 13. Goldstein MH. A tissue-expanding vermilion myocutaneous flap for lip repair. Plast Reconstr Surg 1984;73(5): 768–70. 14. Kawamoto HK, Jr. Correction of major defects of the vermilion with a cross-lip vermilion flap. Plast Reconstr Surg 1979;64(3):315–8. 15. Zhao Z, Li Y, Xiao S, et al. Innervated buccal musculomucosal flap for wider vermilion and orbicularis oris muscle reconstruction. Plast Reconstr Surg 2005;116(3): 846–52. 16. Pribaz JJ, Meara JG, Wright S, et al. Lip and vermilion reconstruction with the facial artery musculomucosal flap. Plast Reconstr Surg 2000;105(3):864–72. 17. McGregor IA. The tongue flap in lip surgery. Br J Plast Surg 1966;19(3):253–63. 18. Sand M, Altmeyer P, Bechara FG. Mucosal advancement flap versus primary closure after vermilionectomy of the lower lip. Dermatol Surg 2010;36(12):1987–92. 19. Jabaley ME, Clement RL, Orcutt TW. Myocutaneous flaps in lip reconstruction. Applications of the Karapandzic principle. Plast Reconstr Surg 1977;59(5):680–8. 20. Jin X, Teng L, Zhang C, et al. Reconstruction of partial-­ thickness vermilion defects with a mucosal V-Y advancement flap based on the orbicularis oris muscle. J Plast Reconstr Aesthet Surg 2011;64(4):472–6.

Chapter

115

Surgical Complications Garrett Vick, Vineet Mishra

INTRODUCTION Complications are adverse events and outcomes.1 Complication rates are low for biopsies, excisions and Mohs micrographic surgery (MMS).2–5 Since 36% of the United States adult population has low health literacy, it is vital to educate and engage patients regarding potential complications.6

PREOPERATIVE Emergencies in cutaneous surgery are rare, but resuscitative equipment must be available and all staff with patient contact should complete life support training.7 Pertinent conditions, medications and allergies should be elicited preoperatively, for which screening tools may be h ­ elpful.8 Physical examination aids planning, consideration of potential complications and identification of baseline functional deficits.8

Medications Medical advances have facilitated an aging population with chronic conditions and polypharmacy is a worldwide concern.9–11 Given that medication lists often differ from medications actually taken, it is important to perform preoperative medication reconciliations.12 Literature suggests that anticoagulant use increases perioperative bleeding, but that rates of severe complications are very low and the risk of events such as stroke following discontinuation outweighs bleeding risk.13 Thus, anticoagulants should be continued perioperatively.13–16 Aspirin irreversibly prevents platelet aggregation for 6–10 days and is used for treatment of coronary artery disease and conditions with atherosclerotic components.17,18 Perioperative aspirin use results in a small, but statistically significant increase in postoperative hemorrhage in cutaneous head and neck surgery.19,20 Clopidogrel is approved by the FDA for rate reduction of stroke, myocardial infarction and death in patients

with recent myocardial infarction or stroke, peripheral arterial disease or acute coronary syndrome.17 It prevents platelet aggregation for 5–7 days. Patients taking concurrent clopidogrel and aspirin perioperatively experience increased bleeding, hematomas, necrosis and dehiscence compared to patients taking only aspirin or no anticoagulants.13 Non-steroidal anti-inflammatory drugs inhibit cyclooxygenase and pose a risk for increased ­bleeding.21 It is reasonable to discontinue these medications pre­operatively. Warfarin prevents production of coagulation factors II, VII, IX and X and is used to treat deep vein thrombosis, prevent thromboembolic events and inhibit clot formation in patients with atrial fibrillation or prosthetic valves.22,23 Rates of bleeding complications are very low in cutaneous surgery with perioperative warfarin, which should be continued to avoid thromboembolic events.16,24 The international normalized ratio is used for monitoring with bleeding risk noted for values greater than four.22,23 Novel oral anticoagulants are antithrombotic agents approved for use since 2010. They have a rapid onset and their predictable dose-dependent effects circumvent the need for close monitoring.25 Examples include argatroban and dabigatran, direct thrombin inhibitors that prevent conversion of fibrinogen to fibrin.26 Oral dabigatran is used as a warfarin alternative in certain conditions.27,28 Others include apixaban, edoxaban and rivaroxaban, all direct factor Xa inhibitors that prevent conversion of prothrombin to thrombin.29 The rate of significant bleeding with use of these agents is very low and current recommendations are to continue them perioperatively.30–32 Heparin binds antithrombin with a 1 hour half-life, allowing preprocedural reversal in patients who require strict anticoagulation.17 Outpatient low molecular weight heparin use (enoxaparin) is seen for venous thromboembolism or bridging patients to warfarin.33 Data regarding risk of surgical complications with steroids and immunomodulators are mixed.34–36 Investigations

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Section 31: Dermatologic Surgery of kidney transplant recipients do not show significantly increased risk of postoperative complications with cyclosporine, mycophenolate mofetil, azathioprine or prednisone, but studies have demonstrated higher rates of superficial wound infections and seromas with sirolimus compared to mycophenolate mofetil.35,37 Perioperative methotrexate use has been studied in patients with rheumatoid arthritis undergoing orthopedic surgeries, and while discontinuation has been associated with a decreased risk of postoperative infections, other sources indicate no significant difference in complication rates.38,39 Perioperative biologic agent (e.g. TNF-α inhibitors) use is not agreed upon. British guidelines recommend discontinuation four h ­ alf-lives preoperatively due to observed, but not statistically significant trends toward surgical site infections (SSIs) with perioperative TNF-α agent use.40 British recommendations suggest it is reasonable to start these agents postoperatively if there are no signs of infection.40 Studies of patients with psoriasis and rheumatoid arthritis regarding perioperative TNF-α agent use demonstrate low rates of complications.41,42 Vitamin E, Garlic, Ginseng, Gingko biloba and Fish oil have anticoagulant properties and are commonly used.16,32,43–46 Preoperative discontinuation is recomm­ended. Ethanol should be avoided 3 days preoperatively and postoperatively to minimize bleeding, especially in patients taking anticoagulants.8,32,47

Allergies Patients should be screened for allergies to agents used in dermatologic surgery.8 Latex allergy affects over 15 million people.48 Type I hypersensitivity reactions can occur and adjustments should be made for affected patients by using latex-free materials.

Anesthesia Local anesthetics contain intermediate ester or amide chains and impair nerve impulse transmission.49,50 Confirmed IgE mediated hypersensitivity to local anesthe­ tics is exceedingly rare, but type I reactions and crossreactivity can be seen with para-aminobenzoic acid, a metabolite of some ester agents.49–51 Type IV reactions can occur with ester or amide agents and it is believed there is little crossreactivity between classes. If a patient has history of hypersensitivity symptoms to ester agents and there is concern for possible type I reaction to an amide agent, preservative-free anesthetics or intralesional

diphenhydramine may be utilized.8 Reported epinephrine allergies are not true allergies, but sensations of epinephrine effects (tachycardia, tachypnea, tremor). Furthermore, epinephrine is the drug of choice for anaphylaxis.52 Using lower concentrations (1:200,000–400,000) may mitigate symptoms.53

Antiseptics Rare cases of anaphylaxis have been documented in response to chlorhexidine gluconate and polyhexadine. Documented cases of allergic contact dermatitis in povidine–iodine, octenidine and polyhexadine are also rare.54

Cardiac Devices Electrosurgery may trigger firing, reprogramming, battery depletion or damage to pacemakers and implantable cardiac defibrillators (ICDs).55 Electromagnetic interference (EMI) may impair pacemaker function, being misinterpreted as cardiac activity.55 This may be prevented by having pacemakers reprogrammed to a fixed (asynchronous) mode, firing instead at a set rate.55 EMI may incite ICD discharge which could induce a fatal arrhythmia.55 Although ICDs can be preoperatively deactivated to avoid inappropriate discharge, this could be devastating should an arrhythmia occur intraoperatively.55 Proposed guidelines regarding cardiac devices were most recently reiterated by LeVasseur et al. in 1998.56 These include preoperative cardiology consultation, preoperative surgical evaluation, use of electrocautery or bipolar instruments, ICD deactivation (if electrocautery is unavailable), changing pacemakers to fixed-rate mode, continuous intraoperative cardiac monitoring, utilization of short electrical bursts (5 seconds) on minimal current settings, establishing a plan for arrhythmias and postoperative evaluation of patients and devices.56 This proposed management was based on theoretical adverse events due to EMI rather than documented events. Commonly employed recommendations include short electrical bursts, minimal current and avoiding proximity (15cm) to implanted devices with complications noted in 0.8 cases per 100 years of surgical practice.56 Complications included skipped beats, pacemaker reprogramming, asystole, bradycardia, battery depletion and an unspecified tachyarrhythmia.56 Thermal cautery can be used due to absence of electrical currents and EMI.16

Chapter 115: Surgical Complications

Immunocompromised State Immunocompromised state increases risk of infection and potentially prolonged healing.57,58 Studies of orthopedic procedures in HIV-positive patients demonstrate early and late postoperative infections.59 Sources suggest infection risk increases with illness severity; with high viral loads and CD4 counts less than 200 posing greater risk than CD4 counts over two hundred.58,59 These patients should be screened and treated for infections preoperatively, or given prophylactic antibiotics in the absence of infection. It may be beneficial to postpone surgery until CD4 counts are greater than 200 and absolute polymorphonuclear counts greater than 1,000.59 Other conditions with increased infection risk incl­ ude obesity, diabetes, neutropenia and chronic illnesses such as cirrhosis and end-stage renal disease on chronic hemodialysis.60–65

Conditions with Bleeding Risk In inherited coagulation disorders like hemophilia A (factor VIII deficiency) and B (factor IX deficiency), bleeding correlates with factor deficiency severity.66 Certain acquired conditions (cirrhotic liver disease) also cause coagulopathy.67 Screening tests for coagulopathy include prothrombin time and activated partial thromboplastin time.68 Patients with hemophilia should be referred to hematology for coagulation factor replacement as indicated.16,69 It may be necessary for cirrhotic patients to receive fresh frozen plasma or prothrombin complex concentrates preoperatively.69 Illness can also decrease platelet production such as chronic liver disease.70 Conditions of platelet consumption include immune thrombocytopenic purpura or sequestration as in splenomegaly.16,71 Conditions causing platelet dysfunction include diabetes, CKD, uremia and others.16,72,73 Useful screening tests include a complete blood or platelet count to assess production and bleeding time to assess platelet function.74 For platelets under 20,000, cutaneous surgery can usually be performed safely when petechiae or gingival bleeding are absent.16 Patients with platelet dysfunction due to CKD or uremia may benefit from perioperative desmopressin or dialysis.69

Hypertension Bleeding risk increases with hypertension which affects 50 million people in the United States.8,9,16 Patients with up to 180 mm Hg of systolic or 100 mm Hg of diastolic blood

pressures, but without unstable angina, decompensated heart failure, symptomatic arrhythmia, or symptomatic aortic or mitral stenosis, are stable for dermatologic surgery.9 Patients with higher pressures likely meet criteria for hypertensive urgency and require urgent medical attention.9

Pathergy and Koebnerization Some conditions can be exacerbated by skin trauma (koebnerization and pathergy).75 An example is pyoderma gangrenosum (PG) which presents as an expanding ulcer at a surgical site approximately 7 days postoperatively.75 Associated conditions include previous PG, rheumatoid arthritis, inflammatory bowel disease or hematologic disorders.75 These lesions have been noted to respond to treatment with steroids, cyclosporine or tacrolimus.75 The Koebner phenomenon is a similar, but distinct process in which injury leads to appearance of lesions in previously uninvolved skin of patients with psoriasis, lichen planus and vitiligo.76

Herpes Simplex Virus Orolabial and facial HSV reactivation is possible and can be pretreated with oral valacyclovir or famciclovir perioperatively.2,8

Smoking Smoking increases risk of flap and graft necrosis, dehi­ scence, postoperative infection and scarring.77–80 Cessation should be encouraged for at least 2 days prior and 1 week after surgery.8,46

Obesity and Malnutrition Obesity increases risk of postoperative infection, dehi­ scence, hematomas and seromas.81 Severely malnourished patients are also at risk for complications.81 Some patients lack specific nutrients, especially after procedures altering intestinal absorption.82 Nutritional deficiencies should be optimized preoperatively.81

Pregnancy Ideally, medications that are not FDA class A or B should be avoided in pregnancy.8 Pregnancy category B anesthe­ tics include etidocaine, lidocaine and prilocaine.50 Category C agents include procaine, chloroprocaine, tetracaine, mepivacaine, articaine and bupivacaine.50

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Section 31: Dermatologic Surgery Epinephrine is pregnancy category C and can be secreted in breast milk.69

Counseling and Informed Consent Informed consent should precede any procedure with documentation of patient acceptance of risks, benefits, and alternatives, and that opportunity was provided to clarify understanding.8 Counseling should include pertinent expected complications and postoperative care should be discussed. Printed materials are beneficial given that patient retention rates twenty minutes after counseling range from 25 to 57%.83

Antibiotic Prophylaxis Risk of bacteremia from dermatologic surgery on clean, intact skin is less than 2% and most procedures do not require antibiotic prophylaxis.57,84–86 Many dermatologists overuse antibiotic prophylaxis based on current guidelines.87 A recent advisory reflecting updated guidelines was published and recommendations are elaborated below.57

Infective Endocarditis and Prosthetic Joints Risks for infective endocarditis include prosthetic val­ ves, prior infective endocarditis, valvulopathy following cardiac transplant and congenital heart disease that is unrepaired, repaired with residual defects or completely repaired for less than 6 months.57 Patients with any of the above should receive prophylactic antibiotics (targeting staphylococcus aureus and β-hemolytic streptococci)

for procedures involving infected skin or breaching oral mucosa (requiring s. viridans coverage).57 Prophylaxis is not recommended for MMS, unless involving infected skin, perforating oral mucosa or involving a site with high risk of infection.57 Additionally, the presence of pacemakers, ICDs, peripheral stents, coronary stents, vascular grafts, breast implants, penile prostheses and central nervous system shunts does not necessitate prophylaxis.57 Suggested prophylactic regimens are a single dose of one of the antibiotics in the table below given 60 minutes preoperatively.57,84,88 Risks for prosthetic joint infection include patients within 2 years of joint replacement, previous prosthetic joint infection, immunocompromised patients and pati­ ents with inflammatory arthropathies, type 1 diabetes mellitus, malignancy, malnourishment or hemophilia.57 Patients with any of the above should receive prophylaxis for procedures perforating oral mucosa, involving infected skin or involving a site with high risk of infection.57 Prophylaxis is not recommended for MMS or sterile, perforating procedures, on non-oral, non-infected skin unless there is a high chance of SSI in a patient who has any of the above risk factors.57 Additional conditions not requiring prophylaxis include pins, plates, screws or joint prostheses after 2 years since placement.57 Suggested regimens for prophylaxis are the same as for prevention of infective endocarditis (Table 115.1).

Surgical Site Infections The threshold for prophylaxis is sometimes lowered by factors that increase infection risk.57 Locations and

Table 115.1: Prophylactic antibiotic regimens: infective endocarditis and prosthetic joint infections.57 Oral mucosa Oral mucosa Keratinized skin Keratinized skin Penicillin tolerant Penicillin allergic Penicillin tolerant Penicillin allergic 500 mg Clarithromycin 2 g Cephalexin Infective 2 g Amoxicillin PO 500 mg Clarithromycin 500 mg Azithromycin 2 g Dicloxacillin endocarditis 500 mg Azithromycin 600 mg Clindamycin 600 mg Clindamycin Unable to tolerate PO: Unable to tolerate PO: Unable to tolerate PO: Unable to tolerate PO: 600 mg Clindamycin IM/IV 600 mg Clindamycin IM/IV 1 g Cefazolin IM/IV 1 g Cefazolin IM/IV 1 g Ceftriaxone IM/IV 1 g Ceftriaxone IM/IV 500 mg Clarithromycin 2 g Cephalexin Prosthetic 2 g Amoxicillin PO 500 mg Clarithromycin 500 mg Azithromycin 2 g Dicloxacillin joint infection 500 mg Azithromycin 600 mg Clindamycin 600 mg Clindamycin Unable to tolerate PO: Unable to tolerate PO: Unable to tolerate PO: Unable to tolerate PO: 600 mg Clindamycin IM/IV 600 mg Clindamycin IM/IV 1 g Cefazolin IM/IV 1 g Cefazolin IM/IV 1 g Ceftriaxone IM/IV 1 g Ceftriaxone IM/IV

Chapter 115: Surgical Complications Table 115.2: Prophylactic antibiotic regimens: SSIs.57 Penicillin tolerant Penicillin allergic 1 tablet TMP-SMX-DS Groin 2 g Cephalexin Levofloxacin 500 mg Lower extremities 1 tablet TMP-SMX-DS Levofloxacin 500 mg Unable to tolerate PO: Unable to tolerate PO: 600 mg Clindamycin + 2 mg/kg Gentamicin IV 1–2 g Ceftriaxone IV 600 mg Clindamycin Wedge excisions (lips 2 g Cephalexin 500 mg Clarithromycin/Azithromycin 2 g Dicloxacillin or ears) Unable to tolerate PO: Nasal flaps 600 mg Clindamycin IM/IV Unable to tolerate PO: All grafts 1 g Cefazolin IM/IV 1 g Ceftriaxone IM/IV

procedures at increased risk for SSI include lesions involving the groin or lower extremities, wedge excisions of lip or ear, and all grafts.89 Suggested regimens include a single dose of one of the agents in Table 115.2 administered 60 minutes preoperatively.

Mohs Micrographic Surgery Most cases of Mohs micrographic surgery (MMS) do not warrant antibiotic prophylaxis.57 Cases most often complicated by infection involve the nose, ear, flaps and grafts.57 For cases with high infection risk or involvement of oral mucosa, one of the above regimens should be utilized.57 For preoperative site infections, cultures should be obtained, treatment initiated, and if indicated, prophylaxis for infective endocarditis or prosthetic joint infection should be given.57

Other Considerations Staphylococcus carriage increases infection risk postoperatively and the 2008 dermatologic advisory includes prophylaxis recommendations for colonized patients.57,89 A randomized, controlled trial investigating SSIs f­ollowing oral antibiotics versus topical decolonization demonstrated that 9% of patients colonized with S. aureus who received oral antibiotics preoperatively developed SSIs, while no SSIs were observed among carriers who ­underwent topical decolonization.89 Thus, topical decolonization may be an alternative to prophylactic antibiotics. Of note, decolonization techniques in this trial were extensive including application of topical mupirocin ointment to the nares twice daily, as well as daily use of 4% chlorhexidine gluconate as a wash to the head, neck and body for five consecutive days preoperatively.89 Clostridium difficile infection (CDI) is an additional consideration since antibiotics commonly associated

with CDI include cephalosporins, aminopenicillins and clindamycin.90,91

INTRAOPERATIVE Standard Precautions Standard precautions minimize risk of infection with blood-borne agents, however, compliance varies.92 A small study regarding intraoperative blood exposure found that blood splash occurred in 66.4% of procedures with a greater number of splashes in MMS repairs, especially with tissue rearrangement.92 A survey of 349 members of the American College of Mohs surgery was performed in conjunction and found that 76.5% reported wearing intraoperative eye protection.92 Universal precautions, including intraoperative eye protection should be enforced.92

Sterilization Surgical equipment is amenable to sterilization and methods include dry heat, steam, cold and gas sterilization, or chemiclaves, with steam most commonly used in outpatient dermatologic procedures.93 Guidelines from the Joint Commission on the Accreditation of Healthcare Organizations (JCAHO) require that in outpatient facilities, any sterilized items must have manufacturers’ instructions for sterilization and that instruments must be sterilized individually with a single indicator for each item.93

Wound Contamination Centers for Disease Control (CDC) guidelines classify wounds as clean, uninflamed and uninfected with sterile procedures ending with primary closure (class I); clean with contamination in which sterility is broken or involvement of the oral cavity, axillary, or inguinal regions or left

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Section 31: Dermatologic Surgery to heal by secondary intention (class II); contaminated involving acute, non-purulent, traumatic wounds or major sterility breaks (class III); or grossly contaminated versus likely infected wounds with purulence, inflammation, necrosis, traumatic penetration or foreign body presence (class IV).88,91 These classifications predict subsequent infection risk (5, 10, 30 and 40% for classes I–IV, respectively).88 The CDC has established acceptable rates of infection for clean (1–3%) and clean-contaminated (5–10%) sites.86 Dermatologic surgery does not have strict protocols due to limited data identifying practices that further decrease the low rates of infection (ranging from 0.07 to 4.25%).94–96

Skin Preparation Patient skin and nares are major sources of wound contamination and antiseptics inhibit pathogenic and resident flora.94,97 Common agents include chlorhexidine and iodophors (both broad spectrum antimicrobials).98 Some studies report comparable efficacy while others suggest chlorhexidine is superior.94,97–100 Chlorhexidine binds the stratum corneum and has a longer action compared to iodophors which can be inactivated by blood, serum and sputum.94,98,101,102 Both agents can cause hypersensitivity reactions or irritant dermatitis, but since ototoxicity, conjunctivitis and keratitis can occur with chlorhexidine gluconate, additional caution should be employed to prevent chlorhexidine products from entering the eyes or ears.54,102,103 Since hair is another purported source of contamination, studies have evaluated preoperative hair removal and risk of infection, including shaving, clipping and depilatory creams.94 Some sources report an increased number of SSIs with hair removal, while others report that

use of depilatory creams showed reduced rates of SSIs, but were associated with hypersensitivity reactions.94 Sealants prevent contamination by bacteria immobilization.94,104 A prospective, randomized, multicenter trial investigating microbial sealants found that patients undergoing open inguinal hernia repair were more likely to have no SSI as well as no bacterial cells found in wounds with use of a cyanoacrylate-based sealant when compared to use of 10% povidone–iodine (Table 115.3).105

Surgical Technique In MMS, wounds stay open for prolonged periods (classified as clean-contaminated).86 A nine-month study was performed from 2008 to 2009 evaluating infection rates among MMS cases in which clean technique was used for tumor extirpation and reconstruction without subsequent antibiotics.86 In this study, 4% chlorhexidine gluconate antiseptic was applied preoperatively.86 Then, patients were draped using clean towels and sterile surgical instruments were utilized for extirpation and reconstruction without repeat sterilization.86 All staff used hand sanitizer before and after each patient encounter, face masks were worn intraoperatively, and clean, but non-sterile gloves were worn during both extirpation and reconstruction.86 Postoperatively, wounds were cleansed with hydrogen peroxide and petrolatum was applied while patients were counseled on wound care.86 The authors reported an infection rate of 0.91% for the treatment of 1,204 tumors suggesting that clean technique is safe for MMS.86 This and similar investigations have questioned the benefit of sterile gloves in dermatologic surgery.86,96,107,108 The cost of sterile glove use is typically three times greater, despite no sign­ ificant difference in SSI rates when compared non-sterile glove use.96,107 Studies with results opposing

Table 115.3: Common antiseptics in dermatologic surgery.102,103,106 Agent Spectrum Not covered or resistant Povidone–iodine Broad-spectrum bactericidal Fungicidal Virucidal Cysts of Acanthameoba castellanii Chlorhexidine gluconate Broad-spectrum bactericidal Not sporicidal Fungicidal Non-enveloped viruses Some protozoa Mycobacteriostatic Lipid-enveloped viruses 70% isopropyl alcohol Broad-spectrum bactericidal Spores Viruses Hydrophilic viruses Fungi

Chapter 115: Surgical Complications such findings include a prospective study investigating infection control practices which found patients undergoing excisions with reconstructive elements in which sterile gloves were not used experienced a significantly greater number of SSIs.109 Thus, for reconstruction, sterile glove use may be appropriate.

Intraoperative Bleeding Blood Supply The head and neck are supplied by angiosomes (threedimensional arterial units) with vessels that are intimately related to the SMAS layer and its continuation into the scalp as the galea aponeurotica.110 Skin perforators from the ophthalmic, superficial temporal, posterior auricular, occipital and facial arteries radiate through regions of the face, ears and scalp.110 Similarly, there is a large venous network that drains the head and neck with major veins often coursing at a distance from corresponding arteries.110

Hemostasis Minor bleeding is the most frequently encountered complication in dermatologic surgery and ranges from oozing to frank blood loss.69,111 Locations with a tendency to bleed include the scalp, ears, lips, nose and digits.16 The method of choice for controlling blood loss depends on the procedure, type of bleeding and underlying source.

Vasoconstrictive Agents Combining anesthetic and vasoconstrictive agents prolongs anesthesia and reduces intraoperative bleeding.16,69 Common formulations in dermatology contain lidocaine and epinephrine.16 The maximum epinephrine dose (0.5–1 mg) should not be exceeded to avoid tachycardia, arrhythmias or ischemia.16 Contraindications to epinephrine include narrow angle glaucoma, primary cardiac arrhythmias, severe hypertension or cardiovascular disease, severe hyperparathyroidism, carcinoid syndrome or pheochromocytoma.16,69 Surgeries involving the penis and digits have been studied and are safe.69 Digital blocks are safe when epinephrine doses are diluted to at least 1:200,000 and 1.5 mL or less is used per side.16 For digital blocks using epinephrine, circumferential blocks should be avoided and epinephrine should not be used for digital blocks in patients with diabetes mellitus, peripheral vascular disease or vasospastic conditions.16

Compression For acute bleeding, compression should be applied to facilitate platelet aggregation and coagulation.16 Some­ times pressure sufficiently stops bleeding, but in patients on anticoagulants, it may only be a temporizing measure.16 Vessels should be addressed largest to smallest (first arteries and then veins).16 A chalazion clamp or the ringed handle of surgical scissors help apply pressure to the ear, nose or lip.16 Bleeding from digits may be reduced with tourniquets made from a penrose drain or surgical glove, or application of a phlebotomy tourniquet to the extremity.16 Patient tolerance will vary and tourniquet use should be limited to 60 minutes.16

Electrosurgery Electrical hemostasis may be monoterminal or biterminal.16,69 Monoterminal electrosurgery includes electro­ fulguration or electrodessication and uses high voltage passing through an electrode held at a distance from tissue and results in tissue dessication and thrombosis of vessels up to 2 mm in diameter.16 Biterminal electrosurgery (electrocoagulation) applies lower voltage through direct tissue contact with a single electrode or when tissue is compressed between two electrodes.16 These methods can be effective for hemostasis, but cause thermal damage (charring) which is more pronounced with electrodessication and electrofulguration.16 Sequelae can be minimized by using the lowest current necessary for hemostasis.16 Since wound edges are at risk for necrosis, application of electrical current to these areas should be avoided.16 Another consideration includes cardiac devices for which thermal cautery can be used with no risk of EMI. Bipolar electrocoagulation can also be used because electricity is concentrated between the two tips of the instrument.16 It is usually recommended that current should not be applied within 15 cm of cardiac devices.16

Ligation and Suturing Vessels of any diameter can be ligated, but vessels greater than 2 mm require ligation for hemostasis.16 Absorbable sutures should be used and to the minimum amount of tissue necessary.16 Vessel damage can cause vasospasm, leading to retraction underneath wound edges, making ­visualization difficult.16 Undermining facilitates visualization, but may damage additional vessels.16 When visualization is not possible, blind ligation with a figure-of-eight stitch is an option.16 Certain suture techniques are useful

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Section 31: Dermatologic Surgery for controlling bleeding such as purse-string and horizontal mattress sutures.16,69 Excising vascular tumors can be difficult due to diffuse bleeding.16 A double imbricating suture is suggested in this scenario where two modified vertical purse-string sutures are situated peripheral to the site, which tamponades peripheral vessels during central area excision.16 A combination of sutures may be required to obtain hemostasis and buried sutures help close dead space.16

Hemostatic Agents Coagulation phases include initiation, amplification and propagation.111 Initiation involves vessel injury which releases tissue factors that initiate thrombin formation.111 Amplification is characterized by platelet activation and aggregation. Lastly, propagation occurs when fibrin stabilizes platelet clots.16 Topical hemostatic agents are adjuncts to previously discussed hemostasis methods and are classified as caustic or non-caustic.111 Caustic agents cause protein coagulation, small vessel occlusion and eschar formation.69,111 Examples include aluminum chloride, ferric subsulfate, silver nitrate and zinc chloride paste.111 Aluminum chloride is the most commonly used caustic agent.111 Of note, silver nitrate and ferric subsulfate may cause persistent skin pigmentation.111 Non-caustic solutions include physical and physiologic agents.111 Physical agents create scaffolding for platelet aggregation.111 Physical agents may generate granulomatous reactions and should be avoided for periocular sites.111 Examples include porcine gelatins, microporous polysaccharide spheres, hydrophilic polymers with potassium salts and oxidized regenerated cellulose.111 Porcine gelatins form a mechanical barrier and are usually absorbed over 4–6 weeks.111 They have proven useful after nail biopsy, MMS and staged excisions of melanoma.111 In addition to inciting granulomatous reactions, porcine gelatin swelling can injure nearby tissues.111 Microporous polysaccharide hemospheres are hydrophilic absorbable (24–48 hours) particles made from potato starch and act by concentra­ting solid particles of blood.111 Hydrophilic polymers with potassium salts (HPPS) cause dehydration and concentration of blood and binding effects of potassium salts create an artificial eschar.111 Since this occurs independently of the coagulation cascade, they are useful for patients on anticoagulants.111 HPPS is not absorbable and cannot be used on wounds that will be sutured closed.111 Oxidized regenerated cellulose (plant cellulose derivative) acts as a barrier, facilitates clotting and is absorbed in 7–14 days.111

Physiologic agents include fibrin sealants, thrombin and platelet gels that augment amplification and propagation.111 Thrombin agents may also enhance wound healing.111 These agents are more costly and less commonly used in dermatologic surgery.111

Tissue Injury Surgical tools facilitate cutting (scalpels, scissors, electrosurgery, lasers), tissue positioning (hooks, forceps, clamps), hemostasis (tourniquets, hemostats, electrosurgery) and wound closure (needles, drivers, suture). All manipulation can lead to inflammation and damage and thus should be performed judiciously.46 The surgeon should use a firm, but gentle grip to avoid crushing tissue.46 Excessive undermining should be avoided to minimize vascular damage and creation of dead space.46 The minimum necessary electrosurgical manipulation should be used to avoid excessive charring and necrosis.

Tension Tension is the sum of mechanical forces opposing wound edge union.112 It impairs healing and decreases wound strength.112 Additionally, pain, dehiscence, necrosis and scarring can result from excessive tension. Thus, tension should be sufficient to maintain closure while avoiding negative effects.112 Different incisions alter tension to optimize healing.112 Incisions may be simple and linear, or complex and involving tissue rearrangement in which a single wound edge is divided into multiple smaller edges that redistribute tension, improving wound strength and appearance.112 Other methods that reduce tension include undermining and special suture techniques.112 The horizontal mattress suture provides hemostasis and increased tensile strength.112 Other useful sutures include subcutaneous sutures and far-near-near-far pulley sutures.112,113 Tissue expansion is another method of addressing tension based on biological and mechanical skin creep.114 Biological creep refers to growth of epithelium, blood vessels, lymphatics, nerves, collagen and elastic fibers that occurs during pregnancy or weight gain.114 Mechanical creep is a rapid process occurring when skin undergoes alternating stretching and relaxation, causing collagen fibers to realign.114 The Miami Suture Tension Adjustment Reel is a skin stretching device shown to reduce tension on experimental wounds in guinea pigs.114 Investigators found this more effective than undermining alone and that effects were synergistic with undermining.114 Tissue

Chapter 115: Surgical Complications expansion over 1–6 weeks has been reportedly useful in MMS and can be accomplished through intraoperative expansion of donor site tissue through cycles of Foley catheter or other expander inflation within subcutan­ eous fat.115

Necrosis Necrosis results from ischemia and tissue death.46 Contri­ buting factors include comorbidities, operative technique and complications.46 Certain locations and procedures prone to infection and prolonged healing include the lower extremities, groin, lips or ears, nasal flaps and all grafts.46 Additional considerations include tissue handling and suture choice.46 Tissues should be handled carefully with skin hooks and toothed forceps rather than serrated forceps to avoid crushing.46 Undermining should be confined to the midsubcutaneous layer and should not be excessive.46 Wound tension can be exacerbated by edema, especially with inelastic suture, and it may be beneficial to use a loop stitch or more elastic material (polypropylene or nylon).46,116 Flaps and grafts are at risk for necrosis, especially with tension to distal edges.46 Flaps are classified by vascular supply with axial-pattern flaps being supplied by septocutaneous arteries whereas random-pattern flaps have no distinct supply.46 Flaps should have a length to base ratio of 3:1 or less.117 Flap elevation on a pedicle and return to the donor site prior to final transfer can be used to improve flap survival, but requires multiple surgeries.46 Grafts are pieces of skin that are severed from original blood supply and transferred to different locations.118 They can be full-thickness (epidermis, entire dermis and adnexa), split-thickness (epidermis and partial dermis) or composite (multiple tissues such as skin and cartilage).118 Factors decreasing graft survival include ischemia, formation of seromas or hematomas, infection, tension or poor wound bed contact.118 Complications are more frequent for full-thickness and composite grafts due to higher metabolic requirements.118

Nerve Injury Nerves may be damaged intraoperatively, making it important to discuss this with patients and to document any baseline neurologic deficits preoperatively. Local anesthesia can cause temporary deficits lasting days to weeks.50 Nerve transection results in sensory deficits that may be subtle and transient or more persistent (months or longer).119 Hypoesthesia is expected for grafts and

may persist for months.118 Motor nerve injury can result in paralysis and dysfunction severity correlates with the location of damage along the nerve. Damage occurring near a nerve root causes greater deficits than more distal injuries. Danger zones in dermatologic surgery mainly involve facial nerve (cranial nerve VII) branches.119 The first branch is the posterior auricular nerve which travels behind the ear.119 The facial nerve divides into superior temporo­facial and inferior cervicofacial divisions prior to or within the parotid gland.119,120 Upon exiting the parotid gland, the facial nerve divides into temporal, zygomatic, buccal, mandibular and cervical branches.119,120 The temporal branch danger zone encompasses temporal skin lateral to the eyelid canthus and superior to the middle third of the zygomatic arch.120 Dissection should remain above temporoparietal fascia.121 Transection can paralyze ipsilateral frontalis muscle, impairing forehead elevation.119,120 The zygomatic branch crosses over the zygomatic arch and damage may impair eyelid closure and cause smile asymmetry.119,120 The danger zone for this nerve spans from the lateral canthus to the anterior parotid gland border.120 Dissection should also remain superficial to the SMAS.121 The buccal branch exits the anterior parotid gland and the danger zone is inferolateral to the zygoma and medial to the anterior parotid gland border.119–121 Damage may result in smile asymmetry or difficulty chewing.120 The marginal mandibular branch exits the parotid gland near the angle of the jaw, traveling along the inferior mandibular border.120 It is most vulnerable to injury crossing over facial vessels around the angle and proximal body of the mandible.119 Damage can result in smile asymmetry and drooling.120 Dissection superficial to the platysma and SMAS should be maintained.121 The cervical branch exits the lower parotid gland and is protected by platysma.119 Damage usually does not produce clinically significant findings.120 The spinal accessory nerve enters the posterior triangle at Erb’s point and crosses the posterior triangle to exit under the trapezius.120 Damage can result in scapula winging, impaired arm abduction and paresthesias.120

POSTOPERATIVE Counseling A study in 2013 found that 27% of patients undergoing Mohs, excision or lesion destruction reported

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Section 31: Dermatologic Surgery experiencing complications, but only 3% of charts documented confirmed complications.122 This emphasizes the importance of discussing wound care, healing and potential complications. Additionally, patients should be given written postoperative instructions and contact information for the surgeon or support staff.15

Bleeding Bleeding is commonly observed within the first 48 hours postoperatively when effects of vasoconstrictive agents dissipate.15,69 This can be addressed with multilayer compressive dressings including topical petrolatum, nonadherent film and absorbent material (gauze) secured with tape or elastic bandaging.69 Dressings should not be so tight that blood flow is compromised. Dressings should remain in place for 6–24 hours postoperatively.46 Activity should be limited (two weeks for head and neck wounds and six weeks for lower extremity wounds) with avoidance of heavy lifting or strenuous activities.69 If bleeding occurs, patients should apply pressure to the area for 15–20 minutes.69 Cool compresses or ice may be applied as tolerated to vasoconstrict vessels.69 Continued bleeding despite compression, internal pressure sensation or throbbing pain require evaluation and possible wound exploration.69 Ecchymoses (bruises) form when blood infiltrates skin interstitium and gradually resolve without sequelae.15 Hematomas are larger blood collections that present as fluctuant masses underneath or in close proximity to surgical sites69 (Figs. 115.1 to 115.3). They may be classified as organized or disorganized depending on the distribution of blood. Rapid or extensive expansion increases internal pressure and suture tension, sometimes causing pain and dehiscence. This can compress subdermal plexi causing ischemia and necrosis. Early hematomas should be addressed by wound exploration, localization of bleeding vessels, ensuring hemostasis and addressing dead space via sutures, hemostatic agents or drains.69 Periorbital or cervical hematomas constitute medical emergencies due to risk of damage to nearby structures.15 Hematomas that are unrecognized during the first postoperative week can be evacuated and left open to heal by secondary intention, or can remain closed with application of massage, warm compresses and observation.69 Over weeks to months, hematomas organize (clot formation), followed by liquefactive necrosis that allows aspiration and drainage with a 16–18 gage needle.69 Once identified, especially if a wound is reopened, prophylactic antibiotics are usually given.69

Fig. 115.1: Hematoma present 36 hours after surgery on the left axilla. Courtesy: Vineet Mishra, MD.

Fig. 115.2: Drain placed status post hematoma evacuation on the back. Courtesy: Vineet Mishra, MD.

Infection Infection may occur if surgical sites become contaminated.116 It is important to maintain sterile or clean technique, and to prevent postoperative contamination while re-epithelialization occurs (48–72 hours following closure).116 Topical antibiotic preparations (neomycin, bacitracin and tobramycin) can cause allergic contact dermatitis and no literature currently supports reduction in rates of infection when compared to petrolatum during postprocedural wound care. Other risks for SSI include: comorbidities; procedure location; procedure duration (greater than 2 hours); ischemia; and hematoma formation.91,116

Chapter 115: Surgical Complications

Fig. 115.3: Hematoma and periorbital ecchymoses after Mohs surgery and reconstruction with an Island pedicle flap advancement, in a female smoker who was otherwise healthy. Courtesy: Bahar Firoz, MD and Amer Almohssen, MD.

Fig. 115.4: Infection. Pustule present on the right shoulder adjacent to Mohs surgery site. Courtesy: Vineet Mishra, MD.

Signs of SSIs usually present 4–8 days postoperatively and diagnosis can be made if there is site involvement within 30 days postprocedure with at least one of the following: purulent discharge, organism isolation, pain, tenderness, swelling, redness, heat or if there is wound reopening88,116 (Fig. 115.4). Infections should be treated aggressively, including culture followed by antibiotics with coverage for probable organisms until culture confirmation.57,84,116 Choice of empiric agents can be guided by anatomic location and expected flora with suggested regimens below.91,117 Antibiotics can be adjusted if culture demonstrates resistant organisms.91 Skin abscesses warrant antibiotics with methicillin resistant staphylococcus aureus (MRSA) coverage and may require drainage and packing.57,116 Risk factors for community acquired MRSA include colonization, athletes, military personnel, children in daycare, incarceration, men who have sex with men, intravenous drug use and homelessness.91 Pseudomonas aeruginosa is a colonizer of the ear and can complicate periauricular wounds (Table 115.4).123

Graft healing initiates with a 24 hour ischemic phase called imbibition during which fibrin binds the graft and wound bed.118 The graft absorbs exudate, moisture and nutrients from the wound bed.118 A period called inosculation follows 48–72 hours after grafting, during which anastomoses form between graft and dermal vessels, followed by full circulation restoration occurring by days 4–7 postgrafting.118 Gradually, granulation tissue replaces fibrin and more permanently bonds the graft and wound bed.118 Epidermal proliferation occurs over days 4–8 postgrafting and is generated by epithelial cells of hair follicles.118 Re-innervation occurs 2–4 weeks postgrafting, but sensation may be postponed for months.118 A blackened graft is usually a sign of necrosis.118 However, necrosis may be limi­ted to epidermis while viable underlying dermis continues to heal.118 Thus, eschars without evidence of infection should be left as a biologic dressing.116,118

Necrosis Necrosis results from ischemia that may first present as cyanosis, pallor, slow capillary refill or coolness.46 High wound tension can strangulate tissue and hematomas can compress blood vessels.46 Hematomas also increase risk of infection, inflammation and edema which further compromise perfusion.46 Flaps may be salvageable for 13 hours and ischemia should be addressed early.46

Dehiscence Dehiscence (wound edge separation) results from tension, necrosis or infection. Skin tensile strength is only 3–5% of normal skin at two weeks postoperatively.116 Even one month postoperatively, the tensile strength is only 35% of uncut skin, which should be emphasized to patients.116 With optimum healing, the maximum expected tensile strength is 80% of uncut skin.116 Closure tape can support newly epithelialized tissue.116 If dehiscence occurs, the surgeon should treat any underlying cause and allow healing of the wound by secondary intention.116 Alternatively,

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Section 31: Dermatologic Surgery Table 115.4: SSI antibiotic selection.91 Location Flora Glabrous skin Streptococcus pyogenes Staphylococcus aureus

Antibiotic Cephalosporin Dicloxacillin

Oral cavity

Amoxicillin

Intertriginous

Ear

Streptococci (viridans) Peptostreptococcus Staphylococci Corynebacteria Bacteroides Staphylococcus Enterococcus Escherichia coli Pseudomonas aeruginosa Serratia marcescens Bacteroides fragilis

Penicillin allergic Clindamycin Azithromycin Clindamycin Clindamycin Azithromycin Clindamycin

Double strength trimethoprim– Cephalosporin sulfamethoxazole Amoxicillin + Clavulanic acid Double strength trimethoprim– sulfamethoxazole Quinolone Quinolone

occur with infection, it is important to examine wounds carefully and to consider antibiotics judiciously. A trapdoor deformity (appearance of outpouching skin) results from tissue redundancy or retraction of U-, C- or V-shaped flaps.124 Intraoperative undermining or postoperative massage, corticosteroid injection or surgical revision with debulking or further undermining can lessen this effect.124 Observation may also be appropriate.

Scarring

Fig. 115.5: Dehiscence. Courtesy: Babar K Rao, MD.

if no cause is found, wound closure can be considered (Fig. 115.5).116

Wound Appearance Wound appearance helps determine intervention. Suture reactions are common in sebaceous areas.116 Natural fibers (silk) cause more inflammation than synthetic materials (polypropylene).116 The inflammatory response may include pustules or abscesses (usually sterile) around suture insertion and exit points.116 Foreign body granulomas can form or the body may attempt to expel suture material (“spitting” sutures).116 “Spitting” sutures can be removed, but a foreign body reaction may persist.116 Since inflammation can also

Any skin break may cause scarring which may be painful, pruritic and can contribute to diminished self-esteem and depression.125–127 Scar assessment includes color, vascularity, texture, pliability, height and distortion.125 Ideal scars are minimally perceptible and do not compromise nearby structures.128 Attempts should be made to incise within folds or parallel to tension lines.128 Wound edge approximation with adequate eversion allows scars to flatten, whereas excessively everted or inverted edges can elevate or depress scars respectively.128 Excessive wound tension can widen scars.128 Subcutaneous sutures, flaps or other tissue rearrangement can reduce tension. Suture tracking occurs with tension and sutures left in place beyond postoperative day ten.116,128 Avoiding delayed removal and minimizing wound tension help prevent tracking.116,128 Postsurgical taping and botulinum toxin A have been be used to reduce tension and scarring.127 Other recommendations for optimizing scar appearance include massage, hydration (emollients and humectants) and avoidance of ultraviolet light.127 Ultraviolet light

Chapter 115: Surgical Complications

Fig. 115.6: Hypertrophic scar after excision. Courtesy: Babar K Rao, MD.

Fig. 115.7: Keloid on the chest after biopsy. Courtesy: Babar K Rao, MD.

increases scar pigmentation and exposure should be minimized until scar maturation.127 Lightening agents (hydroquinone) can be used for hyperpigmentation and require sunscreen use.125 Scars can be addressed surgically or non-surgically. Non-surgical methods include cosmetics, topical silicone gel or sheeting to improve color and texture, as well as dermabrasion and intralesional 5–fluorouracil or steroids to flatten scars.125 Dermabrasion can blend scar borders and increase collagen remodeling.125 Depressed scars may benefit from filler injection.125 Lasers are an emerging option for addressing scar texture, redness, telangiectasias and hyperpigmentation.127 Different lasers can address these qualities including pulsed dye laser, non-ablative fractional laser, CO2 ablative fractional laser and others.125,127 Surgical revision can improve scar appearance, but unless there is dysfunction of nearby structures, revision should be postponed until scar maturation (12–18 months).125,128 Elliptical excision can excise existing scars under 2 cm and following tension lines.128 For scars that cannot be removed by simple excision, an alternative is revision over multiple excisions.128 Hypertrophic scars and keloids become elevated, but keloids extend beyond wound margins whereas hypertrophic scars do not.126 Locations prone to hypertrophic scarring include shoulders, chest, neck, knees and ankles126 (Fig. 115.6). Keloids can further involve arms and ears.126 Hypertrophic scars appear 4–8 weeks postoperatively and may flatten over time.126 Keloids can develop years after injury or spontaneously and persist without regression.126 (Fig. 115.7) Hypertrophic scars can be excised, but

keloids often recur.126 Therapies for hypertrophic scars and keloids include pressure therapy, intralesional corticosteroids, radiotherapy, cryotherapy and pulsed dye laser therapy.126 Surgical revision may be considered for hypertrophic scars and keloids persisting 12 months despite treatment.127 For keloid excision, adjuvant therapies (e.g. corticosteroid injection or pressure) should be included.126

CONCLUSION Complications should be anticipated and discussed with patients. Additionally, steps should be taken to minimize risk and optimize the outcomes. Complications that occur should stimulate learning and improvement.

REFERENCES 1. Aasi SZ, Leffell DJ. Complications in dermatologic surgery: how safe is safe? Arch Dermatol 2003;139(2):213–4. 2. Elliott T, Thom G, Litterick K. Office based dermatological surgery and Mohs surgery: a prospective audit of surgical procedures and complications in a procedural dermatology practice. Australas J Dermatol 2012;53(4):264–71. 3. Alam M, Ibrahim O, Nodzenski M, et al. Adverse events associated with Mohs micrographic surgery: multicenter prospective cohort study of 20821 Cases at 23 Centers. JAMA Dermatol 2013;149(12):1378–85. 4. Asgari MM, Olson J, Alam M. Needs assessment for Mohs micrographic surgery. Dermatol Clin 2012;30(1):167–75. 5. Merritt B, Lee N, Brodland D, et al. The safety of Mohs surgery: a prospective multicenter cohort study. J Am Acad Dermatol 2012;67(6):1302–9. 6. Bickmore TW, Utami D, Matsuyama R, et al. Improving access to online health information with conversational

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Section 31: Dermatologic Surgery agents: a randomized controlled experiment. Eysenbach G, ed. J Med Internet Res 2016;18(1):e1. 7. Fader D, Johnson T. Medical issues and emergencies in the dermatology office. J Am Acad Dermatol 1997;36(1):1–16; quiz 16–8. 8. Otley C. Perioperative evaluation and management in dermatologic surgery. J Am Acad Dermatol 2006;54(1):119–27. 9. Larson R, Aylward J. Evaluation and management of hypertension in the perioperative period of Mohs micrographic surgery: a review. Dermatol Surg 2014;40(6):603–9. 10. Walckiers D, Van der Heyden J, Tafforeau J. Factors associated with excessive polypharmacy in older people. Arch Pub Health 2015;73:50. 11. Cooper JA, Cadogan CA, Patterson SM, et al. Interventions to improve the appropriate use of polypharmacy in older people: a Cochrane systematic review. BMJ Open 2015; 5(12):e009235. 12. Cullinan S, O’Mahony D, Byrne S. Application of the structured history taking of medication use tool to optimise prescribing for older patients and reduce adverse events. Int J Clin Pharm 2016. 13. Cook-Norris R, Michaels J, Weaver A, et al. Complications of cutaneous surgery in patients taking clopidogrel-containing anticoagulation. J Am Acad Dermatol 2011;65(3):584–91. 14. Bordeaux J, Martires K, Goldberg D, et al. Prospective evalua­tion of dermatologic surgery complications including patients on multiple antiplatelet and anticoagulant medications. J Am Acad Dermatol 2011;65(3):576–83:1207–13. 15. Bunick C, Aasi S. Hemorrhagic complications in dermatologic surgery. Dermatol Ther 2011;24(6):537–50. 16. Kaur R, Glick J, Siegel D. Achieving hemostasis in dermatology—Part 1: preoperative, intraoperative, and postoperative management. Indian Dermatol Online J 2013; 4(2):71–81. 17. Weitz JIChapter 30. Blood coagulation and anticoagulant, fibrinolytic, and antiplatelet drugs. In: Brunton LL, Chabner BA, Knollmann BCeditors. Goodman & Gilman’s the pharmacological basis of therapeutics, 12rd ed. New York (NY): McGraw-Hill; 2011. 18. Demir, DM. Aspirin: Therapeutic uses, adverse effects and pharmacokinetics. Hauppauge (NY), USA: Nova Science Publishers, Inc.; 2011. Ch. 3, p. 68–9. ProQuest ebrary. Web. 26 January 2016. 19. Shimizu I, Jellinek N, Dufresne R, et al. Multiple antithrombotic agents increase the risk of postoperative hemorrhage in dermatologic surgery. J Am Acad Dermatol 2008; 58(5):810–6. 20. Dhiwakar M, Khan NA, McClymont LG. Surgical resection of cutaneous head and neck lesions: does aspirin use increase hemorrhagic risk? Arch Otolaryngol Head Neck Surg 2006;132(11):1237–41. 21. Bozimowski G. A review of nonsteroidal anti-inflammatory drugs. AANA J [serial online]. December 2015;83(6):425– 33. Available from: Academic Search Complete, Ipswich, MA [accessed 28.01.16]. 22. Harter K, Levine M, Henderson S. Anticoagulation drug therapy: a review. West J Emerg Med 2015;(16)1:11–7.

23. Alcalay J, Alkalay R. Controversies in perioperative mana­ gement of blood thinners in dermatologic surgery: continue or discontinue? Dermatol Surg 2004;30(8):1091–4. 24. Alcalay J. Cutaneous surgery in patients receiving warfarin therapy. Dermatol Surg 2001;27(8):756–8. 25. Shehab A, Elnour AA, Bhagavathula AS, et al. Novel oral anticoagulants and the 73rd anniversary of historical warfarin. J Saudi Heart Assoc 2016;28(1):31–45. 26. Fujimori Y, Wakui M, Katagiri H, et al. Evaluation of anticoagulant effects of direct thrombin inhibitors, dabigatran and argatroban, based on the Lineweaver–Burk plot applied to the Clauss assay. J Clin Pathol 2016;69: 370–2. 27. Grouzi E. Update on argatroban for the prophylaxis and treatment of heparin-induced thrombocytopenia type II. J Blood Med 2014;5:131–41. 28. Huber K, Connolly SJ, Kher A, et al. Practical use of dabi­ gatran etexilate for stroke prevention in atrial fibrillation. Int J Clin Pract 2013;67(6):516–26. 29. Cabral KP, Ansell JE. The role of factor Xa inhibitors in venous thromboembolism treatment. Vasc Health Risk Manag 2015;11:117–23. 30. Chang T, Arpey C, Baum C, et al. Complications with new oral anticoagulants dabigatran and rivaroxaban in cutaneous surgery. Dermatol Surg 2015;41(7):784–93. 31. Palamaras L, Semkova K. Perioperative management of and recommendations for antithrombotic medications in dermatologic surgery. Br J Dermatol 2015;172(3): 597–605. 32. Brown D, Wilkerson E, Love W. A review of traditional and novel anticoagulant and antiplatelet therapy for dermatologists and dermatologic surgeons. J Am Acad Dermatol 2015;72(3):524–34. 33. Smythe M, Priziola J, Dobesh P, et al. Guidance for the practical management of the heparin anticoagulants in the treatment of venous thromboembolism. J Thromb Thrombolysis 2016;41(1):165–86. 34. Diethelm AG. Surgical management of complications of steroid therapy. Ann Surg 1977;185(3):251–63. 35. Flechner S, 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(12):1729–34. 36. Snäll J, Kormi E, Koivusalo A, et al. Effects of perioperatively administered dexamethasone on surgical wound healing in patients undergoing surgery for zygomatic fracture: a prospective study. Oral Surg Oral Med Oral Pathol Oral Radiol 2014;117(6):685–9. 37. Valente J, Hricik D, Weigel K, et al. Comparison of sirolimus vs. mycophenolate mofetil on surgical complications and wound healing in adult kidney transplantation. Am J Transplant 2003;3(9):1128–34. 38. Carpenter M, West S, Vogelgesang S, et al. Postoperative joint infections in rheumatoid arthritis patients on metho­ trexate therapy. Orthopedics 1996;19(3):207–10. 39. Grennan D, Gray J, Loudon J, Fear S. Methotrexate and early postoperative complications in patients with rheumatoid

Chapter 115: Surgical Complications arthritis undergoing elective orthopaedic surgery. Ann Rheum Dis 2001;60(3):214–7. 40. Smith C, Anstey A, Barker J, et al. British association of dermatologists’ guidelines for biologic interventions for psoriasis 2009. Br J Dermatol 2009;161(5):987–1019. 41. Fabiano A, De Simone C, Gisondi P, et al. Management of patients with psoriasis treated with biological drugs needing a surgical treatment. Drug Dev Res 2014;75(1):S24–6. 42. Bibbo C, Goldberg J. Infectious and healing complications after elective orthopaedic foot and ankle surgery during tumor necrosis factor-alpha inhibition therapy. Foot Ankle Int 2004;25(5):331–5. 43. Chang L, Whitaker D. The impact of herbal medicines on dermatologic surgery. Dermatol Surg 2001;27(8):759–63. 44. Collins S, Dufresne R. Dietary supplements in the setting of Mohs surgery. Dermatol Surg 2002;28(6):447–52. 45. Hathcock J, Azzi A, Blumberg J. Vitamins E and C are safe across a broad range of intakes. Am J Clin Nutr 2005;81(4): 736–45. 46. Delaney A, Diamantis S, Marks V. Complications of tissue ischemia in dermatologic surgery. Dermatol Ther 2011;24(6):551–7. 47. Matsumoto C, Miedema M, Ofman P, et al. An expanding knowledge of the mechanisms and effects of alcohol consumption on cardiovascular disease. J Cardiopulm Rehabil Prev 2014;34(3):159–71. 48. Kahn S, Podjasek J, Dimitropoulos V, et al. Natural rubber latex allergy. Disease-a-month 2016;62(1):5–17. 49. Becker DE, Reed KL. Essentials of local anesthetic pharmacology. Anesthesia progress 2006;53(3):98–109. 50. Harahap M, editor. Basic and clinical dermatology, volume 42: anesthesia and analgesia in dermatologic surgery. New York, NY, USA: CRC Press; 2008. ProQuest ebrary. Web. 7 February 2016. 51. Batinac T, Sotos´ek Tokmadžic´ V, et al. Adverse reactions and alleged allergy to local anesthetics: analysis of 331 patients. J Dermatol 2013;40(7):522–7. 52. Lomas JM, Järvinen KM. Managing nut-induced anaphylaxis: challenges and solutions. J Asthma Allergy 2015;8:115–23. 53. Shoroghi M, Sadrolsadat S, Razzaghi M, et al. Effect of different epinephrine concentrations on local bleeding and hemodynamics during dermatologic surgery. Acta Dermatovenerol Croat 2008;16(4):209–14. 54. Lachapelle JM. A comparison of the irritant and allergenic properties of antiseptics. Eur J Dermatol 2014;24(1):3–9. 55. Matzke T, Christenson L, Christenson S, et al. Pacemakers and implantable cardiac defibrillators in dermatologic surgery. Dermatol Surg 2006;32(9):1155–62. 56. El-Gamal H, Dufresne R, Saddler K. Electrosurgery, Pacemakers and ICDs: a survey of precautions and complications experienced by cutaneous surgeons. Dermatol Surg 2001;27(4):385–90. 57. Wright T, Baddour L, Berbari E, et al. Antibiotic prophylaxis in dermatologic surgery: advisory statement 2008. J Am Acad Dermatol 2008;59(3):464–73.

58. Liu B, Zhang L, Su J, et al. Treatment of postoperative infectious complications in patients with human immunodeficiency virus infection. World J Emerg Med 2014;5(2):103–6. 59. Luck J, Logan L, Benson D, et al. Human immunodeficiency virus infection: complications and outcome of orthopaedic surgery. J Am Acad Orthop Surg 1996;4(6): 297–304. 60. Fisichella L, Fenga D, Rosa M. Surgical site infection in orthopaedic surgery: correlation between age, diabetes, smoke and surgical risk. Folia Med (Plovdiv) 2014;56(4): 259–63. 61. Casqueiro J, Casqueiro J, Alves C. Infections in patients with diabetes mellitus: a review of pathogenesis. Indian J Endocrinol Metabol 2012;16(Suppl1):S27–36. 62. Mohan P, Ramu B, Bhaskar E, et al. Prevalence and risk factors for bacterial skin infection and mortality in cirrhosis. Ann Hepatol 2011;10(1):15–20. 63. Hoen B, Kessler M, Hestin D, et al. Risk factors for bacterial infections in chronic haemodialysis adult patients: a multicentre prospective survey. Nephrol Dial Transplant 1995;10(30):377–81. 64. Joshi N, Caputo G, Weitekamp M, et al. N Engl J Med 1999;341:1906–12. 65. Zinner S. Changing epidemiology of infections in patients with neutropenia and cancer: emphasis on gram-positive and resistant bacteria. Clin Infect Dis 1999;29(3):490–4. 66. Peterson S, Joseph A. Inherited bleeding disorders in dermatologic surgery. Dermatol Surg 2001;27(10):885–9. 67. Cho J, Choi SM, Yu SJ, et al. Bleeding complications in critically ill patients with liver cirrhosis. The Korean J Intern Med. 2016;31(2):288–95. doi:10.3904/kjim.2014.152. 68. Adams R, Bird R. Review article: coagulation cascade and therapeutics update: relevance to nephrology. Part 1: overview of coagulation, thrombophilias and history of anticoa­gulants. Nephrology (Carlton) 2009;14(5):462–70. 69. Henley J, Brewer JD. Newer hemostatic agents used in the practice of dermatologic surgery. Dermatol Res Pract 2013;2013:279–89. 70. Maan R, de Knegt RJ, Veldt BJ. Management of thrombocytopenia in chronic liver disease: focus on pharmacotherapeutic strategies. Drugs 2015;75(17):1981–92. 71. Pineo GF. Chronic idiopathic thrombocytogenic purpura. Can Fam Phys 1984;30:1829–33. 72. Maroz N, Simman R. Wound healing in patients with impaired kidney function. J Am Coll Clin Wound Spec 2013;5(1):2–7. 73. Ozgur M, Yilmaz B. Unexpected intra-operative bleeding due to Hermansky–Pudlak Syndrome. Indian J Anaesth 2015;59(6):393–4. 74. Burns E, Lawrence C. Bleeding time. A guide to its diagnostic and clinical utility. Arch Pathol Lab Med 1989;113(11):1219–24. 75. Zuo K, Fung E, Tredget E, et al. A systemic review of post-surgical pyoderma gangrenosum: identification of risk factors and proposed management strategy. J Plast Reconstr Aesthet Surg 2015;68(3):295–303. 76. Sagi L, Trau H. The Koebner phenomenon. Clin Dermatol 2011;29(2):231–6.

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Section 31: Dermatologic Surgery 77. Bartsch R, Weiss G, Kästenbauer T, et al. Crucial aspects of smoking in wound healing after breast reduction surgery. J Plast Reconstr Aesthet Surg 2007;60(9):1045–49. 78. Metelitsa A, Lauzon G. Tobacco and the skin. Clin Dermatol 2010;28(4):384–90. 79. Reus W, Colen L, Straker D. Tobacco smoking and complications in elective microsurgery. Plast Reconstr Surg 1992; 89(3):490–4. 80. Krueger J, Rohrich R. Clearing the smoke: the scientific rationale for tobacco abstention with plastic surgery. Plast Reconstr Surg 2001;108(4):1063–73; discussion 1074–7. 81. Wilson J, Clark J. Obesity: impediment to postsurgical wound healing. Adv Skin Wound Care 2004;17(8):426–35. 82. Vick G, Mahmoudizad R, Fiala K. Intravenous zinc therapy for acquired zinc deficiency secondary to gastric bypass surgery: a case report. Dermatol Ther 2015;28(4);222–5. 83. Fleischman M, Garcia C. Informed consent in dermatologic surgery. Dermatol Surg 2003; 29(9):952–5. 84. Shurman D, Benedetto A. Antimicrobials in dermatologic surgery: facts and controversies. Clin Dermatol 2010; 28(5):505–10. 85. Maragh S, Brown M. Prospective evaluation of surgical site infection rate among patients with Mohs micrographic surgery without the use of prophylactic antibiotics. J Am Acad Dermatol 2008;59(2):275–8. 86. Rogers H, Desciak E, Marcus R, et al. Prospective study of wound infections in Mohs micrographic surgery using clean surgical technique in the absence of prophylactic antibiotics. J Am Acad Dermatol 2010;63(5):842–51. 87. Bae-Harboe Y, Liang C. Perioperative antibiotic use of dermatologic surgeons in 2012. Dermatol Surg 2013;39(11): 1592–601. 88. Rosengren H, Dixon A. Antibacterial prophylaxis in dermatologic surgery: an evidence-based review. Am J Clin Dermatol 2010;11(1):35–44. 89. Cherian P, Gunson T, Borchard K, et al. Oral antibiotics versus topical decolonization to prevent surgical site infection after Mohs micrographic surgery—a randomized, controlled trial. Dermatol Surg 2013;39(10):1486–93. 90. Carignan A, Allard C, Pépin J, et al. Risk of clostridium difficile infection after perioperative antibacterial prophylaxis before and during an outbreak of infection due to a hypervirulent strain. Clin Infect Dis 2008;46(12):1838–43. 91. Rossi A, Mariwalla K. Prophylactic and empiric use of antibiotics in dermatologic surgery: a review of the literature and practical considerations. Dermatol Surg 2012; 38(12):1898–921. 92. Holzmann R, Liang M, Nadiminti H, et al. Blood exposure risk during procedural dermatology. J Am Acad Dermatol 2008;58(5):817–25.  93. Lieu A, Lawrence N. Incidence of infection after Mohs micrographic and dermatologic surgery before and after implementation of new sterilization guidelines. J Am Acad Dermatol 2014;70(6):1088–91.  94. Dohmen P, Konertz W. A review of current strategies to reduce intraoperative bacterial contamination of surgical wounds. GMS Krankenhhyg Interdiszip 2007;2(2):Doc38.

  95. Martin J, Speyer LA, Schmults C. Heightened infection-control practices are associated with significantly lower infection rates in office-based Mohs surgery. Dermatol Surg 2010;36(10):1529–36.  96. Mehta D, Chambers N, Adams B, et al. Comparison of the prevalence of surgical site infection with use of sterile versus nonsterile gloves for resection and reconstruction during Mohs surgery. Dermatol Surg 2014;40(3):234–9.   97. Brown C, Zitelli J. A review of topical agents for wounds and methods of wounding. Guidelines for wound management. J Dermatol Surg Oncol 1993;19(8):732–7.   98. Darouiche R, Wall M, Itani K, et al. Chlorhexidine-alcohol versus povidone-iodine for surgical-site antisepsis. N Engl J Med 2010;362(1):18–26.   99. Garibaldi R. Prevention of intraoperative wound contamination with chlorhexidine shower and scrub. J Hosp Infect 1988;11(Suppl B):5–9. 1 00. Bibi S, Shah S, Qureshi S, et al. Is chlorhexidine-gluconate superior than povidone-iodine in preventing surgical site infections? A multicenter study. J Pak Med Assoc 2015;65(11):1197–201. 1 01. Mangram A, Horan T, Pearson M, et al. Guideline for prevention of surgical site infection, 1999. Hospital infection control practices advisory committee. Infect Control Hosp Epidemiol 1999;20(4):250–78; quiz 279–80. 1 02. Burkhart CN, Katz KA. Chapter 222. Other topical medications. In: Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K, editors. Fitzpatrick’s dermatology in general medicine, 8rd ed. New York (NY): McGraw-Hill; 2012. http://accessmedicine.mhmedical.com.libproxy.uthscsa.edu/content.aspx?bookid=392&Sectionid=41138958 [accessed 06.02.16]. 1 03. Collins L, Knackstedt T, Samie F. Antiseptic use in Mohs and reconstructive surgery: an American College of Mohs Surgery member survey. Dermatol Surg 2015;41(1):164–6. 1 04. Wilson S. Microbial sealing: a new approach to reducing contamination. J Hosp Infect 2008;70(S2):11–4. 1 05. Towfigh S, Cheadle W, Lowry S, et al. Significant reduction in incidence of wound contamination by skin flora through use of microbial sealant. Arch Surg 2008;143(9):885–91; discussion 891. 1 06. McDonnell G, Russell AD. Antiseptics and disinfectants: activity, action, and resistance. Clin Microbiol Rev 1999; 12(1):147–79. 1 07. Rhinehart B, Murphy M, Farley M, et al. Sterile versus nonsterile gloves during Mohs micrographic surgery: infection rate is not affected. Dermatol Surg 2006;32(2):170–6. 1 08. Xia Y, Cho S, Greenway H, et al. Infection rates of wound repairs during Mohs micrographic surgery using sterile versus nonsterile gloves: a prospective randomized pilot study. Dermatol Surg 2011;37(5):651–6. 1 09. Rogues A, Lasheras A, Amici J, et al. Infection control practices and infectious complications in dermatologic surgery. J Hosp Infect 2007;65(3):258–63. 1 10. Houseman N, Taylor I, Pan W. The angiosomes of the head and neck: anatomic study and clinical application. Plast Reconstruct Surg 2000;105(7):2287–313.

Chapter 115: Surgical Complications 1 11. Kaur R, Glick J, Siegel D. Achieving hemostasis in dermatology—Part II: topical hemostatic agents. Indian Dermatol Online J 2013;4(3):172–6. 1 12. Macpherson N, Lee S. Effect of different suture techniques on tension dispersion in cutaneous wounds: a pilot study. Australas J Dermatol 2010;51(4):263–7. 1 13. Yang D, Venkatarajan S, Orengo I. Closure pearls for defects under tension. Dermatol Surg 2010;36(10):1598–600. 1 14. Lam A, Nguyen Q, Tahery D, et al. Decrease in skin-closing tension intraoperatively with suture tension adjustment reel, balloon expansion, and undermining. J Dermatol Surg Oncol 1994;20(6):368–71. 1 15. Carruthers A. Tissue expansion and Mohs micrographic surgery. J Dermatol Surg Oncol 1993;19(12):1106–9. 1 16. Salasche S. Acute surgical complications: cause, prevention, and treatment. J Am Acad Dermatol 1986;15(6): 1163–85. 1 17. Clayton A, Stasko T. Chapter 151. Surgical complications and optimizing outcomes. In: Bolognia JL, Jorizzo JL, Schaffer JV, editors. Dermatology, 3rd ed. Philedelphia: Elsevier Sanders 2012. https://www-clinicalkey-com.libproxy.uthscsa.edu/ #!/content/book/3-s2.0-B9780723435716001512. 1 18. Johnson T, Ratner D, Neson B. Soft tissue reconstruction with skin grafting. J Am Acad Dermatol 1992;27(2 Pt 1):151–65. 1 19. Christensen KN, Macfarlane DF, Pawlina W, et al. (2016), A conceptual framework for navigating the superficial territories of the face: Relevant anatomic points for the dermatologic surgeon. Clin Anat, 29:237–246. doi:10.1002/ ca.22673

1 20. Brown S, Oliphant T, Langtry J. Motor nerves of the head and neck that are susceptible to damage during dermatological surgery. Clin Exp Dermatol 2014;39(6):677–82; quiz 681–2. 1 21. Roostaeian J, Rohrich R, Stuzin J. Anatomical considerations to prevent facial nerve injury. Plast Reconstr Surg 2015;135(5):1318–27. 1 22. Linos E, Wehner M, Frosch D, et al. Patient-reported problems after office procedures. JAMA Intern Med 2013; 173(13):1249–50. 1 23. Mailler-Savage E, Neal K, Godsey T, et al. Is levofloxacin necessary to prevent postoperative infections of auricular second-intention wounds? Dermatol Surg 2008;34(1): 26–30. Discussion 30–1. 1 24. Koranda F, Webster R. Trapdoor effect in nasolabial flaps: causes and corrections. Arch Otolaryngol 1985;111(7): 421–4. 1 25. Garg S, Dahiya N, Gupta S. Surgical scar revision: an overview. J Cutan Aesthet Surg 2014;7(1):3–13. 1 26. Gauglitz GG, Korting HC, Pavicic T, et al. Hypertrophic scarring and keloids: pathomechanisms and current and emerging treatment strategies. Mol Med 2011;17(1–2): 113–25. 1 27. Monstrey S, Middelkoop E, Vranckx J, et al. Updated scar management practical guidelines: non-invasive and invasive measures. J Plast Reconstr Aesthet Surg 2014;67(8): 1017–25. 1 28. Pérez-Bustillo A, González-Sixto B, Rodríguez-Prieto M. Surgical principles for achieving a functional and cosmetically acceptable scar. Actas Dermosifiliogr 2013;104(1): 17–28.

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Physical Modalities of Therapy

Chapter

116

Phototherapy N Raboobee

INTRODUCTION The term phototherapy refers to a treatment modality consisting of exposure to specific wavelengths of light. Three ranges of radiation are relevant: infrared (800–3000 nm), visible (400–800 nm), and ultraviolet (100–400 nm). Infrared radiation is used mainly in physiotherapy. Visible radiation is used for photodynamic therapy. Ultraviolet radiation, encompassing wavelengths of UVB (280–320 nm) and UVA (320–400 nm),1 is used for the treatment of various skin diseases (Table 116.1). Phototherapy is used to treat a variety of inflammatory skin conditions by the administration of increasing increments of ultraviolet light to the skin in a controlled manner.2 The choice of UV light depends on the patient’s age, the disease being treated, the patient’s skin type, and the previous treatments and current medications.

PROVISION OF PHOTOTHERAPY SERVICES In the provision of phototherapy services, several factors need to be taken into account, including adequate space for the devices offered, attention to electrical supply, a layout that allows for a free flow of patients to the phototherapy facilities, space for waiting and changing, and appropriate training of staff responsible for administering phototherapy.3 Record keeping must be accurate and easily accessible and, at a minimum, should include dose administered

Table 116.1: Therapeutic uses of light in dermatology. Radiation Wavelength (nm) Characteristics or uses UVC 100–290 Absorbed by ozone layer UVB UVA Visible light

290–320 320–400 400–800

Phototherapy PUVA Photodynamic therapy

at each treatment, the response to treatment, any adverse effects encountered and the action taken. Arrangements for lamp replacement, calibration, and general maintenance of the device should be discussed with the supplier at the time of purchase of the device. In general, a phototherapy facility will offer PUVA, narrow-band UVB (NBUVB), hand and foot phototherapy and when possible, excimer laser. UVA1 is currently only offered in selected centers due to its high cost (Figs. 116.1 to 116.3). Informed consent should be obtained from all patients. The consent form should explain the expected benefits, risks, and adverse effects. In particular, mention should be made of possible nausea from psoralen tablets, the possibility of sunburn, need for protection of the eyes (in the case of PUVA, for 24 hours after treatment) and the genitalia during treatment, and the possibility of a flare of herpes simplex in susceptible subjects. The risk of skin cancer, especially with PUVA should be mentioned.4

PHOTOTHERAPY UNITS Commercial units are available with TL-01 lamps (NB-UVB), UVA lamps or a combination of both. Shorter lamps are available for treatment of smaller areas such as the hands and feet.

Home Phototherapy Home phototherapy is a suitable treatment of many patients for whom office-based phototherapy is not accessible. Treatment schedules vary based on skin type. Assistance is usually provided by suppliers of homecare devices to help patients overcome financial obstacles.5 A study of 196 patients with psoriasis showed that UVB phototherapy administered at home is equally safe and effective as UVB phototherapy administered in an outpatient setting. Homecare has also resulted in a lower burden of treatment and led to greater patient satisfaction (Figs. 116.4A and B).6

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Fig. 116.1: Example of a surround-body 48 lamp phototherapy unit from Daavlin. Such units can be fitted with UVA, UVB, or a combination of both lamps.

Fig. 116.3: A UV full-length panel unit allowing for treatment of the front half of the body and then the back.

A Fig. 116.2: Surround-body UV cabinet from National Biological.

Targeted Phototherapy Targeted phototherapy refers to delivery of ultraviolet radiation directly to a skin lesion via a special delivery mechanism, in contrast to conventional phototherapy, which exposes the whole body in a cabinet or parts of the body using machines designed for specific areas, i.e. for treatment of the hands and feet. The most common targeted phototherapy devices are characterized as 308-nm excimer laser, 308-nm excimer non-laser (excimer lamp or excimer light), and nonexcimer light.7,8 The term “excimer” stands for excited dimer, composed of a noble gas and halide, which repel each other.

B Figs. 116.4A and B: Depigmentation with temporary postinflammatory hyperpigmentation of vitiligo within 2 months of homecare phototherapy.

Chapter 116: Phototherapy Targeted phototherapy has the advantages of a lower risk of side effects, avoidance of exposure of unnecessary sites, faster response, shorter frequency, and duration of treatment.9 Disadvantages of targeted therapy include the cost of treatment, which is much higher than conventional phototherapy because of the cost of the devices used, and that only small areas can be treated. Comparison of the excimer laser and excimer lamp shows similar efficacy in treating vitiligo.10,11 With the same fluence, the lamp induces more erythema, which suggests photobiological differences between the two devices (Figs. 116.5 and 116.6).

PUVA PUVA (Psoralen and UVA) is a combination treatment in which radiation of appropriate wavelength (UVA, 320 nm) is used to induce a therapeutic response in the presence of a photosensitizing drug (psoralen). The psoralen makes the skin more sensitive to the ultraviolet light. Two types of reaction cause photosensitivity after PUVA. The first is an anoxic reaction that affects DNA with the formation of photo adducts that may inhibit the proliferation of epidermal cells and induce apoptosis. The second is an oxygen-dependent reaction that gives rise to free radicals and reactive oxygen species that may damage the cellular membrane by lipid peroxidation.12 In vitiligo, a stimulatory effect on melanocytes secondary to action on c-AMP is postulated.

Administration

Fig. 116.5: The Pharos excimer laser showing the XeCl gas canister inside the device.

Fig. 116.6: An excimer light device from German Medical Engineering.

Psoralen may be administered orally, topically, or diluted in bath water. When administered orally, the patient is exposed to UV light typically after 2 hours. The dose of oral psoralen is 0.6 mg/kg body weight. The initial dose of UV light is determined by skin type or phototoxicity testing. If phototoxicity testing is used, the minimum phototoxic dose (MPD) is the initial dose. MPD is defined as the minimum dose of UVA that produces a barely perceptible erythema. The UVA dose is then increased with each treatment. Treatment is usually administered three times a week and continued until the patient goes in to remission. Maintenance treatment is required in some patients. This is usually administered once a week at the last dose tolerated by the patient. If topical psoralen is used, absorption into the epidermis is rapid and exposure to UVA may occur after 10 minutes. Variations of topical PUVA include bath PUVA, bathing suit PUVA and soak PUVA.13 Bath PUVA using diluted psoralen produces low systemic psoralen levels. A bathtub is filled with 100 L of water. A volume of 37.5 mL of 1% 8-methoxypsoralen is added to obtain a concentration of 3.75 mg/L. The whole body is immersed in the water for 20 minutes. After lightly drying the skin, the patient is exposed to UVA light. Bath PUVA has been used successfully in psoriasis, scleroderma, mycosis fungoides, urticaria pigmentosa, lichen planus, and prurigo nodularis. Bathing suit PUVA utilizes a stitched flannel material that is soaked in 2 L of water to which 1 mL of 8-methoxypsoralen has been added, to obtain a concentration of 3.75 mg/L. The patient wears the bathing suit for 15

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Section 32: Physical Modalities of Therapy minutes, covered with a raincoat to prevent evaporation. UVA is administered immediately after. Soak PUVA is used mainly for the hands and feet. The affected areas are soaked in a basin in a 3.75 mg/L solution for 20 minutes. After another 30 minutes, the treatment area is exposed to UVA light. In so-called “turban PUVA”, an absorbent cloth is soaked for 30 seconds in a 3.75 mg/L solution of 8-methoxypsoralen, gently squeezed to remove excess water, and wrapped around the head for 5 minutes. This is repeated four times to provide a total contact time of 20 minutes. The area is then exposed to UVA. Turban PUVA is used mainly for alopecia areata.

Indications Indications for PUVA therapy include psoriasis, vitiligo, atopic dermatitis, lichen planus, cutaneous T-cell lymphoma, morphea, graft-versus-host disease, dermatitis herpetiformis, histiocytosis X, solar urticaria, chronic actinic dermatitis, polymorphic light eruption, prurigo nodularis, palmoplantar pustulosis, eosinophilic dermatosis, pruritic eruptions of HIV, granuloma annulare, necrobiosis lipoidica, pityriasis lichenoides, atopic dermatitis, pruritus of polycythemia vera, urticarial pigmentosa and alopecia areata.14

A

Psoriasis PUVA has similar efficacy to NB UVB for psoriasis; however, NBUVB is now the preferred option for psoriasis in view of the exposure-related risk of skin cancer associated with PUVA. PUVA may be used instead of UVB if UVB is ineffective or if the duration of remission following UVB is short. Today, PUVA is typically reserved for older patients and those with very thick and scaly plaques (Figs. 116.7 and 116.8).

Vitiligo PUVA has been used widely for recalcitrant vitiligo in adults, although it has been surpassed by NB-UVB.15 Patients are treated as if they are Fitzpatrick skin type I. The therapeutic objective is to maintain minimal light pink erythema in patches of depigmented skin. Approximately 100–200 exposures are required to produce maximal repigmentation and about 70% of patients respond (Figs. 116.9A and B).

Atopic dermatitis The dose and frequency for eczema is similar to that of psoriasis. As for psoriasis, NB-UVB is now the preferred option for atopic dermatitis (Figs. 116.10A and B).

B Figs. 116.7A and B: Psoriasis treated with 21 sessions of PUVA.

Mycosis fungoides NB-UVB is effective for patch stage mycosis fungoides but when lesions are palpably thickened, PUVA is more effective.

Polymorphic light eruption Narrow-band UVB is as effective as PUVA for the treatment of polymorphic light eruption. However, if polymorphic light eruption is provoked by UVB, PUVA may be a better option.

Chapter 116: Phototherapy

A A

B Figs. 116.9A and B: Vitiligo before and after treatment with PUVA.

B Figs. 116.8A and B: Psoriasis showing complete resolution with PUVA treatment.

Contraindications and Adverse Effects Contraindications for PUVA therapy include pregnancy, lactation, xeroderma pigmentosum, systemic lupus erythematosus, and a personal or family history of melanoma. Actue side effects include nausea, blistering, and erythema. Side effects of psoralen include nausea, pruritus, dizziness, headache, eye discomfort, and gastrointestinal symptoms. Long-term PUVA therapy can lead to solar elastosis, solar lentigenes, solar keratosis, and skin cancer, especially

Fig. 116.10A: Chronic eczema of the feet before treatment.

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Section 32: Physical Modalities of Therapy (NB-UVB). Although the mechanism of action of NB-UVB is not fully understood, NB-UVB radiation is absorbed by DNA and urocanic acid in the skin and alters antigen presenting cell activity. In psoriatic skin, NB-UVB lowers peripheral natural killer cell activity, lymphocyte proli­ feration, and immune regulatory cytokine production by Th1 and Th2 cell populations. In vitiligo, NB-UVB works by halting the depigmenting process and stimulating residual follicular melanocytes.20

Administration

Fig. 116.10B: Chronic eczema of the feet following successful treatment with PUVA.

squamous cell carcinoma, which may develop even with low exposures and increase linearly with the number of sessions. Tumors may occur in non-exposed skin and the risk persists even after cessation of treatment.16 An increased risk of basal cell carcinomas was observed in patients who received more than one hundred PUVA sessions.16 Skin cancers develop as a result of DNA damage and down regulation of immune responses. Risk factors for skin cancer include high dose PUVA (>160 treatments or a cumulative dose of 1000 j/cm2), history of exposure to ionizing radiation, history of severe sun damage, arsenic ingestion, other skin cancers and genetic defects (e.g. xeroderma pigmentosum). The risk of skin cancer associated with PUVA tends to be lower in patients with vitiligo compared to patients with psoriasis. This may be explained by the fact that tumor suppressor functional wild-type p53 protein expression is greater in patients with vitiligo compared to healthy controls and this protein plays a role in reducing the risk of skin cancers. Studies in the US have found an increased risk of both invasive and in-situ melanoma in patients who received more than 200 PUVA sessions.16 This risk increases approximately 15 years after the first treatment with PUVA.17 However, a Swedish study involving 4799 patients found no increased risk for malignant melanoma.18 In one study, the incidence of invasive scrotal or penile squamous cell carcinoma was reported to be 53-fold higher than in the general population.19

Narrow-band UVB The narrow spectrum of emission in the range of 310–315 nm, with a peak at 312 nm, is known as narrow-band UVB

Treatment is administered based on an individual’s minimal erythema dose (MED) or a starting dose based on the patient’s skin type. In the first regimen, the MED test is performed to identify an individual’s sensitivity to NB-UVB and ensure that the patient receives a starting dose of treatment suitable for his/her individual skin. MED is the threshold amount of UV radiation that produces the minimal erythema (sunburn or redness) within a few hours following exposure.21 MED may be determined using templates with holes. Each hole is irradiated with a different dose, increasing incrementally. An all-in-one device is also available, containing both a UV source and a template, that delivers 10 graded irradiances in a single exposure, employing graded openings in a metal foil. The first dose is often administered at 70% of the MED value, then increasing by 10% to 40% increments three times a week. The second regimen uses a starting dose based on skin type and increases in a stepwise (usually by around 20%) fashion depending on the patient’s erythema response. The dose is held constant once mild erythema develops. Should painful erythema develop, treatment is withheld until resolution of the symptoms, then recommenced at 50% of the last dose, with subsequent increases at 10% increments.

Indications NB-UVB is used for vitiligo, psoriasis, atopic dermatitis, mycosis fungoides, lichen planus, pityriasis rosea, pruritus, seborrheic dermatitis, pityriasis rubra pilaris, scleroderma, polymorphic light eruption, actinic prurigo and hydroa vacciniforme.22

Vitiligo The successful use of NB-UVB for vitiligo was first reported in 1997 by Westerhof and Nieuweboer-Krobotova.23 In 2007, Yones et al. demonstrated the superior efficacy of NB-UVB over oral PUVA in a randomized, double blind trial evaluating 50 patients with non-segmental

Chapter 116: Phototherapy vitiligo. Sixty-four percent of patients in the NB-UVB group had 50% or more improvement compared with 36% in the PUVA group. Also, the reduction of the depigmented surface area was significantly greater in the NB-UVB group. The color match was excellent in all patients receiving NB-UVB compared to only 44% receiving PUVA. The superiority of NB-UVB was maintained 12 months after the cessation of therapy.24 The superiority of NB-UVB compared to PUVA was confirmed in a meta-analysis of the literature where the mean success rate achieved with NBUVB was found to be 63% compared to 51% in those receiving PUVA. PUVA was also associated with a higher rate of side effects.25 In an open prospective study of 50 patients with vitiligo, there was a 67% repigmentation rate with NB-UVB and 54% with PUVA.26 NB-UVB has been shown to be effective and safe in childhood vitiligo in a study of 51 children. Treatment was administered twice weekly for a maximum of 1 year. The results indicated more than 75% overall repigmentation in 53% of patients and stabilization of the disease in 80%.27 Combination therapy with topical corticosteroids and NB-UVB is safe and effective. Studies combining NB-UVB with topical calcineurin inhibitors generally show better improvement and repigmentation compared to monotherapy.28,29 NB-UVB is now considered to be the most effective and safest therapy for generalized vitiligo (Figs. 116.11A and B).30 Assessing the MED for vitiligo is difficult due to limited involved skin. Depigmented skin, however, is similar to Type I skin, for which the average MED is 400. Most protocols in use recommend basing the starting dose on this standard. The dose is increased at each visit by 5% to 20% of the previous dose but set dose increases are commonly used. Some protocols recommend maximum doses ranging from 500–3000 mJ/cm2. Unlike PUVA, there have been no reports of increased skin cancer risk with NB-UVB. There are currently no re­commendations for maximum number of treatments.31

Psoriasis Compared to broad band UVB, several clinical studies have reported a significantly greater improvement of psoriasis with NB-UVB, including a reduced incidence of burning, increased efficacy, longer remission, and possibly a lower risk of carcinogenesis. However, compared to PUVA, there was little difference in efficacy.32

Fig. 116.11A: Vitiligo on the legs prior to treatment with phototherapy.

Fig. 116.11B: Partial repigmentation of vitiligo occurred after 56 sessions of narrow band UVB administered over 1 year.

Psoriasis area and severity index 75 (PASI 75) scores after UVB and PUVA three times a week for up to 12 weeks are 70% and 80%, respectively. These outcomes are comparable or superior to biologics. Outcomes for traditional systemic agents are 30% (acitretin), 60% (methotrexate), and 70% (cyclosporine) (Figs. 116.12 and 116.13).33

Atopic dermatitis The effectiveness of NB-UVB in atopic dermatitis (AD) was demonstrated in 21 patients with severe AD. A 68%

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Fig. 116.13A: Psoriasis on a patient’s thighs and legs prior to treatment with phototherapy. Fig. 116.12A: Psoriasis on a patient’s abdomen before treatment with phototherapy.

Fig. 116.13B: Complete resolution occurred after 21 sessions of ­narrowband UVB.

Fig. 116.12B: Marked improvement occurred after 21 sessions of narrow-band UVB.

reduction in the clinical AD severity score was achieved after 12  weeks of treatment three times a week (Figs. 116.14A and B).34

Other dermatoses NB-UVB may be used as prophylaxis in photosensitive disorders such as polymorphic light eruption, actinic prurigo, hydroa vacciniforme, and the cutaneous porphyrias. In such conditions, 10 to 15 treatments are typically given in the early spring.

Contraindications and Adverse Effects Narrow-band UVB is a safe in children, pregnant women, and lactating mothers and has minimal side effects, including xerosis, pruritus, skin aging, and tanning. The risk of skin cancer is minimal even with multiple treatments although there is a risk of phototoxicity when treating depigmented skin.35

Excimer Laser The excimer laser is a type of targeted phototherapy, which delivers 308 nm of ultraviolet radiation directly to the skin lesions.

Chapter 116: Phototherapy

Fig. 116.14A: Atopic dermatitis on a patient’s trunk and upper extremities before treatment with phototherapy.

Fig. 116.14B: Marked improvement occurred after 21 sessions of n ­ arrowband UVB administered three times a week for 7 weeks.

Fig. 116.15A: Psoriasis on the patient’s posterior neck.

Fig. 116.15B: Psoriasis resolved after six sessions of excimer laser, 1000–1200 mJ/cm2.

Psoriasis

Vitiligo

The excimer laser has been shown to be efficacious in the management of psoriasis vulgaris, scalp, and palmoplantar psoriasis, and in childhood psoriasis. The efficacy of the 308-nm excimer laser appears to be enhanced when combined with topical therapies.31 Psoriasis has been noted to improve even after a single session of treatment.36 There is no consensus excimer laser protocol; however, the initial treatment dose is usually determined by using the minimal erythema dose (MED). In various studies, the fluence ranges from 0.5 MED to 16 MED. Adjustments to fluence are frequently required to minimize side effects.37 The outcome of the 308-nm excimer lamp has been shown to be similar to that of the 308-nm excimer laser (Figs. 116.15A and B).29

The excimer laser is the treatment of choice for localized vitiligo. Its efficacy can be increased when combined with topical corticosteroids, pimecrolimus, or tacrolimus. The best response is noticed on UV sensitive areas such as the face and neck. It has the advantage of treating small, non-accessible, or resistant areas when compared to other forms of non-targeted phototherapy. Excimer laser treatments show a faster onset of repigmentation and needs fewer treatments compared to traditional phototherapy. The light is monochromatic, penetrates deeper into the skin, and allows for the delivery of higher fluences to the treated areas while sparing noninvolved skin. Better results are achieved if the treated areas are of short duration. Frequent sessions are more beneficial than less frequent ones.38

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Fig. 116.16A: A young boy with vitiligo affecting the angle of the mouth prior to treatment.

Fig. 116.17A: Vitiligo of the eyelids before treatment.

Fig. 116.16B: Repigmentation occurred after 10 sessions of excimer laser combined with needling.

Fig.116.17B: Repigmentation occurred after five sessions of excimer laser.

Seven studies with 390 patients with vitiligo revealed no significant differences between 308-nm excimer laser and 308-nm excimer lamp on either >75% or >50% repigmentation rate.29 Excimer laser or light may be used in children with vitiligo (Figs. 116.16 and 116.17).

most prominent effect is seen on the scalp (Figs. 116.19A and B).40

Atopic Dermatitis The 308-nm excimer laser is beneficial in localized atopic dermatitis both in adults and children. It is more effective than clobetasol in controlling prurigo related to atopic dermatitis (Figs. 116.18A and B).39

Lichen Planus Significant resolution of erosive lichen planus has been achieved with the excimer laser.41

Pityriasis Alba Profound improvement was reported in pityriasis alba treated with the excimer laser. No significant side effects were demonstrated.42

Alopecia Areata

Mycosis Fungoides

Both the excimer laser and the lamp are effective in promoting regrowth of hair in children and in adults. The

Using the 308-nm excimer laser in stage IA and IIA mycosis fungoides (MF) was beneficial clinically and pathologically

Chapter 116: Phototherapy

Fig. 116.18A: A patient with atopic dermatitis presented with dermatitis of the nipple and areola.

Fig. 116.19A: A patch of alopecia areata prior to treatment.

Fig. 116.18B: After three sessions of excimer laser, the rash resolved.

Fig. 116.19B: Complete regrowth was experienced after three sessions of excimer laser. No intralesional or topical corticosteroids were administered.

for patients with isolated lesions or lesions in areas that are difficult to treat due to anatomic location. In a retrospective study of six patients with MF, the 308-nm excimer laser was found to be safe and well-tolerated. Three patients had complete response, one partial response, one had stable disease, and one had progressive disease.43 Monochromatic excimer light (308 nm) has also been reported to be of benefit in stage IA patch stage MF. Seven lesions in four patients with patch stage I MF achieved clinical and histologic complete remission and remained in remission after 3 to 28 months (Figs. 116.20A and B).44

UVA1 UVA1 is a relatively recently introduced mode of phototherapy associated with the use of a narrow band of

UVA: 340–400 nm. Although the first devices capable of emitting UVA1 were constructed in 1981, the first published reports on its beneficial effects did not appear until 1992.1 The mode of action of UVA1 radiation is based on the induction of apoptosis by active oxygen molecules such as singlet oxygen, hydrogen peroxide, and superoxide radicals. UVA1 activates programmed and non-programmed cell death, which increases phototherapy effectiveness when compared to PUVA, which causes only programmed apoptosis. Unlike UVB, which has a superficial action affecting mostly keratinocytes and Langerhans cells, UVA1 penetrates deeper into the reticular dermis, influencing fibroblasts, dendritic, and infiltrating inflammatory cells,

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Section 32: Physical Modalities of Therapy medium (50–60 J/cm2), or high (130–150 J/cm2). The dose and the exposure time depend on skin phototype. The patient’s individual sensitivity to light has to be established by determining the minimal tanning dose (MTD), which is the dose that induces a minimal perceptible pigmentation.

Indications UVA1 is to treat four types of skin disease: those with T-lymphocyte or mast cell infiltrates, connective tissue diseases, and dermatoses in patients with HIV infection.

Atopic dermatitis Fig. 116.20A: Mycosis fungoides prior to treatment.

Atopic dermatitis is characterized by infiltrates of CD4 T lymphocytes. High-dose UVA1 (130 J/cm2) produced beneficial results when administered five times a week for 3 weeks.45 Subsequent research revealed that UVA1 was more effective in the treatment of atopic dermatitis than topical used corticosteroids or UVB/UVA irradiation.46 Medium dose UVA1 has also been shown to be of benefit in atopic dermatitis. Low dose UVA1 is not recommenced as the therapeutic effect is comparable to other conventional methods of phototherapy (wide-band UVA, broadband UVB, or NB-UVB).47 UVA1 is recommended even at times of clinical exacerbations, unlike other ranges of radiation.

Scleroderma

Fig. 116.20B: The postinflammatory hyperpigmentation resolved completely in a few months.

particularly CD4 T lymphocytes, as well as mastocytes and granulocytes. UVA1 affects the endothelium of skin blood vessels and has an impact on the extracellular matrix by activating fibroblasts to increase the production of metalloproteinases, which is a mechanism that is used to treat sclerosing skin conditions. UVA1 signifies a great advancement in the therapy of patients with severe skin disease, in whom conventional treatment has not been effective. The effectiveness of UVA1 therapy will be further elucidated as randomized studies and studies with large sample sizes become available.

Administration UVA1 is performed five times a week, usually for 3–4 weeks. Three UVA1 doses are commonly used: low (10–20 J/cm2),

The pathogenesis of scleroderma involves immunemediated fibrosis of the skin due to impairment of skin fibroblast function, resulting in elevated type I and III collagen synthesis with reduced collagenase I expression. The mechanism of action of UVA1 in scleroderma is the increase in mRNA expression of matrix metalloproteinases (MMPs) and reduction in inflammatory infiltrate by inducing CD4 T lymphocyte apoptosis. There is also a decrease in mRNA expression of proinflammatory cytokines. High-dose UVA was used for the first time in 1997.48 Studies comparing high-dose and low-dose UVA1 demonstrated a greater reduction in tension and sclerosing skin lesions and an increase in skin elasticity with high-dose treatment. Low-dose UVA1 has been shown to be of benefit when combined with topical calcipotriol.49 Subsequent reports have also revealed a beneficial therapeutic effect of medium doses (60 J/cm2). A benefit of treatment with UVA1 is the shorter time to achieve clinical improvement as 30 irradiations performed during 6 weeks is comparable to 50 PUVA treatments over 6 months.

Chapter 116: Phototherapy

Cutaneous T-cell lymphoma Cutaneous T-cell lymphoma (CTCL) is a neoplasm characterized by proliferation of Th2 helper T-cells. UVA1 induces apoptosis in these cells. Both high and medium dose UVA1 have been shown to be effective in treating CTCL, often as early as after five exposures, and full recovery was achieved after 16–20 treatments irrespective of the dose used.50 UVA1 was found to be effective even in erythrodermic CTCL.51

Graft-versus-host disease Graft-versus-host disease (GVHD) is a complication seen in patients who receive allogeneic grafts of bone marrow or other organs, and transfusion of blood and its products containing immunocompetent lymphocytes. The T-lymphocytes in the transplanted tissues proliferate and contribute to the destruction of the host’s organs and tissues, mostly the skin. Scleroderma-like lesions are characteristic of GVHD. UVA1 is therefore a promising treatment.

Lupus erythematosus UVA1 has been controversial for the treatment of lupus erythematosus in view of the fact that the majority of patients are hypersensitive to UV radiation. However, clinical evidence seems to indicate a beneficial role for UVA1 in this disease owing to its deep penetration inside the blood vessels and tissues and the lowering of T and B lymphocyte activity through apoptosis. The possibility of reducing systemic medication doses and a lowering of anti-dsDNA antibody titers were seen after 3 weeks of low-dose UVA1 therapy.52

Lichen sclerosus Lichen sclerosus is characterized by fibrosis of the connective tissue in the skin. There are infiltrate of T-lymphocytes which produce cytokines that increase fibrosis (i.e. IL-4, IL-6, and TGF1). There is a higher expression of type IV and VII collagen, changes in type I and II collagen, and a reduction in elastic fibers in the involved skin. Low-dose UVA1 has resulted in softening of the skin of patients with disseminated lesions but lower effectiveness was noted in genital area.31

Cutaneous mastocytosis All three dosage schedules of UVA1 have been found to be effective in treating mastocytosis, on the basis of the induction of mast cell apoptosis. Improvement is manifested by regression of skin lesions, disappearance of diarrhea and migraine headaches, and normalization of histamine in 24-hour urine collection and serum serotonin levels.

Long-term clinical remission has been reported. Pruritus appears to respond dramatically, with improvement noted after as few as three irradiations.31

UVA1 in patients with HIV infection UVA1 treatment in patients with HIV infection has been associated with a complete regression of desquamating papules and plaques refractory to conventional methods of treatment and is considered to be the treatment of choice in such patients.30

Other Indications A beneficial therapeutic effect of UVA1 has been observed in hypertrophic scars and keloids53 dyshidrotic eczema and prurigo nodularis.54

Contraindications and Adverse Effects Side effects of UVA1 include erythema, hyperpigmentation, and pruritus. Rarely, symptoms of polymorphic light eruption and herpes simples may occur.

Extracorporeal Photopheresis Extracorporeal photopheresis (ECP), also known as extracorporeal photochemotherapy, extracorporeal photoimmunotherapy, or just photopheresis, is a variant of PUVA in which irradiation of selective blood fractions is done outside the human body in the presence of psoralens. The first study of ECP was completed in 1983 and approved by the US FDA for the treatment of advanced cutaneous T-cell lymphoma (CTCL) in 1988.55 The process combines leukopheresis with oral administration of 8– MOP or injection of a liquid formulation 8–MOP into the leukocyte rich fraction of blood, followed by selective irradiation of the leukocyte fraction and reinfusion into the body. The latter technique eliminated the systemic effects of psoralen including nausea, vomiting, GI, and ocular side effects. ECP has been found to be effective in several cutaneous disorders such as atopic dermatitis, CTCL, bullous pemphigoid, GVHD, epidermolysis bullosa aquisita, morphea, erosive oral lichen planus, pemphigus, psoriasis, scleroderma, SLE, systemic sclerosis, dermatomyositis, rheumatoid arthritis, chronic HCV infection, multiple sclerosis , nephrogenic fibrosing dermopathy, scleromyxedema, Crohn’s disease, leukemias, and lymphomas. ECP is well tolerated with an excellent safety profile and not associated with an increased incidence of

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Section 32: Physical Modalities of Therapy infections, unlike other immunosuppressives. ECP may be used in children and recent technical developments have subs­tantially reduced treatment times.

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and ultraviolet A radiation (PUVA). The PUVA follow-up study. N Engl J Med 1997;336(15):1041. Lindelöf B1, Sigurgeirsson B, Tegner E, et al. PUVA and cancer risk: the Swedish follow-up study. Br J Dermatol 1999;141(1):108–12. Stern RS, Bagheri S, Nichols K. PUVA Follow Up Study. The persistent risk of genital tumors among men treated with psoralen plus ultraviolet A (PUVA) for psoriasis. J Am Acad Dermatol 2002;47:33-9. Cui J, Shen LY, Wang GC. Role of hair follicles in the repigmentation of vitiligo. J Invest Dermatol 1991;97:410–6. Heckman CJ, Chandler R, Kloss JD, et al. Minimal erythema dose (MED) testing. J Vis Exp 2013;(75):50175. Dogra S, Kanwar AJ. Narrow band UVB phototherapy in dermatology. Indian J Dermatol Venereol Leprol 2004;70: 205–9. Westerhof W, Nieuweboer-Krobotova L. Treatment of viti­ ligo with UV-B radiation vs topical psoralen plus UV-A. Arch Dermatol 1997;133:1525. Yones SS, Palmer RA, Garibaldinos TM, et al. Randomized double-blind trial of treatment of vitiligo: efficacy of psoralen-UV-A therapy vs narrowband-UV-B therapy. Arch Dermatol 2007;143:578. Njoo MD, Spuls PI, Bos JD, et al. Nonsurgical repigmentation therapies in vitiligo: meta-analysis of the literature. Arch Dermatol 1998;134:1532–40. Bhatnagar A1, Kanwar AJ, Parsad D, et al. Comparison of systemic PUVA and NB-UVB in the treatment of vitiligo: an open prospective study. J Eur Acad Dermatol Venereol 2007;21(5):638–42. Njoo MD, Bos JD, Westerhof W. Treatment of generalized vitiligo in children with narrow-band (TL-01) UVB radiation therapy. J Am Acad Dermatol 2000;42:245–53. Esfandiarpour I, Ekhlasi A, Farajzadeh S, et al. The efficacy of pimecrolimus 1% cream plus narrow-band ultraviolet B in the treatment of vitiligo: a double-blind, placebocontrolled clinical trial. J Dermatolog Treat 2009;20(1): 14-8. Majid I. Does topical tacrolimus ointment enhance the efficacy of narrowband ultraviolet B therapy in vitiligo? A leftright comparison study. Photodermatol Photoimmunonol Photomed 2010;26:230. Njoo MD, Westerhof W, Bos JD, et al. The development of guidelines for the treatment of vitiligo. Arch Dermatol 1999;135:1514–21. Dogra S, Kanwar AJ. Narrow band UVB phototherapy in dermatology. Indian J Dermatol Venereol Leprol 2004;70:205–9. Van Welden H, Baart de la Faille H, Young E, et al. A new development in UVB phototherapy for psoriasis. Br J Dermatol 1988;119:11–9. Lim HW, Silpa-archa N, Amadi U, et al. Phototherapy in dermatology: a call for action. J Am Acad Dermatol 2015; 72:1078–80. George SA, Bilsland DJ, Johnson BE, et al. Narrow-band (TL01) UVB air-conditioned phototherapy for chronic severe adult atopic dermatitis. Br J Dermatol 1993;128: 49–56. Jiun-Yit P, Robert PES. A comparison of NB-UVB and PUVA in the treatment of vitiligo, In: Park KK (ed).

Chapter 116: Phototherapy Vitiligo  — Management and Therapy. 2011. Available from: http://www.intechopen.com/books/vitiligo-manage ment-and-therapy/a-comparison-of-nb-uvb-and-puva-inthe-treatment-of-vitiligo 36. Asawanonda P, Anderson RR, Chang Y, et al. 308-nm excimer laser for the treatment of psoriasis: a dose response study. Arch Dermatol 2000;136:619–24. 37. Mudigonda T, Dabade TS, Feldman SR. A review of protocols for 308 nm excimer laser phototherapy in psoriasis. J Drugs Dermatol 2012;11(1):92–7. 38. Alhowaish AK, Dietrich N, Onder M. Effectiveness of a 308nm excimer laser in treatment of vitiligo: a review. Lasers Med Sci 2013;28(3):1035–41. 39. Baltás E, Csoma Z, Bodai L, et al. Treatment of atopic dermatitis with the xenon chloride excimer laser. J Eur Acad Dermatol Venereol 2006;20:657–60. 40. Al-Mutairi N. 308-nm excimer laser for the treatment of alopecia areata. Dermatol Surg 2007;33:1483–7. 41. Trehan M, Taylor CR. Low-dose excimer 308-nm laser for the treatment of oral lichen planus. Arch Dermatol 2004;140:415–20. 42. Al-Mutairi N, Hadad AA. Efficacy of 308-nm xenon chloride excimer laser in pityriasis alba. Dermatol Surg 2012;38:604–9. 43. Deaver D, Cauthen A, Cohen G, et al. Excimer laser in the treatment of mycosis fungoides. J Am Acad Dermatol 2014;70(6):1058–60. 44. Mori M, Campolmi P, Mavilia L, et al. Monochromatic excimer light (308 nm) in patch-stage IA mycosis fungoides. J Am Acad Dermatol 2004;50(6):943. 45. Krutmann J, Schopf E. High-dose UVA1 phototherapy: a novel and highly effective approach for the treatment

of acute exacerbation of atopic dermatitis. Acta Derm Venereol Suppl 1992;176:120–2. 46. Scheinfeld NS, Tutrone WD, Weinberg JM, et al. Phototherapy of atopic dermatitis. Clin Dermatol 2003;21:241–8. 47. Krutman J, Stege H, Morita A. Ultraviolet-A1 ­phototherapy: indications and mode of action. In: J Krutmann, H Honigsman, CA Almets, et al. (eds), Dermatological Phototherapy and Photodiagnostic Methods. Berlin, Heidelberg, New York, Leipzig: Springer-Verlag, 2009: 295–311. 48. Dave RS. Ultraviolet A1 phototherapy. Br J Dermatol 2003;148:626–37. 49. Breuckmann F, Gambichler T, Altmeyer P, et al. UVA/UVA1 phototherapy and PUVA photochemotherapy in connective tissue diseases and related disorders: a research-based review. BMC Dermatol 2004;4:11. 50. Plettenberg H, Stege H, Megahed M, et al. Ultraviolet A1 (340–400 nm) phototherapy for cutaneous T-cell lymphoma. J Am Acad Dermatol 1999;41:47–50. 51. Zane C, Leali C, Airò P, et al. “High-dose” UVA1 therapy of widespread plaque – type, nodular, and erythrodermic mycosis fungoides. J Am Acad Dermatol 2001;44:629–33. 52. McGrath H, Jr. Prospects for UVA1 therapy as a treatment modality in cutaneous and systemic LE. Lupus 1997;6:209–17. 53. Hannuksela-Svahn A, Grandol OJ, Thorstensen T, et al. UVA1 for treatment of keloids. Acta Derm Venereol 1999;79:490. 54. Gamblichler T, Hyun J, Sommer A, et al. Randomised controlled trial on photo (chemo) therapy of subacute prurigo. Clin Exp Dermatol 2006;31:348–53. 55. Knobler R, Berlin G, Calzavara-Pinton P, et al. Guidelines on the use of extracorporeal photopheresis. J Eur Acad Dermatol Venereol 2014;28(1):1–37.

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Photodynamic Therapy Ashwin Ganti, Gabrielle R Vinding, Annie Wang, John Strasswimmer, Thanh Nga Tran

INTRODUCTION Photodynamic therapy (PDT) combines a topical photosensitizer, a light source, and oxygen to induce controlled tissue damage for therapeutic purposes. The process was first documented in the early 1900s by a German medical student, Oscar Raab, who discovered that paramecia incubated with the dye acridine orange died when exposed to sunlight. Raab’s professor, Hermann von Tappeiner, subsequently demonstrated PDT’s therapeutic potential when he applied the xanthene dye eosin on a patient’s basal cell carcinoma and illuminated the lesion with light, resulting in regression of the tumor.1 These discoveries paved the way for the development of more precise photosensiti­zers and light sources that are utilized in dermatologic PDT treatments today. In current practice, PDT is a valuable non-invasive treatment modality that is FDAapproved for the management of certain superficial or large-field skin lesions.2 The following chapter begins with a discussion of the biochemistry of PDT and then highlights the latest dermatologic indications and protocol for PDT administration.

MECHANISM OF ACTION Biology of PDT PDT begins with the topical application of a photosensitizer to target cells. The principal photosensitizer in PDT is protoporphyrin IX (PpIX), the penultimate molecule in the heme synthesis pathway (Fig. 117.1). Typically, rates of PpIX production and elimination are tightly controlled such that intracellular PpIX does not build up. Thus, when exogenous photosensitizer accumulates in target tissue, PpIX concentrations increase, allowing for photodynamic targeting. Once photosensitizer has been delivered, the treatment area is exposed to light, thereby photochemically exciting the photosensitizer. Activation subsequently causes the production of various radical oxygen species, which oxidize vital cellular substrates and induce intracellular damage. This process results in cellular death in the targeted tissue.

Photosensitizers PpIX is generated intracellularly following topical application of prophotosensitizers, the most common of which are 5-aminolevulinic acid (ALA) and methyl aminolevulinate (MAL). In the United States, ALA is commercially available as a 20% solution of ALA in an alcohol-water-surfactant vehicle and has been approved for use with blue light in the treatment of non-hyperkeratotic actinic keratosis (AK). MAL, another commonly used prophotosensitizer, is the methyl ester of ALA; upon entry into the cell, MAL must be demethylated to ALA by intracellular esterases before it can enter the heme synthetic pathway (Fig. 117.1). MAL is available as a cream, indicated for the treatment of nonhypertrophic actinic keratoses of the face.

Light Sources Selection of a light source for photodynamic therapy depends on three factors: the wavelength, the desired depth of penetration, and the duration of irradiance. PpIX has absorption peaks are targeted by blue light (between 400–420 nm,) or red light (between 630–635 nm), both of which have been FDA-approved. In addition, natural sunlight will also produce a PDT reaction; however, this is less commonly used in typical treatment protocol. The depth of penetration of the light is determined by the wavelength. Blue fluorescent light (417 nm), provides only 1–2 mm of penetrations, whereas red light achieves 6 mm of penetration. This makes red light more suitable for the treatment of thicker and deeper skin lesions, including superficial BCCs and Bowen’s disease.3

Light Dosimetry Several variables require consideration when selecting an appropriate dosage of light, including the local concentration of photosensitizer, the availability of molecular oxygen, and the type of light source. Formal guidelines regarding dosimetry have yet to be established, so current dosimetry is based on the results of published studies. The fluence, defined as the total number of photons delivered during

Chapter 117: Photodynamic Therapy

Fig. 117.1: Heme synthesis pathway. The precursor molecule for the heme synthesis is amino acid glycine and succinyl~CoA enzyme. Glycine condenses with succinyl~CoA to form δ-amino levulinic acid (5-ALA). This reaction is catalyzed by ALA synthase and the rate-limiting step of this pathway. The dehydration of two molecules of ALA forms porphobilinogen by the enzyme ALA dehydratase. Subsequent reactions lead to the formation of protoporphyrin-IX (PpIX) and heme molecule. Methyl aminolevulinate (MAL) can also be converted to 5-ALA via intracellular esterases.

a treatment, for AK treatment is 10 J/cm2 for blue light and 75 J/cm2 for red light. In addition, oxygen depletion becomes a concern at irradiance rates above 50 mW/cm2, so treatments should seek to limit irradiance. This can be achieved either by increasing exposure time or by interspersing the treatment session with short breaks.4 It is for this reason that pulsed laser sources, such as the pulseddye laser (PDL), have not been demonstrated to be an appropriate light source.5

INDICATIONS FOR PDT IN DERMATOLOGY Neoplastic Lesions PDT is used for the treatment of mild to moderate AK, squamous cell carcinoma in  situ (SCCis or Bowen’s disease), and superficial and low-risk nodular basal cell carcinomas (BCCs).6–8

Actinic Keratosis AK require careful management because of their potential to transform into SCC.9 Several studies have

demonstrated the efficiency of both MAL and ALAPDT in treating AKs. Clearance rate of 89–92% has been reported for thin and moderate thickness AKs on the face and scalp 3 months after PDT, which is equivalent or superior to that of cryotherapy. Decades of studies have demonstrated the efficacy of PDT for AKs. A systematic review and meta-analysis of PDT revealed that for thin AKs on the face or scalp, PDT has a 14% better chance of lesion clearance compared to cryosurgery. The European Guidelines for actinic keratosis found strong evidence to use MAL-PDT and ALA-PDT if patients had multiple AK lesions (≥6 distinguishable AK lesions in one body region or field). MAL-PDT and ALA-PDT were also recommended for single AKs1–5 and for patients with immunosuppression.10 PDT may be particularly useful in patients with symptoms of field cancerization, which is characterized by large areas of clinical and subclinical premalignant and malignant tumors. Usage of PDT as a field treatment may result in the clearance of numerous lesions with adequate cosmetic results. Furthermore, it is likely to prevent the deve­ lopment of additional AKs.

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Bowen’s Disease/Squamous Cell Carcinoma in Situ PDT using red light, with higher fluence than that used for AKs, is an effective treatment for Bowen’s disease (BD). Clearance rate of 86–93% was found 3 months after treatment with one or two session of MAL-PDT. A 2-year follow up showed sustained clearance of 68–71%. This is comparable to clearance with cryotherapy and 5-FU but with superior cosmetic results. It is also effective in treating large lesions (>3 cm) and has been reported to clear digital, subungual, and nipple BD.6 PDT is contraindicated in invasive SCC.6,11

Basal Cell Carcinoma BCC, is one of the most common skin cancers.12 Red light PDT is an established treatment for superficial and nodular BCC, but is not indicated for the more aggressive basosquamous, morpheaform, or infiltrating subtypes. Treatment of thick lesions yields better results when curretted prior to photosensitizer application. Superficial BCC (sBCC) responds well to treatment with red light high-fluence PDT, which was shown in meta-analyses to have a similar efficiency to cryosurgery and pharmacologic treatment (topical imiquimod and 5-fluorouracil).13,14 PDT had superior cosmetic results compared to both cryosurgery and surgery, although it was found to be less effective than surgical excision.13,15 Repeated PDT cycles have been found to result in an improved clinical outcome, with a response from 75.6 to 79%.15 Red light PDT for the treatment of nodular BCCs (nBCC) shows efficacy inversely related to the thickening of the lesion. Clearance rates vary among treatments. For example, one study found a 3-month clearance of 91% of primary nBCC following MAL-PDT and a 76% clearance after 5 years. Cryotherapy shows similar efficacy when compared with ALA PDT, but yields inferior cosmetic outcomes compared to PDT. PDT is less ­efficacious than surgical excision for nBCC (91% vs. 98% initial clearance, 14% and 4% recurrences at 5-year follow up). Another study found only 33% clearance for nBCC following two treatments of MALPDT, in contrast to 82% clearance of sBCC (mean follow up of 23.5  months).6,8 H-zone BCCs have reduced sustained clearance rates. The limited penetration of photosensitizers (1–2 mm) reduces the efficacy of PDT in thicker lesions. In addition,

blue light should not be used due to poor penetration into the dermis. Long-term recurrence may limit the use of PDT for nodular BCC. However, it may be suitable for cases where surgical excision is not appropriate.

Off-label Usage Off-label treatments with PDT include rejuvenation and treatment of several inflammatory dermatoses, including acne, warts, T-cell lymphoma, other type of benign tumors such as fibrofolliculoma in Birt–Hogg–Dubé syndrome (Figs. 117.2A and B), and vulva neoplasia.7,16,17 PDT is increasingly used for photorejuvenation. Several studies have shown that patients with multiple AKs not only have clearance of the lesions, but also improve

A

B Figs. 117.2A and B: PDT can also be used off-label for benign disease such as fibrofolliculoma in Birt–Hogg–Dubé syndrome. (A) Shows edema and erythema post-red light PDT treatment. (B) Shows resolution of the lesion 3 months post-treatment.

Chapter 117: Photodynamic Therapy signs of photoaging after PDT. Reviews have concluded that topical PDT (using either MAL or ALA) is an effective treatment for skin rejuvenation with limited and mild-to-moderate adverse effects, no scarring, and a fast recovery time. Significant improvements in fine wrinkles, mottled pigmentation, skin roughness, skin laxity, telangiectasias, and facial erythema have been reported. It has been proposed that patients with fair phototypes and a history of actinic damage with different grades of severity are the best candidates. PDT photorejuvenation sessions can both rejuvenate the skin and treat the visible or incipient UV-induced lesions. Supporting data regarding the use of daylight and previous intensification by ablative laser or microneedling have been reported.17–20

CLINICAL PROCEDURES Preoperative Assess whether the patient is a good candidate for PDT. Alternative treatments, including cryotherapy, 5-fluorouracil, and imiquimod, should also be considered.21 • Consider contraindications: Photosensitivity (such as collagen vascular disease), porphyrias, skin fragility (blistering conditions such as bullous pemphigoid), or photosensitizing medications. • Counsel patient on benefits and risks, especially phototoxicity, and obtain informed consent. • Determine treatment parameters: photosensitizer, light source, dosage, and number of treatment sessions. • Skin preparation should include aggressive management of comorbid inflammatory disease such as seborrheic dermatitis. Inflammation condition would allow increased absorption of ALA or MAL to non-photodamaged skin, producing unnecessary reaction.

Intraoperative Topical PDT consists of three steps: lesion preparation, application with ALA or MAL, and light exposure.

Lesion Preparation Lesions may require curettage prior to application of the photosensitizer.23,24 The procedure is usually done immediately prior to PDT but can also be performed days before.

• For superficial lesions (AK): remove only hyperkeratosis, crusts and the stratum corneum to facilitate the MAL or ALA into the skin • For Field-PDT: curettage the whole area • For hard keratotic lesions: use deeper curettage • For Bowen’s disease and BCC: scrape in a margin of 5 mm. Local anesthesia is often needed. In superficial lesions, the general practice has been to carry out abrasion by removing only hyperkeratotic crusts and the stratum corneum to improve the uptake of MAL cream into the skin. This should not be painful and not give rise to bleeding. When two treatment sessions are performed, it is often sufficient only to remove the crust covering the wound surface induced by the first session without further curettage of the treatment area. Debulking is often required for BCC (thicker lesions) to reduce the thickness of the tumor, usually by curetting the thicker lesions. A sharp curette is used to remove hard keratotic tissue. The back of a ring curette or an equivalent blunt instrument used on top of loosely woven tissue makes it easier to feel the transition to healthy skin. As tumors may have subclinical extensions, to minimize the possibility of recurrences, it is recommended to scrape 5 mm of the surrounding tissue of normal appearance. If the patient bleeds, compression can be used to stop the bleeding.22,23

Application of Photosensitizer • Apply topical photosensitizer (ALA solution or MAL cream) to the treatment area and surrounding 5 mm; occlude the area if needed • Following appropriate incubation period (1–4 hours depending on the medication, up to 18 hours total), remove excess medication from the surface of the skin.

Light Exposure • Distribute protective eyewear to patient as well as opaque material to cover skin outside of the treatment area (Figs. 117.3A and B). • Initiate light exposure for the appropriate length of time.

Postoperative • Reduce swelling of treatment area using ice packs, and apply a dressing to the wound; postoperative analgesics or antihistamines may be prescribed. • Emphasize importance of following photoprotective measures and avoiding sun exposure for at least 48 hours.

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A

B

Figs. 117.3A and B: (A) Set up for red light PDT including protection of eyes as well as non-treated areas. Distribute protective eyewear to patient when the face is being treated (B) as well as opaque material to cover skin outside of the treatment area such as shoe cover for the non-treated foot.

TOLERABILITY AND COMPLICATIONS OF PDT Topical photodynamic therapy is generally well tolerated. The most common adverse effects are tingling, discomfort, and a burning sensation during treatment. Discomfort generally begins immediately upon illumination and gradually decreases as the photons photobleach the PpIX, reducing temporarily the amount of photosensitizer in the cells. However, PpIX may reaccumulate and persist over several days. Treating a larger field tends to produce more pain and procedure-associated pain has limit the widespread PDT use as well as leading to early termination of treatment and decreased therapeutic efficacy. A recent meta-analysis of published studies looked at the comparison of two interventions to help reduce pain: paincontrolling therapies and PDT parameter (photosensitizer or photo-irradiation) adjustments. Of these, nerve block, subcutaneous infiltration anesthesia, cold analgesia, and transcutaneous electrical nerve stimulation, but not topical anesthetic gels, were associated with less PDT-related pain; 5-aminolevulinic acid (ALA) tended to be more painful than methyl-5-aminolevulinate (MAL); daylight PDT was less painful than conventional PDT; and lower irradiance delivery produced lower pain scores in general.24 There is no single crystallized protocol for management of PDT-related pain. Evidence suggests that continuous activation of low levels of PpIX with methods using lower fluence rates and possibly shorter incubation times as well as utilizing light. Lower fluence rates result in less painful

treatment sessions, and utilizing light fractionation may alleviate discomfort as well. Pain may be managed with cold air or cold-water analgesia, preoperative, and postoperative oral opioids or NSAIDs, nerve block anesthesia, and, with less success, topical anesthetics that have a pH below 7 so as not to inactivate acidic ALA. However, following ALA-PDT, some patients may experience an inflammatory response characterized by urtication, erythema, and edema immediately post-procedure and subsequently, crusting, and erosion (Figs. 117.4A and  B). It has been demonstrated that these symptoms may be due, in part, to the activation of H1 histamine receptors by an immediate and time-dependent release of histamine, and that the levels peaked 30 minutes after treatment and can remain stably elevated for at least 4 hours post-treatment.25 It may take up to 24 hours to return to baseline. In addition, any pruritus, which is caused local histamine release, may be treated with oral antihistamines. However, a recent study shows that while oral H1 antihistamines mitigated the immediate urticarial response to ALA-PDT, it had no impact on the delayed phototoxic or erythermal response. Furthermore, it did not reduce the signs and symptoms of post-PDT inflammation, nor minimize the impact of treatment on subjects’ lifestyles.26 The authors postulated that the delayed phototoxic adverse effects seen after ALA-PDT are more closely attributable to mediators other than histamine, such as prostaglandin E2 and nitric oxide. Thus, to reduce post-PDT inflammation, other methods can still be used including shortened incubation time, application of superpotent topical corticosteroids, daylight avoidance

Chapter 117: Photodynamic Therapy

A

B

Figs. 117.4A and B: Following ALA-PDT, some patients may experience an inflammatory response characterized by urtication, erythema, and edema mediated by time-dependent release of histamine. (A) Depicts the lesions prior to treatment; and (B) Depicts a post-treatment inflammatory response.

for 24 hours post-procedure, and use of sun-protective clothing. Elevated concentrations of PpIX can produce localized photosensitivity for up to 48 hours.6 Adverse events including erythema, edema, and possible blistering can be mitigated by photoprotective measures following treatment. Patients should wear opaque clothing and avoid exposure to sunlight for 48 hours following the procedure. Two to six weeks after the red light procedure is, patients typically experience erosion of skin and crust formation as part of the natural wound healing process.6 MAL-PDT may also produce allergic contact dermatitis.22

FUTURE DIRECTIONS Future directions of PDT involve improving the clinical efficacy of treatment through improved light sources and photosensitizers. Novel preparations of photosensitizers have utilized nanovesicular preparations that confer better targeting to deeper neoplastic lesions; these vesicles may even be bioengineered to confer additional specificity to the lesion type. In addition, future research into light sources may yield a better understanding of the optimal light source and dosage for photoactivation, allowing for maximal depth of penetration as well as treatment area. Studies have shown daylight PDT to be similar to conventional PDT for the treatment of AKs, nearly painless and more convenient to perform.27 A recent review concluded that initial studies regarding treatment of NMSC indicate recurrence rates much higher than other

accepted therapies, however the numbers and follow-up time are low.28 Future directions of PDT include resolving the more practical concerns that accompany treatment. The primary side effect of PDT is pain; research is required to understand the mechanism behind what causes pain and how to minimize it during treatment. In addition, PDT is not commonly utilized as a treatment modality despite recent advancements that have made it highly effective in treating superficial lesions of the skin. The cost of treatment can be disproportionately high relative to other treatment options, further deterring physicians from recommending PDT. Thus, improving accessibility to PDT in clinics could allow it to become a more standard treatment option in dermatology.

REFERENCES 1. Sharma SK, Mroz P, Dai T, et al. Photodynamic therapy for cancer and for infections: what is the difference? Isr J Chem 2012;52(8–9):691–705. 2. Moan J, Peng Q. An outline of the history of PDT. In: Patrice T, ed. Photodynamic Therapy. 2nd edn. The Royal Society of Chemistry; 2003. pp. 1–18. 3. Blume JE, Oseroff AR. Aminolevulinic acid photodynamic therapy for skin cancers. Dermatol Clin 2007 Jan;25(1):5–14. 4. Ericson MB, Wennberg A-M, Larkö O. Review of photodynamic therapy in actinic keratosis and basal cell carcinoma. Ther Clin Risk Manag 2008;4(1):1–9. 5. Strasswimmer J, Grande DJ. Do pulsed lasers produce an effective photodynamic therapy response? Lasers Surg Med 2006;38(1):225. 6. Morton CA, Szeimies RM, Sidoroff A, et al. European guidelines for topical photodynamic therapy part 1:

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Section 32: Physical Modalities of Therapy treatment delivery and current indications — actinic keratoses, Bowen’s disease, basal cell carcinoma. J Eur Acad Dermatol Venereol 2013;27(5):536–44. 7. Morton CA, McKenna Ke Fau - Rhodes LE, et al. Guidelines for topical photodynamic therapy: update. Br J Dermatol 2008;159(6):1245–66. 8. Braathen LR, Szeimies Rm Fau, Basset-Seguin N, et al. Guidelines on the use of photodynamic therapy for nonmelanoma skin cancer: an international consensus. Inter Soc Photody Ther Dermatol 2005; J Am Acad Dermatol 2007;56(1):125–43. 9. Salasche SJ. Epidemiology of actinic keratoses and squamous cell carcinoma. J Am Acad Dermatol 2000; 42(1 Pt 2):4–7. 10. Werner RN, Stockfleth E, Connolly SM, et al. Evidenceand consensus-based (S3) guidelines for the treatment of actinic keratosis. J Eu Acad Dermatol Venereol 2015;29(11) :2069–79. 11. Stratigos A, Garbe C, Lebbe C, et al. Diagnosis and treatment of invasive squamous cell carcinoma of the skin: European consensus-based interdisciplinary guideline. Eu J Cancer 2015;51(14):1989–2007. 12. Lomas A, Leonardi-Bee J, Bath-Hextall F. A systematic review of worldwide incidence of nonmelanoma skin cancer. Br J Dermatol 2012;166(5):1069–80. 13. Wang H, Xu Y, Shi J, et al. Photodynamic therapy in the treatment of basal cell carcinoma: a systematic review and meta-analysis. Photodermatol Photoimmunol Photomed 2015;31(1):44–53. 14. Griffin LL, Lear JT. Photodynamic therapy and non-­ melanoma skin cancer. Cancers 2016;8(10):98. 15. Roozeboom MH, Arits AH, Nelemans PJ, et al. Overall treatment success after treatment of primary superficial basal cell carcinoma: a systematic review and meta-analysis of randomized and nonrandomized trials. Br J Dermatol 2012;167(4):733–56. 16. Kim M, Jung HY, Park HJ. Topical PDT in the treatment of benign skin diseases: principles and new applications. Inter J Mol Sci 2015;16(10):23259–78. 17. Morton C, Szeimies RM, Sidoroff A, et al. European Dermatology Forum guidelines on topical photodynamic therapy. Eu J Dermatol 2015;25(4):296–311.

18. Karrer S, Kohl E, Feise K, et al. Photodynamic therapy for skin rejuvenation: review and summary of the literature– results of a consensus conference of an expert group for aesthetic photodynamic therapy. J Dtsch Dermatol Ges 2013;11(2):137–48. 19. Szeimies RM, Lischner S, Philipp-Dormston W, et al. Photodynamic therapy for skin rejuvenation: ­ treatment options — results of a consensus conference of an expert group for aesthetic photodynamic therapy. J Dtsch Dermatol Ges 2013;11(7):632–6. 20. Le Pillouer-Prost A, Cartier H. Photodynamic photorejuvenation: a review. Dermatol Surg 2016;42(1):21–30. 21. Bolognia JL, Jorizzo JL, Schaffer JV. Dermatology. St. Louis, MO: Elsevier Health Sciences; 2008. 22. Christensen E, Warloe T, Kroon S, et al. Guidelines for practical use of MAL-PDT in non-melanoma skin cancer. J Eu Acad Dermatol Venereol 2010;24(5):505–12. 23. Morton CA. Methyl aminolevulinate (Metvix) photodynamic therapy — practical pearls. J Dermatol Treat 2003; 14(3):23–6. 24. Ang JM, Riaz IB, Kamal MU, et al. Photodynamic therapy and pain: a systematic review. Photodiagnosis Photodyn Ther 2017;19:308–44. 25. Brooke RC, Sinha A, Sidhu MK, et al. Histamine is released following aminolevulinic acid-photodynamic therapy of human skin and mediates an aminolevulinic acid dose-­related immediate inflammatory response. J Invest Dermatol 2006;126(10):2296–301. 26. Vanaman Wilson MJ, Jones IT, Wu DC, et al. A randomized, double-blind, placebo-controlled clinical trial eva­ luating the role of systemic antihistamine therapy for the reduction of adverse effects associated with topical 5-­aminolevulinic acid photodynamic therapy. Lasers Surg Med 2017;49(8):738–42. 27. Wiegell SR, Wulf HC, Szeimies RM, et al. Daylight photodynamic therapy for actinic keratosis: an international consensus. International Society for Photodynamic Therapy in Dermatology. J Eu Acad Dermatol Venereol 2012;26(6): 673–9. 28. Fitzmaurice S, Eisen DB. Daylight photodynamic therapy: what is known and what is yet to be determined. Dermatol Surg 2016;42(3):286–95.

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118

Laser Treatment Jihee Kim, Thanh Nga Tran, Ju Hee Lee

INTRODUCTION Therapeutic Application of Laser Devices The use of light-based technologies has shown exponential progress in the field of modern dermatology. From Einstein’s concept of “The Quantum Theory of Radiation” in 1917, it took nearly 50 years to the invention of the first functional laser, developed by Dr Theodore Maiman, which consisted of a flashlamp pump device with a ruby crystal. Soon thereafter, Dr Leon Goldman pioneered its practical application and the development of other devices occurred rapidly: neodymium:yttrium-aluminum-garnet (Nd:YAG) in 1961, argon in 1962, carbon dioxide (CO2) in 1964, and dye laser in 1966, were the first few lasers manufactured. Then a breakthrough in the understanding of laser tissue interaction was published as the “Theory of Selective Photothermolysis” by Dr R Rox Anderson, which enabled targeting specific constituents of the skin. Technological advance continues with the introduction of fractional lasers in 2004, which introduced the concept of microthermal zones (MTZs) where selective thermal injury was confined to the small columns while preserving normal tissue characteristics on the surrounding areas. More recently, non-laser systems such as intense-pulsed light (IPL) and radiofrequency (RF) have been available for various skin conditions. Lasers and light-based devices are continually evol­ ving areas of dermatology with ongoing modifications of existing systems and continuous and dynamic development of more innovative technologies. This chapter will discuss the use of laser and related technologies in the treatment of specific medical and esthetic conditions.

Types of Lasers for Various Dermatologic Conditions The lasers are usually named after their respective mediums existing in gas (CO2, excimer, copper vapor, argon),

liquid (rhodamine dye), or solid (ruby, alexandrite, Nd: YAG, erbium:yttrium-aluminum-garnet) (Table 118.1). Each laser device emits distinctive beam with constant wavelength according to its medium. With respect to the absorption spectrum profile of target chromophore of the lesion, the most appropriate device is selected according to its tissue interaction with vascular, pigment, and resurfacing purposes (Figs. 118.1 and 118.2).

LASER TREATMENT FOR VASCULAR LESIONS Type of Vascular Lasers Vascular lesions were the first indications for the medical use of lasers. In general, lasers available for the treatment of vascular lesions span a large spectrum of wavelengths from 488 to 1,064 nm. The target chromophore of vascular lesions is hemoglobin within red blood cells (RBC). Oxygenated hemoglobin (oxyhemoglobin) is the most abundant form and has three primary absorption peaks at 418, 542, and 577 nm. Deoxygenated hemoglobin (deoxyhemoglobin) has an absorption peak of 755 nm. While the 418 nm peak is the most specific to target hemoglobin, light emitted at this wavelength is strongly absorbed by melanin, resulting in epidermal thermal injury and pigmentary side effects. The earliest lasers for vascular lesions were: argon (488, 514 nm), argon-pumped tunable dye (488–638 nm), copper vapor and copper bromide (511, 578 nm), KTP (532  nm), and krypton (568 nm) lasers. Despite their specificity for oxyhemoglobin absorption spectrum, early devices consisted of continuous or quasi-continuous waves and only lead to photothermal effect. Heat energy to surrounding dermal tissue frequently caused non-specific coagulation resulting in atrophic or hypertrophic scarring. The mainstay of the problem was the mismatch between laser pulse duration and the target tissue thermal relaxation time (TRT) (Table 118.2).

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Section 32: Physical Modalities of Therapy Table 118.1: Lasers in dermatology. Wavelength Laser / system (nm) Mode Argon 488, 514 CW Copper vapor 511, 578 Quasi-CW

585–600

Color Target chromophore Applications Blue-green Hemoglobins, melanin Vascular lesions Yellow-green Hemoglobins, melanin Vascular lesions, pigmented lesions Quasi-CW Green Hemoglobins, melanin Vascular lesions, pigmented lesions Pulsed (ns) Green Melanin Vascular lesions, pigmented lesions; tattoo—red Pulsed Yellow Hemoglobins Vascular lesions

694 694

Pulsed Red Pulsed (ns) Red

Alexandrite Q-switched alexandrite

755 755

Pulsed Pulsed

Diode

CW/pulsed Infrared

Q-switched Nd:YAG

800, 810, 940 1,064

Long-pulsed Nd:YAG Erbium:glass Erbium:YAG

1,064 1,540 2,940

CW/Pulsed (ns) Pulsed Pulsed Pulsed

Carbon dioxide

10,600

CW/pulsed Infrared

Potassium titanyl phosphate (KTP) Q-switched, frequencydoubled Nd:YAG Flashlamp-pumpedpulsed dye (PDL) Ruby Q-switched ruby

532 532

Infrared Infrared

Infrared Infrared Infrared Infrared

Melanin Melanin

Photoepilation Deep and superficial pigmented lesions; tattoo—black, blue, green Melanin, hemoglobins Photoepilation Melanin Pigmented lesions; tattoo—blue, black, green Melanin, hemoglobins Vascular lesions, pigmented lesions, photoepilation Melanin Deep and superficial dermal pigment; tattoo—black, blue Hemoglobins, melanin Photoepilation, vascular lesion Water Skin resurfacing Water Skin resurfacing; destruction of superficial lesions Water Skin resurfacing; destruction of superficial lesions

Fig. 118.1: Laser wavelength and penetration depth. (Er: erbium; KTP: potassium titanyl phosphate; Nd: neodymium; PDL: pulsed dye laser; YAG: yttrium-aluminum-garnet).

Chapter 118: Laser Treatment

KTP Laser (Frequency-doubled Nd: YAG Laser)

Fig. 118.2: Absorption spectra. The heterogeneous absorption spectrum of target skin chromophores allows selective photothermolysis.

Table 118.2: Thermal relaxation times based on blood vessel diameter. Vessel diameter (µm) Thermal relaxation time (ms) 30 0.86 40 1.54 50 2.4 100 0.96 150 21.6 200 38.4 250 60.0 300 86.2

The concept of selective photothermolysis demons­ trated the ability to target a specific chromophore in the skin without damaging surrounding structures through the selection of proper wavelength, pulse duration, and fluence. TRT is defined as the time required for a target structure to dissipate half of the absorbed energy into surrounding tissue. The emitted laser beam is selectively absorbed by hemoglobin and transformed into heat energy, which induces coagulation and thermal destruction of endothelial cells. Therefore, even with high ­fluences, short pulse durations can limit the unnecessary dissipation of ­thermal energy and efficiently photocoagulate target vessels. Currently, the most commonly used devices for the treatment of vascular lesions include KTP, PDL (585, 595 nm), and intense-pulsed light (IPL). Other systems with longer wavelengths such as the diode lasers (810, 940 nm) and Nd:YAG lasers (1,064 nm) are also available, after considering the clinical characteristics of each vascular lesion.

Frequency-doubled Nd:YAG lasers use KTP (potassium titanyl phosphate) crystals, which effectively halve the wavelength from 1,064 to 532 nm and double the frequency. The wavelength of KTP laser is close to the first absorption peak of oxygenated hemoglobin at 542 nm and melanin shows significant absorption of this wavelength. Accordingly, KTP laser can be used to treat both vascular and superficial pigmented lesions. With its short wavelength, KTP laser shows efficacy in targeting superficial vascular lesions. Especially for the patients with darker skin types, epidermal cooling is mandatory to prevent the risk of pigmentary complications such as hyper- or hypopigmentation.

Pulsed Dye Lasers The flashlamp-pumped pulsed dye laser (PDL) has become a mainstay of vascular lesion treatment. PDL emits a laser beam which penetrates deeper than KTP lasers and is more selectively absorbed by hemoglobin. Initially, PDL systems were designed to emit 577 nm wavelengths to correspond with oxyhemoglobin peaks. Afterward, PDL systems adopted a slightly longer wavelength (585 or 595 nm) for deeper penetration, enabling more effective treatment of deeper vascular lesions. Early PDL systems were only able to generate laser beam lasting for short pulse width of 0.36 to 0.5 ms. Such short pulse duration was based on short TRT of the hemoglobin, which has 1 ms or less. Due to its short pulse duration, ruptured vessels induce extravasation of RBCs and the immediately acquired purpura and bruising appearance by PDL treatment lasted for more than 2 weeks. Newer technical improvement in PDL system includes the adaptation of longer pulse width (up to 40 ms), which allows gradual accumulation of thermal energy, inducing less or no vessel rupture and minimal-to-no purpura. Additionally, targeting larger vascular lesions with thicker endothelium requires sufficient fluence for clinical improvements. The addition of a dynamic cooling device (DCD) reduced the potential collateral thermal injury following the laser pulse and treatment discomfort. Based on knowledge of TRT in the context of the size of the vessels and expected clinical endpoints, the latest configurations of PDL system enable more effective clearance of lesions in fewer treatments.

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Nd:YAG Laser Laser systems with longer wavelengths have been used to achieve greater depth penetration while minimizing adverse events. Nd:YAG lasers produces light at 1,064 nm wavelength, which enables deeper penetration into the dermis. However, oxyhemoglobin absorption is significantly reduced when compared to PDL or KTP lasers and cause non-specific heating of dermal tissues. Nd:YAG laser can be used to treat deeply located vascular lesions with larger diameter. To generate sufficient energy and overcome a poor oxyhemoglobin absorption coefficient, higher fluences with longer pulse widths are required. Therefore, appropriate surface cooling to prevent excessive accumulation of thermal energy in epidermis and dermal s­ tructures surrounding the target lesion is crucial. Especially for the lesions requiring long pulse duration, tissue cooling during and after the laser pulse may further prevent thermal damage as well as reduce treatment discomfort.

Diode Laser Diode lasers are the most commonly used laser in modern industry with various applications such as fiber optics communication, image scanning and spectrometry, and medical purposes. They are available in a wide range of wavelength while medical use of diode laser is in 810 or 940 nm. The wavelength of diode laser close to the tertiary absorption peak of deoxyhemoglobin. Diode lasers provide continuous pulses of energy with long pulse durations, up to 250 ms. The size and type of the target vessel determines the pulse duration and wavelength of the diode laser. With its ability to generate high fluences and longer pulse duration, diode laser is suitable to treat deeply located large vascular structures such as leg veins.

Intense Pulsed Light IPL is a non-laser device which uses a flashlamp that emits non-coherent polychromatic light with variable pulse width. IPL generates lights broadly ranging from 420 to 1,200 nm, which can be manipulated by applying selective cutoff filters to limit the spectrum of the incident light to the desired wavelength. For vascular lesions, a cutoff filter in the range from 560 to 590 nm selectively emits light that corresponds to the oxyhemoglobin absorption peak. IPL has the advantage of treating more than one chromophores, melanin and hemoglobin, and is efficient at

improving conditions with both pigmentary and vascular changes, such as photo-damaged skin. Additionally, IPL devices have wider application tips and thus are more efficient in treating larger surfaces. Unlike other laser devices, prior to the treatment, ultrasound gel is applied on the surface of the treated area to diffuse surface heat and reduce refractive index. To prevent thermal damage, IPL devices provide a contact cooling system directly applied on the handpiece, which enables dynamic cooling during the laser pulse, allowing the delivery of greater fluence.

Indications for Vascular Laser Treatment Port-wine Stain Capillary malformations, commonly referred to as port wine stain (PWS) or nevus flammeus, are the most common type of vascular malformations. PWS present in up to 2% of newborns, presenting as erythematous macules and patches at birth. Before the development of laser devices, treatment of PWS aimed to physically eliminate abnormal vascular structures with cryotherapy, surgery, and radiotherapy, which resulted in significant scarring. Along with the development of early lasers, argon laser (488–514 nm) was the first to be used for PWS. However, its continuous beam exposure and non-adjustable pulse width leads to non-specific thermal injury and significant post-treatment scarring. The introduction of PDL in the 1980s dramatically improved the treatment of PWS by selectively targeting oxyhemoglobin with the optimal pulse width matching the TRT of the capillaries comprising PWS. Since its deve­lopment, PDL have been the gold standard for treatment of PWS. To achieve sufficient clinical improvement, a series of treatments every 4 to 6 weeks is required. In the first clinical study conducted by Tan et al., complete clearance of the lesions was noted after an average of 6.5 sessions.1 Commonly recommended parameters range from fluences of 4 to 15 J/cm2 with pulse width of 1.5 to 10 ms with 7–10 mm spot size and appropriate cryogen cooling. When using larger spot sizes for extensive lesions, fluence should be lowered to prevent thermal damage. Most PWS show significant improvement with PDL, but total resolution is often not possible. Multiple factors influence effectiveness of treatment, most importantly the location and the patient age. PWS on the face and trunk shows greater rate of improvement compared to the lesions on the extremities. Within the face, PWS located

Chapter 118: Laser Treatment in the midface and second trigeminal nerve distribution responds more poorly than those in the periorbital region or forehead. The size of the lesion affects the treatment outcome. Smaller lesions have greater rate of improvement, requiring less sessions. Early treatment is recommended since the surface area becomes larger and thicker as the child grows. Histologically, small caliber dermal vasculature found in infancy become larger and more tortuous with increased proportion of deoxyhemoglobin. Moreover, some lesions accompany soft tissue hypertrophy, limiting the penetration of PDL. Accordingly, lesions in newborns tend to response faster and resolve more completely than matured lesions.2 It is often possible to achieve effective treatment before 6 months of age. Hypertrophic PWS or lesions showing resistance to PDLs may also be treated with lasers with deeper penetration and longer pulse duration, such as alexandrite or Nd:YAG lasers. Additionally, nodular lesions of PWS can be effectively treated with CO2 lasers. The risk of scarring and pigmentary change after PDL is very low. Newer versions of PDL system allow delivery of high fluence with less pain and spare the epidermis with dynamic cooling devices. Some patient may experience redarkening of the lesions over time, up to 15%, which may require additional treatments3 (Figs. 118.3 and 118.4).

A

B

Infantile Hemangioma Infantile hemangioma (IH) occurs in about 1 ~ 5% of children, and is more common in premature infants of very low birth weight. Generally, one-third of the lesions are present at birth. Others develop during the first week of infancy as telangiectatic macules, which rapidly develop to a nodular appearance. The proliferative phase lasts up to 10 ~ 12 months, followed by a stable period and regression phases, which last until childhood. Common complications of IH include bleeding and ulceration. Involuted hemangiomas can leave behind residual scarring with hypo- or hyperpigmentation, atrophy, or fibrofatty nodules. The role of laser treatment in the treatment of IH is controversial, as the use of systemic or topical β-blockers has become the mainstay of treatment with acceptable safety profile. For deeply located subcutaneous IH, rapidly proliferating lesions, or lesions located in complicated areas, systemic β-blockers should be preferentially considered. Nonetheless, ulcerated IH have been successfully treated by PDL. Small and early lesions of IH respond well to PDL which may lead to growth arrest during the proliferative phase in over 50% patients with few sessions4 (Figs.  118.5A and B). IH lesions are composed of endothelial cell aggregates, which can have both superficial and deep components. Therefore, PDL alone

C

Figs. 118.3A to C: Laser treatment of port-wine stain. (A) Before treatment; (B) After second treatment with PDL; (C) After sixth treatment with PDL.

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Section 32: Physical Modalities of Therapy

A

B

Figs. 118.4A and B: Laser treatment of capillary malformation. (A) Before treatment. (B) After eighth treatment with PDL.

is not sufficient in the treatment of deeper components of IH, which may require longer wavelength lasers. Residual telangiectasia after involution can be treated with either PDL or IPL.

Telangiectasia Facial telangiectasias are commonly encountered conditions. They are associated with rosacea and chronic sun exposure, being more prominent in lighter skin types. Primary or essential telangiectasia is often familial and some lesions may be associated with systemic diseases including hypertension, chronic liver disease, or autoimmune diseases. These lesions are composed of dilated small venules measuring 0.1–1 mm caliber. Superficial and small vessels show good response to KTP laser, IPL, and PDL (Figs. 118.6A and B). PDL is known to be the most effective treatment option to achieve clearance in fewer sessions of treatment. However, PDL results in purpura on the treated area lasting few weeks, which can be inacceptable to some patients. To reduce the degree of bruising, multiple passes of PDL have been tried by applying a series of laser pulses with longer pulse widths below the purpura threshold. This application technique is referred to as pulse stacking, and clearance of telangiectatic vessels can be achieved in a purpura-free manner. KTP lasers also produce good clinical results for telangiectasia with little or no purpura, as seen with PDL. KTP is also shown to be associated with less swelling, pain, and posttreatment erythema than PDL. Diode lasers or the pulsed Nd:YAG laser can be used for vessels with a

A

B

Figs. 118.5A and B: Laser treatment of infantile hemangioma. (A) Eight months old patient with enlarging infantile hemangioma, before treatment; (B) After fifth treatment with PDL. PDL lead growth arrest after two sessions without use of systemic beta blocker.

A

B

Figs. 118.6A and B: Laser treatment of telangiectasia. (A) Patient with rosacea, before treatment; (B) After third treatment with PDL.

Chapter 118: Laser Treatment diameter of more than 1 mm. IPL have also been shown to be effective for telangiectasia and have lower risk of purpura. For the patients with lesions with diffuse erythema associated with rosacea or grouped lesions, IPL can be very effective and tolerable.5

Starburst Veins and Varicosities of the Leg Starburst veins or venous ectasia develop in dependent areas, most commonly in the legs. While vessels involved in facial telangiectasia are superficial and small in caliber, leg veins are deeply located and larger, measuring between 0.2 and 3 mm. Moreover, varicosities may present with tortuous vascular structures at different depths. Accordingly, phlebology evaluation is required prior to treatment and sclerotherapy is the first-line therapy for majority of the lesions. Vessels with a diameter of up to 1 mm are a good indication for PDL and KTP laser but the rate of recanalization is high, requiring multiple treatment sessions. For deep-leg veins, long-pulsed Nd:YAG laser and diode laser have shown efficacy even achieving similar rate of clearance as sclerotherapy.6 However, due to high fluence required for sufficient photocoagulation, the risk of pigmentary change and potential for scarring are high and the treatment-related pain is unavoidable. Recently, the combination therapy using endoluminal diode or Nd:YAG lasers with conventional sclerotherapy has shown successful results and long-term maintenance.

Other Vascular Lesions Cherry angiomas are a good indication for PDL. Treatment is aimed at destruction of the central “feeder” vessels, which can then be followed by destruction of the peripheral capillaries. For small and superficial lesions, KTP laser can also be used. Venous lakes are venous dilated venules in the superficial dermis frequently occurring on the lip. Venous lakes shows good clinical response to PDL, KTP, diode, or Nd:YAG lasers. Venous malformations are usually sporadic varying in size and location. Although surgical excision has been the mainstay of treatment, multimodal approach with sclerotherapy and endoluminal diode laser have shown efficacy with less morbidity.7 The superficial component of low-flow venous malformation can be treated with long wave length vascular laser such as alexandrite, diode, or Nd:YAG lasers. Angiofibromas in tuberous sclerosis patients can be treated with PDL and KTP lasers. For the hypertrophic

component, CO2 lasers can be used to achieve surface ablation. Lymphangiomas can also be targeted by a vascular laser if there is enough hemoglobin content within the lesion. Erythematous to violaceous lesions respond well to alexandrite or Nd:YAG lasers and superficial component can be vaporized with CO2 laser.

LASER TREATMENT FOR PIGMENTED LESIONS AND TATTOOS Type of Lasers Used to Treat Pigmented Lesions The use of lasers and light sources to treat pigmented lesions is also based on the principle of selective photothermolysis as in the treatment of vascular lesions. Target chromophore melanin has a broad absorption spectrum from 400 to 1,200 nm. However, light absorption in melanin decreases with increasing wavelength. Melanosomes are intracytoplasmic organelles of melanocytes where melanin is synthesized. Melanosomes have very short TRT, between 50 and 500 ns. Therefore, laser systems that can generate exceptionally short pulse duration should be used for selective destruction.

Q-switched Lasers Highly selective destruction of melanosomes can be achieved with Q-switch lasers. Continuous wave lasers emit a beam of light in a constant-output power. The power output is relatively low, measured up to 103 W. Quasicontinuous lasers mechanically shutter the continuous beam into shorter segments, resulting in an interrupted emission of constant laser emissions. Whereas in a pulsed mode, the excitation of a laser medium is affected during a short laser pulse with a predetermined electrooptical switch. Peak powers up to 105 W can be developed for duration of 100 µs to 10 ms. Even higher peak energies can be achieved if the pulse duration is shortened. Q-switched lasers can generate extremely high peak intensities up to 1010–1012 W. “Q” refers to the quality factor of optic cavity and represents the rate of discharge of energy. Q-switching, with the use of electrooptical switch, allows the rapid release of stored energy over very short pulse durations of picoseconds or nanoseconds. As a result, thermal energy absorbed by melanosome is emitted as acoustic waves, causing vacuolization. Particularly, such a photoacoustic effect shatters the melanosomes and disrupts its

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Section 32: Physical Modalities of Therapy membrane and internal contents. Histologically, deposition of pigment and nuclear materials is driven at their peripheries8 (Figs. 118.7A and B). Q-switched lasers include the ruby (Qs-ruby; 694 nm), alexandrite (Qs-alexandrite; 755 nm), and Qs-Nd:YAG (1,064 nm) including its frequency doubled (532 nm) mode. Qs-ruby and Qs-alexandrite lasers effectively treat both epidermal and dermal-pigmented lesions since their wavelengths are still within the melanin absorption spectrum. Nd:YAG laser with longer wavelength (1,064 nm) penetrates deeper into the skin with increased ability to reach deeply located melanosomes or thicker lesions. However, this wavelength is poorly absorbed by melanin and 532 nm counterpart is preferable for epidermal pigmentation. Q-switch lasers generate an immediate ash-white discoloration at the site of light impact. Such change is due to the photoacoustic effect of the laser which induces cavitations within melanosomes.9 The adequate laser fluence to sufficiently target melanosomes correlates well with the threshold exposure to cause an ash-white change. Additionally, oxyhemoglobin is a competing chromophore with melanin when using the 532 nm wavelength. Use of a short pulse width causes mild purpura at the treated site,

due to ruptured superficial vessels and RBC extravasation (Table 118.3).

Other Lasers: Less-selective, Non-pigment Selective Lasers, and IPL Less-pigment selective lasers can be used for some clinical indications. KTP lasers can be used to treat epidermal pigmentation, but limitations exist due to shallow penetration depth. Long-pulsed ruby, alexandrite, and Nd:YAG lasers can also be used, but they are not as effective as their Q-switched counterparts. Non-pigment specific ablative lasers have been used to treat pigmented lesions. CO2 (10,600 nm), Er:YAG (2,940 nm) and Er:Glass (1,540) targets water to ablate the entire epidermis, including its melanocytes and keratinocytes with melanin pigments (Figs. 118.8 and 118.9). IPL can also be used to treat epidermal pigmented lesions. The shorter wavelengths emitted by IPL devices are highly absorbed by melanin. The IPL system is well suited for field treatment of the face or other epidermal pigmentation presenting in large areas.

Indications for Laser Treatment Lentigines Lentigines are common hyperpigmented macules often caused by chronic sun exposure, referred to as solar

A

B Figs. 118.7A and B: Selective photothermolysis of pigmented lesions. (A) Laser radiation is selectively absorbed by target chromophore, melanin; (B) Melanosomes in the basal layer and the dermis is scattered due to photothermal and photoacoustic effects of the laser radiation.

Table 118.3: Q-switched lasers. Laser / system Wavelength (nm) Q-switched Nd:YAG, 532 frequency-doubled Q-switched ruby 694 Q-switched 755 alexandrite Q-switched Nd:YAG 1,064

A

Pulse duration (ns) 5–7 25–40 500–100 5–7

B

Figs. 118.8A and B: Laser treatment of pigmented lesions. (A) Patient with labial melanotic macules, before treatment; (B) After second treatment with CO2 laser ablation.

Chapter 118: Laser Treatment proliferation. Superficial ablation often results in immediate lightening of the lesion. However, the recurrences are common and associated hypertrichosis remains in many cases. Pigment selective Qs-lasers alone, or in combination with CO2 laser ablation, can be effective in removing junctional nevi without dermal component. Congenital lesions can be lightened by Qs-lasers.12 However, the deep-dermal component or pigment cells within adnexal structures are hardly affected and are associated with high recurrence. For recurrent lesions, close follow-up to detect any sign of early transformation to malignant lesions is critical.

A

B

Figs. 118.9A and B: Laser treatment of pigmented lesions. (A) Patient with senile lentigo and seborrheic keratosis, before treatment; (B) After first treatment with Q-switch Nd:YAG and CO2 laser ablation.

lentigines. Some lentigines are associated with genetic syndrome such as Peutz-Jeghers syndrome. Histologically, lentigines present with an increased number of basal melanocytes. All three types of Q-switched lasers; Qs-ruby, Qs-alexandrite, and Qs-ND:YAG (532 nm) lasers, are highly effective.10 Although less selective, KTP lasers also provide effective treatment. IPL systems can be a convenient choice of treatment for patients with widespread solar lentigines and telangiectasia. CO2 or Er:YAG lasers can be employed to ablate pigment-laden epidermal lesions.

Nevus of Ota and Nevus of Ito Nevus of Ota and nevus of Ito are dermal melanocytic lesions presenting as gray-blue patches. Histologically, dendritic melanocytes are dispersed within the upper dermis. Nevus of Ota involves the facial distribution of the first- and second-trigeminal nerve, while Nevus of Ito refers to the distribution of the posterior supraclavicular and lateral brachial nerves. Both lesions can be effectively treated with Qs-lasers. High fluences are required, and repeated sessions of treatments can significantly improve or even clear the lesion with long-lasting results. Acquired bilateral Nevus of Ota-like macules (Nevus of Hori) share similar histology and respond excellently to laser therapy. Qs-lasers can generally achieve complete clearance in fewer sessions.13

Café-au-lait Macules

Melasma

Café-au-lait macules (CALMs) are light brown macules presenting as isolated benign lesions. CALMs can appear as multiple lesions in association with genetic syndromes such as neurofibromatosis. Histologically, the number of melanocytes is increased along the basal layer and melanin granules are often present as clustered aggregates within the epidermal keratinocytes. Q-switch lasers are employed, but the outcome is minimally successful and variable. Short-term lightening or even clearance can be achieved after repeated sessions, but recurrences are common, especially in sun-exposed areas.11

Melasma is a common acquired hyperpigmentation in middle-aged females with darker skin types, presenting as grouped brown to gray macules on the face, most frequently on the cheeks. Melasma is often associated with sun exposure, pregnancy, and oral contraceptives. These diverse triggers result in an increased synthesis of melanosomes in melanocytes and an increased transfer of melanosomes to keratinocytes. Histologically, melanin concentration is increased in the epidermis and melanophages are often observed in the dermis. Various treatment options are available, yet treatment outcome is often unpredictable. First-line treatment includes strict sun protection and the use of topical agents. Hydroquinone alone or in combination with retinoids (in non-pregnant patients) is commonly used. Lasers represent an alternative approach and they are offered to patients who are refractory to topical regimens. Unlike other pigmentary lesions, Qs-lasers can

Melanocytic Nevi The removal of melanocytic nevi with laser devices is controversial, since no histologic evaluation is performed after laser ablation. Laser treatment should be selectively employed for benign lesions only, and not for atypical

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Section 32: Physical Modalities of Therapy easily trigger reactive hyperpigmentation and worsen melasma.14 Non-ablative fractional resurfacing system showed efficacy when treated with low fluence. However, in long-term follow-up, most of the patients developed recurrence.15 Treatment with IPL is suited to treat patients with a fair skin type, who have less risk of affecting endogenous epidermal melanin. However, both the pigment-selective lasers and IPL have produced disappointing results with high recurrences, even in patients who showed initial response.16 The concept of low fluence or subthermolytic fluence, using a 1,064 nm wavelength Qs-Nd:YAG laser, was introduced in order to overcome the reactive incitement of epidermal melanocytes. The laser penetrates deeper to target dermal melanophages, while sparing the epidermal keratinocytes or melanocytes from thermal damage. Incidence of hyperpigmentation was significantly improved with subthermolytic fluence. Nevertheless, the recurrence rate is often similar. In addition, low fluence Qs-laser therapy often requires more sessions to achieve clinical improvement.16 Recently, picosecond lasers have become available. However, no randomized clinical trial has been published to analyze its efficacy in melasma. Picosecond lasers act via a photoacoustic mechanism and can be applied to pigmented lesions, similar to low fluence Q-switched laser. Theoretically, it may be more efficient in targeting melanin without inducing thermal damage to surrounding structures, which may overcome the drawbacks of conventional laser devices in melasma treatment. Additionally, since topical regimen remains the mainstay of treatment, laserassisted drug delivery may have a potential role in melasma treatment.

Other Pigmented Lesions Becker’s nevus is a hyperpigmented plaque with variable hypertrichosis that presents during early childhood. Within the lesion, the melanin component is in both epidermal keratinocytes and deeper hair follicles. Qs-lasers can be used to treat the epidermal component, but results in incomplete improvement without epilation of hair follicles. Treatment of Becker’s nevi requires multiple sessions and the outcome is variable.12 Postinflammatory hyperpigmentation (PIH) is a common consequence of inflammatory dermatosis or cosmetic procedure. As with melasma, PIH does not generally respond to laser modalities. Topical treatment

with hydroquinone regimen is often recommended and lasers should be employed with discretion. Drug-induced hyperpigmentation represents deposition of hemosiderin, melanin, or drug metabolites in the skin. Minocycline, amiodarone, and hydroxychloroquineinduced pigmentation commonly presents as blue-gray to brown pigmentation. Use of Qs-lasers showed substantial improvement after the causative medication is discontinued.

Laser Treatment for Tattoos During the cosmetic tattoo process, needles dipped in various colored water-insoluble inks are injected in a constant depth below the dermal-epidermal junction. Once employed, exogenous dye materials are engulfed by dermal macrophages and most of the dyes are deposited in dermis. Prior to current development of laser devices, tattoos were removed by non-selective destructive techniques including dermabrasion, cryosurgery, or surgical excision. Earlier, ablative laser resurfacing was used to remove tattoos and all these modalities resulted in significant scarring. Currently, the most commonly used lasers for tattoo removals are Qs-lasers; Qs-Nd:YAG, Qs-alexandrite, and Qs-ruby. The delivery of high fluence in very short pulse causes cavitation of the tattoo dye particles, which is then eliminated via phagocytosis by macrophage and lymphatic drainage.8 As in 532 nm Qs-lasers, immediate ash-white coloration and purpura occur at the site of contact. To induce selective photothermolysis, lasers should be selected according to the color being treated. However, the absorption spectrum of tattoos is yet unknown, and some colors respond better than others. Blue and black pigments can be removed with all three Qs-lasers, while green tattoo pigment is most effectively removed by Qs-ruby laser, and red is best removed with Qs-Nd:YAG laser. Yellow and orange pigments are very difficult to remove. In multicolored tattoos with brown, white, or red pigments, irreversible darkening may occur. Laser pulse may induce an immediate shift from an oxidized state to a reduced state of the tattoo pigment, as reported in the shift from red pigmentation of ferric oxide to brown or black in reduced-stage ferrous oxide.17 A minimum interval of 4 to 6 weeks is generally required between the laser sessions to allow a sufficient period for rephagocytosis by macrophages and removal by lymphatic drainage. Although the rapid pulse duration

Chapter 118: Laser Treatment of Qs-lasers limits the collateral destruction, absorption peaks of some tattoo inks may coincide with epidermal melanin, resulting in inevitable thermal damage to the epidermis. Patients may experience hypo- or hyperpigmentation and scarring of the treated area because of repetitive epidermal injury. Additionally, the patient may experience an allergic or inflammatory reaction to the altered ink particles, leading to granulomatous reactions. Despite appropriate treatment, tattoos may not respond completely, often requiring multiple treatment sessions. Qs-lasers with pulse durations in the picosecond range were recently developed with the specific goal of shortening the duration of treatment and clearing tattoos that were resistant to previous treatments with a nanosecond laser. Theoretically, a shorter pulse duration should effectively destroy smaller tattoo particles. The use of picosecond-range pulse duration should be validated in further clinical studies. We may expect that conventionally treatment resistant colors (yellow, orange) or partially treated tattoos may benefit from extremely short pulse duration (Table 118.4).18

LASER HAIR REMOVAL Permanent hair reduction refers to the long-term, stable reduction in the number of hairs regrowing after treatment, rather than the total elimination of all hair follicles in the treatment area. The basic principle of laser hair removal is the selective photothermolysis of the pigmented structures of the hair follicle resulting in thermal damage. Photoepilation mainly targets the melanin within the bulge region where follicle stem cells are present, and additionally targets melanin located in the hair shaft, infundibular outer root sheath, and the hair bulb.

Although melanin absorption has broad range, from 400 to 1,200 nm, longer wavelengths between 600 and 1,100 nm are used for photoepilation. The longer wavelengths enable deep penetration into the dermis to reach the hair follicle. Commonly used devices include the long-pulsed ruby (694 nm), alexandrite (755 nm), diode (810 nm), Nd:YAG (1,064 nm) lasers, and IPL. Upon the incident laser light, the hair follicle undergoes direct photothermal injury followed by photomechanical injury induced by photoacoustic waves generated by short nanosecond laser pulses. Consequently, laser or IPL devices induce transient growth arrest by induction of catagen, and permanent hair removal as terminal hair undergo fibrosis or miniaturization into vellus hair. Selection of an appropriate pulse duration is critical for effective photoepilation. TRT of hair follicle is between 10 and 100 ms. To limit the thermal injury to the epidermis, selecting a pulse duration between TRT of the epidermis and hair follicle is ideal. Patients with thick and dark hair and fair skin type may yield the best treatment response, while thin and light-colored hair generally respond poorly. When appropriately used with longer wavelength cutoff filters, IPL can be used for photoepilation. IPL produces a comparable degree of hair reduction to lasers in fair skinned individuals, but is less effective and more likely to cause epidermal injury in dark skin types. For patients with dark skin types, the long-pulsed Nd:YAG laser is less likely to cause side effects. The interval between each treatment should encompass sufficient time for anagen hair to regrow. After multiple treatment sessions, reduction of hair numbers between 40% and 90% is achieved, depending on the anatomic location and hair characteristics.19

Table 118.4: Tattoos colors and pigments. Color Pigment chemical Black India ink, carbon, iron oxide Blue Cobalt aluminate Green Chromium oxide, hydrated chromium sesquioxide, malachite green, lead chromate, ferric cyanide, curcumin green, phthalocyanine dyes Red Mercury sulfide, cadmium selenide, ochre, ferric sulfate Brown Ochre Yellow Cadmium sulfide, curcumin yellow, ochre Tan, nude Iron oxides White Titanium dioxide, zinc oxide

Laser / system Qs-ruby, Qs-alexandrite, Qs-Nd:YAG (1,064 nm) Qs-ruby, Qs-alexandrite, Qs-Nd:YAG (1,064 nm) Qs-ruby, Qs-alexandrite, Qs-Nd:YAG (1,064 nm)

Qs-ruby, Qs-alexandrite, Qs-Nd:YAG (1,064 nm) Qs-ruby, Qs-alexandrite, Qs-Nd:YAG (1,064 nm) Qs-Nd:YAG (532 nm) Qs-Nd:YAG (532 nm) Qs-Nd:YAG (532 nm)

Source: Adapted from Kent KM, Graber EM. Laser tattoo removal: a review. Dermatol Surg. 2012;38(1):1–3.

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Section 32: Physical Modalities of Therapy Patients must be notified at least 6 weeks prior to treatment that they must not pluck or wax the targeted areas. Meanwhile, shaving or using depilatory creams does not affect photoepilation. Shaving the target lesion is required prior to the treatment to avoid epidermal injury. Adverse events occur more frequently in patients with dark skin types including, post-treatment erythema, hypo- and hyperpigmentation, and scarring. However, the complications are rare with proper selection of the target treatment area. Rarely, paradoxical hypertrichosis is triggered in the treatment area, involving facial hair of dark skin type individuals.20

ABLATIVE LASERS AND RESURFACING Water is the target chromophore of CO2 (10,600 nm) and Er:YAG (2,940 nm) lasers. Selective photothermolysis of the epidermis and dermis can be achieved, as water makes up nearly 80% of the skin. CO2 and Er:YAG lasers can effectively ablate the skin to various depths according to the energy applied. Therefore, both can be used to treat variety of medical conditions such as removal of benign or malignant skin tumors or infectious conditions. Nowadays, ablative lasers are commonly used to resurface and rejuvenate the skin by treating rhytides and other textural irregularities (Figs. 118.10A and B).

Carbon Dioxide Laser (CO2 Laser) The first introduced CO2 laser only emitted a continuous wave beam, and is still in use as an incision tool for surgical dissection. Continuous wave lasers led to a greater degree of thermal damage, resulting in excessive scarring. The

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CO2 laser can be delivered in pulsed mode, which allows more selective control of vaporization with coagulation or desiccation of surrounding tissue. When used in continuous or quasi-continuous wave mode, CO2 lasers can efficiently treat benign skin tumors such as xanthelasma, syringomas, and neurofibromas. For the lesions located in areas with risk of scarring, pulsed system mode can be applied. Premalignant lesions including actinic cheilitis can be effectively removed. Another common indication for the CO2 lasers is treatment of genital warts or condyloma acuminata lesions. Common warts that have failed conventional treatment can be an indication for laser ablation. Thick, hyperkeratotic lesions require a higher fluence to debulk the viral load. When treating such lesions, superficial ablation of perilesional skin can be beneficial in preventing recurrence. During the procedure, protection with facial masks and a vacuum system is mandatory, considering the possibility of inhaling the evaporated viral DNA load. Pulsed delivery of CO2 laser is more suitable for resurfacing purposes, which induces ablation of the skin surface by rapid cellular heating and tissue vaporization, while limiting deeper thermal damage. Up to 50 µm of the skin surface is removed and a collateral zone below the treated area, 100–200 µm in depth, also undergoes photothermal changes. At first, homeostasis of papillary dermal vessels is achieved and proteins are denatured by thermal injury, which triggers the remodeling of collagen and elastic tissue. In super-pulse mode, the laser beam is delivered in short bursts, allowing ablation with further prevention of adverse effects. Incorporated with scanning devices, the laser beam can be delivered more accurately and promptly. To date, short-pulsed, high fluence CO2 laser remains the

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Figs. 118.10A and B: Laser resurfacing and fractional photothermolysis. (A) Overview of different laser systems for laser resurfacing. Compared to conventional ablative laser system, fractional lasers generate columns of coagulated and ablated tissue in a controlled pattern; (B) Fractional photothermolysis. An array of microscopic zones of thermal injury, or microscopic treatment zones (MTZs), are generated. Each MTZ is surrounded by unaffected skin allowing fast recovery time. (Er, erbium; YAG, yttrium-aluminum-garnet; YSGG, yttrium-scandium-gallium-garnet).

Chapter 118: Laser Treatment gold standard for photorejuvenation and skin tightening. As a result, CO2 resurfacing can induce photorejuvenation by collagen remodeling. However, the ablative resurfacing procedures require a long recovery period which may last several weeks and cause significant textural or pigmentary change during the process.

Erbium:Yttrium-Aluminum-Garnet Laser (Er:YAG Laser) Er:YAG lasers emit a laser beam at a wavelength of 2,940 nm. This wavelength is more efficiently absorbed by water by 18-fold than with a CO2 laser. As such, Er:YAG ablation results in a more superficial ablation with less thermal damage to the surrounding surface, leading to reduced recovery time and patient morbidity. Compared to the photocoagulation effects of CO2 laser, the Er:YAG laser produces decreased thermal damage of the underlying dermis. Consequently, the degree of tissue remodeling and the skin-tightening phase is less pronounced than that of CO2 laser. To overcome such limitations, Er:YAG systems have been incorporated to generate lengthier pulse durations or higher fluences. However, although the modulated Er:YAG laser achieves similar clinical results as seen in CO2 laser, the overall recovery period is proportionally prolonged when compared to CO2 ablation. Ablative resurfacing poses a significant risk of infection by bacteria, viruses, or fungi. The reported occurrence of disseminated or localized HSV infection is approximately 5 ~ 7 %, which usually develops within the first week. Prophylactic treatment with antiviral medications is required, especially when treating facial lesions, beginning the day of the laser treatment.

FRACTIONAL LASERS The main limitations of traditional ablative resurfacing techniques are prolonged downtime, risk of scarring, and irregular pigmentary changes. Moreover, when performed by an underqualified physician, the results of collagen remodeling and photorejuvenation can be inconsistent. To overcome drawbacks from ablative fractional resurfacing, the concept of fractional photothermolysis was proposed in 2004.21 Fractional photothermolysis (FP) is a technique whereby an ablative laser is administered in a fractionated pattern over a grid rather than full ablation of the treated area. A high fluence laser beam forms multiple, discrete columns of thermal damage with complete sparing of surrounding tissue. These microthermal zones

(MTZs) consist of sharply confined tissue denaturation with a diameter of about 100 µm, at intervals of about 200 µm. MTZs only account for 15 ~ 25% of the skin surface and are separated by uninvolved normal tissue, which acts as a reservoir for tissue regeneration, enabling rapid wound healing. The overall wound healing response is primarily determined by the density of individual MTZs within the treated area. The thermal injury induced by MTZs can induce collagen remodeling and synthesis, as in traditional ablative resurfacing, but to a lesser degree. Fractional resurfacing has been used to treat photoaging and rhytides with the advantage of more rapid healing and less patient morbidity. Compared to traditional ablative resurfacing, multiple treatment sessions are required to achieve sufficient benefit, and the outcome is not as dramatic as with CO2 ablative resurfacing. Fractionated lasers can be either non-ablative or ablative. The former generates MTZs characterized by thermal coagulation and the latter results in full-thickness destruction and a surrounding zone of coagulated tissue.

Non-ablative Fractional Photothermolysis Non-ablative fractional photothermolysis (NFP) generates MTZs with a small diameter zone of thermally damaged epidermis and dermis. Although the skin remains intact visibly, the degree of thermal damage is sufficient to cause cell necrosis and coagulation of collagen. NFP devices have wavelengths between 1,320 and 1,927 nm ; Er:Glass (1,540 and 1,550 nm), Er: Fiber and Er:Thallium (1,927 nm). The most commonly known fractionated laser is the Er:Glass laser with 1,550 nm wavelength. The NFP system usually requires multiple treatment sessions, resulting in moderated improvement in rhytides and skin tightening. The newer generation of NFP systems combines more superficial 1,927 thallium to induce additional improvement in texture and pigmentation. Treatment with NFP lasers induces immediate erythema and edema lasting up to 3 to 5 days. The risk of postinflammatory hyperpigmentation is higher in darker skin type patients, which can be prevented by reducing the fluence and the density of MTZs.

Ablative Fractional Photothermolysis Ablative fractional photothemolysis (AFP) was developed after the clinical success of fractionated non-ablative rejuvenation. AFP devices have longer wavelengths compared to NFP systems; Er:YAG (2,940 nm), Er:YSGG (2,970 nm),

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Section 32: Physical Modalities of Therapy and CO2 (10,600 nm). Theoretically, AFP systems aim to produce clinical results similar to their non-fractionated counterparts. AFP systems generate MTZs by vaporizing full-thickness zones of tissue which may extent to the deep dermis. Surrounding the denatured columns created by MTZs is a collateral area of thermal denaturation which is sufficient to cause cell necrosis and coagulate collagen.22 An aggressive approach with AFP lasers can result in prolonged erythema and delayed wound healing when compared to NFL systems. However, the adverse effect profile is acceptable with a comparable degree of collagen remodeling to traditional ablative resurfacing. Furthermore, MTZs formed by an AFP system can be adjusted to target specific depth and diameter by increasing the fluence and inducing regulated disruption of the epidermal barrier. As such, AFP lasers have been demonstrated to facilitate topical drug delivery in various conditions.23

Indications Acne Scars Atrophic-type acne scarring is the most common, up to 80–90%, and further subdivided into icepick, boxcar, and rolling, according to its morphologic features. Treatment of acne scars remains a therapeutic challenge with a broad range of treatment options in the field, including chemical peels, dermabrasion, punch excision, and laser treatments. Facial resurfacing with fractional lasers is commonly applied to acne scars. Especially for the atrophic scars, ablative fractional laser has demonstrated its efficacy in

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various reports. However, ablative fractional laser may carry significant risk of post-treatment erythema, postinflammatory hyperpigmentation, scarring, infection, and prolonged healing. Especially, the pigmentary complication can be problematic in darker skin type. Non-ablative laser systems can be used for acne scars. As in facial rejuvenation procedures, non-ablative fractional lasers spare the epidermis and shorten the down time with less side effects, but they are also less effective. In a study comparing the effect of ablative and non-­ablative fractional photothermolysis, acne scars treated with the ablative fractional laser system reported a superior improvement range.24 The severity of the acne scar is the most important factor in deciding the potential b ­ enefits of non-ablative systems (Figs. 118.11A and B).

Hypertrophic Scars and Keloids Normal wound-healing process consists of sequentially overlapping phases of coagulation, inflammation, and remodeling. Hypertrophic scars or keloids develop due to an abnormal wound-healing process, which induces excessive collagen and extracellular matrix (ECM) derivative accumulation. There have been numerous treatment options, including intralesional steroids, silicone-gel sheeting, radiation, cryotherapy, and laser treatment. However, most of the treatment options require multiple sessions with variable clinical outcomes. Studies have demonstrated that fractional laser systems can be successfully utilized in the treatment of various forms of scarring with a very favorable safety profile. Fractional photothermolysis, both ablative and

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Figs. 118.11A and B: Laser treatment of acne scar. (A) Before treatment; (B) After second treatment with ablative fractional laser resurfacing.

Chapter 118: Laser Treatment

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Figs. 118.12A and B: Laser treatment of hypertrophic surgical scar. (A) Patient who underwent total thyroidectomy with persistent hypertrophic scar, before treatment; (B) After second treatment with ablative and non-ablative fractional laser resurfacing.

non-ablative, can improve the texture of various scars by promoting collagen remodeling.25 Since hypertrophic scars are well-vascularized, PDL can be used to target vascular component of the entity.26 To prevent hypertrophic scarring in postoperative scars, prompt treatment with ablative and non-ablative fractional lasers can accelerate the wound-healing process.25 To date, the fractional laser is an efficient and safe therapeutic modality for hypertrophic scars and keloids and should be considered as a part of combination therapy for better results (Figs. 118.12A and B).

Striae Distensae Striae distensae are common, resulting from pregnancy, rapid weight gain, or growth spurts. Early lesions present as red-to-violaceous lesions and mature lesions exist as hypopigmented-dermal depressions. Lasers have been used in attempt to promote collagen production and reduce erythema. Non-ablative fractional lasers have demonstrated an increase in collagen and elastic fiber deposition after the treatment. For early lesions with persistent erythema, PDL has demonstrated clinical improvement. For mature, long-standing lesions, pulsed CO2, non-ablative fractional lasers, and IPL have been used with variable degrees of improvement.27

REFERENCES 1. Tan OT, Sherwood K, Gilchrest BA. Treatment of children with port-wine stains using the flashlamp-pulsed tunable dye laser. N Engl J Med 1989;320(7):416–21. 2. van der Horst CM, Koster PH, de Borgie CA, et al. Effect of the timing of treatment of port-wine stains with the flash-

lamp-pumped pulsed-dye laser. N Engl J Med 1998;338(15): 1028–33. 3. Huikeshoven M, Koster PH, de Borgie CA, et al. Redarkening of port-wine stains 10 years after pulsed-dye-laser treatment. N Engl J Med 2007;356(12):1235–40. 4. Hohenleutner S, Badur-Ganter E, Landthaler M, et al. Long-term results in the treatment of childhood hemangioma with the flashlamp-pumped pulsed dye laser: an evaluation of 617 cases. Lasers Surg Med 2001;28(3):273–7. 5. Jorgensen GF, Hedelund L, Haedersdal M. Long-pulsed dye laser versus intense pulsed light for photodamaged skin: a randomized split-face trial with blinded response evaluation. Lasers Surg Med 2008;40(5):293–9. 6. Kunishige JH, Goldberg LH, Friedman PM. Laser therapy for leg veins. Clin Dermatol 2007;25(5):454–61. 7. van der Vleuten CJ, Kater A, Wijnen MH, et al. Effectiveness of sclerotherapy, surgery, and laser therapy in patients with venous malformations: a systematic review. Cardiovasc Intervent Radiol 2014;37(4):977–89. 8. Taylor CR, Anderson RR, Gange RW, et al. Light and electron microscopic analysis of tattoos treated by Q-switched ruby laser. J Invest Dermatol 1991;97(1):131–6. 9. Dover JS, Margolis RJ, Polla LL, et al. Pigmented guinea pig skin irradiated with Q-switched ruby laser pulses. Morphologic and histologic findings. Arch Dermatol 1989;125(1):43–9. 10. Graber EM, Dover JS. Lasers and lights for treating pigmented lesions. In: Nouri K, ed. Lasers in Dermatology and Medicine, vol. 1, 1st edn. New York: Springer, 2011:63–81. 11. Stratigos AJ, Dover JS, Arndt KA. Laser treatment of pigmented lesions--2000: how far have we gone? Arch Dermatol 2000;136(7):915–21. 12. Carpo BG, Grevelink JM, Grevelink SV. Laser treatment of pigmented lesions in children. Semin Cutan Med Surg 1999;18(3):233–43. 13. Polnikorn N, Tanrattanakorn S, Goldberg DJ. Treatment of Hori’s nevus with the Q-switched Nd:YAG laser. Dermatol Surg 2000;26(5):477–80. 14. Taylor CR, Anderson RR. Ineffective treatment of refractory melasma and postinflammatory h ­ yperpigmentation by Q-switched ruby laser. J Dermatol Surg Oncol 1994;20(9):592–7. 15. Niwa Massaki AB, Eimpunth S, Fabi SG, et al. Treatment of melasma with the 1,927-nm fractional thulium fiber laser: a retrospective analysis of 20 cases with long-term follow-up. Lasers Surg Med 2013;45(2):95–101. 16. Dunbar S, Posnick D, Bloom B, et al. Energy-based device treatment of melasma: an update and review of the literature. J Cosmet Laser Ther 2017;19(1):2–12. 17. Anderson RR, Geronemus R, Kilmer SL, et al. Cosmetic tattoo ink darkening. A complication of Q-switched and pulsed-laser treatment. Arch Dermatol 1993;129(8): 1010–4. 18. Reiter O, Atzmony L, Akerman L, et al. Picosecond lasers for tattoo removal: a systematic review. Lasers Med Sci 2016;31(7):1397–405.

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Section 32: Physical Modalities of Therapy 19. Klein A, Steinert S, Baeumler W, et al. Photoepilation with a diode laser vs. intense pulsed light: a randomized, intrapatient left-to-right trial. Br J Dermatol 2013;168(6):1287–93. 20. Desai S, Mahmoud BH, Bhatia AC, et al. Paradoxical hypertrichosis after laser therapy: a review. Dermatol Surg 2010;36(3):291–8. 21. Manstein D, Herron GS, Sink RK, et al. Fractional photothermolysis: a new concept for cutaneous remodeling using microscopic patterns of thermal injury. Lasers Surg Med 2004;34(5):426–38. 22. Thongsima S, Zurakowski D, Manstein D. Histological comparison of two different fractional photothermolysis devices operating at 1,550 nm. Lasers Surg Med 2010;42(1):32–7. 23. Haedersdal M, Erlendsson AM, Paasch U, et al. Translational medicine in the field of ablative fractional laser (AFXL)-

24. 25.

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assisted drug delivery: a critical review from basics to current clinical status. J Am Acad Dermatol 2016;74(5): 981–1004. Ong MW, Bashir SJ. Fractional laser resurfacing for acne scars: a review. Br J Dermatol 2012;166(6):1160–9. Shin JU, Gantsetseg D, Jung JY, et al. Comparison of non-­ablative and ablative fractional laser treatments in a postoperative scar study. Lasers Surg Med 2014;46(10): 741–9. Alster TS. Improvement of erythematous and hypertrophic scars by the 585-nm flashlamp-pumped pulsed dye laser. Ann Plast Surg 1994;32(2):186–90. Hague A, Bayat A. Therapeutic targets in the management of striae distensae: a systematic review. J Am Acad Dermatol 2017;77(3):559–68 e18.

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Cryosurgery Julia May, Allyson Tank, Manas Deolankar, Carl F Schanbacher

INTRODUCTION Cryosurgery (CS), or cryotherapy, refers to the local destruction of tissue via application of extremely cold temperatures. Such low temperatures are produced by using agents such as liquid nitrogen, which is typically applied directly to the target tissue via spray bottle or with a cotton-tipped applicator. Cryosurgery remains a highly versatile technique that is commonly utilized to treat many benign, premalignant, and malignant skin conditions. Since its inception over a century ago, cryosurgery has been shown to be a particularly efficient treatment modality because of its safety, ease of use, versatility, and relatively low cost. Cryosurgery is employed to selectively destroy tissue for both curative and cosmetic purposes. Cryosurgery achieves its effect through one or several mechanisms of action. Initially, freezing induces tissue necrosis from intraand extracellular ice crystal formation. Subsequently, disruption of cellular microcirculation occurs during thawing; vascular damage inhibits blood perfusion to the damaged cells or tissue, greatly diminishing its survival profile. Freezing may also promote cell death via apoptosis, especially at the periphery of the damaged lesion.1 Recent investigation suggests an immunological effect of freezing, although this mechanism has not been fully elucidated.2 The most commonly used cryogen, liquid nitrogen, is the coldest and most versatile agent available, with a boiling point of –196°C. Colder cryogens allow for deeper target tissue destruction within the frozen area. Other currently available cryogens include nitrous oxide, solid carbon dioxide and argon gas; however, these are not routinely used to treat cutaneous lesions.

INDICATIONS AND CONTRAINDICATIONS Cryosurgery is indicated for numerous benign lesions. The most commonly treated skin lesions include warts,

molluscum contagiosum, and seborrheic keratoses.3 It is also widely utilized in treating premalignant lesions such as actinic keratoses (AKs). Cryosurgery can be utilized for malignant lesions as well. Thin skin cancers, such as superficial basal cell carcinomas (BCCs) or squamous cell carcinomas (SCCs) in situ, are particularly amenable to this treatment modality. Cryosurgery implementation is not limited to thin tumors; larger BCCs and SCCs of various subtypes can be effectively ablated in experienced hands. In fact, cure rates for well-defined BCCs and SCCs have been reported at 98–99%.4 Cryosurgery is acceptable for use at almost any anatomical site, which is advantageous for surgically challenging locations. However, additional precaution should be taken when treating central areas on the face, eyebrows, and scalp. As these areas possess greater proclivity to scarring, tissue retraction, and scarring alopecia, alternative treatment modalities should be taken into consideration.1 Cryosurgery should not be utilized for lesions with indistinct borders, such as tumors classified with an infiltrative growth pattern. Patients afflicted with cold urticaria, cryofibrinogenemia, or cryoglobulinemia are not ideal candidates for cryosurgery. Cryosurgery is also not advised for patients with darkly pigmented skin, as hypopigmentation commonly occurs subsequent to treatment. Additionally, it should be avoided in locations closely overlying superficial nerves and tendons, as permanent collateral damage can occur.

INSTRUMENTATION Cryosurgeons can employ various freezing methods depending on the type of lesion being treated, the lesion location, as well as the personal preference of the operator. The most common and versatile method is to use a handheld spray canister, many of which have interchangeable tips that can modify the diameter of the nozzle opening (Fig. 119.1). Cryosurgeons can also freeze a lesion via direct application of a cotton-tipped applicator that has been saturated in liquid nitrogen. This is a particularly

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Fig. 119.1: A liquid nitrogen handheld spray canister.

Fig. 119.2: Cotton-tipped applicators saturated in liquid nitrogen for the dipstick method.

helpful technique for young children who may be frightened by the spray canister apparatus appearance or the unique auditory experience. Less commonly utilized are cryoprobes for contact therapy, in which a metal instrument (needle driver or forceps) is dipped in liquid nitrogen and then applied directly to the lesion. Cryoprobes are very useful in treating pedunculated lesions such as skin tags. A thermocouple is a helpful tool to supplement cryosurgery for particularly deep or malignant lesions. It monitors the skin temperature throughout the freezing process enabling the operator to monitor and adjust the extent of freezing. The thermocouple can be mounted on a 25–30 gage needle and inserted adjacent to the lesion such that the tip comes to rest at the base of the lesion.

TECHNIQUES Cryosurgery can be implemented using a variety of techniques. The appropriate technique should be determined by taking into consideration the characteristics of the lesion, such as size and location on the body, the patient, and the operator preference.

Dipstick The simplest and most cost-effective method of cryosurgery is the use of a cotton-tipped applicator saturated with liquid nitrogen. The dipstick technique is the most common method for treating benign, superficial lesions.5 The applicator is dipped into a cup of liquid nitrogen and then applied to the lesion with a pressure correlating to the depth of freeze desired (Fig. 119.2). Increased pressure

Fig. 119.3: The treatment of a pigmented actinic keratosis of the nose using the dipstick method.

results in an increased depth of freeze; this application may need to be performed several times in series until the desired extent of ice formation occurs (Fig. 119.3). The dipstick method is ideal when treating benign lesions in areas that would be difficult to safely treat with the spray or probe method, such as lesions located on the face.6 Due to the limited freeze depth associated with applicator use, this method is not optimal for malignant lesions.

Spray The spray method is the most common technique used in cryosurgery. The liquid nitrogen is applied to the lesion using a handheld spray unit held perpendicular to the skin

Chapter 119: Cryosurgery surface. The tip of the unit allows interchangeable attachments to be used to compliment lesions of varying sizes and conformations.7 Specific patterns of spray, such as the spiral or rotary pattern, can be applied to the open spray to better treat lesions.8 A plastic cone, held firmly against the skin, can be applied to the open spray to confine it to a more focused skin area. The cone corrals the liquid nitrogen, circumventing juxtaposed healthy tissue damage, and confines it to the intended treatment target.6 Due to its versatility, ability to treat lesions varying sizes, and ability to treat irregular surfaces, the spray technique is indicated for the treatment of premalignant and malignant lesions.

Probe The cryosurgical unit can be equipped with a probe for treating flat lesions on the skin. The probe is placed directly on the lesion and liquid nitrogen flows through the unit and directly into the lesion. The flow is maintained at a constant low temperature and therefore applicable for treating benign, premalignant, and malignant lesions with appropriate freeze time for each.9,10

COMBINED TECHNIQUES Cryotherapy can be combined synergistically with other treatment techniques to increase overall efficacy. For example, cryotherapy can be used in combination with topical antineoplastic creams, such as 5-fluorouracil cream 0.5%, to treat precancerous actinic keratoses. Studies have substantiated using the combination treatment to reduce the recurrence rate of the AKs.11 Similar beneficial outcomes were found with combination treatment of keloid scars using both cryotherapy and intra­lesional corticosteroid injections. Keloid scars are known to be resistant and recur following treatment. However, patients who received both treatments were found to have a lower recurrence rate and better clinical outcome.12

TREATMENT PRINCIPLES The nature and efficacy of cryosurgical treatment is dependent on multiple factors that will vary with lesion type, location, and malignancy, as well as the cryosurgical technique being utilized. The “depth dose” of the freeze, or the temperature beneath and around the lesion, is a parameter that must be determined prior to beginning treatment. The depth dose can be judged clinically via observation of freeze time (duration of cooling),

thaw time, and the lateral spread of freeze (LSF; distance beyond the border of the lesion that is frozen). Freeze time generally falls between 3 and 60 seconds using the open spray technique, or two to three times longer when using a cryoprobe.11 After freezing, the lesion is left to thaw naturally, usually requiring two to three times the freeze time to completely thaw. The LSF generally ranges from 2 to 5 mm, greater when the lesion is malignant.13 The temperature required for destruction of tissue (therapeutic necrosis) is –60°C. The cryosurgeon can use a thermocouple to assure that this temperature is reached, or with experience the surgeon may rely on the abovementioned clinical observations to assure the proper temperature is reached throughout the lesion being treated. Closely monitoring temperature with a thermocouple is not always practical or necessary, and advised only for deep malignant lesions with potential to metastasize, or to assist novice cryosurgeons. Local anesthesia is not necessary when treating small lesions; however, it may be necessary for larger treatment areas that require a longer and deeper freeze. Lesions should be treated with different techniques of cryosurgery depending on their location and level of treatment intensity. In general, benign lesions usually require less freeze time, while premalignant and malignant lesions could require more than 60 seconds of freeze and multiple, serial freeze-thaw cycles for optimal destruction.7

Benign Lesions Benign lesions should be approached conservatively to avoid hypopigmentation, as retreatment may be necessary. Superficial lesions such as thin seborrheic keratoses, lentigines, and hemangiomas can easily be eradicated using the open-spray technique; a brief 3–4s spray with a minimal 1–1.5 mm LSF is generally sufficient for thin lesions. Pedunculated lesions, such as fibroepithelial polyps, can easily be frozen using metal forceps that have been dipped into liquid nitrogen. This offers the cryosurgeon greater control of the area to be treated (Fig. 119.4). Verruca vulgaris and periungual warts are often trea­ ted with the dipstick method, as it offers greater control over the region being treated. With either this or the open-spray technique, an LSF of 1 to 2 mm is recommended14 (Fig. 119.5). Multiple treatments are often required and combination therapy with different home treatment agents such as salicylic acid is often needed to treat plantar warts.

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Section 32: Physical Modalities of Therapy Moderate success has been reported treating keloids with the open spray technique. Care should be taken to avoid freezing healthy tissue around the keloid as to avoid further scarring.3 A newer approach to consider is intra­ lesional cryotherapy, which uses a unique needle probe to deliver liquid nitrogen within the keloid. This technique eliminates potential collateral scarring of juxtaposed normal integument and offers more adequate freezing of the keloid tissue.15

Premalignant Lesions Premalignant lesions are exceptionally amenable to cryosurgery. Actinic keratoses are commonly treated with a 5–10 s open spray freeze; multiple lesions can be treated in one visit.13 While older studies reported cure rates over 98%16, more recent research has suggested less optimistic results. One study found an 80% complete cure rate of AKs

Fig. 119.4: Forceps dipped into liquid nitrogen to treat fibroepithelial polyp of the neck.

using a 10–15 second freeze time, with a 94% favorable cosmetic outcome.17 Notwithstanding, regimented cutaneous surveillance evaluation for patients with extensive sun damage is strongly advised.

Malignant Lesions Lentigo maligna is suitable for cryosurgical treatment, as melanocytes are particularly sensitive to freezing. While surgical excision or Mohs micrographic surgery remain the standard of care, cryotherapy can be utilized for highrisk surgical patients or for lesions that are large and/or in surgically challenging locations. An open spray technique with two freeze-thaw cycles consisting of an approximately 60 second freeze time and an approximately 120 second thaw time can be utilized, achieving a 1 cm LSF.13,18 As BCCs and SCCs are commonly treated with cryosurgery, well-defined margins are crucial to the success of treatment. Ideally, cryosurgery is employed for small, thin tumors. Multiple scout biopsies can confirm the margins of larger tumors, and curettage can be utilized preoperatively to debulk thicker tumors. The volume of tissue destroyed via cryotherapy must equal the amount that would be removed via surgical excision. Margins should be inked prior to injection of anesthetic. Two freeze-thaw cycles including a 30–60 s freeze time are generally performed; however, high success rates have been reported for small BCCs and SCCs with a single freeze-thaw cycle, especially with the assistance of curettage.19,20 Immunocryosurgery is another effective treatment modality for small BCCs and SCCs in situ. This technique involves liquid nitrogen cryosurgery at week 2 of a 5-week

Fig. 119.5: Cryotherapy for verruca vulgaris on the plantar surface of the foot.

Chapter 119: Cryosurgery treatment regimen of topical imiquimod. This approach has demonstrated a greater than 90% cure rate.21 Larger tumors may be treated in sections via segmental cryosurgery, in which the periphery of the lesion is first frozen to decrease the size of the tumor. The wound is allowed to heal, and then the patient returns for further treatment.22 Fractional cryosurgery is a similar technique that involves conservatively freezing the center of the lesion first. When the lesion has sufficiently decreased in size such that traditional cryosurgery will no longer result in disfigurement, the procedure is repeated with the standard method and safety margin.23

PATIENT OUTCOMES AND POSTOPERATIVE CARE The freezing process produces a localized burning sensation that evolves into a more intense pain during the thawing process. Edema and urtication occur within minutes following treatment. More dramatic swelling usually occurs on the face. If treatment is more intense, blistering will occur, typically hours after treatment. Wound care depends on the location and size of the lesion, as well as the nature of the treatment. For smaller benign lesions that did not undergo multiple freeze-thaw cycles, no specific aftercare is required; however, the patient may desire to protect the treatment site with a bandage as it may remain temporarily hypersensitive to contact with clothing. For lesions treated with multiple freeze-thaw cycles resulting in an exudative wound, the patient may dress the wound daily with petroleum jelly and a bandage. Healing may take several weeks for larger wounds.

should be placed in a separate smaller container before saturating the applicator and applying to the lesion. Then dispose of the small container and applicators after use.7 Complications can arise with methods such as the open spray when treating sensitive areas such as the face and ears. In effort to spare the structures surrounding the lesion, precautions should be used to protect the surrounding tissue to make sure unintended parts of the body are not harmed. One way to accommodate this is to exercise the versatility of the cryotherapy device. The tip of the device can be fit inside of a cone. The funnel directs the liquid nitrogen towards the intended lesion and protects the surrounding tissue.26 Serious complications from cryosurgery are rare. Bleeding is possible after deep freezes or during the healing process. Infections may occur in slow-healing wounds. Long-term nerve damage is possible, especially in areas containing superficial nerves. The method is also regarded as inconvenient in certain cases due to the need for multiple treatments, resulting in multiple visits to the clinic.

FUTURE OF CRYOSURGERY Cryosurgery specifically remains popular to this day due to its versatility, low cost, and its utility in treating a broad range of skin lesions. Because of the relatively low degree of expense and procedure complexity, cryosurgery will remain popular among dermatologists for the treatment of benign, premalignant, and malignant lesions when indicated. Improvements in the devices used to deliver liquid nitrogen in addition to the coupling of cryosurgery with other surgical techniques will provide new avenues for treatment of skin lesions.

COMPLICATIONS Temporary hypopigmentation is to be expected in the frozen areas, often accompanied by a ring of hyperpigmentation surrounding the lesion. However, permanent depigmentation is a possible complication of cryosurgery and often seen especially after more intense treatment. Postoperative hypopigmentation is mainly due to the sensitive nature of melanocytes to the extremely low temperatures resulting from treatment.24 This effect will be more dramatic in darkly pigmented patients.25 Special caution should be taken when using the dipstick method, as there have been many documented cases of liquid nitrogen stores being contaminated from cotton-tipped applicator re-use, specifically with contagious lesions such as verrucae. To prevent this, the liquid nitrogen

REFERENCES 1. Afsar FS, Erkan CD, Karaca S. Clinical practice trends in cryosurgery: a retrospective study of cutaneous lesions. Postepy Dermatol Alergol 2015;32(2):88–93. 2. Ahmed I, Agarwal S, Ilchyshyn A, et al. Liquid nitrogen cryotherapy of common warts: cryo-spray vs. cotton wool bud. Br J Dermatol 2001;144(5):1006–9. 3. Rusciani L, Paradisi A, Alfano C, et al. Cryotherapy in the treatment of keloids. J Drugs Dermatol 2006;5(7):591–5. 4. Graham GF, Clark LC. Statistical analysis in cryosurgery of skin cancer. Clin Dermatol 1990;8(1):101–7. 5. Zimmerman EE, Crawford P. Cutaneous cryosurgery. Am Family Physician 2012;86(12):1118–24. 6. Abramovits W, Graham G, Har-Shai Y, et al. eds. Dermatological Cryosurgery and Cryotherapy. 1st edn. London: Springer-Verlag London; 2016. XXIII, 758 p.

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Section 32: Physical Modalities of Therapy 7. Goldsmith LA, Fitzpatrick TB. Fitzpatrick’s Dermatology in General Medicine. 8th edn. New York: McGraw-Hill Professional; 2012. 1495 p. 8. James WD, Berger TG, Elston DM. Andrews’ Diseases of the Skin: Clinical Dermatology. 12 edn. Philadelphia, PA: Elsevier; 2016. 965 p. 9. Fourkas M, Govenji P. Cryogenic probe system. Google Patents; 2013. 10. Fourkas M, Govenji P. Cryogenic probe system and method. Google Patents; 2015. 11. Hoover WD 3rd, Jorizzo JL, Clark AR, et al. Efficacy of cryosurgery and 5-fluorouracil cream 0.5% combination therapy for the treatment of actinic keratosis. Cutis 2014; 94(5):255–9. 12. Hirshowitz B, Lerner D, Moscona AR. Treatment of keloid scars by combined cryosurgery and intralesional corticosteroids. Aesthetic Plast Surg 1982;6(3):153–8. 13. Kuflik EG. Cryosurgery updated. J Am Acad Dermatol 1994;31(6):925–44; quiz 44–6. 14. Kuflik EG. Cryosurgical treatment of periungual warts. J Dermatol Surg Oncol 1984;10(9):673–6. 15. Goldenberg G, Luber AJ. Use of intralesional cryosurgery as an innovative therapy for keloid scars and a review of current treatments. J Clin Aesthetic Dermatol 2013;6(7): 23–6. 16. Lubritz RR, Smolewski SA. Cryosurgery cure rate of actinic keratoses. J Am Acad Dermatol 1982;7(5):631–2.

17. Thai KE, Fergin P, Freeman M, et al. A prospective study of the use of cryosurgery for the treatment of actinic keratoses. Inter J Dermatol 2004;43(9):687–92. 18. de Moraes AM, Pavarin LB, Herreros F, et al. Cryosurgical treatment of lentigo maligna. J Dtsch Dermatol Ges 2007;5(6):477–80. 19. Peikert JM. Prospective trial of curettage and cryosurgery in the management of non-facial, superficial, and minimally invasive basal and squamous cell carcinoma. Inter J Dermatol 2011;50(9):1135–8. 20. Samain A, Boullie MC, Duval-Modeste AB, et al. Cryosurgery and curettage-cryosurgery for basal cell carcinomas of the mid-face. J Eur Acad Dermatol Venereol 2015;29(7):1291–6. 21. Gaitanis G, Bassukas ID. Immunocryosurgery — an effective combinational modality for Bowen’s disease. Dermatol Ther 2016;29(5):334–7. 22. Kuflik EG. The “field-fire” basal-cell carcinoma: treatment by cryosurgery. J Dermatol Surg Oncol 1980;6(4):247–9. 23. Goncalves JC. Fractional cryosurgery for skin cancer. Dermatol Surg 2009;35(11):1788–96. 24. Burge SM, Bristol M, Millard PR, et al. Pigment changes in human skin after cryotherapy. Cryobiol 1986;23(5): 422–32. 25. Elton RF. Complications of cutaneous cryosurgery. J Am Acad Dermatol 1983;8(4):513–9. 26. Andrews MD. Cryosurgery for common skin conditions. Am Family Physician 2004;69(10):2365–72.

Chapter

120

Radiotherapy

Aaron Wallace, Manas Deolankar, Julia May, Yen-Lin Chen, John Strasswimmer, Thanh Nga Tran

INTRODUCTION Over the past 100 years, radiotherapy (RT) has been applied to nearly every skin condition: acne vulgaris, eczema, psoriasis, etc. Today, however, radiotherapy is primarily used to treat the non-melanoma skin cancers (NMSC): basal cell carcinoma (BCC), and squamous cell carcinoma (SCC). There are numerous treatment options available for the treatment of NMSC, including standard excision, curettage, curettage with electrodessication, and Mohs micrographic surgery (MMS), the gold standard for the definitive treatment of NMSC. In addition, low-risk and superficial NMSC can also be treated with topical therapies, such as imiquimod and 5-fluorouracil cream. Additionally, vismodegib and sonidegib, orally administered inhibitors of hedgehog pathway activation, are approved for use in metastatic and locally advanced BCC not amenable to other options. In advanced cases, radiation may also be combined with oral hedgehog medications for advanced and metastatic BCC.1 While radiotherapy has been a viable option for the treatment of NMSC since the 1900s, the use of radiation therapy declined since the development of MMS. However, with advances in radiation technology, there is a resurgence in the use of radiation therapy; particularly, brachytherapy and superficial radiation therapy (SRT) in the treatment  of NMSC. The reason for the resurgence in the use of radiotherapy is multifaceted. For example, there are specific situations where radiation may be preferred. The most common is in elderly patients who do not wish or cannot undergo surgery. Radiation is also commonly used in adjuvant treatment with surgery to reduce the risk of recurrence. Palliative radiotherapy can be used to alleviate symptoms in patients with advanced and/ or incurable disease. With the advent of more portable machines, SRT and brachytherapy have become more widely available to dermatologists, making it convenient for dermatology practices to employ radiotherapy in an office-based setting.

MECHANISM OF ACTION Radiotherapy employs high-energy electrons, photons, or rays to cause double-stranded DNA breaks in cells in the target field. Cells that are rapidly proliferating cannot adequately repair their DNA before replication, triggering apoptosis. Radiation still affects slowly growing, normal tissue, which can accumulate damage at sublethal doses and may cause late (months-to-years-later) reactions. When using radiotherapy, it is imperative to spare as much healthy tissue as possible. Maximizing the ratio between malignant and benign tissue affected is achieved through dividing the radiation dose into fractions. There are several different modes of radiotherapy utilized for dermatologic care and physicians must determine the best in each patient case. The treatment dose of radiotherapy is determined using the International Unit gray (Gy) or centigray (cGy). The dose delivered in a single treatment is known as a fraction. The practice of delivering the doses in fractions was implemented about twenty years after the development of radiotherapy and found to lower side effects and exhibit better control over the lesion being treated.2 A typi­ cal radiotherapy treatment is delivered over a course of 6–9 weeks with an average of four fractions delivered per week.3 However, the treatment schedule of the fractions is ultimately a subjective determination based on the size of the tumor and age of the patient.4 For example, a patient with a larger tumor may need 200 cGy/fraction delivered in 30 fractions; whereas, a patient of the same age with a smaller tumor would be better suited for 250 cGy/fraction over only 20 fractions.4 The delivery of larger doses per fraction, or hypofractionation, lowers the fractions needed for treatment and also the total dose delivered. The larger dose helps exhibit better local control over the tumor and raises the chances of adverse effects, such as necrosis and tissue damage.5 Thus, here are two separate consequences of fractionation. First, if the cGy dose is delivered in just a few fractions, there may be more damage to healthy

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Section 32: Physical Modalities of Therapy tissue. If the does is delivered in too many dosages (for example, twice a day), there is unnecessary inconvenience and expense. Second, the interval between dosages is important. There needs to be enough time for healthy tissue to recover, but not enough for the tumor to recover. Therefore, a fractionation schedule which is too spread out (for example, weekly) will not produce enough tumor-specific killing.

TYPES OF RADIATION In superficial or orthovoltage X-ray therapy, X-rays or photons of energies up to 250 kV are employed for the treatment of superficial skin lesions. This low energy is in contrast to the 6 MeV to 20 MeV produced by high-energy megavoltage machines, which are generated by a linear accelerator. The skin penetration characteristic of the X-rays (“photons”) is very different for each energy and is not linear. Orthovoltage rays have less penetrability and spare underlying structures, while high-energy photons are skin sparing and can target internal malignancies.6 Superficial X-ray therapy (SXRT) was once the standard method to treat cutaneous malignancies, but has been replaced by electron beam therapy, due to the higher energy electrons that can be produced. Nonetheless, orthovoltage X-ray does have potential advantages over electron beam therapy, primarily due to clearly defined field edges due to a sharp penumbra, which is the region over which dose rate rapidly changes, and lower machinery costs.7 Grenz rays, or ultrasoft radiation, are very low energy waves of wavelengths between 0.007 nm and 0.4 nm, and low penetrability. They are nearly entirely absorbed in the first 2 mm of the skin, and with 50% of the energy dissipated in the first 0.5 mm.8 In the past, Grenz rays were employed against chronic inflammatory dermatoses, such as psoriasis, eczema, acne vulgaris, and hand dermatitis. The exact mechanism of Grenz rays is not entirely elucidated, though it is thought that they modulate immunologic pathways as irradiation results in a decrease the number of Langerhans’ cells in the epidermis.9,10 There is still no consensus as to the risk of low doses of Grenz rays for radiogenic skin cancer, with differing case reports and cohort studies.11,12 However, there is a clear association of higher doses of Grenz rays (10,000–29,300 rads) and the induction of NMSC. Due to these concerns and the advent of much better treatment options, Grenz rays are never considered to be first-line therapy, and in fact, are almost never used in modern dermatology.13 Electron beam therapy is especially useful in the treatment of superficial skin cancers and disease as its dose

curve dramatically falls off both laterally and distally. Lesions within 6 cm of the skin surface can be treated, while sparing deeper tissue, including blood vessels, organs, muscle, and bone marrow. Electron beams in the range of approximately 6–20 MeV are used to treat skin and superficial disease. One concern with electron beams is that they can be skin sparing. This is especially true at low energies, with the relative surface dose of approximately 70% at 6 MeV versus a surface dose of approximately 95% at 20 MeV. Initially, after the development and adoption of electron beam therapy, there were concerns that the technique produced inferior results as compared to SRT. However, Griep et al. not only found no difference in local control rates between the two methods, but also actually improved cosmesis with electron beam therapy.6 The authors attributed inferior results to technical challenges. As compared to superficial X-ray therapy, a larger planning target volume is needed with electron beam therapy. This is a result of electron beam’s characteristic dose curve, where the area of highest dose intensity can be up to 1 cm from the target field border. One must be especially conscientious of this fact when treating infiltrating tumors and also compensate for the skin sparing properties of lowenergy electron beams.6,14 Thus, radiation oncologists usually use orthovoltage machines, while dermatologists use SRT due to its more portable nature. A second advance over SRT is the development of brachytherapy. In contrast to external beam radiation (employing SRT or electrons), brachytherapy involves applying the radioactive source directly on the skin cancer  via a surface mold or surface applicator (Fig. 120.1).

Fig. 120.1: Patient’s positioning for high-dose rate (HDR) brachytherapy. Note the external fixation of the contact applicator on the patient’s leg. Courtesy: Dr John Strasswimmer.

Chapter 120: Radiotherapy

A

C

In  other oncology situations (such as breast or prostate cancer), it can also be applied with small catheters inside the tumor body (interstitial). The beam characteristic of brachytherapy produces an intense local (few millimeters) of damage, with a rapid drop-off thereafter. Thus, an advantage of brachytherapy over external beam radiation for NMSC is its ability to irradiate the targeted lesion while sparing damage to deeper healthy tissue. The limitation, however is that brachytherapy is best used for large, thin tumors (Figs. 120.2A to C), or lesions that overlie structures which are vulnerable to radiation, such as the scalp and hand and in areas of poor vasculature such as the legs. Dermatologists have available specific contact disks and tubes designed to treat tumors. The size of the tumor must be much smaller than the size of the applicator, limiting the practical use to NMSC that are both thin (less than 4 mm) and not large (less than 2 cm). Radiation oncologists have the additional ability to treat irregularly shaped

B

Figs. 120.2A to C: Brachytherapy can be a treatment option for large superficial skin cancer. (A) Photograph of a patient with a large superficial basal cell carcinoma before treatment with brachytherapy; (B) Photograph of a patient with a large superficial basal cell carcinoma after treatment with brachytherapy showing resolution of the basal cell clinically; (C) Histopathology showing brachytherapy reaching the upper dermis. Courtesy: Dr John Strasswimmer.

skin areas (such as medial canthus) or larger areas using custom-mold brachytherapy.15 However, the lowest recurrence rates are for tumors that are primary, superficial (2 cm), recurrent, perineural invasion is noted, patient is immunocompromised, lesion is located near

Chapter 120: Radiotherapy the parotid gland, and high-grade.36 For high-risk SCC, the standard of care is Mohs micrographic surgery and adjuvant radiotherapy, if necessary. A study showed that for small cutaneous SCCs (2 cm in diameter) that a 6-mm margin was required to achieve a 95% rate of negative excision margins.37 Recurrent SCC have a significantly higher incidence of regional metastasis, 25–45% depending on site.35 Given these well-established risks, adjuvant radiotherapy, over postexcisional monitoring, is an effective treatment option for patients with an incompletely excised (positive or close to the margin) SCC. One study showed a dramatic decrease in local recurrence rate with use adjuvant radiotherapy for lip SCC, from 37% to 6%.38 Patients with metastatic SCC to regional lymph nodes should be referred to a multidisciplinary cancer service. If possible, patients should proceed to surgery and adjuvant radiotherapy (60 Gy in 30 fractions for head and neck (HN) regional nodes, parotid, ±upper cervical nodes, or 50 Gy in two fractions for non-HN nodal regions—groin/ axilla) to increase loco-regional control.39,40 While these patients have many multiple nodes, extranodal spread, close margins, perineural invasion, they can still expect a 5-year disease-free survival of 70–75% with surgery and adjuvant radiotherapy.41 For patients treated with radiotherapy alone, they are less likely to be cured, but should experience nodal regression with good palliation. Perineural invasion (PNI) is an uncommon, yet serious possibility with SCCs and rarely BCCs. Patients with PNI have a higher risk of metastatic nodal spread. A study of patients with PNI revealed that half of recurrences following surgery and/or radiotherapy were in regional nodes. The authors recommended elective nodal treatment in these cases.42 In addition to nodal metastasis, PNI can cause significant neuropathic pain, cranial nerve palsies, and mortality if cranial nerves (typically facial and trigeminal) are involved, leading to intracranial spread. There is no consensus on the optimal treatment plan. Wide-field radiotherapy is often used. Lesions with focal PNI, especially if located in the periorbital region, should involve wider re-excision or alternatively adjuvant radiotherapy.43 A study showed that asymptomatic or incidental PNI is associated with better outcomes than clinically positive PNI with local control at 5 years 87% vs. 55%.44 However, patients presenting with advanced PNI may still be curable with high-dose radiotherapy.36 Lin et al. recommends targeting radiation at tumor bed, cranial nerve pathways to the skull base, and nodal basins and using

intensity-modulated radiotherapy (IMRT) to maximize coverage of the targets of interest and minimize dose to surrounding organs at risk.45 In Bowen’s disease, or squamous cell carcinoma in situ, only a small percentage (3%) of lesions will progress to invasive SCCs. Radiotherapy is one treatment option, though used infrequently. A retrospective single-institution review showed that RT achieved complete remission in 95% of patients, and that local recurrence was equally low in both high and low-dose regimens.46 A recent Cochrane review found that PDT, 5-FU, and cryotherapy were all efficacious and that PDT appeared to have the best cosmetic outcomes. MAL-PDT (methyl aminolevulinate with photodynamic therapy) cleared significantly more lesions than cryotherapy, but no significant difference was found versus 5-FU. One study showed a significant clearance with ALA-PDT (5-aminolevulinic acid with photodynamic therapy) as compared with 5-FU.47 With these many other effective therapies, radiotherapy should never be considered the first-line treatment. For SCCs in an especially sensitive site, such as the lip, wedge excision (± vermilionectomy) is the optimal procedure and primary closure often possible, thanks to the laxity of the lip. As the lesion size grows, the risk of compromising function with surgery increases. In cases where >30–50% of the lip is involved, radiotherapy is an excellent treatment option. The outcome of surgery vs. radiotherapy for small-to-medium-sized SCCs is comparable. A median dose of 55 Gy (with a range from 40–70 Gy) had 5% local recurrence rate and 5% regional metastases, with no distant metastases.48 Keratoacanthoma (KA) is rarely treated with radiotherapy, with surgery being the first-line treatment modality. However, radiotherapy can be considered in particular situations, including recurrence after surgical excision, patients who cannot undergo surgery, and cosmesis.49 Dosing regimens consisting of 40 Gy by twice weekly fractions of 4 Gy was demonstrated to be effective.

Melanoma Melanoma is generally considered to be a radioresistant.50 Recently, however, studies have shown that radiotherapy may be effective in particular situations. Definitive radiotherapy is only considered for tumors that are deemed inoperable.51 On the subject of adjuvant radiotherapy, a high-quality clinical trial demonstrated that adjuvant RT decreases local and regional recurrence following lymphadenectomy in node-positive melanoma patients, yet the

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Figs. 120.5A to C: Patient with desmoplastic melanoma of the scalp treated with definitive RT to 62.5 Gy in 2.5 Gy per fraction, locally controlled at 7 years post-treatment without side effects. (A) Patient with multifocal desmoplastic melanoma of the scalp; (B) Brachytherapy using Iridium-192 high-dose rate remote after loading applicator allowed delivery of highly conformal dose to the surface of the scalp while keeping brain dose to minimal; (C) Scalp on follow-up for desmoplastic melanoma (blue dot is radiation tattoo) showing clinical clearance. Courtesy: Dr Yen Lin Chen.

authors found no increase in survival.52 Radiotherapy is a very effective palliative tool for metastatic melanoma. In the case of desmoplastic melanoma, a rare form that is characterized by fusiform melanocytes dispersed within collagenous stroma.53 Adjuvant radiotherapy was shown to increase local control (Figs. 120.5A to C). Patients that benefited most from radiotherapy were those with positive margins or deeper tumors.54

Lentigo Maligna The occurrence of lentigo maligna (LM), a form of melanoma in situ, is on the rise. LM arises in photodamaged skin in the elderly, usually in longstanding, large lentigines on the head or neck. Given the size and location of these lesions, excisional surgery is generally not an option. Radiotherapy is a well-established treatment for LM. A review of nine clinical studies of definitive RT for LM documented a 5% recurrence rate. Salvage was mostly successful with further RT, surgery, or other techniques. Only 1.4% of patients

progressed to LM melanoma.40 Fogarty et al. produced a set of recommendations for RT parameters for the treatment of LM. For the RT field, the authors recommended using in-vivo reflectance confocal microscopy to define the treatment volume and then expand the area by 1 cm around in all directions. The authors recommended a depth of 5 mm for adequate treatment, and a total dose 50 Gy for adjuvant treatment and 54 Gy for definitive treatment, with a dose per fraction of 2 Gy, with a maximum at 4 Gy.40

Merkel Cell Carcinoma Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous tumor that most commonly arises in the head/ neck region of elderly white men. These tumors have a high propensity for locoregional and distant relapse. MCC tends to be chemo and radiosensitive and many studies have shown the utility of adjuvant radiotherapy. The most common approach to MCC treatment is local wide-excision (margins of 3–4 Gy), higher with total doses >55 Gy, and when large fields were irradiated.

MANAGEMENT Acute Radiation Dermatitis Grade 1: Management depends on the severity of damaged skin. Hydrophilic moisturizers can be used for dry desquamation, while low-to-mid potency steroids are effective for pruritus and irritation. Grades 2–3: More severe reactions include moist desquamation, and treatment should be focused on preventing infection and proper dressing. In these cases, it is important to use dressings to maintain a wet environment over

Chapter 120: Radiotherapy the deepithelialized skin, which allows for a higher rate of wound healing.68 Grade 4: Severe cutaneous reactions to RT is characterized by full-thickness skin necrosis and ulceration. In these cases, radiotherapy should be discontinued and treatment should have a multidisciplinary approach. Necrotic tissues should be debrided and pedicle flaps may be indicated. In general, grafts do not take well on irradiated tissue, primarily due to its poor vascular bed.

than non-immunosuppressed patients, at 48% vs. 73%, respectively.72 Adjuvant radiotherapy should always be considered for immunosuppressed patients, especially for particularly high-risk cases, including involved lymph nodes, perineural invasion, size greater than 2 cm, poorly differentiated or spindle cell histology, or ear/lip primary tumor.73

Chronic Cutaneous Reactions

Radiotherapy is an incredibly effective palliative tool for locally advanced tumors or dermal metastases. These tumors are usually present among the elderly, debilitated, or mentally ill patients and while the tumors are incurable, they can be palliated. Often, these tumors are ulcerated, bleeding, painful, or infected, and significantly affect the patient’s quality of life and are challenging for caregivers. In such cases, a single large fraction of superficial radiation can yield dramatic results. Dermal metastases, most commonly from breast, lung, or ovarian cancers, indicate poor prognosis, but can be treated palliatively by radiotherapy with a single-fraction of 8 Gy.74 Palliative radiation is also effective for both B- and T-cell cutaneous lymphomas.

Treatment approach to chronic ulcerations and wounds is the same as for acute radiation dermatitis, where proper moist dressing is emphasized, but debridement and pedicle flaps may be considered. Radiation-induced fibrosis is one of the most difficult skin complications to treat, but can be approached with pentoxifylline (PTX) alone or with vitamin E.69 Telangiectasias can be treated with pulse dye laser, with excellent clinical improvement and clearance rates of over 70%.70

RADIATION-INDUCED MALIGNANCY One of the greatest concerns when treating with ionizing radiation is the long-term risk of development of secondary cutaneous malignancies. The elevated risk for skin cancer persists for the entire lifespan following radiation, is dose dependent, and increases with patient’s age.71 Both SCCs and BCCs that present in RT field are often more aggressive or unusual variants; these SCC have a higher risk of metastasis and prompt surgery is required.69 The link between RT and melanoma is less clear.

IMMUNOSUPPRESSED PATIENTS One of the greatest risks of immunosuppression is the development of malignancies, particularly lymphoma and cutaneous cancers (BCC, SCC, melanoma, Merkel cell carcinoma, Kaposi sarcoma). The immunosuppressed are primarily patients with solid organ transplants, but this also includes those infected with HIV and those with chronic lymphocytic leukemia, particularly when undergoing treatment. Studies have shown that the development of SCCs outnumbers that of BCCs in solid organ transplant recipients, and that these SCCs behave significantly more aggressively than in immunocompetent patients. Immunosuppressed patients with locally advanced head and neck SCC also had a lower 2-year recurrence-free survival rate after resection and adjuvant radiotherapy

PALLIATION

ETHICAL CONSIDERATIONS The ethics of self-referral in the context of radiotherapy is hotly debated. Dr Grant-Kels and Dr VanBeek presented a case scenario in the journal of the american academy of dermatology (JAAD) outlining the potential for abuse.75 They describe that in an era of declining reimbursements, many have been interested in ways to diversify their practice and increase profits. Company representatives for new United States food and drug administration (FDA)approved radiotherapy devices have been attempting to sell their products this way. They tell doctors that instead of referring their patients for Mohs surgery, they can treat them with radiation. The procedure will be conducted by a radiation oncologist, whose fee is much less than the code the company suggests using for reimbursement. Is it ethical for a physician to immediately buy this machine and begin treating NMSC in this method instead of Mohs micrographic surgery? The authors argued no. Radiotherapy is almost never first-line treatment. It serves its purpose in adjuvant treatment or in those who cannot tolerate surgery, but its cure rates are significantly inferior to that of Mohs surgery. Both of these are potentially violated in this case if the dermatologist chooses profits over judicious patient

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Section 32: Physical Modalities of Therapy care. The authors end with “the ethical argument demonstrated by this case is that choosing therapy on the basis of how lucrative it is to the treating physician or allowing such factors to influence medical decision-making clearly is not in the patient’s best interest, and in fact violates the physician’s fiduciary obligations to the patient”.75

FUTURE TRENDS Radiotherapy is again on the rise. When considering this treatment option for patients, it is important to ensure that the patient’s best interests are first, not financial incentives. Definitive radiotherapy should never be considered first-line treatment, but should be used in specific cases, such as in elderly patients who cannot undergo surgery. Going forward, the main role of radiation will be in adjuvant treatment. Surgery and adjuvant radiotherapy is the standard of care in the setting of large, aggressive tumors. A recent advance in the field of radiation oncology is the development of IMRT. IMRT is exciting as it can deliver precise doses to a target area while minimizing radiation to adjacent normal tissues. This is accomplished by modu­ lating the intensity of the radiation beam.76 Excitingly, there have been major developments in oral chemotherapy agents for advanced skin cancers in the past decade. Recently, several studies have shown the utility of combining radiotherapy and oral chemotherapy. Vismodegib, approved by the FDA in 2012, is a small molecule inhibitor of the hedgehog signaling pathway, which is implicated in the proliferation of basal cell carcinoma.75,77 The molecule has been shown to have nearly 60% response rate in patients with advanced in BCC, but is not effective in the treatment of SCC. In addition to vismodegib, a phase I in-human study of DT01, a DNA-repair inhibitor, with concurrent radiotherapy for unresectable metastatic melanoma was demonstrated to be safe and potentially efficacious, with a response rate of 59%.78 The future of radiotherapy is bright with expansion of concurrent and adjuvant treatment, development of more precise techniques, and an aging population that may not be able to undergo surgery.

REFERENCES 1. Strasswimmer JM. Potential synergy of radiation therapy with vismodegib for basal cell carcinoma. JAMA Dermatol 2015;151(9):925–6. 2. Gianfaldoni S, Gianfaldoni R, Wollina U, et al. an overview on radiotherapy: from its history to its current applications in dermatology. Open Access Maced J Med Sci 2017;5(4):521–5.

3. Piotrowski T, Milecki P, Skórska M, et al. Total skin electron irradiation techniques: a review. Postepy Dermatol Alergol 2013;30(1):50–5. 4. McGregor S, Minni J, Herold D. Superficial radiation therapy for the treatment of nonmelanoma skin cancers. J Clin Aesthet Dermatol 2015;8(12):12–4. 5. Silva JJ, Tsang RW, Panzarella T, et al. Results of radiotherapy for epithelial skin cancer of the pinna: the Princess Margaret Hospital experience, 1982–1993. Int J Radiat Oncol Biol Phys 2000;47(2):451–9. 6. Griep C, Davelaar J, Scholten AN, et al. Electron beam therapy is not inferior to superficial X-ray therapy in the treatment of skin carcinoma. Int J Radiat Oncol Biol Phys 1995;32(5):1347–50. 7. Wang Y, Wells W, Waldron J. Indications and outcomes of radiation therapy for skin cancer of the head and neck. Clin Plas Surg 2009;36(3):335–44. 8. Lindelöf B. Grenz ray therapy in dermatology. An experimental, clinical and epidemiological study. Acta Derm Venereol Suppl (Stockh) 1987;132:1–67. 9. Lindelöf B, Forslind B. Electron microscopic observations of Langerhans’ cells in human epidermis irradiated with grenz rays. Photodermatol 1985;2(6):367–71. 10. Lindelöf B, Liden S, Ros AM. Effect of grenz rays on Langerhans’ cells in human epidermis. Acta Derm Venereol 1984;64(5):436–8. 11. Lindelöf B, Eklund G. Incidence of malignant skin tumors in 14,140 patients after grenz-ray treatment for benign skin disorders. Arch Dermatol 1986;122(12):1391–5. 12. Dabski K, Stoll HL. Skin cancer caused by grenz rays. J Surg Oncol 1986;31(2):87–93. 13. Warner JA, Cruz PD. Grenz ray therapy in the new millennium: still a valid treatment option? Dermatitis 2008; 19(2):73–80. 14. Goldschmidt H, Panizzon RG. Radiation reactions and sequelae. Modern Dermatology Radiation Therapy. New York: Springer, 1991:25–36. 15. Rudoltz MS, Perkins RS, Luthmann RW. High-doserate brachytherapy with a custom-surface mold to treat recurrent squamous cell carcinomas of the skin of the forearm. J Am Acad Dermatol 1998;38(6 Pt 1): 1003–5. 16. Alam M, Nanda S, Mittal BB, et al. The use of brachytherapy in the treatment of nonmelanoma skin cancer: a review. J  Am Dermatol 2011;65(2):377–88. 17. Ouhib Z, Kasper M, Perez Calatayud J, et al. Aspects of dosimetry and clinical practice of skin brachytherapy: the American Brachytherapy Society working group report. Brachytherapy 2015;14(6):840–58. 18. Morrison WH, Garden AS, Ang KK. Radiation therapy for nonmelanoma skin carcinomas. Clin Plastic Surg 1997;24(4):719–29. 19. Karimpour S, Young G, Lockett MA, et al. Radiotherapy for epithelial skin cancer. Int J Radiat Oncol Biol Phys 2001; 51(3):748–55. 20. Panje WR, Ceilley RI. The influence of embryology of the mid-face on the spread of epithelial malignancies. Laryngoscope 1979;89(12):1914–20.

Chapter 120: Radiotherapy 21. Fleming ID, Amonette R, Monaghan T. Principles of management of basal and squamous cell carcinoma of the skin. Cancer 1995;75(2 Suppl):699–704. 22. Guerin S, Dupuy A, Anderson H, et al. Radiation dose as a risk factor for malignant melanoma following childhood cancer. Eur J Cancer 2003;39(16):2379–86. 23. Cantwell MM, Murray LJ, Catney D. Second primary cancers in patients with skin cancer: a population-based study in Northern Ireland. Br J Cancer 2009;100(1):174–7. 24. Preston DS, Stern RS. Nonmelanoma cancers of the skin. N Engl J Med 1992;327(23):1649–62. 25. Gul A, Faaruq S, Abbasi NZ, et al. Estimation of absorbed dose to thyroid in patients treated with radiotherapy for various cancers. Radiat Prot Dosimetry 2013;156(1):37–41. 26. Arno AI, Gauglitz GG, Barret JP, et al. Up-to-date approach to manage keloids and hypertrophic scars: a useful guide. Burns 2014;40(7):1255–66. 27. Ji J, Tian Y, Zhu Y, et al. Ionizing irradiation inhibits keloid fibroblast cell proliferation and induces premature cellular senescence. J Dermatol 2015;42(1):56–63. 28. Joseph D, Irukulla MM, Ahmed SF. Radiotherapy in aggressive cutaneous pseudolymphoma: a case report and review of literature. Radiol 2016;34(1):76–80. 29. Olson LE, Wilson JF, Cox JD. Cutaneous lymphoid hyperplasia: results of radiation therapy. Radiol 1985;155(2):507–9. 30. Paul S, Bach D, LeBoeuf NR, et al. Successful use of brachytherapy for a severe hidradenitis suppurativa variant. Dermatol Ther 2016;29(6):455–58. 31. Trombetta M, Werts ED, Parda D. The role of radiotherapy in the treatment of hidradenitis suppurativa: case report and review of the literature. Dermatol Online J 2010;16(2):16. 32. Smeets NW, Krekels GA, Ostertag JU, et al. Surgical excision vs Mohs’ micrographic surgery for basal-cell carcinoma of the face: randomised controlled trial. Lancet 2004;364(9447):1766–72. 33. Porceddu SV. Prognostic factors and the role of adjuvant radiation therapy in non-melanoma skin cancer of the head and neck. Am Soc Clin Oncol Educ Book. 2015;35: e513–8. 34. Lohuis PJFM, Joshi A, Borggreven PA, et al. Aggressive basal cell carcinoma of the head and neck: challenges in surgical management. Eur Arch Otorhinolaryngol 2016;273(11): 3881–9. 35. Rowe DE, Carroll RJ, Day CL. 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): 976–90. 36. Veness MJ. The important role of radiotherapy in patients with non-melanoma skin cancer and other cutaneous entities. J Med Imaging Radiat Oncol 2008;52(3):278–86. 37. Brodland DG, Zitelli JA. Surgical margins for excision of primary cutaneous squamous cell carcinoma. J Am Acad Dermatol 1992;27(2 Pt 1):241–8. 38. Babington S, Veness MJ, Cakir B. 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(8):621–5.

39. Veness MJ, Morgan GJ, Palme CE. 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(5):870–5. 40. Fogarty GB, Hong A, Scolyer RA, et al. Radiotherapy for lentigo maligna: a literature review and recommendations for treatment. Br J Dermatol 2014;170(1):52–8. 41. Veness MJ, Porceddu S, Palme CE, et al. Cutaneous head and neck squamous cell carcinoma metastatic to parotid and cervical lymph nodes. Head Neck 2007;29(7):621–31. 42. Garcia-Serra A, Hinerman RW, Mendenhall WM. Carcinoma of the skin with perineural invasion. Head Neck 2003;25(12):1027–33. 43. Veness MJ, Biankin S. Perineural spread leading to orbital invasion from skin cancer. Australas Radiol 2000;44(3):296–302. 44. Mendenhall WM, Amdur RJ, Hinerman RW, et al. Skin cancer of the head and neck with perineural invasion. Am J Clin Oncol 2007;30(1):93–6. 45. Lin C, Tripcony L, Keller J, et al. Perineural infiltration of cutaneous squamous cell carcinoma and basal cell carcinoma without clinical features. Int J Radiat Oncol Biol Phys 2012;82(1):334–40. 46. VanderSpek LAL, Pond GR, Wells W. Radiation therapy for Bowen’s disease of the skin. J Radiat Oncol 2005; 63(2):505–10. 47. Bath-Hextall FJ, Perkins W, Bong J, et al. Interventions for basal cell carcinoma of the skin. Cochrane Database Syst Rev 2007;(1):CD003412. 48. Pham T, Cross S, Gebski V, et al. Squamous cell carcinoma of the lip in Australian patients. Dermatol Surg 2015;41(2):219–25. 49. Bruscino N, Corradini D, Campolmi P, et al. Superficial radiotherapy for multiple keratoacanthomas. Dermatol Ther 2014;27(3):163–7. 50. Khan N, Khan MK, Almasan A, et al. The evolving role of radiation therapy in the management of malignant melanoma. Int J Radiat Oncol Biol Phys 2011;80(3):645–54. 51. Shi W. Role for radiation therapy in melanoma. Surg Oncol Clin N Am 2015;24(2):323–35. 52. Burmeister BH, Henderson MA, Ainslie J, et al. Adjuvant radiotherapy versus observation alone for patients at risk of lymph-node field relapse after therapeutic lymphadenectomy for melanoma: a randomised trial. Lancet Oncol 2012;13(6):589–97. 53. Busam KJ, Mujumdar U, Hummer AJ. Cutaneous desmoplastic melanoma: reappraisal of morphologic heterogeneity and prognostic factors. Am J Surg Pathol 2004; 28(11):1518–25. 54. Strom T, Caudell JJ, Han D, et al. Radiotherapy influences local control in patients with desmoplastic melanoma. Cancer 2014;120(9):1369–78. 55. Harrington C, Kwan W. Radiotherapy and conservative surgery in the locoregional management of Merkel cell carcinoma: the British Columbia Cancer Agency experience. Ann Surg Oncol 2016;23(2):573–8. 56. Harrington C, Kwan W. Outcomes of Merkel cell carcinoma treated with radiotherapy without radical surgical excision. Ann Surg Oncol 2014;21(11):3401–5.

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Section 32: Physical Modalities of Therapy 57. Tsao MN, Sinclair E, Assaad D. Radiation therapy for the treatment of skin Kaposi sarcoma. Ann Palliat Med 2016; 5(4):298–302. 58. Mendenhall CM, Werning JW, Reith JD. Cutaneous angiosarcoma. Case Rep Oncol  Med 2006;29(5):524–8. 59. Sasaki R, Soejima T, Kishi K, et al. Angiosarcoma treated with radiotherapy: impact of tumor type and size on outcome. Int J Clin Oncol 2002;52(4):1032–40. 60. Wilcox RA. Cutaneous T-cell lymphoma: 2016 update on diagnosis, risk-stratification, and management. Am J Hematol 2016;91(1):151–65. 61. Conill C, Navalpotro B, López I, et al. Results of radiotherapy in primary cutaneous lymphoma. Clin Trans Oncol 2006;8(6):430–4. 62. Jawed SI, Myskowski PL, Horwitz S, et al. Primary cutaneous T-cell lymphoma (mycosis fungoides and Sézary syndrome). J Am Acad Dermatol 2014;70(2):223e.1–17. 63. Wilson LD, Kacinski BM, Jones GW. Local superficial radiotherapy in the management of minimal stage IA cutaneous T-cell lymphoma (mycosis fungoides). Int J Radiat Oncol Biol Phys 1998;40(1):109–15. 64. Wilcox RA. Cutaneous B-cell lymphomas: 2016 update on diagnosis, risk-stratification, and management. Am J Hematol 2016;91(10):1052–5. 65. Senff NJ, Noordijk EM, Kim YH, et al. European Organization for Research and Treatment of Cancer and International Society for Cutaneous Lymphoma consensus recommendations for the management. Blood 2008;112(5):1600–9. 66. Kiyohara Y, Yoshikawa S, Kasami M. Treatment strategy for cutaneous apocrine carcinoma. Int J Clin Oncol 2014; 19(4):712–5. 67. Bray FN, Simmons BJ, Wolfson AH, et al. Acute and chronic cutaneous reactions to ionizing radiation therapy. Dermatol Ther 2016;6(2):185–206. 68. Winter GD. Formation of the scab and the rate of epithelialization of superficial wounds in the skin of the young domestic pig. Nature 1962;193(4812):293–4.

69. Hymes SR, Strom EA, Fife C. Radiation dermatitis: clinical presentation, pathophysiology, and treatment 2006. J Am Acad Dermatol 2006;54(1):28–46. 70. Rossi AM, Nehal KS, Lee EH. Radiation-induced breast telangiectasias treated with the pulsed dye laser. J Clin Aesth Dermatol 2014;7(12):34–7. 71. Shore RE. Radiation-induced skin cancer in humans. Med Pediatr Oncol 2001;36(5):549–54. 72. Manyam BV, Gastman B, Zhang AY, et al. Inferior outcomes in immunosuppressed patients with high-risk cutaneous squamous cell carcinoma of the head and neck treated with surgery and radiation therapy. J Am Acad Dermatol  2015;73(2):221–7. 73. Koyfman SA, Joshi N, Vidimos A. Adjuvant radiotherapy in high-risk cutaneous squamous cell cancer of the head and neck in immunosuppressed patients. JAAD Case Rep 2015;1(6):S5–7. 74. Kähler KC, Egberts F, Gutzmer R. Palliative treatment of skin metastases in dermato-oncology. J Dtsch Dermatol Ges 2013;11(11):1041–6. 75. Grant-Kels JM, VanBeek MJ. The ethical implications of “more than one way to skin a cat”: increasing use of radiation therapy to treat nonmelanoma skin cancers by dermatologists. J Am Acad Dermatol 2014;70(5): 945–7. 76. Nakamura K, Sasaki T, Ohga S, et al. Recent advances in radiation oncology: intensity-modulated radiotherapy, a clinical perspective. Int J Clin Oncol 2014;19(4): 564–9. 77. Sekulic A, Migden MR, Oro AE, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med 2012. 78. Tourneau LC, Dreno B, Kirova Y, et al. First-in-human phase I study of the DNA-repair inhibitor DT01 in combination with radiotherapy in patients with skin metastases from melanoma. Br J Cancer 2016;114(11): 1199–205.

Section

Cosmetic Surgery

33

Chapter

Introduction to Skin Aging

121

Doris Day

INTRODUCTION Skin is the largest and most highly elaborate organ in the human body. It is comprised of numerous layers and different types of cells which act as a means of physical obstruction between the outside environment and the human body. Apart from its most obvious role as the major organ offering physical protection, it has various other functions such as prevention of percutaneous evapotranspiration, regulation of body temperature, and it works as a means of sensory perception. It acts as a facilitator for neurosensory, circulatory, and immunological surveillance functions occurring at the surface of the human body.1 It also serves as a major force on an emotional level, affecting self-esteem and revealing much about us to the external world. Humans age with the passage of time and this process leads to a progressive loss of function in all organs. Skin aging, just like overall aging of the human body, is a continuous process affected by numerous internal as well as external factors. It is defined as the accumulation of damage with the progression of time, causing changes on a cellular level, and possibly leading to disease or death.2

ANATOMICAL STRUCTURE OF THE SKIN Skin is made of three different layers called the epidermis, dermis, and the hypodermis. The epidermis is the topmost layer of the skin which offers primary physical defense against outside forces such as pathogens as well as harsh environmental elements. A thick layer of tough cells, known as the stratum corneum, or the keratin layer along with melanocytes provides protection against extrinsic aging.

Epidermis Epidermis originates from the embryonic ectoderm and comprises keratinocytes, melanocytes, Langerhans’ and Merkel’s cells. Epithelial cells of the dermis, also known

as the keratinocytes, are situated directly on top of a basal lamina. There are five distinct layers in the epidermis, namely: • Stratum corneum (upper-most layer): Also known as the “horny layer”. It is made up of dead keratinocytes comprising keratin and lipids. Keratin helps the skin to retain moisture and makes this layer waterproof. Thickness of this layer varies in different parts of the body. • Stratum lucidum: A thin layer of cells translucent in appearance, comprised of Eleidin, which is an intermediate form of keratin. • Stratum granulosum: Cells in this layer contain granules that produce keratin. This layer of cells is not dead. • Stratum spinosum: Cells in this layer are living and they produce vitamin D in the presence of sunlight. Langerhans’ cells are also present in this layer; they represent the immune system and carry out phagocytosis. • Stratum germinativum (bottom-most layer): This layer contains melanocyte stem cells (MSCs) which gene­ rate melanocytes. Their primary function is to produce melanin which filters out UV radiation. Cells from this bottom-most layer divide by the process of mitosis and move upward to become a part of the more superficial layers. The basal layer of the epidermis is made up of epidermal stem cells (ESCs) which are able to self-renew and differentiate into specific cell types, as mentioned above.

Dermis This layer originates from the embryonic mesoderm which is the primary source of mesenchymal stem cells (MSCs) in this layer. The dermis is a significantly denser layer of the skin made of fibrous and elastic connective tissue. It is made up of dermal fibroblasts separated in the upper dermis and lower dermis. The fibroblasts in the upper dermis help with hair follicle formation and the ones in the lower

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Section 33: Cosmetic Surgery dermis form collagen that gives the skin its tensile strength and fibril extracellular matrix (ECM). Of the major types of collagen in the dermis, 75–80% is type I, 15% type III, and the last 5% is made up of type V and VI. Elastin and fibrillin provide the skin with elasticity and strength, respectively. This layer also consists of salts, water, a gel of glycosamine proteoglycans, hosts nerve endings, sweat and sebaceous glands, hair follicles, and blood vessels.

Subcutaneous or Hypodermis A layer of fat called the hypodermis, comprised mainly of adipocytes, lies directly beneath the dermis and provides insulation to the body from extreme temperatures. It provides additional padding and energy reserves in the form of fat hosted by living cells, held together by fibrous tissue. The speed at which the physiological changes that occur during the course of aging is governed by genetic as well as environmental factors. The natural process of aging which is predetermined by genetics that happens in a chronological manner is known as intrinsic aging. On the other hand, the process by which the effects of environmental factors induce aging is known as extrinsic aging3 also known as photoaging.4 The effects of both types of aging are cumulative in nature.5 Intrinsic and extrinsic agings have different modes of mechanism and they cause different visual changes of the skin.6 The aging process manifests itself differently in both the epidermal and dermal layers. The primary cause of aging in the upper layer of the dermis is the occurrence of disorder in the extracellular matrix. The adult human body requires a high rate of cell turnover and a constant number of cells in skin epidermis in order maintain homeostasis. Additionally, the microenvironment within the skin needs to be regulated for proper maintenance of stem cells, as an increase in inflammatory responses of the body as well as the numbers of senescent cells could impair the function of these stem cells disrupting homeostasis.7 These stem cells have a highly active DNA repair system8 which can be compromised with the advancement in age and high exposure to UV radiation.9 Signs of premature aging are distinguishable from chronological aging signs.

Intrinsic Aging The only known cause of intrinsic aging is chronological advancement in the age of the body. This particular type of aging is associated with functional changes in the skin. The effects of intrinsic aging include a dry and pale

appearance, lack of tautness, occurrence of benign neoplasia,3 an increase in the roughness of skin, atrophy of subepidermal layers, and the formation of fine lines and wrinkles.10 The rate of intrinsic aging is independent of ethnicity and does not vary among individuals.3

Extrinsic Aging The main cause of extrinsic, or premature aging, is sun exposure and exposure to harmful rays such as UV and infrared. This was originally established by Unna in 1894 and shortly after by Dubreuilh in 1896 when they compared the differences between the skin of sailors and farmers, respectively, with people who worked indoors. In 1971, Harry Daniell11 recognized the link between nicotine consumption, exposure to tobacco smoke, and premature aging signs. In 2010, Vierkötter et al. found a significant correlation between environmental pollution and exposure to airborne particles such as soot, particles from traffic, and generic background particle pollution to pigment spots and wrinkling. This particular type of aging is associated with morphological as well as physiologic changes.3 Photoaging effects are superimposed on the effects of intrinsic aging, meaning that the end result is cumulative, leading to changes in skin pigmentation, solar elastosis, deepening of lines and appearance of coarse wrinkles12 (Figs. 121.1 to 121.3). The rate of extrinsic aging varies in different ethnicities and also among different individuals. Individually, this rate depends on the genes inherited and the amount of exposure to environmental factors mentioned above. The most apparent difference between ethnicities manifests in the form of a difference in skin type, along with genetic as well as habitual factors.3

ENVIRONMENTAL IMPACT ON AGING OF THE SKIN Sun Exposure Sun irradiates an electromagnetic spectrum which spreads over a wide range of frequencies, half of which is invisible to the naked eye. Visible light spans at about 46–47%, ultraviolet (UV) rays make up about 8–9%, and the rest of 45% comprises of near-infrared range of the spectrum. There are three different types of UV radiation, namely UV-A (315–400 nm), UV-B (280–315 nm), and UV-C (100–280 nm). The length of the wavelength for each type of wavelength is parenthesized above. Atmosphere

Chapter 121: Introduction to Skin Aging

A

B

C

B

C

Figs. 121.1A to C: Effects of photoaging.

A Figs. 121.2A to C: Effects of photoaging.

absorbs most of the harmful radiation and the ozone layer is responsible for completely filtering out UV-C; however, the portion that is not absorbed (UV-A and UV-B) causes skin damage, among other nuances.13

Effects of Ultraviolet Radiation Damage caused by ultraviolet (UV) rays can be triggered through several pathways such as receptor initiated signaling, mitochondrial damage, oxidation of proteins, DNA damage at the telomeres, and arylhydrocarbon receptor signaling.14 This particular change in the cellular mechanisms leads to major changes in the cellular mechanism of skin cells.

Damage via Receptor initiated Signaling The trigger behind the induction of receptor-initiated signaling pathway is the presence of reactive oxygen species (ROS) brought about by photoproduction which starts the following chain reactions: • The ROS activate cell surface receptors of fibroblasts which are cells in connective tissue that produce collagen, cytokines which are cell signaling molecules that help with communication between cells, and those of keratinocytes which are epidermal cells that produce keratin. • This activation of cell-surface receptors of various cells in turn activates kinases.

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A

B

C

D

E

Figs. 121.3A to E: Severe photoaging.

• Activation of kinases culminates in signaling between cells leading to the transcription of nuclear transcription factors AP-1 and NF-kB.15 • An increase in the presence of AP-1 and its activity in the cell is a downregulatory factor in fibroblast cells for genes that produce collagens I and III, hence lower production of collagen.16 High levels of AP-1 also degrade mature dermal collagen in fibroblasts and keratinocytes by triggering the production of a matrix metalloproteinases (MMP) in these cells. • NF-kB also contributes to degradation of collagen by triggering the transcription of cytokines that are inflammatory in nature. They act as recruiters of neutrophils that contain collagenases, enzymes that break down collagen.17

Mitochondrial Damage Studies conducted by Berneburg et al. in 1997 and 2004 and by Berneburg and Krutmann in 199818–20 have shown

a strong link between photoaging and mitochondrial DNA (mtDNA). By irradiating skin cells with sublethal doses of UV radiation both in vivo and in vitro, they found that the rate of mtDNA mutations caused by such UV exposure had increased by 10 times in comparison with skin cells that were kept protected from the sun. Berneburg, Plettenberg, and Krutmann also observed in 200021 that mtDNA mutations are linked to MMP-1 levels, which links back to degradation of dermal collagen. These mtDNA mutations are most likely linked to the accelerated production of ROS due to UV exposure, in addition to basal levels of ROS already produced by mitochondria during the process of ATP synthesis (Fig. 121.4).

Damage via Protein Oxidation Exposure to UV radiation triggers oxidation of proteins and impairs proteosomal function,22 specifically brought about by ROS or products of stress through covalent changes within the proteins. This can manifest itself in the

Chapter 121: Introduction to Skin Aging

Fig. 121.4: Pathophysiology of mtDNA mutations as adapted from Berneburg et al. in 2000.21 As per this figure, exposure to UV radiation triggers the production of ROS which induces mtDNA mutations which not only serve as an imprint to the cell’s memory for history of damage imposed, but also negatively affects the cell’s capacity to carry out oxidative phosphorylation. This accelerates further production of ROS.

form of structural, physical, or chemical changes induced in the protein that alter its properties, resulting in a gain or loss of function. ROS are particularly disruptive as they can cause the oxidation of side chain (s) of a protein as well as its backbone. This leads to fragmentation of formation of cross linkages between proteins.23 Normally, damaged proteins present in a cell are degraded by proteosomes. This process is important to delay the onset of skin aging.24 However, the presence of oxidized proteins inhibits this breakdown pathway, rendering the cell’s capability to get rid of damaged proteins compromised.25

DNA Damage UV radiation is mutagenic and long-term exposure can result in accelerated skin aging as well as the development of skin cancers.26 There are two main ways in which this damage occurs: • Damage caused by UV exposure is minimized through nucleotide base excision repair mechanism that employs nine major proteins. Deficiencies associated with these proteins result in poor DNA repair and therefore premature aging.27 • Photons from UV radiation have an excitation effect on the electrons of cellular components that are able to absorb light, also known as photosensitizers. Due to this photon absorption, the excited electrons are transferred from such photosensitizers to molecules of oxygen which form radical singlet oxygen anions.28 These anions oxidize guanine residues in DNA and by the formation of 8-oxo-7,8 dihydroguanosine (8-oxo-G) and 8-oxo-7,8-dihydro-2’-deoxyguanosine (8-oxo-dG). These two formations are biochemical signatures of damage brought about by exposure to UV-A radiation. These new products, 8-oxo-G and

8-oxo-dG, are more inclined toward pairing with adenine rather than cytosine, creating C to T transition mutations.29 • An indirect effect but signatory for UV-induced damage is the introduction of mutations of C to T and CC to TT transitions due to the erroneous nature of DNA polymerase.30 • UV radiation can directly affect DNA via UV-B, which involves absorption of photons which triggers rearrangement of nucleotides, which results in two different types of products. The areas most susceptible to damage by UVR are tandem pyrimidine repeats within the DNA such as TT, TC, CT, and CC.31 Cyclobutane pyrimidine dimers (CPD): Photons from UV-B source are directly absorbed and induce cycloaddition between C5 and C6 of two pyrimidine that are adjacent to each other. This turns them into a CPD. Pyrimidine (6–4) pyrimidones, also known as 6–4 photoproducts (Ravanat, Douki, and Cadet, 2001): Covalent bonds formed between two adjacent pyrimidines produce a 6–4 PP which converts into a valence isomer when excited by UV radiation at precisely 314-nm range characteristic of UV-A. The human body has natural defense and repair mechanisms in place to counter changes induced by outside elements. The effects of photoaging become even more pronounced when such repair mechanisms are compromised. For example, low levels of human 8-oxo­ guanine DNA glycosylase (hOGG1), which aids in the DNA repair through the base excision pathway (NER) by cleaving glycosidic bonds from the DNA and creating abasic sites, impair the repair mechanism of damage created by the formation of 8-oxo-G and 8-oxo-dG in keratinocyte HaCat cells.32 Such type of damage in cells that are primed to differentiate into separate lineages becomes one of the most highlighted factors leading toward premature aging. In this sense, stem cells are unable to differentiate due to mutagenesis in the DNA or aberrations in one of the repair pathways, caused by exposure to ionizing radiation or depletion of proteins needed for repair mechanisms.

Accelerated Telomere Damage Telomeres are repetitive, non-coding nucleo protein complexes at the end of each chromosome. They form a protective cap which protects the chromosomes from degradation, abnormal recombination and the coding genetic material carried by chromosomes from being lost during

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Section 33: Cosmetic Surgery each replication process. With each cell division that takes place, the length of the telomeres is shortened. Human body employs a repair mechanism to maintain telomere length, known as the nucleotide excision repair (NER) pathway. It has been recently observed that UVR exposure disrupts this repair mechanism and culminates in premature shortening of telomeres.33 Repetitive shortening of telomeres ultimately results in cellular senescence. It has also been speculated that human stem cell aging is probably brought about by the dysfunction of telomeres with respect to p53-dependent premature cell aging, which will be discussed later.

Effects of Infrared-A Radiation The effects of infrared-A (IRA) radiation on the skin are strikingly similar to those of UV rays. According to studies conducted by Schieke et al. in 2002, exposure to IRA radiation leads to increased levels of matrix metalloproteinases (MMP-1) without an increase in MMP-1 tissue

Flowchart 121.1: Factors leading to premature/extrinsic skin aging.

inhibitors. IRA exposure also increases expression of collagen I,34 increases ROS levels in mitochondria,35 increases the number of mast cells in human skin,36 and induces angiogenesis. All of these effects are hallmarks of extrinsic aging.37

Effects of Smoking It was first recognized by Harry Daniell in 196936 that there was a remarkable esthetic difference between smokers and non-smokers. Later on, smoking was established as a significantly important factor that contributed toward aging in conjunction with sun exposure in a multiplicative or cumulative manner.38 Similar to the effects of IRA and UV radiation exposure, smoking results in a reduction of collagen I and collagen III levels.39 It also directly impacts the expression of MMP-1 and MMP-3 mRNA in a positive manner, without affecting the production of inhibitors for these proteins40 (Flowchart 121.1).

Chapter 121: Introduction to Skin Aging

Effect of Aging on Properties of Skin as a Barrier The integrity of skin as a barrier is determined by para­ meters such as: • pH at the surface of the skin, which increases with age • Hydration of the outermost layer of the skin known as stratum corneum which decreases with age to reveal rougher skin • The evaporation and/or diffusion of water from inner body into the outside environment through the epidermis known as transepidermal water loss which decreases with age.41 These changes cause pigmentation irregularities, increase in the number and depth of wrinkles, and skin becomes more prone to sagging.42 In a study conducted by Trojahn et al. published in 2015,43 aging was also related to the yellowing of skin due to accumulation of collagen and cross-links of elastic fibers brought about by exposure to UV rays. Another reason for the yellowing phenomenon could also be the thinning of the epidermal layer as a result of fat loss and subsequent formation of wrinkles due to chronological aging. They also noted that sagging of the skin was caused by a reduction in elastic fiber content in the dermal layer.

Microcirculation and Aging Effective microcirculation in the human body is of paramount importance in processes such as tissue hemostasis and immunological responses in the event of stress or injury. Impaired microcirculation directly affects the above mentioned processes. Microcirculation comprises terminal lymphatic vessels (which will not be discussed in this chapter) as well as blood vessels in the body of the smallest two orders, namely arterioles, capillaries and venules. These blood vessels have an endothelial cell lining through which the transfer of water, nutrients, and waste material takes place between the blood and the neighboring tissues. A comprehensive breakdown of each type is enlisted below: • Arterioles The diameter of arterioles ranges from 10 μm to 100 μm. They are richly innervated with adrenergic fibers and have one or more additional layers of smooth muscle that regulates blood flow and blood pressure. The primary function of arterioles is to regulate flow by maintaining adequate delivery of oxygen, water and nutrients and the removal of metabolic waste as

discussed above. This also culminates in the regulation of capillary hydrostatic pressure which directly affects capillary fluid exchange. • Capillaries Arterioles supply blood to capillaries, which are smaller in diameter (5–8 μm) and they have a single-cell thick epithelium which is not innervated nor encapsulated by smooth muscle. They are the site of exchange of oxygen, water, nutrients and waste. • Venules Blood flows out of capillaries into venules which have a diameter ranging between 10 μm and 200 μm. These vessels are surrounded by smooth muscle and their role is to take away the blood carrying waste material back to the heart and ultimately to the lungs for purification.

Changes in Microcirculation Associated with Aging One of the main causes of the progressive loss of function in organs is changes in microcirculation in the aging phenomenon which would otherwise be compensated physiologically under normal circumstances, as long as the body is not subjected to stress, which undermines the efficacy of physiological compensation.44 Any changes in the function of dysfunction of cutaneous microcirculation are known to be representative of the changes in the rest of the body as well and are a good indication of the health of the human body. Blood flow to the skin decreases by as much as 40%, starting from the age of 20 and up until 7045 which is a reflection of the changes brought about in microcirculation. • Difficulty in accessing microvascular reserve The human body is equipped with an abundance of vessels and it keeps a certain percentage of microvasculature non-perfused, so that it may be used in periods of high metabolic demand or under conditions of stress.46 As the human body ages, it becomes increasingly difficult to access this reserve of microvasculature due to changes brought about in how the blood flow is controlled.47 An example of such change is reduction in the reactivity of arterioles leading to reduced vasodilation48 and reduced vasoconstriction.49 A progressive decrease in the availability of nitric oxide is also observed as the aging process continues which affects vasodilatory response directly dependent on nitric oxide synthase present in endothelial cells of the arterioles.50 Aging affects the levels of adrenaline

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Fig. 121.5: Effects of aging on microcirculation.

in the human body. As the body ages, the production of this hormone decreases which impairs the ability of arterioles to perform vasoconstriction. On the contrary, activation of local Rho-kinase pathways associated with aging is a leading cause of hypertension and erectile dysfunction.51 Therefore, aging reduces the body’s ability to respond to a low body temperature, a critical condition that requires feedback mechanism for maintenance, due to lesser production of the hormone adrenaline. • Increased vascular stiffness The main cause of stiffness of arterioles is arteriosclerosis. This is brought about by a multitude of factors including the progressive deterioration of the arteriolar middle coat known as media and the accumulation of debris comprising of extracellular matrix, fats, and cholesterol. Additionally, the occurrence of agerelated diseases results in the deposition of plasma proteins, intercellular connective tissue and debris from the cell itself .52 • Decreased vascular density The ability of the human body to form new microvessels from existing ones is known as angiogenesis, a process which is diminished due to aging. This results in a reduced number of blood vessels in the skin and other organs.53 A reduction in microvascular density is brought about by renal diseases and degeneration of neurons related to an advancement in age.54 Aging

also results in disorderly spread of vascular branches leading to hyper- and hypo-vascularization in different areas of the body as the aging process continues (Fig. 121.5).55

REFERENCES 1. Farage MA, Miller KW, Elsner P, et al. Characteristics of the aging skin. Adv Wound Care (New Rochelle) 2013;2(1): 5–10. 2. Gkogkolou P, Böhm M. Advanced glycation end products: key players in skin aging? Dermatoendocrinol 2012;4(3):259–70. 3. Vierkötter A, Krutmann J. Environmental influences on skin aging and ethnic-specific manifestations. Dermatoendocrinol 2012;4(3):227–31. 4. Wlaschek M, Tantcheva-Poór I, Naderi L, et al. Solar UV irradiation and dermal photoaging. J Photochem Photobiol 2001;63(1):41–51. 5. Quan T, Fisher GJ. Role of age-associated alterations of the dermal extracellular matrix microenvironment in human skin aging: a mini-review. Gerontol 2015;61(5):427–34. 6. Flament F, Bazin R, Laquieze S, et al. Effect of the sun on visible clinical signs of aging in Caucasian skin. Clin Cosmet Investig Dermatol 2013;6:221. 7. Doles J, Keyes WM. Epidermal stem cells undergo age-­ associated changes. Aging (Albany NY) 2013;5(1):1. 8. Racila D, Winter M, Said M, et al. Transient expression of OCT4 is sufficient to allow human keratinocytes to change their differentiation pathway. Gene Ther 2011;18(3):294. 9. Makrantonaki E, Zouboulis CC. Molecular mechanisms of skin aging. Ann N Y Acad Sci 2007;1119(1):40–50.

Chapter 121: Introduction to Skin Aging 10. Edwards C, Heggie R, Marks R. A study of differences in surface roughness between sun-exposed and unexposed skin with age. Photodermatol Photoimmunol Photomed 2003;19(4):169–74. 11. Daniell HW. Smoker’s wrinkles. A study in the epidemiology of “crow’s feet”. 12. Guinot C, Malvy DJ, Ambroisine L, et al. Relative contribution of intrinsic vs extrinsic factors to skin aging as determined by a validated skin age score. Arch Dermatol 2002;138(11):1454–60. 13. Wobrock W, Eiden R. Direct solar radiation: spectrum and irradiance derived from sun-photometer measurements. Appl Opt 1988;27(11):2253–60. 14. Yaar M, Gilchrest BA. Photoageing: mechanism, prevention and therapy. Br J Dermatol 2007;157(5):874–87. 15. Fisher GJ, Voorhees JJ. Molecular mechanisms of photoaging and its prevention by retinoic acid: ultraviolet irradiation induces MAP kinase signal transduction cascades that induce Ap-1-regulated matrix metalloproteinases that degrade human skin in vivo. J Investig Dermatol Symp Proc 1998;3(1):61–8. 16. Varani J, Warner RL, Gharaee-Kermani M, et al. Vitamin A antagonizes decreased cell growth and elevated collagen-degrading matrix metalloproteinases and stimulates collagen accumulation in naturally aged human skin. J  Investig Dermatol 2000;114(3):480–6. 17. Varani J, Spearman D, Perone P, et al. Inhibition of type I procollagen synthesis by damaged collagen in photoaged skin and by collagenase-degraded collagen in vitro. Am J  Pathol 2001;158(3):931–42. 18. Berneburg M, Gattermann N, Stege H, et al. Chronically ultraviolet-exposed human skin shows a higher mutation frequency of mitochondrial DNA as compared to unexposed skin and the hematopoietic system. Photochem Photobiol 1997;66(2):271–5. 19. Berneburg M, Plettenberg H, Medve-König K, et al. Induction of the photoaging-associated mitochondrial common deletion in vivo in normal human skin. J Investig Dermatol 2004;122(5):1277–83. 20. Schroeder P, Gremmel T, Berneburg M, et al. Partial depletion of mitochondrial DNA from human skin fibroblasts induces a gene expression profile reminiscent of photoaged skin. J Investig Dermatol 2008;128(9):2297–303. 21. Berneburg M, Plettenberg H, Krutmann J. Photoaging of human skin. Photodermatol Photoimmunol Photomed 2000;16(6):239–44. 22. Carrard G, Bulteau AL, Petropoulos I, et al. Impairment of proteasome structure and function in aging. Int J  Biochem  Cell  Biol 2002;34(11):1461–74. 23. Zhang W, Xiao S, Ahn DU. Protein oxidation: basic principles and implications for meat quality. Crit Rev Food Sci Nutr 2013;53(11):1191–201. 24. Hwang JS, Hwang JS, Chang I, et al. Age-associated decrease in proteasome content and activities in human dermal fibroblasts: restoration of normal level of proteasome subunits reduces aging markers in fibroblasts from elderly persons. J Gerontol A Biol Sci Med Sci 2007;62(5):490–9.

25. Widmer R, Ziaja I, Grune T. Protein oxidation and degradation during aging: role in skin aging and neurodegeneration. Free Radic Res 2006;40(12):1259–68. 26. Bernstein EF, Underhill CB, Hahn PJ, et al. Chronic sun exposure alters both the content and distribution of dermal glycosaminoglycans. Br J Dermatol 1996;135(2):255–62. 27. Kamenisch Y, Berneburg M. Progeroid syndromes and UV-induced oxidative DNA damage. J Investig Dermatol Symp Proc 2009;14(1):8–14. 28. Ravanat JL, Douki T, Cadet J. Direct and indirect effects of UV radiation on DNA and its components. J Photochem Photobiol 2001;63(1):88–102. 29. Klungland A, Rosewell I, Hollenbach S, et al. Accumulation of premutagenic DNA lesions in mice defective in removal of oxidative base damage. Proc Natl Acad Sci U S A 1999; 96(23):13300–5. 30. Brash DE, Rudolph JA, Simon JA, et al. A role for sunlight in skin cancer: UV-induced p53 mutations in squamous cell carcinoma. Proc Natl Acad Sci U S A 1991;88(22): 10124–8. 31. Rochette PJ, Therrien JP, Drouin R, et al. UVA-induced cyclobutane pyrimidine dimers form predominantly at thymine–thymine dipyrimidines and correlate with the mutation spectrum in rodent cells. Nucleic Acids Res 2003; 31(11):2786–94. 32. Javeri A, Guy Lyons J, Huang XX, et al. Downregulation of Cockayne syndrome B protein reduces human 8-oxoguanine DNA glycosylase-1 expression and repair of UV radiation-induced 8-oxo-7, 8-dihydro-2’-deoxyguanine. Cancer Sci 2011;102(9):1651–8. 33. Stout GJ, Blasco MA. Telomere length and telomerase activity impact the UV sensitivity syndrome xeroderma pigmentosum C. Cancer Res 2013. 34. Kim MS, Kim YK, Cho KH, et al. Regulation of type I procollagen and MMP-1 expression after single or repeated exposure to infrared radiation in human skin. Mech Ageing Dev 2006;127(12):875–82. 35. Schroeder P, Lademann J, Darvin ME, et al. Infrared radiation-induced matrix metalloproteinase in human skin: implications for protection. J Investig Dermatol 2008;128(10):2491–7. 36. Daniell HW. Smooth tobacco and wrinkled skin. New Eng J Med 1969;280(1):53-. 37. Chung JH, Eun HC. Angiogenesis in skin aging and photoaging. J Dermatol 2007;34(9):593–600. 38. Ernster VL, Grady D, Miike R, et al. Facial wrinkling in men and women, by smoking status. Am J Public Health 1995;85(1):78–82. 39. Yin L, Morita A, Tsuji T. Skin aging induced by ultraviolet exposure and tobacco smoking: evidence from epidemiological and molecular studies. Photodermatol Photoimmunol Photomed 2001;17(4):178–83. 40. Yin L, Morita A, Tsuji T. Alterations of extracellular matrix induced by tobacco smoke extract. Arch Dermatol Res 2000;292(4):188–94. 41. Rogiers V. EEMCO guidance for the assessment of transepidermal water loss in cosmetic sciences. Skin Pharmacol Physiol 2001;14(2):117–28.

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Section 33: Cosmetic Surgery 42. Dobos G, Lichterfeld A, Blume-Peytavi U, et al. Evaluation of skin ageing: a systematic review of clinical scales. Br J Dermatol 2015;172(5):1249–61. 43. Trojahn C, Dobos G, Schario M, et al. Relation between skin micro-topography, roughness, and skin age. Skin Res Technol 2015;21(1):69–75. 44. Montagna W, Carlisle K. Structural changes in ageing skin. Br J Dermatol 1990;122(s35):61–70. 45. Tsuchida Y. The effect of aging and arteriosclerosis on human skin blood flow. J Dermatologi Sci 1993;5(3):175–81. 46. Levy BI, Schiffrin EL, Mourad JJ, et al. Impaired tissue perfusion. Circulation 2008;118(9):968–76. 47. Jackson DN, Moore AW, Segal SS. Blunting of rapid onset vasodilatation and blood flow restriction in arterioles of exercising skeletal muscle with ageing in male mice. J  Physiol 2010;588(12):2269–82. 48. DeSouza CA, Clevenger CM, Greiner JJ, et al. Evidence for agonist-specific endothelial vasodilator dysfunction with ageing in healthy humans. J Physiol 2002;542(1):255–62.

49. Thompson CS, Kenney WL. Altered neurotransmitter control of reflex vasoconstriction in aged human skin. J Physiol 2004;558(2):697–704. 50. Mayhan WG, Arrick DM, Sharpe GM, et al. Age-related alterations in reactivity of cerebral arterioles: role of oxidative stress. Microcirculation 2008;15(3):225–36. 51. Nunes KP, Labazi H, Webb RC. New insights into hypertension-associated erectile dysfunction. Curr Opin Nephrol Hypertens 2012;21(2):163. 52. Sawabe M. Vascular aging: from molecular mechanism to clinical significance. Geriatr Gerontol Int 2010; 10(s1). 53. Rivard A, Fabre JE, Silver M, et al. Age-dependent impairment of angiogenesis. Circulation 1999;99(1):111–20. 54. Brown WR, Thore CR. Cerebral microvascular pathology in ageing and neurodegeneration. Neuropathol Appl Neurobiol 2011;37(1):56–74. 55. Bentov I, Reed MJ. The effect of aging on the cutaneous microvasculature. Microvasc Res 2015;100:25–31.

Chapter

122

Injectable Fillers Guillermo Antonio Guerrero-Gonzalez, Ocampo-Candiani J

INTRODUCTION As people age, dermal hydration is lost, and wrinkles and skin folds appear as hyaluronic acid, fat, and bone are progressively lost.1,2 Soft tissue augmentation is a minimally invasive procedure that can restore facial symmetry and volume that is lost as people age. These techniques have undergone remarkable growth in the past years, as more and more filler materials enter the market. The American Society of Plastic Surgeons reported that 2.4 million soft tissue fillers were used in 2015, representing an increase of greater than 250% compared with 2000.3 Dermal fillers are typically combined with skin resurfacing procedures and botulinum toxin to address the different aspects of skin aging. These treatment modalities effectively help maintain and restore a youthful appearance without the risks, recovery time, and cost of more invasive surgical procedures. The ideal filler would be characterized by its safety, efficacy, reproducibility, ease of administration, non-­ carcinogenicity or teratogenicity, and cost-effectiveness.4 It should also be temporal and approved by the corres­ pondent government agencies. This chapter reviews the most commonly used dermal fillers, their applications, and injection techniques.

HISTORY OF FILLERS IN DERMATOLOGY Soft-tissue fillers have been investigated as early as the late 19th century, when Franz Neuber described the use of injected autologous fat for the correction of depressed facial defects. Shortly afterwards, correction of facial lines and wrinkles were treated with paraffin, the first organic filler. After several years, the high incidence of foreignbody granulomas, migration, and embolization resulted in the discontinuation of its use.5,6 Silicone was used from the 1950s to the 1980s and probably afterward. Although several medical-grade silicone products were available,

there were also many reports of adulterated industrialgrade silicones that caused similar complications to those noted with paraffin. Medical-grade silicone never received Food and Drug Administration (FDA) approval for esthetic purposes.7 The development of collagen implant materials started in the 1970s. In 1981, a purified bovine dermal collagen filler (Zyderm) was approved by the FDA.7 Collagen remained the only FDA-approved filler for 22 years. In 2003, a human-derived collagen filler was approved. This material eliminated the frequent hypersensitivity reactions observed with bovine products, but its effect had a rather limited duration (3–4 months). In the same year, the first hyaluronic acid dermal filler was approved. Hyaluronic acid, which is non-protein based and safer and more effective than collagen products, quickly became the filler of choice of many dermatologists around the world.7,8

CLASSIFICATION Injectable soft-tissue fillers are classified according to the duration of their effect: as temporary (5 years) (Table 122.1). Other classifications are based upon their origin (animal versus non-­ animal) or application site (dermal versus subcutaneous).

RHEOLOGY OF FILLERS Rheology is the study of the flow of matter, primarily in a liquid or “soft solid” state. When comparing dermal fillers, rheological properties such as elasticity, viscosity, and plasticity must be considered in that they determine how the fillers behave during and after injection. Understanding the rheology of each filler allows the dermatologist to recognize the optimal product for treatment of a given anatomical area. All fillers are considered to be “gels”, composed of solid particles suspended in a fluid medium. Gel hardness (or elasticity) is described with the variable G’,

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Section 33: Cosmetic Surgery Table 122.1: General dermal fillers classification. Depending on duration Examples Temporary • Bovine collagen • Porcine collagen • Cadaveric human collagen • Bioengineered human collagen • Cadaveric human fascia • Autologous fibroblasts and collagen • Hyaluronic acid derivatives Semipermanent • Poly-L-lactic acid • Calcium hydroxylapatite Permanent • Silicone • Polymethylmethacrylate • Autologous fat Depending on its origin Natural • Fat • Collagen • Fibroblasts • Hyaluronic acid Synthetic • Poly-L-lactic acid • Calcium hydroxylapatite • Silicone • Polymethylmethacrylate

which refers to the force required to deform the gel. Thus, G’ reflects the initial force required to extrude the filler through the syringe and needle. G’ also reflects the resistance to other forces, such as gravity or muscle movement.9 After the initial force is applied to the syringe, the viscosity of the gel determines the force required to complete the injection. Viscosity is represented with the variable η*. Fillers with higher viscosity spread less and tend to remain where they are injected. Increased elasticity and viscosity result in a reduced required volume to achieve a certain effect. When filling the nasolabial folds, for example, less volume of CaHA is required when compared with HA.10 Both fillers require less volume when the initial studies compared these fillers with collagen fillers.11 Understanding these basic concepts on the rheo­logy of dermal fillers allows for a better product selection in a given clinical scenario. A specific patient may wish to achieve certain results without wanting to have a very palpable product injected; if the clinician understands how a dermal filler will behave during and after the injection, the best product for that patient will be chosen.

HYALURONIC ACID Hyaluronic acid (HA) is a naturally occurring glycosaminoglycan, and it is found in all connective tissues and the most common glycosaminoglycan in human skin. It is highly hydrophilic, and by binding and retaining water, it gives volume and support to the skin and fascia. HA plays other biochemical roles, including regulating inflammation, cell motility, and wound healing, among others.9

Chemical Composition HA is a very large molecule (4–5 million Da) consisting of alternating disaccharides of D-glucuronic acid and N-acetyl-D-glucosamine. The molecules are arranged in long, unbranched chains that form entangled coils that interact with each other, providing a viscous solution.9,12,13 Whether derived from animal sources or bacterial fermentation, the molecular structures of all HA fillers are identical. The first HA fillers were avian-derived (Hylaform, Hylaform Plus [Allergan, Santa Barbara, CA]), developed and popularized in the mid-1980s. Non-animal stabilized hyaluronic acid (NASHA) fillers are derived from Staphylococcus equi. Given its non-animal origin, there is a theoretical elimination of hypersensitivity risk. Currently, avian-derived HA fillers are no longer produced due to the longer-lasting results of NASHA fillers.14 HA must be altered and stabilized to delay its breakdown and allow for a longer-lasting result once injected. This alteration is called cross-linking, and the type and degree of this define the difference between the different HA fillers available. The chemical and physical properties that are most often noted for the different HA fillers are as follows: • Type and degree of cross-linking • Hyaluronic acid concentration • Particle size • Gel hardness (G’)

Mechanism of Action Cross-linked HA fillers provide instant volume replacement; however, whether their role is purely passive remains unclear. In skin biopsies from human volunteers at 4 and 13 weeks after injection of HA fillers, researchers from one study observed activated fibroblasts at the edge of the implant along with increased intracellular and extracellular dermal staining for type I procollagen.15 It is still

Chapter 122: Injectable Fillers debated whether this fibroblast activation was induced via mechanical stretch receptors or low-level inflammation. In addition to cross-linking, there are other elements that help understand why HA maintains its filler effect. Injected HA is, in fact, no longer found in skin biopsies after 4 months.16 Collagen breakdown is inhibited by reduction of gene expression of metalloproteinases 1, 2, and 3 induced by HA fillers.15

Supporting Evidence The FDA of the United States approved the first hyaluronic acid filler in 2003 (Restylane [Q-Med, Uppsala, Sweden]). The main study that supported this approval compared Restylane with Zyplast, a bovine collagen filler. Restylane demonstrated less mean total volume required to achieve optimal results that were longer-lasting.11 A similar study compared Perlane with Zyplast for 1 year. Similar results were observed, but a lower rate of local injection site reactions with HA was noted compared with collagen.17

Safety and Adverse Effects HA fillers have many of the characteristics described for an “ideal filler”. HA fillers do not bind to the surrounding cells or tissues, produce a minimal inflammatory reaction, are easy to inject, maintain their shape, and are temporary. Given these properties, HA fillers were approved as devices instead of drugs, which was key to hasten the approval process.18

the microspheres in place and is subsequently absorbed weeks after the injection. Fibroblasts use the injected bone microspheres as scaffolding to lay down a collagenous extracellular matrix. As new collagen fibrils are deposited, the implant becomes integrated and is less palpable over time as the implant is degraded into calcium and phosphate ions and then excreted.19 Based on long-term efficacy studies, CaHA filler works with a two-stage action mechanism, providing immediate volume replacement for up to 12 months and a longer-term corrective effect based on the induced neocollagenesis. A total effect duration of 30 months has been described.20

Supporting Evidence In the United States, FDA approval of CaHA injection for aesthetic purposes was based on a study comparing a human-based collagen filler (Cosmoplast; Allergan, Irvine, CA) in the treatment of nasolabial folds. In the 6-month study period, CaHA provided a longer-lasting correction that required almost half of the injected volume.21 Another advantage is that the injected volume exactly reflects the corrected tissue volume, avoiding the need to overcorrect.22 Although not approved for this purpose, CaHA is safe and effective for the rejuvenation of the hands. CaHA is the filler of choice by many dermatologists, with an added advantage of obscuring visible veins and tendons given its opacity.23

Safety and Adverse Effects

Because of its naturally occurring components, skin testing is not required prior to treatment. CaHA is inert and Calcium hydroxylapatite fillers are composed of synthetic non-toxic, and does not produce any significant inflambone microspheres combined with a carrier gel. Calcium matory reaction. Due to the lack of bone progenitor cells hydroxylapatite has FDA approval for two facial soft-­ in the product, there is no risk of bone formation even with tissue augmentation indications: treatment of moderate supraperiosteal implantation.24 to severe nasolabial folds and correction of facial volume Once implanted, CaHA does not interfere with any loss due to HIV-related lipoatrophy. radiological diagnostic procedures. On routine X-rays, the implant may be invisible or rarely seen as wispy streaks.25 However, the implant can be detected on CT and MRI Chemical Composition and scans.24,25 Mechanism of Action Common side effects related to the injection site are Radiesse (Merz Aesthetics, San Mateo, CA) is composed pain, edema, erythema, and ecchymosis. These effects are of 30% concentration of calcium hydroxylapatite micro- typically resolved within two weeks. Superficial injection spheres that are 25–45 m in diameter, combined with 70% may result in visible volumes, which mostly resolve after 4 carboxymethylcellulose carrier gel. The carrier gel holds weeks. However, some require surgical excision.26

CALCIUM HYDROXYLAPATITE

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POLY-L-LACTIC ACID Poly-L-lactic acid (PLLA) is a dermal stimulatory agent that promotes neocollagenesis, resulting in progressive volume restoration.

Chemical Composition and Mechanism of Action PLLA is a biodegradable, biocompatible, biologically inert, synthetic polymer. PLLA has been widely used in absorbable sutures, bone implants, and plates and screws in reconstructive surgery.27 It is manufactured as a lyophilized preparation composed of PLLA microparticles in a carboxymethylcellulose carrier gel. Particle size ranges from 40 to 60 μm, which discourages phagocytosis and intracapillary dispersion.9 Injectable PLLA creates the appearance of immediate volume correction due to the mechanical effect of the injected product. After a couple of days, the suspension fluid is absorbed, and the effect reversed. Although the precise mechanism of action of PLLA as a dermal filler is not completely understood, the progressive effect results from the degradation of the PLLA particles and a natural foreign body reaction, which involves capsule formation with an inflammatory reaction of macrophages and myofibroblasts and the formation of fibrous connective tissue and neocollagenesis.27,28

Supporting Evidence PLLA is effective for the treatment of facial lipoatrophy in HIV-positive patients as well as wrinkles and folds of the lower face, with volume augmentation persisting for greater than 2 years.29–31 Creases and furrows in the upper face can also be treated, especially in combination with botulinum toxin. Augmentation of atrophic areas, such as cheeks, upper lip, and chin, is also achievable with this product.30

Safety and Adverse Effects During the first years of experience with PLLA, a high incidence of papule and nodule formation was reported. As the experience increased, a change in the reconstitution parameters and injection technique was proposed, leading to less than 1% of the patients presenting such side effects.30 Common side effects include bruising, erythema, and transitory swelling, all of which resolve within a few days.30

POLYMETHYLMETHACRYLATE Polymethylmethacrylate (PMMA) is an inert synthetic implant material commonly used in bone and dental implants and intraocular lenses. PMMA has the trade name of ArteFill (Suneva Medical) and is the only FDAapproved permanent filler used for the correction of nasolabial folds.19

Chemical Composition and Mechanism of Action The dermal filler is composed of 20% PMMA microspheres with a diameter from 30 to 45 μm in a carrier gel consisting of bovine-based collagen (3.5%) and lidocaine (0.3%). Immediate volume correction is achieved by the collagen component, which is degraded within 1 to 3 months. The collagen component prevents clumping of the PMMA microspheres and allows tissue ingrowth. The size and smooth texture of the PMMA particle prevents phagocytosis and promotes granulomatous inflammation, with macrophages, fibroblasts, and collagen deposition in the interstitial space between the microspheres. After 4 weeks, the implant consists of 20% PMMA microspheres and 80% granulation tissue.9 Histology after 10 years reveals intact PMMA particles surrounded by mature collagen fibers and intact capillaries. The implant is fully integrated into the connective tissue.32

Supporting Evidence The current FDA-approved indication for PMMA is the treatment of nasolabial folds. However, the proposed indications include horizontal forehead lines, glabellar frown lines, nasojugal folds, periocular wrinkles, cheek depressions, acne and traumatic scars, and lip enhancement.33 PMMA is the only permanent facial filler with FDA approval. Nasolabial fold correction lasts after 5 years, demonstrating continuous improvement over time.34

Safety and Side Effects Given the bovine collagen in the carrier gel, skin testing is required at least 1 month prior to injection. Patients treated with the original formulations presented a high incidence of granulomas, which forced refinement of the process to produce a smooth sphere. Such modifications

Chapter 122: Injectable Fillers resulted in a decreased incidence of granulomas from 2.5% to less than 0.01%.9 Lumpiness is the main side effect observed, which is typically mild.34 Granulomatous reactions have been reported, with a probable natural history of spontaneous resolution indicating that treatment may not be necessary.35 In general terms, the safety profile is consistent with that of HA and CaHA fillers.34

AUTOLOGOUS FAT Fat is one of the oldest fillers and ideal for patients with significant volume loss. Fat is harvested via liposuction from areas, including the abdomen or thighs, under sterile conditions and then centrifuged to separate viable fat cells from blood, water, and lidocaine and oil from ruptured fat cells. Autologous fat covers almost all requisites of the ideal filler, missing perhaps only the desired predictability and persistence of results over time.36

Mechanism of Action As initial results were unpredictable with considerable volume loss, fat was considered a temporary filler that should be applied with large volumes to make an initial overcorrection that would result in partial volume resorption and a desired effect. This technique typically resulted in unpleasant results with frequent asymmetries. With better understanding after empirical and scientific research, it is now accepted that fat should be treated as a living graft, applying small parcels of fat in different tissue planes to facilitate blood supply to such parcels, reducing fat ischemia and resorption rate.37 Although the long-term effect is variable, with a 20–60% resorption rate, fat grafting is considered a permanent filler that is not suitable for patients who have not undergone procedures with temporary fillers or novice injectors. Factors that improve the survival rate of the transplanted fat include atraumatic harvest and injection of fat, smaller particle size and injected volume, and contact with muscles to enhance vascular perfusion.36 Fat grafting provides volumetric rejuvenation; fat integrates with the surrounding tissues, producing natural results when injected in correct quantity. A stem cell effect that has not been completely defined is presumed to further improve facial tissues.38

Supporting Evidence Autologous fat is considered a safe and effective treatment option for patients with HIV-related facial lipoatrophy. When compared with poly-l-lactic acid, fat grafting required less reinjections and offers the same or superior long-term results than injectable fillers.39 In addition to facial rhytides, folds and volume loss, fat can also be used to restore volume in other areas, such as breasts and hands, and to correct deformities caused by morphea, lupus, and depressed defects covered with skin grafts and others.40–42

Safety and Side Effects The overall complication rate for all fat augmentation techniques is quite low. The most feared complication of autologous fat transfer, as with liposuction only, is fat embolism. Many cases were reported before the introduction of local tumescent anesthesia.43 However, more recent cases, including a fatal case and another case of a patient who developed a massive cerebral infarction 8 hours after injection, have also been reported.44,45 Vascular occlusion can be prevented with deep knowledge of the anatomy and use of blunt-tip cannulae instead of hypodermic needles, small-volume syringes (1 mL), and light pressure when injecting the fat. The most common complication is overcorrection, especially when treating the infraorbital region. For this reason, applying small boluses in a plane that is not very superficial is preferred. As a permanent filler, overcorrection is difficult to treat. All patients should be screened preoperatively for any infection in the facial region, including the sinuses, dental, and ocular areas. When found, infections should be treated before performing the procedure. Antibiotic prophylaxis is recommended in all patients, along with a sterile technique that covers all treated areas, instruments, and the centrifuge.

PATIENT PREPARATION Although minimal preoperative preparation is required for soft-tissue augmentation, certain key points must be discussed with the patient during consultation. Physicians should set realistic expectations, not only regarding achievable results, but also for possible side effects (minimal or not), downtime, and potential complications.

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Section 33: Cosmetic Surgery Contraindications for dermal fillers are very rare but include the following:46

Absolute • Hypersensitivity to a given product or lidocaine (in case of considering a product mixed with lidocaine) • Active infection at or near the site of injection • Unrealistic expectations

Relative Keloid Tendency There is no certainty regarding whether autoimmune diseases represent a relative risk factor as a causal agent. Immunosuppression does not increase the risk of complications when using dermal fillers.46 History of previous cosmetic procedures and surgeries must also be taken into consideration, and physical examination should be thorough to notice preoperative asymmetries. Standard photographs should be taken before any procedure and, if possible, compared with previous photographs if the patient is able to provide them to better determine the required volume needed for a natural appearance. To reduce the risk of ecchymosis, patients should be instructed to stop medications, supplements, and herbs that would impair platelet aggregation or blood coagulation at least 10 days before the procedure. Preoperative asymmetries should be noted and discussed with the patient. Patient marking, although not

mandatory, is advised and should be performed with the patient in an upright position and prior to local anesthetic injection (Fig. 122.1). Topical or local block anesthesia can be used to reduce pain. As with all procedures, photographs should be taken before and after. In the case of HA fillers, the maximum effect is observed after 24 to 48 hours (Figs. 122.2 to 122.4). There is no correct filler for a given anatomical area or application. A good starting point when choosing a dermal filler is to consider the desired effect and injection depth. For example, a very soft and spreadable filler will not work to create a sculpted shape in the cheeks. High-viscosity, high-cohesivity HA, and CaHA fillers work well in the ­subcutaneous or periosteal plane, whereas lower viscosity HA fillers are suitable for intradermal injection.47

A

B

Fig. 122.1: Patient marking.

Figs. 122.2A and B: Before (A) and immediately after; (B) photographs. Hyaluronic acid filler was placed in the zygomatic area and nasolabial folds.

Chapter 122: Injectable Fillers

A

B

Figs. 122.3A and B: Before and 24 hours after hyaluronic acid filler injection in the zygomatic area and nasolabial folds.

A

B

Figs. 122.4A and B: Before and 48 hours after hyaluronic acid filler injection in the zygomatic area, nasolabial folds, and prejowl sulcus.

INJECTION TECHNIQUES Although there is no consensus regarding the best injection technique for dermal fillers, several principles are universally accepted. The decision on how deep the injection is placed will depend both on the desired effect and the product used. Fine lines can be addressed using a product with small particle size placed in the papillary dermis; whereas, deeper folds require a deeper injection in the deep dermis or fat with a large-particle product. According to the treated area, fillers can be injected using one or more of the described techniques (Fig. 122.5).

Linear Threading With this technique, the area to be filled is punctured, and the needle is advanced in a parallel plane to the skin. The needle is then withdrawn, applying constant pressure to the plunger to deposit the filler in a linear fashion. When using this technique in superficial planes, the needle bevel is directed down to avoid visible nodules or blue discoloration. For deeper defects, the same technique can be used with a layered approach with successive passes at different depths. A triangular or vertical fanning approach was proposed for filling the nasolabial folds with calcium

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Section 33: Cosmetic Surgery significantly less pain and a reduced incidence of bruising and ecchymosis.49 The theoretical background of such findings is that blunt-tip cannulae displace blood vessels rather than puncturing them. Patients are also usually more comfortable watching a cannula than a needle.

Concept of Volumization

Fig. 122.5: Common injection techniques.

hydroxylapatite, injecting in successive passes that were from 10° to 20° lower than the initial plane.48

Serial Puncture With this technique, microdroplets (less than 0.03 mL) are placed with successive spaced injections along a skin fold or wrinkle. Placing injections one close to the next allows the filler to blend after a small massage.

Fanning and Crosshatching These techniques involve multiple linear passes of injection to add volume to a larger area. The fanning technique places filler in multiple different directions evenly spaced without completely withdrawing the needle from the skin. The crosshatching technique places the filler in crossing lines that result in a grid. Both techniques are good options when treating concave areas, such as the lipoatrophic cheek, other large areas and also oral commissures and nasolabial folds.

Use of Cannulae Most filler products are provided with hypodermic needles. Although blunt-tip cannulae have been used for fat transfer procedures for many years, their use with dermal fillers was only proposed in the last few years. Compared with hypodermic needles, cannulae use resulted in

One well-accepted trend is performing volumetric rejuvenation, which indicates the use of a “zone approach” instead of filling a single fold. This technique is a consequence of better understanding of the aging face. Facial aging involves a loss of volume: loss of bony support in the maxilla, mandible, and periorbital areas, and loss of fat volume from the different fat compartments. This volume loss results in deflation, flattening, and pseudoptosis of the soft tissues.50 The use of high-density fillers in the supra-periosteal plane in the temples, zygomatic and cheek area, and prejowl sulcus effectively replaces lost volume. Less-dense products can be used to further correct specific folds or wrinkles.

REVERSAL AND MANAGEMENT OF ADVERSE EFFECTS AND COMPLICATIONS Although current FDA-approved products are considered safe, there is a certain risk for adverse effects and complications. The true incidence is unknown given the lack of reports of serious complications and the fact that minor adverse effects are typically not brought to attention. Avoidance of complications starts with perfect awareness of the anatomy and knowledge of the characteristics and rheology of the product most suitable for a given area. Adverse effects can be classified according to their timing as acute or late (Box 122.1).51 Minor side effects, such as bruising, edema, and light pain, are typically self-limited and spontaneously resolve within a couple of days. Such effects can be avoided with gentle tissue manipulation and experience. Hypersensitivity reactions are now extremely rare because HA fillers and other recent available products are not bovine-derived. When using fillers derived from bovinematerial, skin testing is recommended. Local site infections must be treated and can generally be prevented by never injecting an area with signs of infection.

Chapter 122: Injectable Fillers Box 122.1: Dermal fillers side effects and complications.51 Early • Local site reactions (bruising, erythema, edema, pain) • Acute infections (bacterial) • Type I hypersensitivity reactions • Tyndall effect (blue discoloration due to superficial injection) • Other discoloration (red, white) • Vascular occlusion/Local tissue necrosis • Irregular contour or nodules secondary to excessive material injection or technique error Late • Persistent malar edema • Persistent discoloration • Type IV hypersensitivity reactions • Late infections (mycobacteria or biofill-related) • Inflammatory nodules and granulomatous reactions • Filler migration

Bruising and bleeding are not infrequent, especially in patients taking aspirin, anticoagulants, vitamin E and herbs, such as ginkgo biloba. These medications should ideally be suspended 10 days before the procedure, unless contraindicated. Bleeding must be treated using direct pressure. Bruising and swelling can be avoided by applying cold pads after the injection. Factors associated with a higher risk of bruising include the fanning technique, rapid injection and flow rate, and high volume in a given area.52 One serious acute complication is tissue necrosis due to vascular occlusion, compression, or laceration. It is most commonly observed in the glabellar region; however, it has also been reported in the nasal ala and nasolabial fold. It can present as immediate blanching followed by purple discoloration of the area and accompanying pain. If left untreated, a livedoid pattern, vesicles, scabs, and subsequent scarring can present. In the periorbital region, vascular occlusion can result in visual loss or compromise. The condition is characterized by visual loss, impaired eye movements, or palpebral ptosis.53 When noted during the procedure, the injection should be stopped. Therapy includes massage with nitroglycerin paste, hyaluronidase injection, warm compresses, and aspirin. Patients should be followed on a daily basis for signs of tissue necrosis.54 In the case of visual compromise, intra-arterial and retrobulbar injection of hyaluronidase along with the aforementioned measures are effective.53

Hyaluronidase Hyaluronidase is a naturally occurring enzyme capable of local degradation of hyaluronic acid, both natural and synthetic. Hyaluronidase is a soluble protein responsible for the degradation of glycosaminoglycans. Although it is an off-label indication, it has effectively been used to treat complications of hyaluronic acid injection, such as nodules, granulomatous reactions, vascular occlusion, and impending tissue necrosis. Although different HA fillers respond differently to hyaluronidase and the response is time and dose dependent, it has proven to be effective in the most critical situations and must be always kept in stock. Due to the risk of allergic reactions, skin testing is recommended before its use.55 The effect is immediate with a duration of 24 to 48 hours. There is no consensus on the recommended dose, varying between 5 and 75 IU. The concentration of HA in the used product and the time the filler is exposed to hyaluronidase both affect the amount of degradation achieved.

CONCLUSION Soft-tissue augmentation is currently one of the most requested and performed esthetic procedures. Deep knowledge of the facial anatomy and aging process as well as the characteristics of the different available and upcoming products and injection techniques are mandatory for achieving effective, reproducible results and avoiding the risk of complications. As a fast-changing subject, it is necessary to always be updated on the most recent advances. As with all surgical procedures, the physician is obliged to know about the procedure and how to manage the side effects and complications.

REFERENCES 1. Lee DH, Oh JH, Chung JH. Glycosaminoglycan and proteoglycan in skin aging. J Dermatol Sci 2016;83(3):174–81. 2. DeVore DP, Hughes E, Scott JB. Effectiveness of injectable filler materials for smoothing wrinkle lines and depressed scars. Med Prog Technol 1994;20(3–4):243–50. 3. American Society of Plastic Surgeons. 2015 Cosmetic Plastic Surgery Statistics. https://www.plasticsurgery.org/ news/plastic-surgery-statistics?sub=2015+Plastic+Surgery+ Statistics 4. Baumann L. Dermal fillers. J Cosmet Dermatol 2004;3(4): 249–50. 5. Heidingsfeld ML. A further contribution to the histopathology of paraffin prosthesis. JAMA 1908;LI(24):2028–31. 6. Kontis TC, Rivkin A. The history of injectable facial fillers. Facial Plast Surg 2009;25(2):67–72.

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Section 33: Cosmetic Surgery 7. Glogau RG. Fillers: from the past to the future. Semin Cutan Med Surg 2012;31(2):78–87. 8. Chacon AH. Fillers in dermatology: from past to present. Cutis 2015;96(5):E17–9. 9. Gilbert E, Hui A, Waldorf HA. The basic science of dermal fillers: past and present Part I: background and mechanisms of action. J Drugs Dermatol 2012;11(9):1059–68. 10. Moers-Carpi MM, Tufet JO. Calcium hydroxylapatite versus nonanimal stabilized hyaluronic acid for the correction of nasolabial folds: a 12–month, multicenter, prospective, randomized, controlled, split-face trial. Dermatol Surg 2008;34(2):210–5. 11. Duranti F, Salti G, Bovani B, et al. Injectable hyaluronic acid gel for soft tissue augmentation. A clinical and histological study. Dermatol Surg 1998;24(12):1317–25. 12. Piacquadio D, Jarcho M, Goltz R. Evaluation of hylan b gel as a soft-tissue augmentation implant material. J Am Acad Dermatol 1997;36(4):544–9. 13. Hamburger MI, Lakhanpal S, Mooar PA, et al. Intraarticular hyaluronans: a review of product-specific safety profiles. Semin Arthritis Rheum 2003;32(5):296–309. 14. Rao J, Chi GC, Goldman MP. Clinical comparison between two hyaluronic acid-derived fillers in the treatment of nasolabial folds: hylaform versus restylane. Dermatol Surg 2005;31(11 Pt 2):1587–90. 15. Wang F, Garza LA, Kang S, et al. In vivo stimulation of de novo collagen production caused by cross-linked hyaluronic acid dermal filler injections in photodamaged human skin. Arch Dermatol 2007;143(2):155–63. 16. Lemperle G, Morhenn V, Charrier U. Human histology and persistence of various injectable filler substances for soft tissue augmentation. Aesthetic Plast Surg 2003;27(5):354– 66; discussion 67. 17. Lindqvist C, Tveten S, Bondevik BE, et al. A randomized, evaluator-blind, multicenter comparison of the efficacy and tolerability of Perlane versus Zyplast in the correction of nasolabial folds. Plast Reconstr Surg 2005;115(1):282–9. 18. Greene JJ, Sidle DM. The hyaluronic acid fillers: current understanding of the tissue device interface. Facial Plast Surg Clin North Am 2015;23(4):423–32. 19. Kontis TC. Contemporary review of injectable facial fillers. JAMA Facial Plast Surg 2013;15(1):58–64. 20. Bass LS, Smith S, Busso M, et al. Calcium hydroxylapatite (Radiesse) for treatment of nasolabial folds: long-term safety and efficacy results. Aesthet Surg J 2010;30(2):235–8. 21. Smith S, Busso M, McClaren M, et al. A randomized, bilateral, prospective comparison of calcium hydroxylapatite microspheres versus human-based collagen for the correction of nasolabial folds. Dermatol Surg 2007;33(2):S112–21; discussion S21. 22. Marmur ES, Phelps R, Goldberg DJ. Clinical, histologic and electron microscopic findings after injection of a calcium hydroxylapatite filler. J Cosmet Laser Ther 2004;6(4):223–6. 23. Sadick NS. A 52-week study of safety and efficacy of calcium hydroxylapatite for rejuvenation of the aging hand. J Drugs Dermatol 2011;10(1):47–51. 24. Emer J, Sundaram H. Aesthetic applications of calcium hydroxylapatite volumizing filler: an evidence-based

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review and discussion of current concepts: (part 1 of 2). J Drugs Dermatol 2013;12(12):1345–54. Carruthers A, Liebeskind M, Carruthers J, et al. Radiographic and computed tomographic studies of calcium hydroxylapatite for treatment of HIV-associated facial lipoatrophy and correction of nasolabial folds. Dermatol Surg 2008;34(1):S78–84. Luebberding S, Alexiades-Armenakas M. Facial volume augmentation in 2014: overview of different filler options. J Drugs Dermatol 2013;12(12):1339–44. Simamora P, Chern W. Poly-L-lactic acid: an overview. J Drugs Dermatol 2006;5(5):436–40. Bartus C, William Hanke C, Daro-Kaftan E. A decade of experience with injectable poly-L-lactic acid: a focus on safety. Dermatol Surg 2013;39(5):698–705. Lowe NJ, Maxwell CA, Lowe P, et al. Injectable poly-llactic acid: 3 years of aesthetic experience. Dermatol Surg 2009;35(1):344–9. Woerle B, Hanke CW, Sattler G. Poly-L-lactic acid: a temporary filler for soft tissue augmentation. J Drugs Dermatol 2004;3(4):385–9. Moyle GJ, Brown S, Lysakova L, et al. Long-term safety and efficacy of poly-L-lactic acid in the treatment of HIVrelated facial lipoatrophy. HIV Med 2006;7(3):181–5. Lemperle G, Knapp TR, Sadick NS, et al. ArteFill permanent injectable for soft tissue augmentation: I. Mechanism of action and injection techniques. Aesthetic Plast Surg 2010;34(3):264–72. Lemperle G, Sadick NS, Knapp TR, et al. ArteFill permanent injectable for soft tissue augmentation: II. Indications and applications. Aesthetic Plast Surg 2010;34(3): 273–86. Cohen SR, Berner CF, Busso M, et al. Five-year safety and efficacy of a novel polymethylmethacrylate aesthetic soft tissue filler for the correction of nasolabial folds. Dermatol Surg 2007;33(2):S222–30. Gelfer A, Carruthers A, Carruthers J, et al. The natural history of polymethylmethacrylate microspheres granulomas. Dermatol Surg 2007;33(5):614–20. Haiavy J, Elias H. Injectable fillers in the upper face. Atlas Oral Maxillofac Surg Clin North Am 2016;24(2):105–16. Fulton JE, Suarez M, Silverton K, et al. Small volume fat transfer. Dermatol Surg 1998;24(8):857–65. Marten TJ, Elyassnia D. Fat grafting in facial rejuvenation. Clin Plast Surg 2015;42(2):219–52. Shuck J, Iorio ML, Hung R, et al. Autologous fat grafting and injectable dermal fillers for human immunodeficiency virus-associated facial lipodystrophy: a comparison of safety, efficacy, and long-term treatment outcomes. Plast Reconstr Surg 2013;131(3):499–506. Pulagam SR, Poulton T, Mamounas EP. Long-term clinical and radiologic results with autologous fat transplantation for breast augmentation: case reports and review of the literature. Breast J 2006;12(1):63–5. Butterwick KJ. Lipoaugmentation for aging hands: a comparison of the longevity and aesthetic results of centrifuged versus noncentrifuged fat. Dermatol Surg 2002; 28(11):987–91.

Chapter 122: Injectable Fillers 42. Yoon J, Kim HM, Kim TH, et al. Autologous fat transfer in a patient with lupus erythematosus profundus. Case Rep Dermatol 2012;4(3):207–10. 43. Feiner R. Letter: letter to editor regarding “Acute fatal fat tissue embolism after autologous fat transfer in a patient with lupus profundus”. Dermatol Surg 2011;37(6): 887–8. 44. Gleeson CM, Lucas S, Langrish CJ, et al. Acute fatal fat tissue embolism after autologous fat transfer in a patient with lupus profundus. Dermatol Surg 2011;37(1):111–5. 45. Shen X, Li Q, Zhang H. Massive cerebral infarction following facial fat injection. Aesthetic Plast Surg 2016;40(5): 801–5. 46. Lafaille P, Benedetto A. Fillers: contraindications, side effects and precautions. J Cutan Aesthet Surg 2010;3(1):16–9. 47. Bass LS. Injectable filler techniques for facial rejuvenation, volumization, and augmentation. Facial Plast Surg Clin North Am 2015;23(4):479–88. 48. Alam M, Yoo SS. Technique for calcium hydroxylapatite injection for correction of nasolabial fold depressions. J Am Acad Dermatol 2007;56(2):285–9.

49. Fulton J, Caperton C, Weinkle S, et al. Filler injections with the blunt-tip microcannula. J Drugs Dermatol 2012;11(9): 1098–103. 50. Lorenc ZP, Lee JC. Composite volumization of the aging face: supra-periosteal space as the foundation for optimal facial rejuvenation. J Drugs Dermatol 2016;15(9):1136–41. 51. Funt D, Pavicic T. Dermal fillers in aesthetics: an overview of adverse events and treatment approaches. Clin Cosmet Investig Dermatol 2013;6:295–316. 52. Cohen JL, Brown MR. Anatomic considerations for soft tissue augmentation of the face. J Drugs Dermatol 2009; 8(1):13–6. 53. Hwang CJ. Periorbital injectables: understanding and avoiding complications. J Cutan Aesthet Surg 2016;9(2):73–9. 54. Dayan SH, Arkins JP, Mathison CC. Management of impending necrosis associated with soft tissue filler injections. J Drugs Dermatol 2011;10(9):1007–12. 55. Rao V, Chi S, Woodward J. Reversing facial fillers: interactions between hyaluronidase and commercially available hyaluronic-acid based fillers. J Drugs Dermatol 2014; 13(9):1053–6.

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Neurotoxins in Aesthetic Medicine Patricia K Farris, Leah G Jacobs

INTRODUCTION The use of botulinum toxin to treat dynamic rhytides is perhaps the most significant advance in modern esthetic medicine. Lines and wrinkles that previously had been virtually impossible to eradicate with non-invasive procedures can now be effectively treated using properly placed injections of botulinum toxin. Frown lines, crow’s feet, and horizontal forehead lines were among the first areas treated by early injectors of botulinum toxin A (BoNT-A).1 As usage evolved, BoNT-A was found to be valuable for treating the mid and lower face.2 BoTN-A injections are now used to reduce bulky masseter muscles and reshape the face, prevent a gummy smile, turn up the corners of the mouth, treat peau d’orange appearance of the chin, and reduce the appearance of platysmal bands. These advanced techniques have made BoTN-A invaluable to esthetic physicians who continue to discover new ways to utilize neurotoxins to improve appearance. Like physicians, cosmetic patients worldwide have embraced the rejuvenating benefits of botulinum toxin. According to the American Society of Plastic Surgery, BoTN-A injections are the number one non-invasive cosmetic procedure in the US with a reported 6.8 million procedures performed in 2015. With a high degree of patient satisfaction, an excellent safety profile, and a cost far below surgical procedures, the use of BoTN-A has lowered the barrier of entry for cosmetic procedures. The notion that neurotoxin might be helpful for preventing wrinkles has attracted younger patients into the esthetic market. In addition, men who have been reluctant to undergo cosmetic surgery have embraced this simple yet effective in-office procedure. Without a doubt, the use of neurotoxin for esthetic purposes has changed the face of esthetic medicine forever.

HISTORY Botulinum toxin is a neurotoxic protein produced by the bacterium Clostridium botulinum and responsible for the

clinical syndrome known as botulism. The first description of food-borne botulism was published in the early 1800s by German physician and poet, Dr Justinus Kerner. An outbreak of lethal food poisoning from improperly prepared blood sausages in southern Germany prompted Kerner, who was the district medical officer at the time, to investigate and publish a report describing the clinical symptoms of what he referred to as “sausage poisoning” in 76 patients. His published case histories are the first to accurately and completely describe what would eventually be known as botulism. The term botulism is derived from the Latin word botulus, which means sausage. Although Kerner was not able to identify the causative agent, he hypothesized that the condition, characterized by flaccid paralysis, was related to a biological toxin found in spoiled sausage. Using extracts isolated from spoiled sausages, he conducted extensive experiments on both animals and himself, and recognized the toxin’s inhibitory effects on both the autonomic and motor nervous systems. He described his findings in detail; in the final chapter of his monograph, he recognizes the potential therapeutic uses of the toxin on a variety of overactive neurologic diseases. His suggestions for using the toxin to therapeutically block neural hyperactivity earned him recognition as the intellectual founder of modern botulinum toxin therapy.3 A subsequent botulism outbreak in Belgium in 1895 led to the discovery of the causative toxin-producing bacterium by Belgian microbiologist Emile Pierre van Ermengem, which he named Bacterium botulinum. Its name was subsequently changed to Clostridium botulinum. Interest in the research of botulinum neurotoxins increased during World War II. Dr Edward Schantz, using techniques developed by Carl Lamanna and James Duff, first isolated the botulinum type A toxin in crystalline form in 1946 for the US Army. He eventually was able to produce a highly purified batch of medical-grade toxin for use in humans in 1979, known as batch 79–11. In the 1970s, ophthalmologist Dr Alan Scott, using botulinum toxin A produced by Dr Schantz, was the first to successfully

Chapter 123: Neurotoxins in Aesthetic Medicine harness the effects of botulinum toxin for medical use in monkey strabismus. In 1973, he published the first study demonstrating therapeutic value for botulinum exotoxin; namely, that injections of the toxin could weaken extraocular muscles in monkeys. He began to investigate its usefulness in treating strabismus in humans as a nonsurgical ­alternative. After receiving US Food and Drug Administration (FDA) approval for human testing, Dr Scott led the first multicenter clinical trial of botulinum toxin to establish its safety and efficacy in treating strabismus in more than 7,000 subjects and published his findings in a landmark paper.4 Initial positive results expanded his clinical research to other ocular indications. This eventually led to approval by the FDA in 1989 of botulinum toxin type A (trade name Oculinum®) not only for the treatment of strabismus, but also for blepharospasm and hemifacial spasm in adults. Allergan Inc. later acquired Oculinum® in 1990 and changed the product’s name to “Botox®”. Further trials of ophthalmologic uses of botulinum toxin A led to the inadvertent discovery of its cosmetic benefits. Dr Jean Carruthers, an ophthalmologist working with Dr Scott in clinical trials of Oculinum®, noticed diminished wrinkles in the glabella of patients being treated for blepharospasm. She and her husband, ­dermatologist Dr  Alastair Carruthers, performed further studies on the use of botulinum toxin type A for cosmetic purposes. In 1992, the Carruthers published their findings demonstrating the safe and effective treatment of dynamic rhytides in the glabella with botulinum toxin type A.5 Their studies are credited as some of the first to demonstrate the use of botulinum toxin for purely cosmetic purposes. After formal trials, in 2002 the FDA approved the use of botulinum toxin type A (BOTOX Cosmetic®, Allergan Inc., Irvine, CA) for glabellar rhytides. Since its initial approval, the use of botulinum toxin has expanded dramatically in both the cosmetic and therapeutic realms, and successful off-label uses of the botulinum toxin products have been widespread.6 In 2013, Botox® (onabotulinumtoxinA) received additional approval for the treatment of lateral canthal lines; to date, it is the only botulinum toxin with this additional cosmetic indication. While onabotulinumtoxinA remains the most extensively studied, two other formulations of botulinum toxin A are currently available and approved for cosmetic use in North America. Following several phase III studies establishing its efficacy and safety, abobotulinumtoxinA (Dysport®, Galderma) received FDA approval in 2009 for the temporary improvement of glabellar rhytides.7–9

IncobotulinumtoxinA (Xeomin®, Mertz Pharmaceuticals, Greensboro, NC) was also approved for the treatment of glabellar lines in 2011, with several studies establishing its efficacy and safety.10–12

MECHANISM OF ACTION Botulinum exotoxin is produced by several strains of Clostridium botulinum, a species of anaerobic, rodshaped, spore-forming bacteria. Seven distinct serotypes of botulinum exotoxin are produced and are all neurotoxic: A, B, C1, D, E, F, and G; of these, serotype A seems to be the most potent in humans. All serotypes of botulinum toxin cause chemode­ nervation of skeletal muscles by blocking acetylcholine release from motor neurons at the neuromuscular junction, thus preventing muscular contraction. Once botulinum toxin enters the human system, it binds to receptors on the terminal ends of nerve cells. The toxin then enters the cytoplasm of the presynaptic neuronal terminal plate via endocytosis. Once inside the cytoplasm, the toxin binds to the SNARE (Soluble N-ethylmaleamide-sensitive factor Attachment protein receptor) complex, a membrane-bo­ und ­protein complex composed of synaptobrevin, SNAP-25 (synaptosome-associated protein of 25 kd), and syntaxin, that is required for fusion of acetylcholine-containing vesicles with the cell membrane, allowing the release of acetylcholine into the neuromuscular junction. When botulinum toxins attach to and cleave various components of the SNARE complex, acetylcholine is unable to enter the presynaptic cleft and muscle contraction is inhibited. Different serotypes of botulinum toxin target different sites of cleavage within the SNARE complex. SNAP-25 is targeted and cleaved by serotypes A, C1, and E; serotypes B, D, F, and G cleave VAMP (vesicle-associated membrane protein), also known as synaptobrevin. Following cleavage of these respective membrane protein complexes by the botulinum toxins, acetylcholine is unable to be released and the associated muscle cell is paralyzed and contraction ceases. The chemodenervation achieved with therapeutic botulinum toxin injections is temporary, with results usually lasting 3–6 months. After this time, the original neuromuscular junction is functionally restored, with regeneration of the SNAP-25 proteins and reestablishment of their connection within the neuromuscular junction.13 Additionally, new neuromuscular junctions and collateral nerve ends are formed during recovery due to axonal sprouting but appear to be transient and retract over time.

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PROPERTIES OF COMMERCIALLY AVAILABLE BOTULINUM TOXIN FORMULATIONS To date, four different botulinum toxin formulations are available and approved for medical use in the United States. Three of these are botulinum toxin A products: onabotulinumtoxinA (Botox®, Botox Cosmetic®, Allergan, Inc., Irvine,  CA), abobotulinumtoxinA (Dysport®, Galderma), and incobotulinumtoxinA (Xeomin®, Merz Aesthetics, Inc, San Mateo, CA). The fourth formulation consists of serotype B and is named rimabotulinumtoxinB (Myobloc, Solstice Neurosciences LLC, San Francisco, CA). As only botulinum toxin A products are approved for cosmetic use, we will focus our discussion on these. All commercially available botulinum toxin formulations contain the core 150-kDa neurotoxin but differ in regards to the presence of non-toxin excipient molecules, yielding products of varying molecular weights. Excipients are added by the manufacturer and serve to stabilize the botulinum toxin protein at the proper pH and promote uniform dispersion of the protein molecules. In addition to variations in the non-toxin protein constituents, each botulinum toxin formulation is unique in terms of the manufacturing process, packaging, and storage requirements; these will be reviewed briefly (Table 123.1).

OnabotulinumtoxinA OnabotulinumtoxinA is the most extensively studied of the available botulinum toxin formulations. It is supplied in both 50 and 100 unit vials; each vial contains the botulinum type A neurotoxin in a 900 kDa protein complex as a preservative-free, vacuum-dried powder in addition to a small amount of sodium chloride and human albumin that serve as stabilizers. Unopened vials of onabotulinumtoxinA should be refrigerated at a temperature of 2–8°C

and can be stored for up to 36 months prior to reconstitution.14 Prior to use, the product must be reconstituted with saline. While the package insert for the 100 U vial suggests that 2.5 mL of 0.9% non-preserved saline be used for reconstitution, the amount of saline used varies considerably among practitioners.

AbobotulinumtoxinA AbobotulinumtoxinA is supplied as a 300 or 500 unit vial containing lyophilized toxin in addition to albumin and lactose. Unopened vials require refrigeration; however, the manufacturer does not specify how long the unopened vial can be kept before use (both onabotulinumtoxinA and incobotulinumtoxinA have specified shelf-lives of 36  months). AbobotulinumtoxinA has an estimated size that varies between 500 kDa and 900 kDa, reflecting the presence of accessory proteins. Manufacturer instructions specify that abobotulinumtoxinA should be used within four hours of reconstitution.15

IncobotulinumtoxinA IncobotulinumtoxinA is supplied as a lyophilized powder containing either 50 or 100 units of botulinum toxin as well as human albumin and sucrose. IncobotulinumtoxinA has unique storage requirements and is the only botulinum type A toxin that does not require refrigeration prior to reconstitution. Unopened vials may be stored at room temperature, refrigerated, or frozen for up to 36 months. Another unique property of incobotulinumtoxinA is that it contains only the 150 kD core neurotoxin without the presence of non-toxic accessory proteins, theoretically reducing the risk of sensitization and antibody formation against the toxin. Manufacturer instructions specify that incobotulinumtoxinA should be used within 24 hours of reconstitution.16

Table 123.1:  Properties of commercially available neurotoxins. Neurotoxin type OnabotulinumtoxinA (Botox®) AbobotulinumtoxinA (Dysport®) Supplied As 50 unit or 100 unit vials 300 unit or 500 unit vials Molecular weight 900 kDa protein complex Varies between 500 kDa and 900 kDa Additional constituents Sodium chloride, human Albumin, lactose albumin Storage Refrigerated at 2–8°C Refrigerated at 2–8°C Shelf life of unopened vials 36 months

Unspecified

IncobotulinumtoxinA (Xeomin®) 50 unit or 100 unit vials 150 kDa Human albumin, sucrose Can be room temperature, refrigerated or frozen 36 months

Chapter 123: Neurotoxins in Aesthetic Medicine

RECONSTITUTION All commercially available botulinum toxin A formulations require the addition of saline to each vial to reconstitute the product prior to use. While the manufacturers of onabotulinumtoxinA, abobotulinumtoxinA, and incobotulinumtoxinA all recommend the use of 0.9% sterile, preservative-free saline for reconstitution, many practitioners prefer to use preserved saline containing benzyl alcohol due to decreased injection pain.17 Several randomized-controlled trials have demonstrated that reconstitution with preservative-containing saline is effective in reducing injection pain and does not decrease efficacy.18,19 Preserved saline contains benzyl alcohol, which has anesthetic properties; caution should be used in patients with a history of fragrance-sensitivity, as contact dermatitis has been reported in these patients following the use of botulinum toxin reconstituted with preserved saline.20

STORAGE AFTER RECONSTITUTION All botulinum toxin A formulations require refrigeration after reconstitution. According to their respective manufacturers, both onabotulinumtoxinA and incobotulinumtoxinA should be used within 24 hours after their reconstitution. The package insert of abobotulinumtoxinA specifies that the vial should be used within 4 hours of reconstitution. Most practitioners allow for longer storage times of reconstituted vials and will continue to use the same vial for several days to weeks. Hexsel and colleagues found no significant differences in efficacy among patients treated with reconstituted onabotulinumtoxinA of varying ages ranging from one day to six weeks.21 Several other studies have confirmed retained efficacy of botulinum toxin A reconstituted up to 2 weeks prior to use.22,23 A recent consensus statement from a task force authorized by the American Society for Dermatologic Surgery concluded that a vial of toxin reconstituted appropriately can, for facial muscle indication, be refrigerated or refrozen for at least 4 weeks before injection without significant risk for contamination or decreased effectiveness.24

DILUTION The amount of saline used for reconstitution is highly variable among practitioners and ultimately depends on the preference and experience of each individual injector. Package inserts for onabotulinumtoxinA specify a diluent volume of 2.5 mL for a 100 unit vial when treating glabellar rhytides, resulting in a dose of 4 units per

0.1 mL. The abobotulinumtoxinA package insert gives two options for reconstitution, either 1.5 (10 units per 0.05 mL) or 2.5 mL (10  units per 0.08 mL) per 300 unit vial. IncobotulinumtoxinA package inserts provide a table outlining eight different diluent volume choices. A concentration of 100 U/mL (1 mL per 100 unit vial) for onabotulinumtoxinA has been recommended to allow for lower volume injections that permit precise placement of the product with little spread to non-targeted areas.25 Expert consensus panels recommend a dilution of 1–3 mL for onabotulinumtoxinA and 1.5–2.5 mL for abobotulinumtoxinA.26–29 There is much discussion regarding the relationship between diluent volume and product dilution with clinical efficacy, product diffusion, and clinical duration. Theoretically, increasing the concentration of toxin and decreasing the volume injected will reduce spread of the toxin to unintended targets, especially when treating functionally sensitive areas such as the eyes or mouth. The use of more dilute preparations with higher volumes may be beneficial for larger areas where more spread is desired, such as the forehead. Hsu and colleagues demonstrated this concept in their study comparing two different dilutions of botulinum toxin A on either side of the forehead of 10 subjects; although the number of units injected was the same on each side, a larger affected area was noted in the side treated with a higher injection volume.27 Several notable studies have evaluated the effect of varying dilutions of botulinum toxin on treatment outcomes. Carruthers and colleagues followed 80 patients over 48 weeks treated with four different dilutions of onabotulinumtoxinA for glabellar rhytides, ranging from 10 units/mL up to 100 units/mL (each group was treated with a different dilution). No statistical differences were seen in treatment efficacy or adverse events among the different dilutions, although six cases of eyebrow ptosis were noted in the higher dilution group.28 Another study evaluated 20 patients treated for lateral canthal rhytides with two different dilutions of onabotulinumtoxinA (20 and 100 units/mL). Although the lower dilution group showed a slightly better response, no statistically significant differences were detected in terms of treatment efficacy or adverse events.29 De Almeida and colleagues performed a literature review of studies examining differences in efficacy and safety of varying dilutions of onabotulinumtoxinA; the authors concluded that, in facial muscles, the clinical effect of different dilutions does not appear significant, although increased pain is associated with higher injection volumes.30

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DOSE EQUIVALENCE AND POTENCY There has been much discussion regarding the optimal conversion ratio and dose equivalence between onabotulinumtoxinA and abobotulinumtoxinA. Due to differences in the US and UK assays used to test Dysport® and Botox®, initial studies resulted in a different efficacy per unit for each formulation. To adjust for this difference in unit potency, various conversion ratios have been suggested for these two formulations. Ratios as high as 6:1 are reported in the literature; however, most recent data suggest an optimal conversion ratio that is much lower. A systematic review of published evidence regarding the unit equivalence of onabotulinumtoxinA and abobotulinumtoxinA found that dose ratios of less than 3:1 (2–2.5:1) were most appropriate for cosmetic purposes. Ratios of 3:1 or lower will minimize adverse effects while still maintaining therapeutic efficacy. IncobotulinumtoxinA has demonstrated e­ quivalent c­ linical efficacy to onabotulinumtoxinA using a conversion ratio of 1:1.31

Fig. 123.1: Muscular anatomy of the face, anterior view.

CONTRAINDICATIONS Absolute contraindications to receiving botulinum toxin injections include active infection at planned injection sites or known hypersensitivity to any component of the product. Due to the presence of lactose in its preparation, abobotulinumtoxinA is contraindicated in patients with allergies to cow’s milk protein. Treatment should be avoided in patients with neuromuscular disorders in whom toxin-induced muscular paralysis could be exaggerated, such as myasthenia gravis, Eaton-Lambert syndrome, and amyotrophic lateral sclerosis. The potential for drug interactions exists with medications known to interfere with neuromuscular transmission. These include aminoglycoside antibiotics, cholinesterase inhibitors, quinidine, magnesium sulfate, succinylcholine, calcium channel blockers, lincosamides, polymyxins, and curare-type depolarizing blockers; caution should be taken in treating patients taking any of these types of medications. All botulinum toxin type A formulations are denoted pregnancy class C. Although there have been no reports of teratogenic effects, use in pregnant or lactating women should be avoided and is not recommended.

ANATOMY/DOSING/INJECTION TECHNIQUES Effective administration of BoNT-A requires an in-depth understanding of the muscular anatomy of the area being

Fig. 123.2: Muscular anatomy of the midface and nasal region.

treated (see Figures 123.1 to 123.3). As such, the regional muscular anatomy of commonly treated areas will be briefly reviewed along with a description of proper injection techniques and toxin placement for each area. Suggested toxin doses are provided in onabotulinumtoxinA units; conversion ratios for abobotulinumtoxinA and incobotulinumtoxinA are discussed separately. Additionally, awareness of potential complications of

Chapter 123: Neurotoxins in Aesthetic Medicine

Fig. 123.3: Skin tension lines overlying facial muscles.

BoNT-A injections in the upper and lower face is essential for any injector and will be discussed below.

Glabellar Frown Lines Glabellar frown lines are the result of repetitive contractions of several muscles whose fibers are closely associated and interwoven. A detailed understanding of the anatomy of this area is essential to ensure proper injection techniques and desirable outcomes, as these muscles are intricately interwoven and interconnected. Vertical frown lines are attributed to the actions of a complex of muscles responsible for brow adduction and depression: the procerus, corrugator supercilii, and medial fibers of the orbicularis oculi. The corrugator supercilii muscle originates from the frontal bone medial to the eyebrow near the supraorbital ridge and extends laterally, inserting gradually into the dermis above the middle third of the eyebrow. Contraction produces adduction and depression of brows, and over time repetitive contraction leads to vertical glabellar creases. Fibers of the corrugator muscle are located deep medially but become more superficial in the lateral dermal insertion point where they interdigitate with the frontalis

and orbicularis muscles. The lateral insertion point can be visualized as a skin dimple over the mid-brow during muscle contraction. The procerus muscle is responsible for producing horizontal glabellar wrinkles over the nasal bridge, acting as a medial brow depressor. It originates on the lower part of the nasal bone and upper lateral nasal cartilage and travels superiorly and superficially to insert on the skin overlying the nasal root, interdigitating with fibers of the orbicularis, frontalis, and corrugator muscles. The medial fibers of the orbicularis oculi muscle also contribute to the glabellar frown complex by acting as medial brow depressors. When overly active, the upper orbicularis acts as a brow adductor and creates a vertical crease in the mid-brow. Treatment sites and dosages vary between individuals and depend on the brow shape and position, muscle mass, muscle locations, and contraction patterns of the glabellar complex. Typically, three to seven injection sites are used when treating this area, distributed among the corrugators, procerus, and orbicularis oculi muscles. One injection site is used for the procerus, located at the midline of the muscle slightly below the nasal root, with a dose of 4–10 units of onabotulinumtoxinA. Standard dosing for treating the entire glabellar complex is around 20 units, although doses may be higher in male patients and in those with larger muscle mass. Each medial corrugator is injected above the bony supraorbital ridge, directly above the inner canthus. In individuals with horizontal brows, the lateral portion of each corrugator can be injected in the mid-pupillary line approximately 1 cm above the bony supraorbital rim. This mid-pupillary injection site is at highest risk for brow ptosis and can be avoided; if left untreated, some mid to lateral brow furrowing may still be visible with contraction. The dosage varies depending on individual regional muscle mass; men typically require higher starting doses due to greater muscle mass in the brow. When performed correctly, treatment of the glabellar frown complex with toxin injections results in flattening and smoothening of glabellar lines and an overall more relaxed and less-angry appearance. Effects typically last for 3–4 months. Medial brow and eyelid ptosis are the most troublesome complications resulting from treatment of the glabellar complex. The most common cause of medial brow ptosis is placing the injections too high above the orbital rim, resulting in unintended weakening of the lower frontalis. High volume or high dosing can also result in diffusion into the lower portion of the medial frontalis muscle causing brow ptosis. Eyelid ptosis results from diffusion

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Section 33: Cosmetic Surgery of BoNT-A into the levator palpebrae muscle, causing a weakness of the upper eyelid. Eyelid ptosis is transient and usually resolves in several weeks but can be quite concerning to patients. Keeping injection sites no closer than 1 cm above the central bony orbital rim will minimize this potential complication. Eyelid ptosis should be treated with the α2-adrenergic agonist eye drop apraclonidine 0.5%. Apraclonidine causes Muller’s muscle contraction thus elevating the upper eyelid. Dosing of apraclonidine is 1–2 drops three times a day until ptosis resolves.32

Brow Lifting The use of neurotoxin to lift the brow is an effective treatment option for patients with blepharoptosis. With age, the lateral portion of the eyebrow becomes ptotic before the medial brow. Lateral brow descent lowers the arch of the brow and places the lateral brow below its medial counterpart. Temporal brow lifting with neurotoxin can be achieved by treating the lateral portion of the orbicularis oculi muscle leaving the frontalis muscle unopposed. Injection of 7–10 units of onabotulinumtoxinA into the lateral portion of both orbicularis oculi muscles results in a significant elevation in the mid and temporal brow.33 These lateral brow injections are often combined with a single dose of 4–7 units of onabotulinumtoxinA into the procerus muscle.

Horizontal Forehead Lines Horizontal forehead wrinkles are due to repetitive contractions of the frontalis muscle. The frontalis is a broad vertically oriented muscle that extends superiorly from the galea aponeurotica inferiorly to the level of the brow, where it inserts intradermally and interdigitates with ­fibers of the procerus, corrugator, and orbicularis oculi muscles. It is responsible for brow elevation. In patients with ptotic or heavy upper eyelids, the frontalis provides crucial support for maintaining proper brow position. As such, treatment of the frontalis should be approached with caution and a conservative approach should be used. The goal of treatment is to soften and relax hyperkinetic horizontal forehead wrinkles through muscle weakening while still maintaining some degree of muscle function. Complete paralysis can lead to undesired brow ptosis and interfere with upward visualization in patients with heavy upper lids; additionally, overtreatment leads to an overall loss of expression and an unattractive “frozen” appearance. Injections should be kept well above the brow, especially when treating the lateral aspect of the frontalis, to

avoid ptosis. Consideration should be given to the desired eyebrow shape when planning injection sites. While an arched brow is considered feminine and desirable in females, most men prefer a more masculine-appearing horizontal brow shape. Placing injection sites horizontally across the forehead (rather than in a “v” shape) results in a more horizontal brow. The number of injection sites depends on the overall size and shape of the forehead, with more injection sites and higher doses utilized in individuals with broader brows. Typically, 10–20 units of onabotulinumtoxinA are administered over four to six injection sites. In individuals with high foreheads or receding hairlines, two additional injections of 1–2 units should be placed in the uppermost forehead near the hairline to prevent residual isolated rhytides in this area. Consideration should be given to the lateral fibers of the frontalis as well. When left untreated, these lateral fibers can excessively pull the brow upward and cause an undesirable quizzical or “Spock” look. A  small amount of toxin (1–3 units) can be injected into these lateral fibers to prevent or correct this excessive pulling; higher doses should be avoided as overtreatment results in a hooded brow that covers part of upper eye.

Crow’s Feet Lateral canthal lines, or “crow’s feet”, can be effectively treated by relaxing the lateral portion of orbicularis oculi. Orbicularis oculi is a sphincteric muscle that passes superficial to the temporalis fascia laterally. Crow’s feet injections are relatively easy to administer and associated with a high degree of patient satisfaction; however, injecting around the eye should be done with caution. It is important to take a careful history documenting any preexisting ocular conditions or eye surgeries. Neurotoxin should be placed superficially when treating the lateral orbicularis oculi in order to target the muscle and avoid bruising. The injections are placed 1–1 ½ cm lateral to the orbital rim using three injection points. Aliquots of 4 units of onabotulinumtoxinA are considered a standard dosing for a total of 12 units per side. Patients can be asked to smile in order to identify the proper injection points for orbicularis oculi. However, injections should not be performed while the patient is smiling but rather while at rest, as toxin may diffuse into the ipsilateral zygomaticus muscles, resulting in upper lip ptosis, an uneven smile and weakening of perioral movement. While lateral canthal lines can extend inferiorly onto the cheek, these lines should not be “chased” with neurotoxin as this can leave an undesirable

Chapter 123: Neurotoxins in Aesthetic Medicine flattening of the malar area. Complications such as diplopia, epiphora, and dry eyes have been reported following periorbital toxin injections.

Bunny Lines The oblique wrinkles originating from the nasal dorsum during smiling are commonly known as “bunny lines”. Isolated treatment of the glabellar complex can lead to a compensatory exaggeration in the appearance of these lines; as such, these areas are often treated simultaneously. Produced by contraction of the upper portion of the nasalis muscle along with the levator labii superioris alaeque nasi, bunny lines can be improved with strategic neurotoxin injections into the upper nasalis muscle. One to two injection sites (1–2 units each) on each side of the upper nasalis muscle as it crosses the lateral nasal dorsum can improve the appearance of these lines. Caution must be taken to keep the injection sites well above the nasofacial groove to avoid diffusion of toxin into the levator labii superioris, which can lead to ipsilateral lip ptosis.

Upper Gum Show Excessive exposure of the upper gum line and bases of the canines and upper incisors can lead to what is referred to as the “gummy smile”. This unflattering expression is due to abnormally high retraction of the upper lip due to contraction of the levator labii superioris alaeque nasi, resulting in show of the bases of the incisors, canines, and the gum line. Injection of small doses (3-5 units) of onabotulinutoxin toxin into each levator complex at the nasofacial groove on either side of the bony nasal prominence can allow for lengthening of the upper lip and a decrease in the amount of gingival exposure. This injection is best reserved for younger patients, as it can excessively accentuate an already elongated upper cutaneous lip in older patients.

Vertical Lip Rhytides (Perioral Lines) Vertical wrinkles around the mouth are exacerbated by a number of factors, such as environmental damage, smoking, and age-related skin changes. These perioral lines are exaggerated through repetitive pursing of the lips via contractions of the orbicularis oris muscle, a sphincteric muscle encircling the mouth, ultimately contributing to deep wrinkles radiating from the lips. While resurfacing procedures and filler injections can help in the appearance of these undesirable “lipstick lines”, low-dose botulinum toxin injections are a useful adjunctive tool in combination

with these treatments, especially when deeper wrinkles are present. The goal of botulinum toxin injections into this area is to weaken the hypertrophic orbicularis oris muscle while still maintaining the muscle’s functional properties. Because the orbicularis oris is responsible for closure of the lips and aids in mastication and phonation, a conservative approach is optimal in order to preserve the muscle’s primary functions. Between two and four injection sites are utilized along the upper vermillion border with no more than 1–2 units of onabotulinumtoxinA per site; if lower lip perioral rhytides are prominent, 1–2 units distributed between two injection sites along the lower medial vermillion border at least 1 cm medially to each oral commissure are beneficial. Injections into the lateral lip corners can lead to weakness of the lateral lip elevators and drooping of the lateral lip, and should be avoided. Also, injections into the midline should be avoided as flattening of the cupid’s bow can be an undesirable effect. Most adverse effects are dose-dependent and include difficulty with lip puckering, using a straw, whistling, and pronunciation of the letters “p” and “b”. Careful patient selection is important when using botulinum toxin in the perioral region; for example, public speakers or musicians needing precise control of their lips may not be optimal candidates for treatment.

Mouth Frown/Melomental Folds (Marionette Lines) Hyperfunctional depressor anguli oris (DAO) muscles can lead to excessively downturned lateral oral commissures extending into the lateral mentum creating “marionette lines”. Botulinum toxin injections of the depressor anguli oris muscles can balance the actions of the zygomaticus muscles to elevate the corners of the mouth more effectively, resulting in a more pleasant appearance and reducing the appearance of the marionette lines. Often, a combination approach is best used in this area with dermal fillers in addition to botulinum toxin injections to treat severe and deep marionette lines. Injections should be placed into the inferior-most posterior aspect of each DAO muscle along the mandible, using 2–5 units on each side. Injections should remain lateral to the lateral oral commissure to prevent diffusion into the depressor labii inferioris.

Peau d’Orange Chin Injection of botulinum toxin into the mentalis muscle can improve the appearance of a dimpled chin. The mentalis muscle extends from the mentum with multiple dermal

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Section 33: Cosmetic Surgery insertions, acting as a chin depressor. Contraction of the mentalis muscle creates a pebbly texture of the overlying skin, which becomes more apparent with aging and subsequent loss of subcutaneous tissue. Injection of small amounts of botulinum toxin into the lower mentalis muscle, whether alone or in conjunction with soft tissue augmentation, can lead to softening of the chin and a more relaxed appearance. Typically, 2–4 units of onabotulinumtoxinA are injected into either one site at the mental protuberance or into two sites into each muscle belly (in patients with clefted chins). It is important to restrict injections to the medial and inferior portions of the mentalis, thus reducing inadvertent paralysis of orbicularis oris and depressor labii inferioris.

Patients desiring improvement in the contour of the jawline may benefit from a “Nefertiti Lift”. In this procedure, the platysmal bands are treated with standard dosing and the upper portion of the platysma that comes up over the mandible is treated at the jawline. These injections are placed along the mandible making sure that they start 1  cm posterior to the insertion of depressor labii inferioris. This combined injection pattern improves the appearance of the neck while at the same time lifting the jawline. A maximum total dose of 50 units of onabotulinumtoxinA is recommended for the Nefertiti lift in order to avoid complications. Patients with excessive skin laxity and jowling are not good candidates for this necklifting procedure.

Masseteric Hypertrophy

Horizontal Necklace Lines

Reshaping the lower face with BoTNA is an advanced technique requiring a thorough understanding of facial anatomy. Lower face contour is affected by the mandible, soft tissues, and masseter muscles. Masseter muscle hypertrophy gives the lower face a square or “boxy” appearance and is often seen in Asian patients. Masseter muscle hypertrophy can be unilateral or bilateral and should be treated accordingly. With the patient’s teeth clenched tightly the masseter muscle can be visualized and marked. The point of maximal muscle hypertrophy can be palpated along the mandible and serves as the primary injection point. Two additional injections sites within the masseter should be marked. Dosing range for onabotulinumtoxinA is 20–30 units/side. Facial asymmetry and/or smile limitation is a complication that can occur from diffusion into the risorius muscle.

Horizontal necklace lines occur in young patients and are sometimes, but not always, associated with accumulation of fat between the lines. The genesis of these lines are the subcutaneous muscular aponeurotic system attachments in the neck. To treat horizontal necklace lines, neurotoxin is injected superficially into the deep dermal plane. The lines are skirted with small doses of 1–2 units of onabotulinumtoxinA per injection site. A total dose of 10–20 units per injection treatment represents maximum dosing for this procedure.

Vertical Platysmal Bands and the Nefertiti Lift Platysmal bands are unsightly ropey bands that occur on the anterior neck and become more prominent with age. As the neck loses elasticity, cervical fat becomes more noticeable and the platysma separates into two distinct bands. While the definitive treatment for platysmal banding is still platysmaplasty combined with lower face lifting, chemodenervation with BoNT-A is an excellent non-surgical alternative. The platysmal bands should be grasped in one hand while 2–3 units of onabotulinumtoxinA is administered at 1 cm intervals down the band. A total of 30–40 units is average dosing. Transient muscle weakness, dysphagia, and dystonia have been reported so careful injection technique is essential.

POSTPROCEDURAL CARE Immediately after withdrawal of the needle, manual pressure can be applied briefly to injection sites to minimize any bruising; this is especially useful in the periorbital area where bruising is more common. Many practitioners instruct patients to remain upright for 2–4 hours following injections to prevent unwanted toxin spread; however, there is no clinical evidence to support this anecdotal practice. Theoretically, stimulating treated muscles through repetitive contractions may facilitate toxin uptake at the neuromuscular junction and increase efficacy; as such, some practitioners instruct patients to contract and relax the treated muscles as much as possible for 2–3 hours after the procedure.

COMPLICATIONS The most common complications from the cosmetic use of BoNT-A are injection-related and transient. These include bruising, swelling, and injection site pain. Patients should be advised to discontinue supplements and medications

Chapter 123: Neurotoxins in Aesthetic Medicine that can exacerbate bruising two weeks before treatment, if possible. Applying pressure after the injection and use of postprocedure ice may be helpful to minimize bruising. Mild headaches have been reported and can be treated with over-the-counter analgesics. Persistent headaches are rare but do occur in some patients. In 2009, the FDA issued a “black-box” warning cautioning that BoNT-A can diffuse beyond the site of injection. Signs and symptoms of systemic spread include generalized muscle weakness, double vision, blurred vision, inability to talk or swallow, urinary incontinence, breathing difficulties, and even death. According to the package insert for onabotulinumtoxinA (Botox Cosmetic®, Allergan, Irvine, California), there has not been a confirmed serious case of spread of toxin effect away from the injection site when used at the recommended dose to treat frown lines and/or crow’s feet lines.

BOTULINUM TOXIN IMMUNOGENICITY As with all therapeutic proteins, repeat treatment with botulinum toxin can lead to the development of neutralizing antibodies. Case reports of patients receiving long-term treatment with neurotoxins have documented that secondary non-response can occur. Secondary nonresponse is defined as a patient who initially responds to the effects of neurotoxin but over time develops resistance to its effects. Secondary treatment failure can result in a partial or total lack of response and usually occurs within 40 months of starting neurotoxin treatments.33 Secondary treatment failure occurs when immunoglobulin-G neutralizing antibodies are produced against the 150 kD neurotoxin molecule. It is important to note that both the neurotoxin and the complexing proteins have potential for immunogenicity.34 Antibodies against the non-toxic clostridial proteins or hemagglutinins are non-neutralizing and do not cause secondary non-response. Although the exact role of complexing proteins in immunogenicity is unclear, many believe that the presence of complexing proteins increases the overall protein load and may make the formation of neutralizing antibodies more likely.35 To date, there are no controlled studies comparing the immunogenicity of different botulinum toxin A products. According to worldwide literature, the rate of formation of neutralizing antibodies when BoNT-A is used for medical purposes is 0.3–6%. Although there are no published studies on the prevalence of neutralizing antibodies with esthetic use, case reports document that this does occur.36 Testing for antibodies can be done with enzyme linked immunosorbent assay (ELISA) and fluorescent

immunoassays, although these tests do not distinguish between neutralizing and non-neutralizing antibodies. The best test to detect neutralizing antibodies is using the mouse hemidiaphragm assay (HDA), although this assay is not widely available. Additionally, HDA is capable of detecting very low levels of antibody that may not be clinically significant. More sophisticated testing is currently under development and necessary in order to better understand the immunogenicity of neurotoxins. Best practices may help to prevent antibody formation. Lower dosing of neurotoxin, such as those used in cosmetic treatments, seems to be less likely to elicit immunogenicity. The use of neurotoxins such as incobotulinumtoxinA with no complexing proteins may be less antigenic and less likely to elicit antibody formation. Finally, avoiding booster doses between treatments and waiting at least three months before repeat dosing may also be helpful.36

FUTURE DEVELOPMENTS There are currently several neurotoxins undergoing clinical trials in the U.S. The Korea-based company, Daewoong, has licensed the rights to its botulinum toxin A to Alphaeon. The product will be marketed under the name Evolus™. This neurotoxin is currently in phase III clinical testing. In addition, Revance (Revance, Therapeutics, Newark, CA) has a proprietary injectable BoTN-A(RT002) that is in phase II clinical trials.38 Preliminary studies demonstrated greater longevity compared to currently available neurotoxins, making this a promising novel neurotoxin.37 Of great interest is the potential to deliver botulinum toxin topically. Allergan recently acquired a topical neurotoxin from biotech company Anterios. The compound, called ANT-1207, is currently being studied for use in hyperhidrosis, crow’s feet, and acne. Ongoing clinical studies show promising results.

REFERENCES 1. Carruthers JA, Lowe NJ, Menter MA et al. A multicentre, double-blind, placebo-controlled study of the efficacy and safety of botulinum toxin type A in the treatment of glabellar lines. J Am Acad Dermatol 2002;46:840–9. 2. Carruthers JD, Carruthers JA. Botox use in the mid and lower face and neck. Semin Cut Med Surg 2001:20(2):85–92. 3. Erbguth FJ, Naumann M. Historical aspects of botulinum toxin: Justinus Kerner (1786–1862) and the “sausage poison”. Neurol 1999;53:1850–3. 4. Scott AB. Botulinum toxin injection into extraocular muscles as an alternative to strabismus surgery. Ophthalmol 1980;87:1044–9.

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Section 33: Cosmetic Surgery 5. Carruthers JD, Carruthers JA. Treatment of glabellar frown lines with C. botulinum-A exotoxin. J Dermatol Surg Oncol 1992;18:17–21. 6. Carruthers J, Carruthers A. The evolution of botulinum neurotoxin type A for cosmetic applications. J Cosmet Laser Ther 2007;67:669. 7. Brandt F, Swanson N, Baumann L, et al. Randomized, placebo-controlled study of a new botulinum toxin type A for treatment of glabellar lines: efficacy and safety. Dermatol Surg 2009;35(12):1893–901. 8. Kane MA, Brandt F, Rohrich RJ, et al. Evaluation of variable-dose treatment with a new U.S. botulinum toxin type A (Dysport) for correction of moderate to severe glabellar lines: results from a phase III, randomized, double-blind, placebo-controlled study. Plast Reconstr Surg 2009;124(5):1619–29. 9. Rubin MG, Dover J, Glogau RG, et al. The efficacy and safety of a new U.S. botulinum toxin type A in the retreatment of glabellar lines following open-label treatment. J Drugs Dermatol 2009;8(5):439–44. 10. Jones D, Carruthers J, Narins RS, et al. Efficacy of incobotulinumtoxinA for treatment of glabellar frown lines: a post hoc pooled analysis of 2 randomized, placebo-controlled, phase 3 trials. Dermatol Surg 2014;40:776–85. 11. Carruthers A, Carruthers J, Coleman WP III, et al. Multicenter, randomized, phase III study of a single dose of incobotulinumtoxinA, free from complexing proteins, in the treatment of glabellar frown lines. Dermatol Surg 2013;39:551–8. 12. Hanke CW, Narins RS, Brandt F, et al. A randomized, ­placebo-controlled, double-blind phase III trial investigating the efficacy and safety of incobotulinumtoxinA in the treatment of glabellar frown lines using a stringent composite endpoint. Dermatol Surg 2013;39:891–9. 13. Carruthers A, Carruthers J. Botulinum Toxin: Cosmetic and Medical Uses. Oxford: Elsevier; 2005. 14. Allergan, Inc. BOTOX Cosmetic [package insert]. Irvine, CA: Allergan, Inc; 2011. 15. Dysport (abobotulinumtoxinA) [package insert]. Wrexham, UK: Ipsen Biopharm, Ltd.; 2010. 16. Merz Aesthetics Inc. Xeomin [package insert]. San Mateo, Calif: Merz Aesthetics Inc; 2010. 17. Liu A, Carruthers A, Cohen JL, et al. Recommendations and current practices for the reconstitution and storage of botulinum toxin type A. J Am Acad Dermatol 2012;67:373. 18. Alam M, Dover JS, Arndt KA. Pain associated with injection of botulinum A exotoxin reconstituted using isotonic sodium chloride with and without preservative: a double-blind randomized controlled trial. Arch Dermatol 2002;138:510. 19. Allen SB, Goldenberg NA. Pain difference associated with injection of abobotulinumtoxinA reconstituted with preserved saline and preservative-free saline: a prospective, randomized, side-by-side double-blind study. Dermatol Surg 2012;38:867. 20. Amado A, Jacob SE. Letter: benzyl alcohol preserved saline used to dilute injectables poses a risk of contact dermatitis in fragrance-sensitive patients. Dermatol Surg 2007;33:1396–7.

21. Hexsel DN, de Almeida At, Rutowitsch M, et al. Multicenter, double-blind study of the efficacy of injections with botulinum toxin type A reconstituted up to six consecutive weeks before application. Dermatol Surg 2003;29(5):523–29. 22. Sloop RR, Cole BA, Escutin RO. Reconstituted botulinum toxin type A does not lose potency in humans if it is refrozen or refrigerated for 2 weeks before use. Neurol 1997;48:249–53. 23. Yang GC, Chiu RJ, Gillman GS. Questioning the need to use Botox within 4 hours of reconstitution: a study of fresh vs. 2-week-old Botox. Arch Facial Plast Surg 2008;10:273. 24. Alam M, Bolotin D, Carruthers J, et al. Consensus statement regarding storage and reuse of previously reconstituted neuromodulators. Dermatol Surg 2015;41(3):321–6. 25. Kane M, Donofrio L, Ascher B, et al. Expanding the use of neurotoxins in facial aesthetics: a consensus panel’s assessment and recommendations. J Drugs Dermatol 2010;9:S7–22. 26. Asher B, Talarico S, Casuto D, et al. International consensus recommendations on the aesthetic usage of botulinum toxin type A (Speywood Unit) – part I: upper facial wrinkles. J Eur Acad Dermatol Venereol 2010;24:1285–95. 27. Hsu TS, Dover JS, Arndt KA. Effect of volume and concentration on the diffusion of botulinum exotoxin A. Arch Dermatol 2004;140:1351. 28. Carruthers A, Carruthers J, Cohen J. Dilution volume of botulinum toxin A for the treatment of glabellar rhytids: does it matter? Dermatol Surg 2007;33:S97–104. 29. Carruthers A, Bogle M, Carruthers J, et al. A randomized, evaluatory-blinded, two-center study of the safety and effect of volume on the diffusion and efficacy of botulinum toxin type A in the treatment of lateral orbital rhytides. Dermatol Surg 2007;33:567–71. 30. de Almeida AR, Secco L, Carruthers A. Handling botulinum toxins: an updated literature review. Dermatol Surg 2011;37:1553–65. 31. Karsai S, Raulin C. Current evidence on the unit equivalence of different botulinum neurotoxin A formulations and recommendations for clinical practice in dermatology. Derm Surg 2009;35:1–8. 32. Scheinfeld N. The use of apraclonidine eyedrops to treat ptosis after the administration of botulinum toxin to the upper face. Dermatol Online J 2005;11(1):9. 33. Ahn M, Catten M, Maas CS. Temporal brow lift using botulinum toxin A. Plast Reconstr Surg 2000;112(5)S:S98–104. 34. Dressler D. Clinical features of antibody-induced complete secondary failure of botulinum toxin therapy. Eur Neurol 2002;48:26–9. 35. Benecke R. Clinical relevance of botulinum toxin immunogenicity. Biodrugs 2012;26(2):e1-e9. 36. Dressler D, Hallett M. Immunologic aspects of botox, dysport and myoblock/neurobloc. Eur J Neurol 2006;13(1):11–5. 37. Torres S, Hamilton M, Sanchez E, et al. Neutralizing antibodies to botulinum neurotoxin type A in aesthetic medicine: five case reports. Clinic Cosmet Invest Dermatol 2014;7:11–7. 38. Garcia-Murray E, Velasco Villasenore ML, et al. Safety and efficacy of RT002, an injectable botulinum toxin A, for treating glabellar lines: result of a phase ½, open-label, dose escalation study. Dermatol Surg 2015;41:S47–55.

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Current Concepts and Techniques in Liposuction  Surgery​​​ Khan AJ

INTRODUCTION Liposuction is the most commonly performed surgical esthetic procedure, according to the statistics of the American Society of Aesthetic Plastic Surgery in 2016.1 Dermatologists are able to safely perform liposuction surgery, as it can now be performed in the office setting or in an ambulatory surgery center, rather than in the operating room under general anesthesia with its associated risks, owing to the development of tumescent technique introduced in 1987 by Klein.2 Liposuction involves the suction of fat deposits using cannulas which are hollow, straw-like devices. Liposuction cannulas typically have a blunt end to prevent them from injuring body tissues or organs, as sharp cannulas can damage these structures (Fig. 124.1). These cannulas have varying types of holes, known as ports, which vary in placement, shape, and size along the shaft of the cannula. Cannulas come in different diameters and lengths,

Fig. 124.1: Some of the generally used cannulas wrapped and sterilized for facial liposuction. Please note the ports and the size as the measuring tape is placed for the reference in centimeters markings.

ranging from 18 G to 6 mm in diameter in most cases, and ranging in length from a couple of inches to about 1 to 1.5 feet long. Smaller diameter cannulas are known as “microcannulas” and have been mostly developed, refined, and advocated by dermatologists. Subcutaneous fat is composed of adipocytes, which are formed into fat lobules, that are interspersed among the neurovascular bundles in fibrous septa that traverse from the underlying muscles and associated fascia through fat compartment to the skin. These septa are important in liposuction surgery for two reasons: 1. They contain blood vessels which need to be protected and constricted, so that blood loss does not occur while suctioning the surrounding fat. 2. They are believed to be a source of skin contraction after liposuction. Historically, liposuction was plagued with major blood loss and the complications of general anesthesia when performed without the use of vasoconstrictiveagent-infiltration in the adipose tissue before liposuction. These shortcomings were overcome by dermatologists by using an extremely dilute amount of lidocaine to anesthetize large areas and very small amounts of epinephrine to constrict the blood vessels. Epinephrine aids in avoiding blood loss through vasoconstriction, and the act of vasoconstriction prevents the entry of the drug into the circulation; thus, liposuction could be done without the fear of systemic lidocaine toxicity. Since a large volume ranging from 1 to 4 L is injected subcutaneously in most cases, this volume makes the skin hard or “tumescent”; therefore, the term “tumescent” liposuction was coined. The fluid volume infiltrated in the subcutaneous tissue itself causes a physical pressure on the subcutaneous blood vessels, in addition to the vasoconstrictive action of the epinephrine in the tumescent solution. With this technique, liposuction became free of any major blood loss and is thus extremely safe.

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TOTAL TUMESCENT ANESTHESIA VS. TUMESCENT ANESTHESIA WITH INTRAVENOUS SEDATION Two schools of thoughts exist among the dermatologists’ community as far as total tumescent anesthesia vs. tumescent with some form of sedation is concerned. The pros of a total tumescent technique are the use in completely outpatient office setting, without jumping through the hoops of ever-increasing restrictions of regulatory agencies on the outpatient surgical establishments, as local anesthesia without sedation does not require as meticulous patient monitoring as is required with the sedated patient. In such cases where local anesthesia needs to be infiltrated aggressively to make the procedure painless, very large amounts, in the range of 35 mg/kg to 55 mg/ kg, of lidocaine have been demonstrated as safe in the tumescent solution.3,4 Lidocaine, when given without epinephrine, has a very low safety dose threshold. The 4 mg/ kg body weight is sufficient to cause toxicity, and a dose of up to 7 mg/kg body weight is safe if given with epinephrine. Contrarily, lidocaine is safe at doses of up to 55 mg/ kg in tumescent anesthesia for liposuction when diluted to 0.1–0.05% in normal saline with epinephrine of 1:1000,000 dilutions. The most recent study published by Klein indicates that without liposuction, infiltration of tumescent lidocaine anesthesia at 45 mg/kg is risky, while 28 mg/kg is a more reasonable maximal safe if liposuction is not performed. Otherwise, a 45 mg/kg lidocaine dose was shown to be safe in the liposuction cases.5 Such solutions are believed to compartmentalize the lidocaine into the subcutaneous space with very slow release into the systemic circulation due to the vasoconstrictive effect of epinephrine. Although many studies have proven the safety of such doses of lidocaine in the tumescent fluid during liposuction, concerns about lidocaine toxicity remain in the minds of many dermatologists. Although extremely safe and effective, total tumescent anesthesia can only be achieved at a very slow injection or infiltration rate. If given at a rapid rate, the infusion causes pain because of the rapid-filling effect of the subcutaneous tissue. Slow infusions take hours to complete and are timeconsuming and labor intensive for the surgeon as well as for the patient who is fully awake. The very obvious advantages of this technique include a fully awake patient who can communicate if something seems unusual, like inadvertent penetration of a muscle in the abdominal wall or the penetration of a deeper structure than subcutaneous

tissue with the cannula, for example. Furthermore, local anesthesia is devoid of any nuances of general anesthesia, including low muscle tone and muscle paralysis, which increases the risk of pulmonary and fat embolism, throat soreness of endotracheal intubation, and time taken to recuperate after general anesthesia. To take the full advantage of the local anesthesia and keep the procedure painless, the surgeon should use smaller caliber suction cannulas which decrease the injury to the septa containing neurovascular bundles, thus decreasing the pain. Use of these fine cannulas is less efficacious, as they take longer to suction the fat out when compared to their larger-bore counterparts. For example, a 3-mm cannula is perceived as much less painful or even painless in most cases, as compared to even a 4-mm cannula when used in tumescent liposuction with light sedation. Conversely, general anesthesia alone has attendant risks that are so distinct, that having an alternative in the form of local anesthesia seems to be a logical choice. However, one must keep in mind that general anesthesia is quick to achieve and completely painless for the patient. Since the patient experiences no pain under general anesthesia, larger diameter cannulas can be used, which can lead to much faster liposuction and shorter procedure times. Nonetheless, the risks of general anesthesia for a purely cosmetic surgery cannot be underestimated. Before the advent of tumescent anesthesia, disasters in liposuction surgery history have forced many plastic surgery colleagues to move away from “dry liposuction” which used no subcutaneous fluid infiltration to “wet liposuction” and “super-wet” liposuction in which varying amounts of physiologic fluids were injection with varying amounts of epinephrine to avoid life-threatening blood loss. In fact “tumescent technique” has become the standard of care in liposuction surgery across the board, ranging from dermatologists to plastic surgeons.6 On the other hand, the limitations of the pure “tumescent technique” have led some dermatologists to develop a middle-of-the-road anesthetic technique, in which there is an attempt to achieve maximum benefit. This is done by limiting blood loss with the use of epinephrine in the subcutaneously injected tumescent solution, just like the pure-tumescent technique, along with almost half of the dose of lidocaine to avoid lidocaine toxicity. Moreover, the benefits of intravenous sedation are reaped by using very light sedation through the use of a quick induction and reversible agent like propofol, that puts patients in a “twilight” sleep rather than general anesthesia. The use of propofol eliminates the need for muscle paralysis, as

Chapter 124: Current Concepts and Techniques in Liposuction Surgery intubation is not required. A  published study, in which this approach was used in 5,000 cases, demonstrated it as an extremely safe approach with all the benefits of tumescent liposuction while reducing the amount of lidocaine needed in the tumescent fluid. A marked reduction in operating times was reported.7 As the tumescent solution can be infiltrated at a higher rate/min and suction can be performed using cannulas in the range of 3–5 mm, this approach as an ideal choice if an accredited ambulatory surgery center is available, as it requires meticulous monitoring by an anesthesiologist or a CRNA (Certified Registered Nurse Anesthetist) throughout the surgical procedure and thereafter until the patient is fully awake. In a recent study, monitored anesthesia care was found to be safe, even in office-based cosmetic procedures.8

LIDOCAINE INTERACTIONS WITH OTHER COMMONLY USED DRUGS Lidocaine is metabolized by cytochrome enzymes CYP3A4 and CYP 1A2.9 The most commonly used medicines metabolized by CYP3A4 are alprazolam (Xanax), cimetidine (Tagamet), calrithromycin, cyclosporine, daizepam, erythromycin, isoniazid, ketoconazole, itraconazole, omeprazole, and many others. The most commonly used medicines metabolized by CYP 1A2 are caffeine, cimetidine, ciprofloxacin, clarithromycin, erythromycin, isoniazid, ketoconazole, omeprazole, and many other less-common drugs. The physician should be aware of the potential to increase the blood levels of lidocaine if these drugs are simultaneously used with large amounts of lidocaine injected in total tumescent technique. In such cases, any of these agents should be stopped about 2 weeks prior to liposuction. If this is not possible, lower concentrations of lidocaine must be used.

PATIENT SELECTION AND PREOPERATIVE EVALUATION Liposuction is not meant to be an alternative to weight loss and should only be used as a contouring procedure aimed at getting rid of unwanted fat deposits which are resistant to diet and exercise. Liposuction should not be offered to morbidly obese patients, as a few inches of reduction may not satisfy their expectations in most cases. Keeping this in mind, this objective should be clearly explained to the patient and preoperative measurements of the target

area, patient’s weight, and standardized photographs of the target area should be taken for documentation as well as postoperative evaluation purposes. The patient should be given detailed pre- and postoperative instructions in a written format, and the consent form detailing all the possible untoward effects that may occur must be reviewed and signed by the patient, preferably one day in advance if the plan is to give any anxiolytic or sedative medications on the morning of the surgery. Consents signed with sedatives on board can later be questioned, as the patient may be considered to have been under the influence of such medications. The patient should understand that by using fine cannulas with minimal injury to the subcutaneous septa, major contraction of the remaining loose skin is expected, but not guaranteed, as everyone heals differently. The surgeon should consel that excess skin may need to be removed at a later stage using a procedure such as a “tummy tuck” in the case of abdominal liposuction with major deposits of fat. The patient should be clearly informed about the financial implications of the subsequent procedures, should they be required. The patient should be told that it will usually take a few months to see the full effects of liposuction, as it takes a few days to a few weeks to resolve the edema, and then a few months for the resultant loose skin to contract. The author typically tells patients to wait for 6 months before evaluating the final results and generally does not recommend any further procedure in the same area for 1 year after liposuction. The patient will need to wear the appropriate postoperative compression garments initially for 3 weeks, 24 hours a day, and then during the subsequent 3 weeks, only 12 hours a day. These compression garments help with drainage of the excess tumescent fluid in the first 12–24 hours and help thereafter with the fibrosis or contraction of the skin. Compression garments help to avoid seroma or hematoma formation, which may develop in the large undermined area that results after liposuction. Depending upon the kind of anesthesia the surgeon plans to use, the preoperative evaluation includes CBC, PT/APTT, LFTs, BUN, Creatinine, X-ray of the chest, and an EKG. We always get a viral screening with Anti-HCV, HBsAg, and HIV testing as a standard protocol. If only tumescent anesthesia is planned without the use of any sedation, then some may justify the omission of the chest X-Ray and EKG. All anticoagulants, including herbal alternative medications that have reported anticoagulant properties, as well as the inhibitors of P-450 cytochrome enzymes, must be stopped 2 weeks prior to the procedure

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Fig. 124.2: An example of a well-equipped dermatologic ambulatory surgery suite.

Fig. 124.3: Marking of the patient’s skin for the proposed liposuction.

with the consent of the primary care physician, if required. Lidocaine dose can inadvertently increase if medications are present in the blood which are metabolized by the same hepatic enzymes as lidocaine itself. Depending upon the jurisdiction, legislation, and standards of care, appropriate use of outpatient ambulatory surgery facility or the well-equipped office setting should be used. We use only ambulatory surgical suites which are fully equipped to handle emergencies, should they develop, under the strict supervision of the anesthesiologist (Fig. 124.2). Dermatologists interested in performing liposuction, or any other invasive procedure, should be very familiar with the emergency equipment in the operating room setting, be it in the hospital, in the ambulatory surgery center, or in an office setting. Emergency equipment must be available to deal with any untoward emergency. Depending on the jurisdiction and the local laws, one may use a CRNA instead of an anesthesiologist if intravenous sedation is planned. Most centers do not use a CRNA or anesthesiologist if only pure tumescent technique is used.

avoidance of liposuction in those areas. The patient is then thoroughly scrubbed with iodine scrub and positioned in supine, lateral, or any other appropriate position, depending on the area that needs to be treated. One must keep in mind the ease of movement of the liposuction cannula and the surgeon’s ability to maneuver to reach the target area through small incisions or ports, through which the liposuction cannulas are entered.

PREOPERATIVE PREPARATION The patient is evaluated in the standing position to determine the exact location of the unwanted fat deposits, and these bulging fat deposits are marked with indelible ink/ pen (Fig. 124.3). The areas which need the most significant fat reduction versus the areas which needs moderate or no treatment are marked in different colors or with different signs or shapes. We usually mark the areas with cross hatches, which denotes no liposuction or complete

PROCEDURE Once the patient is scrubbed, placed on the operating table, and relaxed with anxiolytic or mild sedatives in the case of completely tumescent technique or with IV induction of monitored sedation by the anesthesiologist or CRNA, insertion sites for liposuction cannula are anesthetized with 1:100,000 lidocaine with epinephrine, buffered with 8.4% bicarbonate to avoid injection pain, as it neutralizes the acidic pH of Lidocaine. Next, the ports or entry points are made using a no.11 surgical blade and slight undermining is performed to facilitate the entry of the cannula into the correct subcutaneous plane. The subcutaneous plane is then infiltrated with tum­ escent anesthetic solution containing varying amounts of lidocaine (0.05–0.1% lidocaine) depending on the surgeon’s preference, the site location, and total surface area that needs liposuction (Fig. 124.4). More sensitive and highly vascular, but smaller in size, areas are generally infiltrated with higher concentrations of lidocaine as well as higher concentration of epinephrine; whereas, larger areas with relatively less blood supply need diluted

Chapter 124: Current Concepts and Techniques in Liposuction Surgery

Fig. 124.4: Infiltration of the tumescent solution.

lidocaine solutions due to the concern of lidocaine toxicity. For example, the larger abdominal areas are anesthetized with dilute 0.05% lidocaine, whereas more vascular and nerve-rich facial areas need a stronger lidocaine solution, as well as a bit more epinephrine for vasoconstriction. This is done to avoid intravascular entry, and thus toxicity, of the concentrated lidocaine as well as to avoid bleeding. Great care should be given to create a space in between the skin and the muscle layer, staying in the safe zone of the subdermal fat layer. Further refinement can be achieved by staying in the mid-fat layer, as very superficial liposuction can create uneven contour and the risk of the disruption of the dermal capillary plexus, causing skin necrosis. Large volumes of anesthetic fluid are injected using infiltration cannulas attached to a large syringe or an infiltration pump. This makes the process very comfortable for the patient. The infiltration process becomes almost painless by injecting very small amounts of anesthetic solution per minute; especially, if the patient is awake and can perceive pain. The addition of bicarbonate in the tumescent fluid, along with a very slow infiltration rate and the use of small caliber infiltration cannulas, have made this part of the procedure much more comfortable for the patient. Care should be taken to thoroughly anesthetize all areas and preferably a couple of centimeters around the targeted area. This practice helps to maintain hemostasis when the edges of the target area are contoured with partial liposuction, which acts to blend the treated area with the surrounding untreated areas.

Once the area is infiltrated with the tumescent lidocaine solution to make it “tumesce”, liposuction is started using cannulas ranging in sizes from 2 mm to 5 mm in most cases, depending on the type of anesthesia used. If the tumescent anesthesia is used exclusively or in combination with intravenous sedation, smaller cannulas are used on the face, e.g. 2-mm cannulas are used for microliposuction of the jowls and submental areas, whereas larger caliber cannulas are used for body liposuction. The author prefers to use 3-mm to 5-mm cannulas with three ports on the bottom of the tip of the cannula for very efficient, yet safe, suction of the adipose tissue on the body areas using suction equipment (Figs. 124.5A to C). The diameter of the cannula, as well as the number and symmetry of the ports, plays a major role in the speed with which fat can be suctioned. Many different options exist for the creation of the suction vacuum, including simple syringes attached to the base of cannula which maintains suction by applying “locks” to keep the plunger in a suction-position while the surgeon moves the cannula in an in and out movement in the fat layer, attached to the negative-pressured syringe. This is an extremely inexpensive and safe method but requires frequent removal of the accumulated fat into a waste canister. We prefer this approach when the suctioned fat is planned to be reinjected into another area as a “fat-transfer” procedure. In fat transfer, we generally take the fat from an unwanted bulge of fat and inject that fat where it is desired most, like in the face for wrinkles or the breasts for breast enhancement. Since this fat stays in a closed syringe until injected, it provides a very safe “closed system”, which is advocated by many surgeons as it avoids aerosolized contamination of the fat transplant. Other vacuum options are different types of suction pumps with tubing, attached to the cannula handle that attaches the cannula at one end and the tubing at the other end. These suction pumps are much more convenient and time saving with variable speeds achieved. The plane of suction is established with the help of hydrodissection by the tumescent fluid, which is a safe compartment lined by the skin above and the fascia covering the muscles below. Upon establishment of this plane, suction can be safely initiated by inserting the cannula parallel to the surface of the skin, but with a slight superior or superficial directionality of the tip. The tip of the cannula should always be felt with the left “intelligent” hand to know exactly where the cannula tip is going, to avoid any major complication of inadvertent

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A

C

penetration of the abdominal cavity, thoracic cavity, or any major deep vital organ. The ports of the cannula should always be directed downward and away from the undersurface of the dermis to avoid damage to the dermal vascular plexus that would result in skin necrosis. The cannula is moved in to-and-fro motion in a spokewheel pattern with the right or the dominant hand, while the skin overlying the target area is stabilized with the left “sensing” or “intelligent” hand. An assistant can spread the skin overlying the target area to make the area tense. This action makes the movement of the cannula easier and more predictable. No or minimal force should be applied to the cannulas, as subcutaneous fat poses the least resistance in most cases; except in those cases where more fibrous fat exists or in the region of a

B

Figs. 124.5A to C: Liposuction using cannula attached to a suction machine.

previous surgery with significant postoperative fibrosis. Such cases, although rare, pose significant challenge to the surgeon. Difficulties include a very slow infiltration of the anesthetic fluid, owing to the rigidity of the skin and tissues, and difficulty in maneuvering the suction cannula secondary to old fibrotic subcutaneous tissue. The art of liposuction lies not in “what you suction, but rather what you leave behind” which gives the final outcome. Over-aggressive liposuction can be as dissatisfying to the patient as suboptimal liposuction. As a general rule, a 1-cm-to-1-inch-thick final flap should remain at the end of liposuction to avoid any vascular compromise to the overlying skin. Avoiding very superficial liposuction prevents untoward side effects, like contour irregularity and skin necrosis.

Chapter 124: Current Concepts and Techniques in Liposuction Surgery A systematic approach that involves initiating the liposuction from one specific starting point and gradually working throughout the area toward an endpoint gives predictable outcomes every time. Haphazard strokes of the cannula without maintaining the distance between the two successive spoke-wheel patterned strokes can cause a less-than-even outcome. Moreover, suction of the same area from two different entry points and making the cannula tunnels at 90°from two ports give more even results. Use of smaller cannulas is also an important factor for smooth contouring. Once the systematic in and out movements of suction cannula have resulted in major volume loss that is visible and palpable with the non-dominant hand with frequent pinching of the resultant flap (i.e. the skin over the suctioned area), care should be taken to recognize when the endpoint is reached. In addition to the above endpoints, the change of aspirate from pure yellow fat, followed by fat mixed with a slight amount of blood, and finally the serous fluid with least amount of fat signals the endpoint of the liposuction surgery. After the suction is complete, the author prefers to manually squeeze the remaining fluid out of the treated area, as it assists in the avoidance of gross leakage of the tumescent fluid through the ports in the first 12 hours. A massive amount of soakage may concern the patients and soils their clothing and bed linens on the night after surgery; manually squeezing to drain excess trapped subcutaneous fluid has made its way as a standard step in our routine postoperative care. Depending on the size of the cannula, insertion ports can be left open to heal by secondary intention, or the sites can be stitched with subcutaneous Vicryl 5-0 or Prolene 4-0 or 5-0 sutures, with one small stitch on each port for the 3-mm to 5-mm cannula (Fig. 124.6). Smaller cannulas used on the face or used in exclusive tumescent technique require no sutures, as ports in the range of 1–2 mm in length heal extremely well with a small strip of Steri-Strips placed to approximate the edges. Open ports are useful in terms of drainage of the excess tumescent fluid postoperatively and resolution of postoperative edema and ecchymosis/bruising is greatly decreased with open drainage.

POSTOPERATIVE CARE, INSTRUCTIONS, AND FOLLOW-UP The patient is instructed to wear the appropriate compression garments, and we prefer that antithrombotic stockings

Fig. 124.6: Stitch being placed to close the incision. It can be left open to heal by secondary intention.

are worn for the first 3 days, as we usually perform liposuction under IV sedation with tumescent anesthesia. Use of compression stockings can be avoided in small cases involving only local tumescence. The patient is kept under observation depending on the kind of anesthesia used. We routinely keep the patient in the postoperative area for a couple of hours, as they regain the full consciousness in about 30–45 minutes. Nonetheless, they are fully arousable throughout the procedure and usually awake by the time we are closing the ports. We generally apply steri-strips over the ports, which may or may not be needed. A thick dressing, made of absorbent cotton gauzes, is placed on the most dependent area of the ports to soak the draining tumescent fluid within next 24 hours. The patient is educated on the changing of such pads/gauze at home on the night after surgery to avoid soakage of the clothes or bed linen. Ambulation is strongly encouraged and the patient is strongly advised not to stay in bed for long intervals. We generally see the patient back the next day, and then at 1–2 weeks, and finally at 1, 3, and 6 months postoperative; and thereafter, if required. The frequency of these visits may change if the patient is visiting out of town.

POSTOPERATIVE COMPLICATIONS, THEIR AVOIDANCE, AND TREATMENT Use of the tumescent technique has abolished most of the grave complications that were attendant to liposuction a couple of decades ago; namely, large volume blood loss,

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Section 33: Cosmetic Surgery hemodynamic instability, hematoma, and seroma formation, and admission to the intensive care unit after liposuction to name a few. These complications are almost non-existent with the tumescent technique or tumescent technique with IV sedation used by most dermatologists throughout the world. Although rare, the following important postoperative complications must be picked up and treated immediately, should they occur. • Hematoma: Hematomas used to occur more readily when epinephrine was not infiltrated, such as in the “dry technique” used years ago, which may still be in practice in some parts of the world. The use of the tumescent technique and the cessation of further liposuction once a serous aspirate is encountered, paired with good postoperative compression, can help to avoid hematoma formation. The author has not seen such cases in the past couple of decades of practice due to the aforementioned measures. If encountered, the hematoma can be aspirated aseptically, and depending on the physical characters of the aspirate and the physical findings of the patient, the aspirate can be sent for culture if secondary infection is suspected. • Seromas: These are the accumulation of the serous fluid. Seromas are rarely encountered if the patient has failed to follow the strict instructions of wearing compression garments or if aggressive liposuction was performed. Again, good compression and conscientious liposuction are the keys to avoiding this complication. Should seroma formation occur, it can be aseptically aspirated using a large bore needle, such as an 18 G needle. Serous fluid aspiration, in the absence of signs of infection, leads to the diagnosis. • Infection: Although rare with the tumescent technique, as lidocaine in tumescent fluid has been shown to inhibit bacterial growth,10 utmost care must be taken to maintain an aseptic technique. Many surgeons prefer to give routine antibiotic coverage to all patients, while others prefer a dose of a 2nd generation cephalosporin or a similar antibiotic intraoperatively. Others advocate for no antibiotics at all. Should infection occur, early recognition and treatment must be performed with culture and sensitivity of the aspirate in orde to dictate proper antibiotic coverage. In difficult cases characterized by fat necrosis or inflammation, caused by the release of free fatty acids after trauma to adipocytes, a consult with general surgery and an infectious diseases specialist colleague may be considered, especially in cases near the groin.

• Necrosis of the skin: Although extremely rare, skin necrosis may occur secondary to over-aggressive liposuction, or due to overcompression of the already compromised vasculature of the treated area. Once recognized, it must be observed patiently to determine the extent of the necrosis. In this instance, debridement with secondary intention healing of the defect versus grafting of the defect should be considered. • Surface irregularities or uneven liposuction: This can be avoided fairly easily by using care during liposuction to avoid overzealous liposuction of one area with lessthan-optimal fat removal in the adjacent area. In addition, the use of multiple ports to target the area from different angles, preferably 90° to each other, gives very smooth results. Taking pauses during the procedure to assess the progress by pinching the skin of the area being treated at multiple sites gives a fair idea as to which area needs further liposuction and when the endpoint has been achieved. • Inadvertent puncture of the abdominal cavity or other vital organ: Keeping the tip upward toward the skin, where it can be felt throughout the procedure on every stroke by the non-dominant hand, must be a standard practice by the surgeon. Using the left or non-dominant hand as an “intelligent hand” to continuously monitor the tip of the cannula can avoid this grave complication. The tumescent technique gives the surgeon a major advantage as the patient can communicate with the surgeon about any unusual pain encountered during the procedure. Since the local anesthesia is limited to the skin and subcutaneous tissue, any cannula insertion going deeper to these structures will be felt by the patient, making local anesthesia a safety net.

AREAS THAT CAN BE TREATED WITH LIPOSUCTION Virtually any body area can be amenable to liposuction, but the most commonly requested areas include: the abdomen, including upper abdomen, arbitrarily marked above the umbilicus, and lower abdomen considered under the umbilicus; flanks or love handles; lateral hips and lateral thighs; medial thighs; medial aspect of knees; anterior thigh; calves; male chest (pseudogynecomastia); thoracic “rolls”; upper arms; face, including double chin (submental area) and jowls, to name a few. In females, breast liposuction has gradually replaced major breast

Chapter 124: Current Concepts and Techniques in Liposuction Surgery reduction surgery with inverted-T excision resulting in unsightly scars. While a detailed discussion of each area is beyond the scope of this book, a brief mention of each area with some salient features of the procedure and important points to remember while considering the liposuction of these areas are enumerated below.

Facial Liposuction Involving the Submental Region and Jowls Mainly performed to get rid of the double chin and “turkey neck”, liposuction is performed under local anesthesia without the need of IV sedation in most cases. A slightly stronger solution of lidocaine in the tumescent solution is considered by many surgeons to keep the procedure painless and blood-loss-free. Jowls are mainly liposuctioned at the same time which offers a great alternative to early laxity of the jowls, requiring facelift surgery in the past. Many people are able to delay the facelift by having this muchless invasive outpatient liposuction, which is performed using 1–2 mm in diameter cannula and three tiny incisions, one under the chin and one in front of each tragus. Results are very satisfying for most patients (Figs. 124.7A and B).

Arms Mostly requested by females having heavy upper arms, liposuction provides a great alternative to much moreinvolved brachioplasty that is marred with major surgery

A

and extensive scarring. Performed on the outer ¾th of the circumference of the arm, avoiding the medial aspects to protect neurovascular structures, patients are extremely satisfied in most cases. The fear of most patients and surgeons is unfounded about the laxity of skin after the liposuction, as the use of microcannulas has greatly improved the contraction. This is believed to be the result of less injury to the fibrous septa in the adipose tissue.

Abdomen This is by far the most requested area by males and females alike (Figs. 124.8A and B). The abdomen is usually divided into upper abdomen above the umbilicus and the lower abdomen below the umbilicus. This arbitrary demarcation helps in those who are just concerned with a hanging lower belly (apron) without the concern of the upper abdomen. Such patients can be treated with only lower abdominal liposuction with blending performed to make it look more natural and seamless with the upper abdomen. Importantly, this isolated lower abdominal liposuction approach serves those extremely well who have a large apron of hanging lower abdominal fat that is deemed to be fit only for abdominoplasty. To our surprise, in most of these cases, serial or stepwise liposuction in which we initially treat the lower abdomen, let it contract, and then treat the upper abdomen 6–12 months later, has obviated the need of abdominoplasty in most cases.

B

Figs. 124.7A and B: Liposuction of the chin and jowls. Preoperative (A) and Postoperative (B).

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A

B

Figs. 124.8A and B: Liposuction of the abdomen. Preoperative (A) and Postoperative (B).

A

B

Figs. 124.9A and B: Liposuction of the flanks. Preoperative (A) and Postoperative (B).

Flanks and Love Handles Sides of the abdomen or flanks and love handles are extremely satisfying areas in terms of liposuction, as they do not respond to diet and exercise in most cases in both sexes (Figs. 124.9A and B).

Male Chest (Pseudogynecomastia) Many males may start accumulating fat in their chest area. These patients need to be clearly differentiated from those having true gynecomastia, caused by enlargement of mammary glands due to a hormonal disorder. Those

having normal breast tissue (mammary glands) but accumulation of fat only known as “pseudogynecomastia” are the best candidates for liposuction. Most of these patients have excessive fat accumulation elsewhere as well, but the pseudogynecomastia bothers them the most. Liposuction of the chest in these males can be an excellent option with a high satisfaction rate (Figs. 124.10A and B).

Female Heavy Breasts (Macromastia) In females, heavy breasts or macromastia can be a purely cosmetic concern for some females, but in many women, it can be the source of back pain and other physical

Chapter 124: Current Concepts and Techniques in Liposuction Surgery

A

B

Figs. 124.10A and B: Liposuction of the male chest (psudogynecomastia). Preoperative (A) and Postoperative (B).

A

A

B

B

Figs. 124.11A and B: Liposuction of the heavy female breasts that caused patient great discomfort. Preoperative (A) and Postoperative (B).

Figs. 124.12A and B: Liposuction of the lateral thighs/high hips. Preoperative (A) and Postoperative (B).

problems. This is called as symptomatic macromastia. Surgical breast reduction (reduction mammoplasty) is traditionally performed with inverted-T resection, often resulting in unsightly extensive scarring after a major surgical intervention. It is well known that such females suffer from excessive accumulation of fat in the breasts rather than hypertrophy of the breast tissue, and thus suction of these fat deposits under local anesthesia using tumescent liposuction proves to be a logical choice with outstanding results, without significant morbidity or scarring as an outpatient procedure (Figs. 124.11A and B).

Unfortunately, this area does not respond to exercise or dieting either, and thus makes a perfect target for liposuction with very high satisfaction rates (Figs. 124.12A and B). In summary, dermatologists have played a pivotal role in making liposuction a very safe outpatient surgical procedure over the past 2–3 decades. Many areas of the body which were not considered to be treatable with liposuction alone are now successfully treated with tumescent liposuction. Although this procedure requires a steep learning curve and is physically challenging, it must be a critical part of any dermatologic surgical training program. Even those dermatologists not interested in pursuing dermatologic surgery as their career choice must be familiar with the advantages that this great innovation can offer to their patients.

Lateral Thighs/ High Hips Lateral thighs or high hips are a major problem area for many females who are otherwise in good physical shape.

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REFERENCES 1. 2016 Cosmetic Surgery National Data Bank Statistics. American Society for Aesthetic Plastic Surgery. https:// www.surgery.org/sites/default/files/ASAPS-Stats2016.pdf. (Last accessed 16 July 2019.) 2. Klein JA. Tumescent technique for liposuction surgery. Am J Cosm Surg. 1987;4:263. 3. Klein JA. Tumescent technique for regional anesthesia permits lidocaine doses of 35 mg/kg for liposuction. J Dermatol Surg Oncol. 1990;16:248–63. 4. Ostad A, Kageyama A, Moy RL. Tumescent anesthesia with lidocaine dose of 55 mg/kg is safe for liposuction. Dermatol Surg. 1996;22:921–7. 5. Klein JA, Jeske DR. Estimated maximal safe dosages of tumescent lidocaine. Anesth Analg. 2016;122:1350–9.

6. Chia CT, Neinstein RM, Theodorou SJ. Evidence-based medicine: liposuction. Plast Reconstr Surg. 2017;139(1): 267e-74e. 7. Scarborough DA, Herron JB, Khan A, et al. Experience with more than 5,000 cases in which monitored anesthesia care was used for liposuction surgery. Aesthetic Plast Surg. 2003;27(6):474–80. 8. Bitar G, Mullis W, Jacobs W, et al. Safety and efficacy of office based surgery with monitored anesthesia care/ sedation in 4778 consecutive plastic surgery procedures. Plast Reconstr Surg. 2003;111:150–6; discussion 157. 9. Klein J, Kassasjdian N. Lidocaine toxicity with tumescent liposuction: a case report of probable drug interactions. Dermatol Surg. 1997;23:1169–74. 10. Klein J A. Antibacterial effects of tumescent lidocaine. Plast Reconstr Surg. 1999;104(6):1934–6.

Chapter

125

Hair Transplantation Shannon Watkins, Marc Avram

INTRODUCTION Hair transplantation has been carried out as a procedure for over 5 decades. For the past 20 years, men and women can expect natural-appearing results. This chapter will review the current concepts and surgical techniques in hair transplantation. As with all surgical procedures, techniques and approaches may vary from surgeon to surgeon.

MEDICATIONS AND HAIR TRANSPLANTATION Male- and female-pattern hair loss is ongoing. This affects the long-term planning and perceived density of a hair transplant. The net density gained from a surgery equals the hair transplanted minus the hair lost over time. Medical therapies can slow down and, at times, reverse hair loss; thereby increasing the perceived density of a procedure. The surgical plan should be made with the assumption that at some point medical therapies will be stopped and hair loss will progress. Failing to plan for future hair loss can lead to compromised results down the road that require corrective surgery. For this reason, we discuss medical therapy with all of hair transplant patients during their consult. There are currently two FDA-approved medications for hair loss that can be used in conjunction with hair transplantation: minoxidil (Rogaine 2% and 5%) and finasteride (Propecia, 1 mg tab).1–3 Low-level light therapy is an FDA-approved device to stimulate hair growth.4,5 Combining medical therapies with hair-transplant surgery may be more beneficial than either treatment alone. Spironolactone and finasteride are sometimes used off-label for female-pattern hair loss.6–8 Finasteride is used only in postmenopausal women. Investigational medications for hair loss include prostaglandin analogs such as bimatoprost (Latisse→), travoprost, and latanoprost, and platelet-rich plasma therapy (PRP). For the purpose of this chapter, we will focus on the FDA-approved medical treatments for hair loss.

Minoxidil and Hair Transplantation Minoxidil has been shown to increase hair counts and the diameter of hair shafts.1,9,10 One study showed that 45% of men applying topical minoxidil 2.8% solution for 32 months noted hair growth, with no serious side effects.11 The 2% and 5% formulations are approved for male- and female-pattern hair loss, but some studies have shown that the 5% formulation may be more effective.12 Minoxidil’s exact mechanism of action is unknown. Studies investigating minoxidil use in conjunction with hair-transplant surgery suggest that minoxidil may allow for better graft survival, eliminate post-transplant shedding, and can speed the regrowth of hair after a postsurgical telogen effluvium.13,14 A roundtable consensus meeting of hair transplant surgeons also advocated for the use of minoxidil in conjunction with hair transplantation to increase hair density and anagen hair, decrease postsurgical shedding, speed regrowth of transplanted follicles, and slow hair loss. Most surgeons prefer the 5% to the 2% formulation due to increased efficacy, and recommend stopping minoxidil 2–3 days prior to surgery and resuming minoxidil 2–14 days postoperatively.15 Minoxidil is very safe. The most common side effect is hypertrichosis, noted in about 4% of female patients;16 it is reversible on discontinuation of minoxidil. Patients who experience hypertrichosis typically see a response on the scalp as well. Switching from 5% to 2% can decrease unwanted hair growth while preserving the positive effect on the scalp.1,16,17 Minoxidil can also have cutaneous side effects such as irritation and allergic contact dermatitis to both propylene glycol (contained in most formulations) and minoxidil itself, in a small percentage of patients.18,19 Rogaine 5% foam (Pfizer, Inc, New York, NY) does not contain propylene glycol, so patients may be able to tolerate this, and studies have shown that once daily 5% minoxidil foam has a similar efficacy as twice daily minoxidil 2% solution.3 Topical minoxidil is pregnancy category C, and not approved for use in pregnancy or breastfeeding.20–23

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Section 33: Cosmetic Surgery See Table 125.1 for a summary of patient counseling for minoxidil.

Finasteride and Hair Transplantation Finasteride 1 mg is approved by the FDA for androgenetic alopecia in men. It is metabolized by the liver so it should be used with caution in patients with liver dysfunction.1 Finasteride is a competitive inhibitor of type 2 of 5α-reductase, an enzyme that catalyzes the conversion of testosterone to dihydrotestosterone (DHT).1 Treatment with finasteride increases hair weight, promotes anagen hair, and can reverse the miniaturization of hair.24–27 Of note, type 2 of 5α-reductase levels may be higher in younger men, so finasteride may not be as effective in treating men over the age of 60 years old.1 A randomized double-blind placebo study investigating the role of finasteride in hair surgery showed that finasteride, 1 mg beginning 4 weeks prior to and continuing 48 weeks after hair transplantation, significantly improves hair counts and hair density versus the placebo.24 Finasteride 1 mg daily is safe and well tolerated. In clini­cal trials, the only adverse events reported were decreased libido (1.8% in finasteride group versus 1.3%

Table 125.1: Minoxidil patient counseling.** Mechanism of action Unknown. May increase blood flow, open K+ channels, increase cellular proliferation, have an immunoregulatory effect on T-cells. Patient instructions Apply 5% formulation or 2% formulation QD or BID Time to see results 8 months to 1 year (peak results) Side effects • Hypertrichosis • Allergic contact dermatitis • Not to be used if pregnant or breastfeeding FDA-approved formulations* • 2% Solution (30% propylene glycol) • 5% Solution (50% propylene glycol) • 5% Foam (propylene glycol free) FDA-approved for– Men and Women (2% Solution and 5% foam)* *Available over-the-counter **Table from Hair transplantation, Jaypee Brothers Medical Publishers

in placebo), erectile dysfunction (1.3% versus 0.7% of placebo), and ejaculatory dysfunction (1.2% versus 0.7% of placebo).1,2 These side effects were temporary and disappeared during prolonged treatment and within days to weeks after medication discontinuation. One study estimated that finasteride increases the risk of sexual side effects by 1.5% versus placebo.28 More recently, there have been reports suggesting a possible link between finasteride and more permanent sexual side effects, postfinasteride syndrome, and psychological side effects like depression. These side effects could prove independent of finasteride but further investigation is needed to determine whether there is a valid association.29,30 Until clarified, patients should be made aware of these reports before beginning the medication. Finasteride has been shown to reduce overall prostate cancer risk but may increase the risk of high-grade disease.31 See Table 125.2 for a summary of patient counseling for finasteride.

Low-Level Light Therapy and Hair Transplantation Low-level light therapy (LLLT) of 650–900 nm has been reported to enhance hair growth.5 The mechanism by which light sources cause hair growth is unclear.5,32–35 We use LLLT as an adjunct to medical therapy or in patients who cannot tolerate minoxidil or finasteride. Table 125.2: Finasteride patient counseling.** Mechanism of action Competitive inhibitor of type 2 5α-reductase FDA-approved formulation/patient instructions 1 mg tablet PO daily Time to See the Results 8 months to 1 year Side effects • Sexual side effects 1.5% versus placebo • Prostate-specific antigen (PSA) score must be doubled • Lower risk of prostate cancer, but may increase risk of high-grade disease • Case reports of permanent sexual side effects and worsening depression (may be circumstantial and further studies needed to validate claims) FDA-approved for– Men 18–41 years of age with mild to moderate hair loss **Table from Hair transplantation, Jaypee Brothers Medical Publishers

Chapter 125: Hair Transplantation

CANDIDATE SELECTION AND PREOPERATIVE CONSIDERATIONS A patient’s hair loss history, including medical treatment to date, is vital to obtain during a consult. Patients on medical therapy with stable loss can expect a visible increase in density from a procedure. In contrast, patients with rapid hair loss or those who cannot tolerate medical therapy should be aware that ongoing hair loss will impact the perceived density from a hair transplant pro­cedure. As hair loss progresses, patients can return for additional hair-transplant procedures. The limiting factor for how many procedures can be performed is the amount of donor hair available. Patients should be made aware of the limited donor supply and how this impacts surgical planning during the initial consultation. For most patients, transplanting the frontal half of the scalp will have the greatest cosmetic impact with the least long-term cosmetic risk. The area of greatest cosmetic risk is the vertex of the scalp. As hair loss progresses in most patients, there is not enough donor hair to create a natural distribution of hair in this area. Therefore, a limited number of men and women are candidates for transplantation of the vertex. Appropriate candidate selection is key to success with hair-transplant surgery. Surgical complications are un­usual on the scalp. The majority of disappointed patients arise from unrealistic expectations and poor surgical planning by the surgeon. The donor density (follicular units/cm2) and caliber of hair follicles are two key physical cha­racteristics for the procedure. Patients with greater donor density have more hair that can be transplanted. The caliber of hair follicles also affects perceived density. With transplantation of the same number of hair, patients with fine, thin caliber hair follicles will have thinner coverage than patients with thick, coarse hair. Prior to surgery, patients fill out a health questionnaire. For healthy patients under 55 years old, the author does not require medical clearance. For patients 55 years and older and younger patients with preexisting medical conditions, the author requires medical clearance. A negative pregnancy test is also required for females of childbearing age. For patients on anticoagulants, they are asked to speak with their primary doctor about discontinuing their medications prior to the surgery. If this is not possible, the author does not perform the surgery due to increased bleeding risk. It is also requested that patients abstain from alcohol and minoxidil for 24 hours prior to

and 1–3 days after the surgery due to theoretical increased bleeding risk. Antibiotic prophylaxis is not typically indicated for hair-transplant surgery as it is considered a clean procedure. Some hair transplant surgeons, however, administer prophylactic antibiotics to patients at higher risk of infection such as those who are immunocompromised or with diabetes. Many surgeons also give prophylactic antibiotics for patients at increased risk of prosthetic joint infections or endocarditis.36 When indicated, prophylactic antibio­tics should be taken 30–60 minutes prior to the procedure. See Table 125.3 for a summary of preoperative regimens recommended for skin surgery, as no specific guidelines for hair-transplant surgery exist.36,37

ANESTHESIA Lidocaine is the most commonly used local anesthetic. Some hair surgeons prefer bupivacaine due to its longer duration of action.38–41 Lidocaine without epinephrine lasts about 60 minutes; lidocaine with epinephrine lasts 120 minutes. Bupivacaine without epinephrine lasts 120–240 minutes.42 Bupivacaine 0.25% provides a similar analgesia to 1% lidocaine.39 Advantages of lidocaine include that it has a faster time to onset of anesthesia and causes less infiltration pain than bupivacaine. The cumulative dosage of local anesthesia should be monitored and there should be constant surveillance for signs of toxicity. The maximum recommended dosage for lidocaine with epinephrine is 7 mg/kg. This is 0.7 mL/ kg of 1% lidocaine with epinephrine. Lidocaine 1% has 10 mg of lidocaine/1 mL. For an average 70 kg man, the maximum dose of 1% lidocaine with epinephrine would be 50 mL. The maximum dose of 0.25% bupivacaine with epinephrine is 225 mg or 90 mL. These maximum dosages do not take into account the vascularity of the area, rate of usage, or number of administrations. For example, with Table 125.3: Preoperative regimens for skin surgery. Non-penicillin allergic Penicillin allergic Clindamycin 600 mg Community Cephalexin 2g OR with low MRSA Azithromycin 500 mg prevalence OR OR Clarithromycin 500 mg Dicloxacillin 2g Bactrim DS Community Bactrim DS PO AND with high MRSA AND Clindamycin 600 mg prevalence Penicillin VK 500 mg

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Section 33: Cosmetic Surgery tume­scent liposuction, up to 50 mg/kg of diluted lidocaine can be safely given.39 Further studies are needed to explore the safety of locale anesthetics in hair-transplant surgery. Toxicities of local anesthetic correlate with plasma levels of the drug. The half-life of lidocaine when injected locally (with normal liver function) is 120 minutes or 2 hours.43 Signs of lidocaine toxicity include feelings of light-headedness, dizziness, drowsiness, muscle fasciculations, tinnitus, paresthesias, and a metallic taste.39 With very high levels, seizures, coma, respiratory, and cardiac arrest can occur.43 CNS toxicity can occur with plasma bupivacaine levels of 1 mg/L.39,44 See Figure 125.1 for a list of side effects seen with increasing doses of lidocaine plasma concentrations. It is easier to prevent toxicity than to treat it; thus, a flow sheet recording the administration of local anesthesia administered should be kept. Medications such as flumazenil (antidote for valium toxicity) and naloxone (antidote for opiate toxicity) should be readily available in case of an overdose.42 The surgeon should also be aware of potential interactions between the patient’s medications and anesthetics utilized during hair-transplant surgery. Programs such as Epocrates (www.epocrates.com) can be utilized to check for medication interactions. Effective local anesthesia can be maintained for the duration of the hair-transplant surgery. Innervation of the scalp is from branches of the supraorbital, supratrochlear, zygomaticotemporal, auriculotemporal, lesser occipital, greater occipital, and third occipital nerves.39 To anesthetize the donor area, most practitioners use a local ring

Fig. 125.1: Signs of lidocaine toxicity with escalating doses of lidocaine. (Figure adapted from Seager and Simmons. Local Anesthesia in Hair transplantation, and Unger et al. Hair transplantation, 5th edn. In: Goldberg DJ LN, Lask GP (eds), New York: Informa Healthare; 2011.)

block followed by dermal infiltration of local anesthetic. A ring block involves blocking all nerves innervating an area by infiltrating a continuous path along the edge of the area (Fig. 125.2). Some practitioners also incorporate a supraorbital or supratrochlear nerve block. For anesthesia of the recipient site, Swineheart reports that he rubs lidocaine and epinephrine-soaked gauze over the recipient area, allowing the anesthetic to soak down recipient “slits”; thus, anesthetizing without additional injections.45 There are several techniques to minimize the pain of local anesthesia, which include vibration, warming anesthetic solution, a small caliber needle, as well as decreasing the rate of injection.42

DONOR HARVESTING There are two methods which can be utilized for obtaining donor hair — elliptical donor harvesting and follicular unit extraction (FUE). Both techniques yield good results, but the advantages and disadvantages of each should be discussed with patients during their consult (Table 125.4). A comparison of standard ellipse to robotic FUE harvesting, adapted from a recent paper by Avram and Watkins.46

Elliptical Donor Harvesting Donor elliptical harvesting employs the same technique used for a cutaneous excision. Harvesting is typically performed using a No. 10 or 15 Personna blade with either a single- or double-blade approach. Prior to harvesting, the donor

Fig. 125.2: Ring block. Inject anesthesia in a subcutaneous plane in a continuous path along the edge of an area.

Chapter 125: Hair Transplantation Table 125.4: A comparison of standard ellipse to FUE harvesting. Standard ellipse Follicular unit extraction Scarring Linear scar No linear scar Time to harvest 10–20 minutes for 300–2,000 Manual/Powered FUE grafts grafts Operator-dependent

Healing time Cost

Transection rate

Physician skill

Technician skill Reliability

7–10 days Minimal

Low with experienced team, Widely variable with inexperienced team

Robot 45–60 minutes for 300–600 grafts, 60–120 minutes for 600–1200 grafts 3–5 days Manual/Powered FUE Affordable, device-dependent Robot Significant to purchase machine and additional per surgery fee for each harvest attempt Manual/Powered FUE Operator-dependent

Standard skin excision techniques

Robot Low to low-moderate Manual/Powered FUE High degree of manual dexterity

Skilled technician mandatory to create follicular units with low transection Technician + Physiciandependent

Robot Knowledge of software program and robot Manual/Powered FUE/Robot Skilled technician needed to remove grafts from scalp and assess quality under magnification before placing in recipient site Manual Physician-dependent Powered FUE Device + Physician-dependent

Area of donor site shaved Space requirement

1.5 cm × 8–20 cm Can be done in office space used for standard excisions

Robot Technician + Physician + Robot-dependent Manual/Powered FUE/Robot 4–8 cm × 10–20 cm Manual/Powered FUE Can be done in office space used for standard excisions Robot Minimum office space: 10 foot × 10 foot; Large procedural space

Electrical requirement

Technical requirements

Power supply of a standard patient room

None

Robot Dimensions Cart: length (l) 48 inches, width (w) 27 inches, height (h) 68 inches Chair: (l) 57 inches, (w) 33 inches, (h) 48 inches Weight: cart = 872 lbs, chair = 550 lbs Manual/Powered FUE Power supply of a standard patient room Robot 1. 208 VAC ±10%, single phase, 50/60 Hz, 10 A. Required power outlet configuration is NEMA L6–20R twist lock Manual/Powered FUE None Robot 1. Ethernet port, no WiFi 2. Personal computer 3. Secondary Monitor, with HDMI cables from robot to monitor 4. Desk (workstation), at least 2’ × 3’ working surface

Source: Adapted from Avram and Watkins, Robotic FUE in hair transplantation. Dermatol Surg. 2014;40(12):1319–27.

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Section 33: Cosmetic Surgery area is trimmed (not shaved) with a mustache trimmer. See Figure 125.3 for a diagram of the safe donor area. Standard forceps and skin hooks can be used to retract the scalp skin and directly visualize hair follicles, thereby minimizing follicle transection. Transection rates as low as 1.59% have been reported.47 A standard needle driver, forceps, and 3.0 sutures (nylon, prolene, or polydioxanone sutures (PDS)), or a staple gun are utilized to close the scalp defect (Fig. 125.4). The size of the donor ellipse is a reflection of the number of hair follicles needed for the procedure. There are approximately 65–80 follicular units per cm2. The surgeon

can extrapolate the size of the ellipse needed. To reduce wound tension, ellipses should be “longer rather than wider”, and most surgeons prefer the diameter to be less than 1.5 cm. After the donor strip is removed, it takes approximately 45–60 minutes for an experienced team of 3–4 technicians to process the donor strip into individual 1,000–1,500 follicular units.48 Follicular units are typically stored in chilled normal saline or a holding solution until they are planted into the recipient area. The primary disadvantage of donor ellipse harvesting is a linear scar. This is of no cosmetic significance for patients who do not wear their hair short such as women and many men. For patients who wear their hair short or may want to wear their hair short in the future, or those who want a less invasive harvesting technique with no sutures or staples, FUE is a good alternative method for donor harvesting.

Follicular Unit Extraction (FUE)

Fig. 125.3: Safe donor area. Superior border 1–2 cm above horizontal line from top of ear helices. Inferior border determined by occipital protuberance.

Fig. 125.4: Standard instruments for elliptical donor harvesting. Top row: 3M skin staple remover, 3M precise MS skin stapler, Kelly clamp, Bottom row: Double-bladed scalpel, single-bladed scalpel, skin forceps, tissue-cutting scissors, and skin hook (usually 2 in set-up).

FUE reflects the growing trend in medicine toward minimally invasive surgery. FUE uses 0.75–1.25 mm circular trephine punches to extract follicular units. It is less invasive than elliptical harvesting, no sutures or staples are required, and does not create a linear scar. This is appealing to both patients and physicians. There are many factors to consider when purchasing a FUE device such as metal type, diameter, cutting edge location, punch wall thickness, sharpness, and shape. There are manual, motorized (SAFE system and the NeograftTM are two of the more popular models), and one robotic FUE device (The ARTAS → Robot system, Restoration robotics, Inc. San Jose, CA). Manual and motorized FUE devices rely on the skill and accuracy of the operator to harvest follicular units. One study reported a transection rate of 17.3% with a manual FUE device versus a 5.4% transection rate with a motorized FUE device.49 Another study using the SAFE (surgically advanced follicular extraction system) motorized FUE device reported a 6.14% average transection rate.50 These reported transection rates are based on highly skilled operators, and do not reflect a novice user. The robotic system automizes the FUE process, which allows inexperienced users to harvest many high quality grafts in a short period of time. It consists of a 0.9–1 mm sharp punch surrounded by a blunt outer punch. The sharp inner punch creates a shallow incision, subsequently the blunt outer punch dissects deeper and separates the follicular units from surrounding tissue. A suction system elevates the follicular unit from

Chapter 125: Hair Transplantation surrounding skin and the graft is manually extracted. A combination of stereoscopic cameras managed by image processing software allows the robot to identify the precise angle and direction of hair growth.46,51 The high degree of automation allows the extraction of 400–600 grafts per hour, with an average transection rate of around 6.6% which is comparable to other FUE devices and manual dissection of a donor ellipse.46 Patients should be aware that while there is no linear scar, there may be pinpoint white scars evident on close inspection. FUE reflects the growing trend in medicine toward minimally invasive surgery46 (Figs. 125.5A and B).

HAIRLINE DESIGN Hairlines should be designed anticipating future hair loss. Doing so will ensure long-lasting cosmetically acceptable results. A few principles the authors recommend to create a natural hairline are as follows: • Avoid bringing the hairline further forward than it already is (or was, before hair loss) • Preserve the natural temporal recession. Avoid bringing the hairline too straight across on either side • Create an irregular “feathered” hairline that anticipates further hair loss • Avoid transplanting the vertex in young patients, which can appear as an “island” of hair later in life as hair loss progresses. A safe long-term hairline design is to keep the transplanted hair anterior to the vertex transition point of the scalp52

A

Creating a natural hairline is a combination of technical skill and artistic ability, which ensures the hairline frames a patient’s face.52 The most anterior aspect of the frontal hairline should be at least 8–9 cm above the glabella for men. One should also prioritize the placement of limited donor hair to areas that have the most esthetic impact. Priority should be placed on framing the face; by placing hair in the frontal 1/3 – 1/2 of the scalp, we are able to accomplish this. This maximizes cosmetic impact and minimizes long-term cosmetic risk with ongoing hair loss. The vertex has the least short-term cosmetic impact with the greatest cosmetic risk for the majority of patients and thus should only be transplanted in a minority of patients. The precise number of hair transplanted depends on the density of the donor region and the need for hair in the recipient area. Care should be taken not to transect existing hair follicles, and the goal is to create random and irregular recipient sites with a density of 20–35 sites per cm2 (approximately 30–50% of the original density) depending on the density of existing hair. In patients with good donor supply and healthy (non-scarred) recipient tissue, the density may reach 40–50 FU/cm2.52 The size of the patient’s head can play an integral role in how many grafts are required for the procedure (patients with wide skulls need more hair than those with narrower skulls).52 A general guide of natural appearing hairlines for men can be seen by examining the Norwood scale for male-pattern hair loss (Fig. 125.6).53 For female hairlines, one study of 360 female volunteers described four important characteristics of a

B

Figs. 125.5A and B: Devices for FUE. (A) Manual FUE devices and a motorized FUE device (bottom); (B) ARTAS robotic system. Source: Rose PT, Nusbaum B. Robotic hair restoration. Dermatologic clinics. 2014;32(1):97–107.

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Section 33: Cosmetic Surgery

Fig. 125.6: Norwood scale for male-pattern hair loss. Source: Norwood OT, Hair Transplant Surgery, 2nd edn, Charles C. Springfield, Illinois: Thomas Publisher, Ltd., 1984.

female hairline (Fig. 125.7): a widows peak (present in 81%), lateral mounds (present in 98%), temporal points (present in 100%), and temporal recessions (present in 87%). Additionally, they noted the mean distance from the mid eyebrow to the frontal midpoint was 5.5 cm on average.54 Another study classified the hairline contour of Asian women into five categories: Round, M-shaped, Rectangular, Bell, or Triangular (Fig. 125.8). This study also noted the average height of forehead was 6.38 ± 0.89 cm.55 One important difference between male and female hairlines is the static nature of female hairlines compared to the ever changing and receding nature of male hairlines. Prior to each procedure, the physician should mark off the area to be transplanted and the anticipated hairline. This way the patient is aware of where their transplanted hair will and will not grow.

RECIPIENT SITE CREATION AND GRAFT PLACEMENT Recipient sites are created by a variety of small needles. The 18, 19, and 20 gage needles are the most common sizes used. These measure 1.27 mm, 1.09 mm, and 0.9 mm, respectively.52 Needles can be bent to accommodate the length of the individual graft. The 18-gage needles are typically used for three hair grafts, 19-gage needles for two hair grafts, and 20 gage needles for one hair grafts.56 Spear point tips such as SP-88s (1 mm) and SP-89s (1.25 mm) can

Fig. 125.7: Four important characteristics of a female hairline.* TP, temporal point; WP, widow,s peak; LM, lateral mound; TR, temporal recession. Source: Nusbaum BP et al., Naturally occurring female hairline patterns. Dermatol Surg. 2009;35(6):907–13.

Fig. 125.8: Classification of hairline contours. Round: no front temporal recess. M-shaped: deep front temporal recess. Rectangular: squareshaped hairline, upper forehead parallel to temporal recess. Bell: forehead width normal, but height 2 cm higher than normal (6.38 cm). Triangular: hairline without a temporal recession, straight line from midfrontal point to temporal point. Source: Jung et al. Classification of the female hairline and refined hairline correction techniques for Asian women. Dermatol Surg. 2011;37:495–500.

also be used with a lightening knife handle for recipient site creation. Recipient sites should be created parallel to naturally occurring hair. Failure to orient sites in this fashion will lead to greater transection of existing hair follicles and unnecessary loss of hair.

Chapter 125: Hair Transplantation Graft creation and placement is done by two to five technicians. Each team uses different techniques. Most utilize specialized microvascular forceps with curved or straight tips. It is vital that grafts are grasped by perifollicular tissue so follicles are not destroyed. Technicians often use a cotton-tipped applicator or gauze to prevent “popping” of grafts (grafts coming out of recipient sites) and deal with any bleeding.52 Grafts should also be placed flush to slightly above recipient skin. Placing grafts too high results in cobblestoning, and too low results in pitting.57

POST-OP WOUND CARE AND INSTRUCTIONS After the hair transplant procedure, the author applies aquaphor ointment, a non-stick dressing, and a pressure bandage to the scalp. For patients who have had hair transplanted to their frontal scalp, the author recommends prednisone 40 mg orally for 3 days to minimize postoperative frontal edema if there are no contraindications. It is also recommended that they avoid heavy lifting for 2–3 days. On post-op day 1, the author recommends that the patient remove the pressure bandage and gently allow water to run over the donor and recipient sites in the shower. On post-op day 2–6, they should gently wash the scalp daily (no rubbing or scrubbing grafts) and apply aquaphor ointment to the donor site for the next 7 days. The recipient site requires no after-care other than gentle washing described above. If the patient is diabetic or at an increased risk of infection, the author typically prescribes mupirocin ointment to be applied instead of the aquaphor. Sutures or staples are typically removed on postoperative day 7–10.52

COMPLICATIONS Complications from hair transplantation surgery are rare but can rarely include bleeding and infection (more prevalent following a high-tension closure due to circulatory compromise), telogen-effluvium, recipient and donor region numbness, necrosis, dehiscence, hypertrophic scarring, cyst formation, folliculitis, neuralgia, neuromas, and hematomas.57

CORRECTIVE SURGERY Patients presenting for corrective surgery often feel as though they are having reconstructive rather than esthetic

surgery. There are two groups of patients which present for corrective hair-transplant surgery: • Patients who underwent large graft “pluggy” transplants and are self-conscious about the unnatural appearance of their hair. • Patients who underwent follicular unit transplantation but had grafts placed in areas of their scalp that became increasingly unnatural as hair loss continued. The most commonly employed technique in corrective surgery is adding a large number of follicular units to increase density and soften a hairline either alone or in combination with removing unnatural grafts. Grafts placed too low on the hairline or into the vertex should be removed either surgically or by laser hair removal. Adding grafts would only accentuate a mistake. When removing grafts, the author often reimplants them into an area that is more appropriate for short- and long-term cosmetic impact. Follicular unit extraction can be of great use in patients with extensive donor scarring since it does not create another full thickness wound. Some patients request a “return to status quo ante”. They will not accept any further surgery. A series of five to ten laser hair removal sessions can be an excellent treatment option for pigmented hair. For others, a combination of laser hair removal and punch or elliptical removal of grafts can be performed. For patients who had procedures with larger grafts, a textural change in the scalp skin can be a major cosmetic concern. Non-ablative or fractional ablative lasers can help improve the texture of the scalp for these patients. This is similar to improving unnatural texture on the face due to acne scars.58,59

NON-SCALP TRANSPLANTATION Body hair can be used as alternative donor source for patients with poor donor hair on their scalp and a good density and caliber of body hair. One should be aware that the characteristics of body hair differ from that of scalp hair, and may not be a perfect cosmetic match; however, there are case reports of leg hair, which is of finer caliber than scalp hair, being used successfully for eyebrow transplantation and to soften an unnatural hairline.60,61 Umar also reports using finer hair from the nape of the neck and preauricular area to transplant thinning eyebrows.62 It is important to note that a higher percentage of body hair is in the telogen phase compared to head hair (i.e. about 40–85% of body hair in telogen versus