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| FOURTH EDITION VOLUME ONE

MCKEE’S
PATHOLOGY
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EDUARDO CALONJE •THOMAS BRF.NN

SAUNDERS ALEXANDER LAZAR* PHILLIP H MCKEE
ELSEVIER
 

McKee’s
Pathology
of the Skin
Commissioning Editor: William R. Schmitt
Development Editors: Louise Cook & Rachael Harrison
Editorial Assistant: Kirsten Lowson
Project Manager: Nancy Arnott
Design: Kirsteen Wright
Illustration Manager: Merlyn Harvey
Marketing Manager (USA): Tracie Pasker
 
IFourth Edition

McKee’s
Pathology
of the Skin
Volume 1
with Clinical Correlations I
Eduardo Calonje MD, DipRCPath Alexander Lazar MD, PhD
Director of Dermatopathology Associate Professor
Department of Dermatopathology Departments of Pathology and Dermatology
St John's Institute of Dermatology Sections of Dermatopathology and Sarcoma Pathology
St Thomas' Hospital Faculty, Sarcoma Research Center and Graduate School
London, UK of Biomedical Science
The University of Texas M.D. Anderson Cancer Center
Thomas Brenn MD, PhD, FRCPath Houston, Texas, USA
Consultant Dermatopathologist and Honorary Senior
Lecturer Editor-in-Chief
Department of Pathology
Western General Hospital and The University
Phillip H McKee MD, FRCPath
Formerly Associate Professor of Pathology and
of Edinburgh
Director, Division of Dermatopathology
Edinburgh, UK
Department of Surgical Pathology
Brigham and Women's Hospital and Harvard Medical
School
Boston, MA, USA

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LSEVIERI
ELSEVIER
SAUNDERS

SAUNDERS an imprint of Elsevier Limited

© 2012, Elsevier Limited All rights reserved.

First edition 1989

Second edition 1996
Third edition 2005
Fourth edition 2012

The right of Eduardo Calonje, Thomas Brenn, Alexander Lazar and Phillip H McKee to be identified as author
of this work has been asserted by them in accordance with the Copyright, Designs and Patents Act 1988. No
part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical,
including photocopying, recording, or any information storage and retrieval system, without permission in
writing from the publisher. Details on how to seek permission, further information about the Publisher's
permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the
Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the
individual contributions contained in it are protected under copyright by the Publisher (other than as may be
noted herein).

Notices
Knowledge and best practice in this field are constantly changing. As new research and experience broaden our
understanding, changes in research methods, professional practices, or medical treatment may become necessary.
Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any
information, methods, compounds, or experiments described herein. In using such information or methods they
should be mindful of their own safety and the safety of others, including parties for whom they have a professional
responsibility.
With respect to any drug or pharmaceutical products identified, readers are advised to check the most current
information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered,
to verify the recommended dose or formula, the method and duration of administration, and contraindications.
It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make
diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate
safety precautions.
To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability
for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or
from any use or operation of any methods, products, instructions, or ideas contained in the material herein.

British Library Cataloguing in Publication Data

McKee's Pathology of the Skin. – 4th ed.

1. Skin–Diseases. 2. Skin–Histopathology.
I. Pathology of the skin II. Calonje, Eduardo. III. McKee,
Phillip H. Pathology of the skin.
616.5'07-dc22
ISBN-13: 978 1 4160 5649 2

Working together to grow

libraries in developing countries
www.elsevier.com | www.bookaid.org | www.sabre.org
BOOK AID
ELSEVIER International Sabre Foundation

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

List of Contributors vii

Preface to the fourth edition x
Acknowledgements xi
Dedications xii
Glossary xiii

Volume 1

1 The structure and function of skin 1 11 Diseases of the oral mucosa 362
John A. McGrath Sook-Bin Woo

2 Specialized techniques in dermatopathology 32 12 Diseases of the anogenital skin 437

Pratistadevi A. Ramdial, Boris C. Bastian, John Goodlad, Eduardo Calonje, Sallie Neill, Chris Bunker,
John K. McGrath and Alexander Lazar Nick Francis, Alcides Chaux and Antonio C Cubilla

3 Disorders of keratinization 46 13 Degenerative and metabolic diseases 520

Dieter Metze Nooshin Brinster and Eduardo Calonje

4 Inherited and autoimmune subepidermal blistering 14 Cutaneous adverse reactions to drugs 590
diseases 99 Nooshin Brinster
5 Acantholytic disorders 151
15 Neutrophilic and eosinophilic
6 Spongiotic, psoriasiform and pustular dermatoses 631
dermatoses 180
16 Vascular diseases 658
7 Lichenoid and interface dermatitis 219
17 Idiopathic connective tissue
Wei-Lien Wang and Alexander Lazar disorders 711
Bostjan Luzar and Eduardo Calonje
8 Superficial and deep perivascular inflammatory
dermatoses 259
18 Infectious diseases of the skin 760
9 Granulomatous, necrobiotic and perforating Wayne Grayson
dermatoses 281
10 Inflammatory diseases of the subcutaneous fat 326
Bostjan Luzar and Eduardo Calonje

Volume 2

19 Human immunodeficiency virus (HIV) 22 Diseases of the hair 967

and acquired immunodeficiency Rodrigo Restrepo and Eduardo Calonje
syndrome (AIDS)-associated cutaneous
diseases 896 23 Diseases of the nails 1051
Pratistadevi K. Ramdial and Wayne Grayson Josette Andre, Ursula Sass and Anne Theunis

20 Disorders of pigmentation 912 24 Tumors of the surface epithelium 1076

21 Diseases of collagen and elastic tissue 935 25 Melanocytic nevi 1150
Wei-Lien Wang and Alexander Lazar Bostjan Luzar, Boris C. Bastian and Eduardo Calonje
vi Contents

26 Melanoma 1221 30 Cutaneous metastases and Paget's disease

Boris C. Bastian and Alexander Lazar
27 Tumors of the conjunctiva 1268
Jacob Péer and Shahar Frenkel
28 Sentinel lymph node biopsies 1296
Alistair J. Cochran
29 Cutaneous lymphoproliferative
diseases and related
disorders 1311
John Goodlad and Eduardo Calonje
of the skin 1421
Doina Ivan, Alexander Lazar and Eduardo Calonje
31 Tumors of the hair follicle 1445
32 Tumors and related lesions of the sebaceous
glands 1488
33 Tumors of the sweat glands 1508
34 Cutaneous cysts 1571
35 Connective tissue tumors 1588

Index I1
 Chapter

List of Contributors

Josette André, MD Alistair J. Cochran, MD

Head of the Dermatology and Dermatopathology Department. Distinguished Professor of Pathology and Laboratory
CHU Saint-Pierre - CHU Brugmann Medicine and Surgery
Hôpital Universitaire des Enfants Reine Fabiola Department of Pathology and Laboratory Medicine
Université Libre de Bruxelles David Geffen School of Medicine at UCLA
Brussels, Belgium Los Angeles, CA, USA
Ch 23: Diseases of the nails with Ursula Sass and Anne Ch 28: Sentinel node biopsies
Theunis

Boris C. Bastian, MD Antonio C. Cubilla, MD

Instituto de Patología e Investigación
Chairman, Department of Pathology
Asuncion, Paraguay
The James Ewing Alumni Chair
Ch 12: Diseases of the anogenital skin with Eduardo
Member, Human Oncology and Pathogenesis Program
Calonje, Sallie Neill, Chris Bunker, Nick Francis and Alcides
Memorial Sloan-Kettering Cancer Center
Chaux
Professor of Pathology
Weill Cornell Medical College
New York, NY, USA Nick Francis, FRCPath
Ch 2: Specialized techniques in dermatopathology with
Consultant Histopathologist
Pratistadevi K Ramdial, John Goodlad, John A. McGrath and
Imperial College Healthcare NHS trust
Alexander Lazar
Honorary Senior Lecturer
Ch 25: Melanocytic nevi with Eduardo Calonje
Imperial College Faculty of Medicine
Ch 26: Melanoma with Alexander Lazar
London, UK
Ch 12: Diseases of the anogenital skin with Eduardo
Nooshin K. Brinster, MD Calonje, Sallie Neill, Chris Bunker, Alcides Chaux, Antonio C
Assistant Professor Cubilla
Department of Pathology and Dermatology
Director of Dermatopathology
VCU Medical Center Shahar Frenkel, MD, PhD
Richmond, VA, USA Ocular Oncologist and Ophthalmic Pathologist
Ch 13: Degenerative and metabolic diseases Specialized Ocular Oncology Service
Ch 14: Cutaneous adverse reactions to drugs Ophthalmic Pathology Laboratory
Jerusalem, Israel
Chris Bunker, MA, MD, FRCP Lecturer in Ophthalmology
Department of Ophthalmology
Consultant Dermatologist
Hadassah – Hebrew University Medical Center
University College and Chelsea and Westminster Hospitals
Jerusalem, Israel
London;
Ch 27: Tumors of the conjunctiva with Jacob Pe'er
Professor of Dermatology
University College London
London, UK John Goodlad, MD, FRCPath
Ch 12: Diseases of the anogenital skin with Eduardo Calonje,
Consultant Haematopathologist and Honorary
Sallie Neill, Nick Francis, Alcides Chaux, Antonio C Cubilla
Senior Lecturer
Department of Pathology
Alcides Chaux, MD Western General Hospital and University of Edinburgh
GU Research Fellow, Edinburgh, UK
Department of Pathology Ch 2: Specialized techniques in dermatopathology with
Johns Hopkins University School of Medicine Pratistadevi K Ramdial, Boris C. Bastian, John A. McGrath and
Baltimore, MD, USA Alexander Lazar
Ch 12: Diseases of the anogenital skin with Eduardo Calonje, Ch 29 Cutaneous lymphoproliferative diseases and related
Sallie Neill, Chris Bunker, Nick Francis, and Antonio C Cubilla disorders with Eduardo Calonje
viii List of Contributors

Wayne Grayson, MBChB, PhD, FCPath(SA) Sallie Neill, MB ChB, FRCP

Consultant Anatomical Pathologist and Dermatopathologist Consultant Dermatologist
AMPATH National Laboratories; Guys and St Thomas' NHS Trust
Honorary Associate Professor London, UK
School of Pathology Ch 12: Diseases of the anogenital skin with Eduardo Calonje,
University of the Witwatersrand, Johannesburg Chris Bunker, Nick Francis, Alcides Chaux, Antonio C Cubilla
Johannesburg, South Africa
Ch 18: Infectious diseases of the skin
Ch 19: Human immunodeficiency virus (HIV) and Jacob Pe'er, MD
acquired immunodeficiency syndrome Professor and Chairman
(AIDS)-associated cutaneous diseases with Department of Ophthalmology
Pratistadevi K Ramdial Jonas Friedenwald Professor of Ophthalmic Research
Hadassah – Hebrew University Medical Center
Jerusalem, Israel
Doina Ivan, MD Ch 27: Tumors of the conjunctiva with Shahar Frenkel
Assistant Professor
Departments of Pathology and Dermatology
Section of Dermatopathology Pratistadevi K. Ramdial, MBChB, FCPath(SA)
The University of Texas M.D. Anderson Cancer Center Professor and Head
Houston, TX, USA Department of Anatomical Pathology
Ch 30: Cutaneous metastases and Paget's disease Nelson R. Mandela School of Medicine
of the skin with Alexander Lazar and Eduardo Calonje University of Kwazulu-Natal and the National Health
Laboratory Service
Durban, South Africa
Boštjan Luzar, MD, PhD Ch 2: Specialized techniques in dermatopathology with
Professor of Pathology Boris C. Bastian, John Goodlad, John A. McGrath and
Consultant Pathologist Alexander Lazar
Institute of Pathology Ch 19: Human immunodeficiency virus (HIV) and acquired
Medical Faculty University of Ljubljana immunodeficiency syndrome (AIDS)-associated cutaneous
Ljubljana, Slovenia diseases with Wayne Grayson
Ch 10: Inflammatory diseases of the subcutaneous fat with
Eduardo Calonje
Ch 17: Idiopathic connective tissue disorders with Eduardo Rodrigo Restrepo, MD
Calonje Director, Dermatopathology Fellowship Program
Universidad CES;
Professor of Dermatopathology
John A. McGrath, MD, FRCP Universidad Pontificia Bolivariana;
Professor of Molecular Pathology Director, Laboratory of Pathology
St John's Institute of Dermatology Clinica Medellin
King's College London Medellin, Colombia
Guy's Hospital Ch 22: Diseases of the hair with Eduardo Calonje
London, UK
Ch 1: The structure and function of skin
Ch 2: Specialized techniques in dermatopathology with Ursula Sass, MD
Pratistadevi K Ramdial, Boris C. Bastian, John Goodlad and Assistant Professor
Alexander Lazar Dermatology and Dermatopathology Department
CHU Saint-Pierre
Université Libre de Bruxelles
Dieter Metze, MD Brussels, Belgium
Professor of Dermatology Ch 23: Diseases of the nails with Josette André and Anne
Director, Dermatopathology Unit Theunis
Department of Dermatology
University Hospital Münster
Münster, Germany
Ch 3: Disorders of keratinization
 List of Contributors ix

Anne Theunis, MD Sook-Bin Woo, DMD, MMSc

Assistant Professor Associate Professor
Dermatopathology and Pathology Department Department of Oral Medicine, Infection and Immunity
CHU Saint-Pierre and Institut Bordet Harvard School of Dental Medicine, Boston, MA, USA;
Université Libre de Bruxelles Attending Dentist and Consultant Pathologist
Brussels, Belgium Brigham and Women's Hospital
Ch 23: Diseases of the nails with Josette André and Ursula Boston, MA, USA
Sass Co-Director
Center for Oral Pathology Strata Pathology Services Inc.
Wei-Lien Wang, MD Lexington, MA, USA
Assistant Professor Ch 11: Diseases of the oral mucosa
Department of Pathology
Sections of Dermatopathology and Sarcoma Pathology
The University of Texas M.D. Anderson Cancer Center
Houston, TX, USA
Ch 7: Lichenoid and interface dermatoses with Alexander
Lazar
Ch 21: Diseases of collagen and elastic tissue with Alexander
Lazar
 Preface to the fourth edition
It is hard to believe that sometime in 1988, when I was just starting my
training in dermatopathology, I met Phillip McKee at a course on soft tissue
tumors organized in London by an unforgettable teacher, Dr Chris Fletcher.
When Phillip heard about my interest in dermatopathology he said to me
“I am writing a textbook in dermatopathology and you must buy it”. So I
did, little suspecting that I was going to become heavily involved in the third
edition and the main editor to the fourth edition with the invaluable help
of Thomas Brenn and Alex Lazar. During the 1980s immunohistochemistry
was a relatively new diagnostic technique becoming in this age an invaluable
ancillary tool that has been instrumental in research and in diagnostic pathol-
ogy. During the same period molecular biology was being developed as a
powerful research mechanism in pathology, becoming an additional and cru-
cial aid in diagnosis in the fields of hematopathology and soft tissue tumors in
the 1990s. Furthermore, some of these developments in the latter fields have
allowed an understanding of many aspects of the pathogenesis of neoplasia,
and this has led to the ever expanding use of targeted therapy in the 21st cen-
tury. These advances have had an important impact in dermatopathology, and
more exciting developments have followed in research, diagnosis and under-
standing of the pathogenesis of neoplastic processes that are of particular
importance in the skin, particularly melanocytic neoplasms. This is ongoing
work with many questions still unanswered and although with great limita-
tions particularly in the field of diagnosis, it has nonetheless allowed immense
understanding of pathogenesis and the development of some targeted thera-
pies for melanoma some with very promising although limited results.
In this edition we have invited a number of experts to contribute in their
areas of expertise realizing that it is very difficult if not impossible for a hand-
ful of people to cover such an extensive area as dermatopathology. We have
tried to include as much material as possible encompassing most of what is
new in the literature but realize that inevitably this cannot be achieved to
complete satisfaction. The third edition of this book was received with great
enthusiasm by many people all over the world and we hope to have fulfilled
the task and answered their criticisms in this new edition.
Eduardo Calonje
The fourth edition has been a huge undertaking and taken an immense amount
of time and energy. I would first like to congratulate Eduardo Calonje for doing
a wonderful job against a background of a heavy daily workload and lecture
commitment. I decided that having left hospital practice and been in charge of
the book for three editions, that it was high time for new blood to take over
control of the new edition while I became overall editor-in-chief. I have known
Eduardo since the early 1980's during which time he has become more than just
a close friend; both Gracie and I regard him as one of the family. He is a superb
dermatopathologist (without question Europe's leading light) and I had every
confidence that he would produce a wonderful new edition of Pathology of the
Skin. Needless to say he has gone beyond my greatest expectation and produced
a truly magnificent fourth edition. Words cannot express my gratitude.
Thomas Brenn and Alex Lazar are also both very close friends and also
regarded by me as members of the family. They both took on much greater
responsibilities in the fourth edition than in the third edition and have done
a wonderful job. I am deeply indebted to them. Similar to Eduardo this was
accomplished in a background of both a heavy routine workload and research
commitment.
When planning a new edition, it has been my practice to try to make the
new edition as different as possible from the preceding one to ensure that
people who buy the book get true value for money. To this end, a number
of new chapters have been added including, specialized techniques in der-
matopathology, sentinel lymph node biopsy pathology, the pathology of
HIV/AIDS and tumors of the conjunctiva. The oral pathology chapter has
been expanded to include tumors of the salivary glands. We have taken
on a large number of very experienced excellent new authors to bring per-
sonal experience to many of the more difficult topics and this has certainly
paid dividends. Much progress has been achieved in our understanding of
the pathogenesis of disease and this is reflected in the new text with up-to-
date scientific data. I am deeply indebted to all of our new contributors.
The Fourth edition is certainly a very different book than the first edition
which I wrote for fun almost single handedly as an atlas with integrated
text.
In order to increase valuable space for the increased figures, enlarged text and
new chapters, it was decided to make the references an online only component
of the book. This has allowed us to considerably expand the text and increase
the number of figures in the book, a large proportion of which are new.
I am also heavily indebted to my two friends in the publishing world -
Louise Cook and Bill Schmitt. I have been associated with Louise for more
years than I choose to remember and she has always proven to be a pillar of
support particularly during the numerous episodes of stress that are inevi-
table in a task of this magnitude. I thank her for always being there when
help was necessary. I met Bill when I moved to the United States and he has
also become a great friend in addition to being the senior Elsevier represen-
tative overseeing the progress of the book. Similar to Louise he has had to
put up with much from me and has always steered the project with a steady
hand during all of its crises which have been innumerable. Producing the
Fourth edition would have been an even harder task without their input.
More recently I have worked with Nancy Arnott in Edinburgh. She has been
the senior editor of the project and most certainly done a wonderful job. The
editors and contributors owe her an awful lot.
Lastly and most importantly, I owe so much as always to Gracie. She has
had to put up with me for the past 4 years while working on the new edition.
This has been no mean feat. She has let my ill temper and moods of depres-
sion and anxiety wash over her and in her own thoughtful quiet way made
the seemingly impossible possible. I would never have been able to complete
this task without her loyalty, support and love.
Phillip H. McKee
 Acknowledgements
Working for so many years on a book of this proportion, especially when the
task is something that has to be done as a “hobby” after formal work hours,
represents a daunting task. I often wondered in times of despair whether the
job was ever going to be finished. It has finally been completed and I would
not have been able to achieve this without the invaluable help of many peo-
ple. They not only gave me emotional support but often went out of their
way to help me with the many details necessary to finalize the numerous
tasks that this job entailed. My wife Claudia has always given me her unwav-
ering support no matter how trying the challenge ahead. My children Mateo
and Isabella have given me their patience and understanding. Numerous col-
leagues, many of them visiting fellows from many different countries, have
made my life easy in millions of ways and I cannot thank them enough for
their patience, hard work and mainly for being wonderful human beings sup-
porting me in what for many reasons were the darkest days of my life. I espe-
cially want to show my appreciation to Drs Maiko Tanaka, Anoud Zidan,
Vicki Howard, Viky Damaskou, Thomas Brenn, Bostjan Luzar, Ravi Ratnavel,
Rathi Ramakrishnan and Gregory Spiegel (who sadly died last year).
EC
The path of life is often determined by the people we encounter. There are
many ways in which certain individuals touch our hearts, steer us in the right
direction and help us achieve goals which would have been unattainable oth-
erwise. Words aren't ever enough to really show one's true appreciation for
the generosity, support and motivation received over the years.
My wonderful, loving parents, Sonja and Walter, have always been there
for me and supported my every move. My wife and daughter, Anne and Yaëlle,
have had a terrible time dealing with my tempers throughout the writing of
this book. They have always stood by my side and saved a smile for me for
which I am ever so grateful. My professional life could have gone very wrong
indeed had it not been for the kindness and gracious support from these truly
unique mentors and teachers Uta Francke, Heinz Furthmayr, Ramzi Cotran
and Christopher Fletcher. Finally, there is so much I owe to these two won-
derful individuals who have become very close friends, Phillip McKee and
Eduardo Calonje.
TB
Academic life is a complex web of mentors, colleagues and students. I have
been lucky to have worked with a number of fine mentors and colleagues
who strongly influenced my thinking in pathology in general and/or in der-
matopathology specifically: Chris Fletcher, Scott Granter, George Murphy,
Ramzi Cotran (deceased), Chris Crum, Bill Welch, Rob Odze, Jon Aster,
Felix Brown (deceased), Jason Hornick, John Iafrate, Marcus Bosenberg,
Jonathan Fletcher, Marty Mihm, Lyn Duncan, Steve Tahan, Steve Lyle, Victor
Prieto, Harry Evans, Sharon Weiss, Bogdan Czerniak, Frasier Symmans,
Ken Aldape, Russell Broaddus, Greg Fuller, Mike Davies, Jon Reed, John
Goldblum, David Berman, Vinay Kumar, Marc Ladanyi, Matt van de Rijn,
Brian Rubin, Jesse McKenney, Steve Billings, Howard Gerber, Ron Rapini,
Julia Bridge, Paula dal Cin, Andre Oliveira, Pancras Hogendoorn, Paulo Dei
Tos, Andrew Folpe, Judith Bovee, Lola Lopez-Terrada, Cristina Antonescu,
along with numerous others I have encountered either directly or through
their writing and lecturing. This extended list testifies not only to my good
fortune in meeting so many wonderful people, but also the generosity of
academic pathologists as a group. I have many other friends in pathology
and medicine who shall have to remain nameless due to space constraints,
but this line hails that brilliant group. The other authors and editors of
this present work have been a joy to work with and I have benefited much
from these interactions. The Dermatopathology Section at my institution
has a delightful combination of great people and fascinating diagnostic
material. My former Chairman of Pathology, Janet Bruner, was enthusi-
astic and supportive of this project from our first conversation regarding
it. Another group of colleagues including Ralph Pollock, Dina Lev and the
entire Sarcoma Research Center have done more than their share to help
me balance the demands of clinical work, research, grants, papers and this
book. The talented staff at Elsevier provided invaluable support through-
out this project. Last, but certainly not least, I am indebted to my trainees.
On a daily basis, they remind me of the marvels of what we do, ask difficult
and challenging questions, prompt re-examination of assumptions, expose
biases, and force clarity and reproducibility in diagnostic criteria; may we
all retain these characteristics of motivated students throughout our career.
For all of this, I am humbled and grateful.
AL
 Dedications

To my wife Claudia who always gives without expecting anything in return.

To my children Mateo and Isabella and to the memory of my parents Julio
and Alicia both of whom passed away while this edition was in production.
EC

To Anne, Yaelle, Sanja and Walter.

TB

I am assured that my two beautiful children, Elliott and Abigail, have no

memories that predate me working on this book. I hope that this example of
what fascination with a subject, continued application to a task, and working
as a disciplined team can accomplish will be a small, but meaningful substi-
tution for the time designated to this endeavor. My wife, Victoria, has been
ever supportive in every way despite having an extremely busy and demand-
ing career in law as has been my mother-in-law Sara. My parents, Joe and
Glenda, always allowed me the freedom to pursue my own interests and the
encouragement and support to accomplish them, a wonderful gift I hope to
pass on to my children as well.
AL

This new edition is dedicated to my wife and best friend Gracie with all my
love
PHM
 Glossary

5-ARD 5-a-reductase CRASP complement regulator-acquiring surface FAMMM familial atypical multiple mole
AA alopecia areata protein melanoma [syndrome]
ACE angiotensin converting enzyme CREST calcinosis, Raynaud’s phenomenon, FAP familial adenomatous polyposis
[inhibitor] esophageal dysfunction, sclerodactyly, FAPA fever, aphthous stomatitis, pharyngitis,
AgNORS argyrophilic nucleolar organizer regions telangiectasis [syndrome] adenitis [syndrome]
AHNMD associated clonal hematological CTCL cutaneous T-cell lymphoma FHIT fragile histidine triad
non-mast cell lineage disease dcSSc diffuse cutaneous systemic sclerosis FIGURE facial idiopathic granulomata with
AIDS acquired immunodeficiency syndrome DDEB dominant dystrophic epidermolysis regressive evolution
AILD angioimmunoblastic lymphadenopathy bullosa FISH fluorescent in situ hybridization
with dysproteinemia DEB dystrophic epidermolysis bullosa GA granuloma annulare
ALA aminolevulinic acid DH dermatitis herpetiformis GABEB generalized atrophic benign
ALK anaplastic lymphoma kinase DIC disseminated intravascular coagulation epidermolysis bullosa
ALK1 activin-like receptor kinase 1 DIMF direct immunofluorescence GCDFP gross cystic disease fluid protein
ALM acral lentiginous melanoma DLE discoid lupus erythematosus G-CSF granulocyte-colony stimulating
AN acanthosis nigricans DNCB dinitrochlorobenzene factor
ANA antinuclear antibodies DSAP disseminated superficial actinic GFAP glial fibrillary acidic protein
ANCA antineutrophil cytoplasmic antibodies porokeratosis GM-CSF granulocyte–macrophage colony
API2 apoptosis inhibitor-2 Dsc desmocollin stimulating factor
ARC AIDS-related complex dsDNA double-stranded DNA GSE gluten-sensitive enteropathy
ATF1 activating transcription factor 1 Dsg desmoglein GVHD graft-versus-host disease
ATLL adult T-cell leukemia/lymphoma DSP disseminated superficial porokeratosis HA hyperandrogenism
BANS back, arm, neck and scalp [sites] EB epidermolysis bullosa HAART highly active antiretroviral therapy
BB mid borderline leprosy EBA epidermolysis bullosa acquisita HAIR-AN hyperandrogenism–insulin resistance–
BCC basal cell carcinoma EBS epidermolysis bullosa simplex acanthosis nigricans [syndrome]
BCG bacille Calmette–Guérin EBS-DM epidermolysis bullosa simplex, HBV hepatitis B virus
B-FGF basic fibroblast growth factor Dowling–Meara HDL high density lipoprotein
BIDS brittle sulfur-deficient hair, intellectual EBS-K epidermolysis bullosa simplex, Koebner HF hemorrhagic fever
impairment, decreased fertility and EBS-MD epidermolysis bullosa simplex with HG herpes gestationis
short stature muscular dystrophy HHV human herpesvirus
BL borderline lepromatous leprosy EBS-WC epidermolysis bullosa simplex, HIT heparin-induced thrombocytopenia
BLAISE Blaschko linear acquired inflammatory Weber–Cockayne [syndrome]
skin eruption EBV Epstein–Barr virus HIV human immunodeficiency virus
BMP bone morphogenetic protein ECE endothelin-converting enzyme HLA human leukocyte antigen
BP bullous pemphigoid ECM extracellular membrane HMFG human milk fat globulin
BPA bullous pemphigoid antigen EDS Ehlers–Danlos syndrome HNPCC hereditary non-polyposis colorectal
BSAP B-cell-specific activator protein EGFR endothelial growth factor receptor carcinoma [syndrome]
BSLE bullous systemic lupus erythematosus ELAM endothelial leukocyte adhesion HPF (hpf) high power fields
BT borderline tuberculoid leprosy molecule HPL hyperlipoproteinemia
C3NeF C3 nephritic factor ELISA enzyme-linked immunosorbent assay HPV human papillomavirus
CAD chronic actinic dermatitis EM electron microscopy HRF histamine-releasing factor
cAMP cyclic adenosine 3'-5'- monophosphate EMA epithelial membrane antigen HSP heat shock protein
c-ANCA cytoplasmic-antineutrophil cytoplasmic ENA extractable nuclear antigen HSV herpes simplex virus
antibodies ENL erythema nodosum leprosum HTLV human T-cell lymphotropic virus
CDC Centers for Disease Control and EPPER eosinophilic, polymorphic and hTR telomerase RNA
Prevention pruritic eruption associated with HUS hemolytic uremic syndrome
CEA carcinoembryonic antigen radiotherapy IBIDS ichthyosis and BIDS (see BIDS above)
CGRP calcitonin-gene-related polypeptide EPPK epidermolytic palmoplantar ICAM intercellular adhesion molecule
CHILD congenital hemidysplasia with keratoderma ICH indeterminate cell histiocytosis
ichthyosiform nevus and limb defects EPS extracellular polysaccharide substance IDL intermediate density lipoproteins
[syndrome] ESR erythrocyte sedimentation rate IEN intraepidermal neutrophilic [IgA
CK cytokeratin ETA exfoliative toxin A dermatosis variant]
CLA cutaneous lymphocyte antigen ETB exfoliative toxin B IFAP ichthyosis follicularis–alopecia–
CLL chronic lymphocytic leukemia EV epidermodysplasia verruciformis photophobia [syndrome]; intermediate
CMG capillary morphogenesis protein EWSR1 Ewing’s sarcoma [proto-oncogene] filament associated protein
CNS central nervous system FACE facial Afro-Caribbean childhood IFN interferon
CP cicatricial pemphigoid (mucous membrane eruption Ig immunoglobulin
pemphigoid) FADS fetal akinesia deformation sequence IIMF indirect immunofluorescence
xiv Glossary

ILVEN inflammatory linear verrucous NFII neurofibromatosis type II SALE summertime actinic lichenoid eruption
epidermal nevus NFP neurofilament protein SALT skin-associated lymphoid tissue
IMF immunofluorescence NIH National Institutes of Health SAPHO synovitis, acne, pustulosis, hyperostosis,
IP inducible protein; immunoprecipitation NISH non-isotopic in situ hybridization osteitis [syndrome]
IR insulin resistance NK natural killer SCC squamous cell carcinoma
ISSVD International Society for the Study of NL necrobiosis lipoidica SCH squamous cell hyperplasia
Vulvovaginal Disease NRAMP1 natural resistance-associated SCID severe combined immunodeficiency
JEB junctional epidermolysis bullosa macrophage protein 1 SCLE subacute cutaneous lupus
JEB-H junctional epidermolysis bullosa, NSAIDs non-steroidal anti-inflammatory drugs erythematosus
Herlitz NSE neuron-specific enolase scRNP small cytoplasmic ribonuclear protein
JEB-nH junctional epidermolysis bullosa, OL-EDA- osteopetrosis, lymphedema, SEA staphylococcal enterotoxin A
non-Herlitz ID anhidrotic ectodermal dysplasia, SEB staphylococcal enterotoxin B
JEB-PA junctional epidermolysis bullosa with immunodeficiency [syndrome] Shh Sonic Hedgehog
pyloric atresia ORF open reading frame SIBIDS osteosclerosis and IBIDS (see IBIDS
KID keratitis–ichthyosis–deafness PAIN perianal intraepithelial neoplasia above)
[syndrome] p-ANCA perinuclear-antineutrophil cytoplasmic SIL squamous intraepithelial lesion
KOH potassium hydroxide antibodies SLE systemic lupus erythematosus
KPAF keratosis pilaris atrophicans facei PAPA pyogenic sterile arthritis, pyoderma SLL small lymphocytic lymphoma
L&H cells lymphocytic and/or histiocytic gangrenosum and acne [syndrome] SMA smooth muscle actin
Reed–Sternberg cell variants PAS periodic acid–Schiff snRNP small nuclear ribonuclear protein
LAD linear IgA disease PBG porphobilinogen SPD subcorneal pustular dermatosis
LATS long-acting thyroid stimulator PCNA proliferating cell nuclear antigen SPRRs small proline rich proteins/cornifins
LCA leukocyte common antigen PCR polymerase chain reaction SPTL subcutaneous panniculitis-like T-cell
LCH Langerhans’ cell histiocytosis PDGFβ platelet-derived growth factor b lymphoma
lcSSc limited cutaneous systemic sclerosis PECAM platelet endothelial cell adhesion SRP signal recognition particle
LDL low density lipoprotein molecule ssDNA single-stranded DNA
LE lupus erythematosus PEComa perivascular epithelioid cell tumor SSSS staphylococcal scalded skin syndrome
LFA lymphocyte function-associated PGL phenolic glycolipid STD sexually transmitted disease
antigen PGP protein gene product sub-LD sub-lamina densa
LH–RH luteinizing hormone–releasing hormone PGWG purely granulomatous Wegener’s TCR T-cell receptor
LL lamina lucida; lepromatous leprosy granulomatosis TEN toxic epidermal necrolysis
LP lichen planus PI protease inhibitor TFIIH transcription/DNA repair factor IIH
LPP lichen planus pemphigoides PIBIDS photosensitivity and IBIDS (see IBIDS TGF transforming growth factor
LS lichen sclerosus above) thio- triethylene thiophosphoramide
LYVE lymphatic vessel endothelial PILA papillary intralymphatic TEPA
[hyaluronan receptor] angioendothelioma TIMP tissue inhibitor of metalloproteinase
MAC membrane attack complex PLEVA pityriasis lichenoides et varioliformis acuta TNF tumor necrosis factor
MAI M. avium intracellulare PNET primitive neuroectodermal tumor TORCH toxoplasmosis, other infections, rubella,
MALT mucosa-associated lymphoid tissue POEMS polyneuropathy, organomegaly, cytomegalovirus and herpes simplex
MART-1 melanoma antigen recognized by endocrinopathy, M-protein and skin [syndrome]
T-cells 1 changes [syndrome] TRAPS tumor necrosis factor receptor-
MBP myelin basic protein PPD purified protein derivative associated periodic syndrome
MC1R melanocortin-1 receptor PPDL pure and primitive diffuse leprosy TSST toxic shock syndrome toxin
MCGN mesangiocapillary glomerulonephritis PPK palmoplantar keratoderma TT tuberculoid leprosy
MCP molecule chemoattractant protein pRB retinoblastoma protein tTA tetracycline transactivator [transcription
M-CSF macrophage colony stimulating factor PSS progressive systemic sclerosis factor]
MCTD mixed connective tissue disease PTEN phosphatase and tensin homolog TTF-1 thyroid-transcription factor 1
MDR multidrug resistance gene PUPPP pruritic urticarial papules and plaques tTG tissue transglutaminase
Mel-CAM melanoma cell adhesion molecule of pregnancy TTP thrombotic thrombocytopenic
MEN multiple endocrine neoplasia PUVA psoralen plus ultraviolet light of purpura
[syndrome] A [long] wavelength UPS undifferentiated pleomorphic sarcoma
MFH malignant fibrous histiocytoma r IL-2 recombinant interleukin 2 URO uroporphyrinogen
MGS/ melanoma growth stimulatory RBC red blood cell URO-D uroporphyrinogen decarboxylase
GRO activity RDEB recessive dystrophic epidermolysis URR upstream regulatory region
MHC major histocompatibility complex bullosa UV ultraviolet
miH minor histocompatibility complex RDEB-HS recessive dystrophic epidermolysis UVA ultraviolet A
MITF microphthalmia transcription factor bullosa, Hallopeau–Siemens UVB ultraviolet B
MMP matrix metalloproteinase RDEB- recessive dystrophic UVL ultraviolet light
MMR mismatch repair nHS epidermolysis bullosa, non-Hallopeau– VCAM vascular cell adhesion molecule
MSA muscle-specific actin Siemens VEGF vascular endothelial growth factor
MSI microsatellite instability RER rough endoplasmic reticulum VEGFR vascular endothelial growth factor receptor
NADH nicotine adenine dinucleotide, reduced RNP ribonucleoprotein VIN vulval intraepithelial neoplasia
nDNA native [double-stranded] DNA RT-PCR reverse transcription polymerase chain VIP vasoactive intestinal peptide
NEMO nuclear factor [NF]-kappaB gene reaction VLDL very low density lipoprotein
modulator SA syphilitic alopecia VZV varicella-zoster virus
NF necrotizing fasciitis SA1 slowly adapting type-1 wrfr wrinkle free [mouse model]
NFI neurofibromatosis type I [mechanoreceptor] XP xeroderma pigmentosum
 The structure and function
See
www.expertconsult.com
for references and
additional material
of skin
Properties of skin 1 Melanocytes 10
Normal epidermal histology 1 Merkel cells 12
Regional variations in skin anatomy 2 Intercellular junctions 13
Skin development 2 Pilosebaceous units 15
Keratinocyte biology 5 Eccrine glands 17
Epidermal stem cells 6 Apocrine glands 19
Skin barrier 8 Dermal–epidermal junction 21
Skin immunity 9 Dermal collagen 22
Skin is a double-layered membrane covering the exterior of the body and
consists of a stratified cellular epidermis and an underlying dermis of con-
nective tissue. In adults, the skin weighs over 5 kg and covers a surface area
approaching 2 m2. The epidermis is mainly composed of keratinocytes and is
typically 0.05–0.1 mm in thickness. The dermis contains collagen, elastic tis-
sue and ground substance and is of variable thickness, from 0.5 mm on the
eyelid or scrotum to more than 5 mm on the back (Fig. 1.1).
The dermis is subdivided into a more superficial component (the papillary
dermis) which is bounded inferiorly by the superficial vascular plexus and an
underlying much thicker reticular dermis. Below the dermis is a layer of sub-
cutaneous fat which is separated from the rest of the body by a vestigial layer
of striated muscle.
Properties of skin
A key role of skin is to provide a mechanical barrier against the external
environment. The cornified cell envelope and the stratum corneum restrict
water loss from the skin while keratinocyte-derived endogenous antibiot-
ics (defensins and cathelicidins) provide an innate immune defense against
bacteria, viruses and fungi. The epidermis also contains a network of about
2 × 109 Langerhans cells which serve as sentinel cells whose prime function
is to survey the epidermal environment and to initiate immune responses
against microbial threats. Melanin, which is mostly found in basal keratino-
cytes, provides some protection against DNA damage from ultraviolet radia-
tion. An important function of skin is thermoregulation. Vasodilatation or
­vasoconstriction of the blood vessels in the deep or superficial plexuses helps
regulate heat loss. Eccrine sweat glands are found at all skin sites and are
present in densities of 100–600/cm2; they play a role in heat control and
aspects of metabolism. Secretions from apocrine sweat glands contribute to
body odor. Skin lubrication and waterproofing is provided by sebum secreted
from sebaceous glands. Subcutaneous fat has important roles in cushioning
trauma as well as providing insulation and a calorie reserve. Fat also has an
endocrine function and contributes to tissue remodeling and phagocytosis.
Nails provide protection to the ends of the fingers and toes as well as being
important in pinching and prising objects. Hair may have important social
and psychological value. Skin also has a key function in synthesizing various
metabolic products, such as vitamin D.
Chapter
John A. McGrath
1
Dermal elastic tissue 24
Ground substance 26
Fibroblast biology 26
Cutaneous blood vessels and
lymphatics 27
Nervous system of the skin 28
Subcutaneous fat 30
Normal epidermal histology
Although the basic structure is relatively constant at various skin sites, there
are often clear differences which enable one to determine the site of origin.
The epidermis consists of four clearly defined layers or strata:
• Basal cell layer (stratum basale)
• Prickle cell layer (stratum spinosum)
• Granular cell layer (stratum granulosum)
• Keratin layer (stratum corneum)
An eosinophilic acellular layer known as the stratum lucidum is sometimes
seen in skin from the palms and soles (Fig. 1.2).
Basal cells are cuboidal or columnar with a large nucleus typically con-
taining a conspicuous nucleolus. Small numbers of mitoses may be evident.
Clear cells are also present in the basal layer of the epidermis; these repre-
sent melanocytes. Cells with clear cytoplasm seen in the stratum spinosum
represent Langerhans cells. Very occasional Merkel cells may also be present
but these are not easily identified in hematoxylin and eosin stained sections.
Histologically, prickle cells are polygonal in outline, have abundant eosino-
philic cytoplasm and oval vesicular nuclei, often with conspicuous nucleoli.
Keratohyalin granules typify the granular cell layer (Fig. 1.3). Further matu-
ration leads to loss of nuclei and flattening of the keratinocytes to form the
plates of the keratin layer (stratum corneum). Adjacent cells are united at
their free borders by intercellular bridges (prickles), which are most clearly
identifiable in the prickle cell layer and in disease states of the skin where
there is marked intercellular edema (spongiosis) (Fig. 1.4).
Toker cells represent an additional clear cell population, which may be
found in nipple epidermis of both sexes in up to 10% of the population.1 The
cells are large, polygonal or oval and have abundant pale staining or clear
cytoplasm with vesicular nuclei often containing prominent, albeit small,
nucleoli. The cytoplasm is mucicarmine and PAS negative.1 The cells may be
distributed singly but more often they are found as small clusters, not uncom-
monly forming single layered ductules.1 They are located along the basal layer
of the epidermis or suprabasally and are also sometimes seen within the epi-
thelium of the terminal lactiferous duct.
Toker cells are of particular importance as they may be mistaken by the
unwary as Paget cells. They are thought to be the source of mammary Paget's
disease in those exceptional cases where an underlying ductal carcinoma is
2 The structure and function of skin

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Skin from forearm: there is a fairly thin epidermis. Compare the thickness of the Fig. 1.4
dermis with that from the back (see Fig. 1.5). Spongiosis: the
intercellular bridges
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absent.2 Toker cells express CK7, AE1, CAM 5.2, epithelial membrane anti-
gen (EMA), cerbB2, estrogen and progesterone receptors.3,4 They do not
express p53 or CD138. Carcinoembryonic antigen (CEA) may also be present
albeit weakly.4 Paget's cells by way of contrast are often negative for estrogen
and progesterone receptors and are p53 and CD138 positive.4

rm Regional variations in skin anatomy

rtw®Fig. 1.2
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Skin from palm: note the eosinophilic stratum lucidum clearly separating the
>W
j There are two main kinds of human skin: glabrous skin (nonhairy skin)
and hair-bearing skin. Glabrous skin is found on the palms and soles. It
has a grooved surface with alternating ridges and sulci giving rise to the
dermatoglyphics (fingerprints). Glabrous skin has a compact, thick stratum
­corneum, and contains encapsulated sense organs within the dermis but no
hair follicles or sebaceous glands. In contrast, hair-bearing skin has both
hair follicles and sebaceous glands but lacks encapsulated sense organs.
granular cell layer from the overlying stratum corneum. Hair follicle size, structure and density can vary between different body
sites. For example, the scalp has large hair follicles that may extend into
subcutaneous fat whereas the forehead has only small vellus hair-producing
follicles although sebaceous glands are large. The number of hair follicles
does not alter until middle life but there is a changing balance between vel-
lus and terminal hairs throughout life. In hair-bearing sites, such as the
axilla, there are apocrine glands in addition to the eccrine sweat glands.
Sg®T "r : Sebaceous glands are active in the newborn, and from puberty onwards,
and the relative activity modifies the composition of the skin surface lipids.
: The structure of the dermal–epidermal junction also shows regional vari-
ations in the number of hemidesmosomal-anchoring filament complexes
(more in the leg than the arm). In the dermis, the arrangement and size
of elastic fibers ­varies from very large fibers in perianal skin to almost no
fibers in the scrotum. Marked variation in the cutaneous blood supply is
found between areas of distensible skin such as the eyelid and more rigid
areas such as the fingertips.
Regional variation in skin structure is illustrated in Figures 1.5–1.20.

Skin development
Two major embryological elements juxtapose to form skin. These comprise
Fig. 1.3 the prospective epidermis that originates from a surface area of the early
Skin from palm: there is a conspicuous granular cell layer. ­gastrula, and the prospective mesoderm that comes into contact with the
 Skin development 3

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Skin of the nose: there are conspicuous sebaceous glands: at this site, they often
drain directly onto the skin surface. These appearances should not be confused
with that of sebaceous hyperplasia.
inner surface of the epidermis during gastrulation. The mesoderm generates
the dermis and is involved in the differentiation of epidermal structures such
as hair follicles.1 Melanocytes are derived from the neural crest. After gastru-
lation, there is a single layer of neuroectoderm on the embryo surface: this
layer will go on to form the nervous system or the skin epithelium, depend-
ing on the molecular signals (e.g., fibroblast growth factors or bone mor-
phogenic proteins) it receives.2 The embryonic epidermis consists of a single
layer of multipotent epithelial cells which is covered by a special layer known
as periderm that is unique to mammals. Periderm provides some protection
to the newly forming skin as well as exchange of material with the amniotic
fluid. The embryonic dermis is at first very cellular and at 6–14 weeks three
types of cell are present: stellate cells, phagocytic macrophages and granule-
­secretory cells, either melanoblasts or mast cells (Fig. 1.21). From weeks
Skin from the scalp: there are numerous terminal hair follicles with many of the
bulbs in the subcutaneous fat.
14 to 21, fibroblasts are numerous and active, and perineural cells, pericytes,
melanoblasts, Merkel cells and mast cells can be individually identified. Hair
follicles and nails are evident at 9 weeks. Sweat glands are also noted at 9
weeks on the palms and the soles.3 Sweat glands at other sites and sebaceous
glands appear at 15 weeks. Touch pads become recognizable on the fingers
and toes by the sixth week and development is maximal by the 15th week.
The earliest development of hair occurs at about 9 weeks in the regions of the
eyebrow, upper lip and chin. Sebaceous glands first appear as hemispherical
protuberances on the posterior surfaces of the hair pegs and become differ-
entiated at 13–15 weeks. Langerhans cells are derived from the monocyte–
macrophage–histiocyte lineage and enter the epidermis at about 12 weeks.
Merkel cells appear in the glabrous skin of the fingertips, lip, gingiva and
nail bed, and in several other regions, around 16 weeks. Although some cells
of the dermis may migrate from the dermatome (venterolateral part of the
somite) and take part in the formation of the skin, most of the dermis is
formed by ­mesenchymal cells that migrate from other mesodermal areas.4
These ­mesenchymal cells give rise to the whole range of blood and ­connective
4 The structure and function of skin

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Skin from axilla: apocrine glands as seen at the Skin from the outer aspect of the lip: note the Mucosal aspect of lip: at this site the squamous
bottom of the field are typical for this site. keratinizing stratified squamous epithelium and epithelium does not normally keratinize. Minor salivary
skeletal muscle fibers. glands as shown in this field are not uncommonly present.

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 Keratinocyte biology 5

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Fig. 1.15 Fig. 1.16
Skin from the ear: note the vellus hairs, and a fairly (A, B) Vulval vestibule: at this site the stratum corneum is absent and there is no granular cell layer. The
thin dermis overlying the auricular cartilage. suprabasal keratinocytes have clear cytoplasm due to abundant glycogen and revealed by the periodic ­
acid-Schiff reaction.

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Variation of skin: sample of skin from the forearm of a 92-year-old female. Note the Stasis change: skin from the lower leg. Although abnormal, the presence of
epidermal thinning and dermal atrophy. stasis change characterized in this example by papillary dermal lobular capillary
proliferation is a very common feature at this site.

tissue cells, including the fibroblasts and mast cells of the dermis and the fat
cells of the subcutis. In the second month, the dermis and subcutis are not
discernible as distinct skin layers but collagen fibers are evident in the dermis
by the end of the third month. Later, the papillary and reticular layers become
established and, at the fifth month, the connective tissue sheaths are formed
around the hair follicles. Elastic fibers are first detectable at 22 weeks.
Keratinocyte biology
The cytoskeleton of all mammalian cells, including epidermal keratinocytes,
comprises actin containing microfilaments ≈7 nm in diameter, tubulin contain-
ing microtubules 20–25 nm in diameter, and filaments of intermediate size,
7–10 nm in diameter, known as intermediate filaments. There are six types
of intermediate filaments of which keratins are the filaments in keratinocytes
(Figs 1.22, 1.23). The human genome possesses 54 functional keratin genes
located in two compact gene clusters, as well as many nonfunctional pseudo-
genes, scattered around the genome.1 Keratin genes are very specific in their
expression patterns. Each one of the many highly specialized epithelial tissues
has its own profile of keratins. Hair and nails express modified keratins con-
taining large amounts of cysteine which forms numerous chemical cross-links
to further strengthen the cytoskeleton. The genes encoding the keratins fall
into two gene families: type I (basic) and type II (acidic) and there is coex-
pression of particular acidic–basic pairs in a cell- and tissue-­specific manner.
Keratin heterodimers are assembled into protofibrils and ­protofilaments by
6 The structure and function of skin

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Variation of normal skin: in dark-skinned races, the presence of intense basal cell
melanin pigmentation is a normal histological finding.
Fig. 1.22
Cytoskeleton of a keratinocyte: the major intermediate filament of a keratinocyte is
keratin, highlighted in green.
an antiparallel stagger of some complexity. Simple epithelia are characterized
by the keratin pair K8/K18, and the stratified squamous epithelia by K5/K14.
Suprabasally, keratins K1/K10 are characteristic of epidermal differentiation
genetic disorder of keratin to be described was epidermolysis bullosa sim-
(Fig. 1.24). K15 is expressed in some interfollicular basal keratinocytes as
plex, which involves mutations in the genes encoding K5 or K14 (Fig. 1.25).
well as keratinocytes within the hair-follicle bulge region at the site of pluri-
About half of the keratin genes are expressed in the hair follicle, and muta-
potential stem cells. K9 and K2e expression is site restricted in skin: K9 to
tions in these genes may underlie cases of monilethrix as well as hair and nail
palmoplantar epidermis and K2e to superficial interfollicular epidermis.
ectodermal dysplasias.5
Apart from their structural properties, keratins may also have direct roles
in cell signaling, the stress response and apoptosis.2 In epidermal hyperprolif-
eration, as in wound healing and psoriasis, expression of suprabasal keratins Epidermal stem cells
K6/K16/K17 is rapidly induced.
Currently, 21 of the 54 known keratin genes have been linked to ­monogenic To maintain, repair and regenerate itself, the skin contains stem cells which
genetic disorders, and some have been implicated in more complex traits, reside in the bulge area of hair follicles, the basal layer of interfollicular epi-
such as idiopathic liver disease or inflammatory bowel disease.3,4 The first dermis and the base of sebaceous glands (Fig. 1.26).1 Stem cells are able to
 Epidermal stem cells 7

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* Clinicopathological consequences of mutations in the keratin 14 gene: (left) typical
Fig. 1.23 appearances of Dowling-Meara epidermolysis bullosa simplex which results from
Mid-prickle cell layer of normal epidermis: the abundant keratin filaments heterozygous missense mutations in the KRT14 gene; (right) ultrastructurally, there
(tonofibrils) form a distinct interlacing lattice within the cytoplasm of keratinocytes. is keratin filament disruption and clumping as well as a plane of blistering just above
the dermal–epidermal (DE) junction.

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Fig. 1.24
Normal skin: suprabasal keratinocytes preferentially express keratins 1 and 10 as
Outer root sheath
shown in this picture. Anti-Keratin1 antibody courtesy of I.M. Leigh, MD, Royal
London Hospital Trust, London, UK.

Inner root sheath

self-renew as well as give rise to differentiating cells.2 It is not clear, however,
whether every basal keratinocyte or only a proportion of cells is a stem cell.3
Two possible hypotheses have emerged. One theory divides basal keratino-
cytes into epidermal proliferation units, which comprise one self-renewing
stem cell and about 10 tightly packed transient amplifying cells, each of which
is capable of dividing several times and then exiting the basal layer to undergo
terminal differentiation.4 This unit gives rise to a column of larger and flat-
ter cells that culminates in a single hexagonal surface. The process of divi-
sion of basal cells in this model is viewed as a symmetrical process in which
equal daughter cells are generated with the basal cells progressively reducing
their adhesiveness to the underlying epidermal basement membrane, delami-
nating and committing to terminal differentiation. The alternative theory is
that some basal cells (perhaps up to 70% of cells) can undergo asymmetrical
cell division, shifting their spindle orientation from lateral to perpendicular.5
Asymmetrical cell divisions provide a means of maintaining one proliferative
daughter while the other daughter cell is committed to terminal differentia-
tion. Asymmetrical cell divisions, therefore, can bypass the need for transient
amplifying cells.
Dermal papilla
Fig. 1.26
Diagrammatic representation of the location of stem cells in human skin: stem cells
are located within the bulge area of hair follicles (where the arrector pili muscle
attaches) as well as in the basal keratinocyte layer in the interfollicular epidermis
and at the base of sebaceous glands. Stem cells from the bulge area are capable of
regenerating all parts of the pilosebaceous unit and interfollicular skin.
Hair follicle stem cells are found in the bulge regions below the sebaceous
glands. These stem cells are slow cycling and express the cell surface mol-
ecules CD34 and VdR as well as the transcription factors TCF3, Sox9, Lhx2
and NFATc1 (Fig. 1.27). The bulge area stem cells generate cells of the outer
root sheath, which drive the highly proliferative matrix cells next to the mes-
enchymal papillae. After proliferating, matrix cells differentiate to form the
hair channel, the inner root sheath and the hair shaft. Hair follicle stem cells
8 The structure and function of skin

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can also differentiate into sebocytes and interfollicular epidermis. Despite this
multipotency, however, the follicle stem cells only function in pilosebaceous
unit homeostasis and do not contribute to interfollicular epidermis unless the
skin is wounded.6
Stem cells are also found in the base of sebaceous glands: the progeny of
these cells differentiate into lipid-filled sebocytes. Apart from stem cells in
the hair follicles, sebaceous glands and interfollicular epidermis, other cells
in the dermis and subcutis may have stem cells properties. These include cells
that have been termed skin-derived precursors (SKPs), which can differentiate
into both neural and mesodermal progeny.7 In addition, a subset of dermal
fibroblasts can have adipogenic, osteogenic, chondrogenic, neurogenic and
hepatogenic differentiation potential.8
Skin barrier
A major function of the epidermis is to form a barrier against the external
environment. To achieve this, terminal differentiation of keratinocytes results
in formation of the cornified cell envelope. This physical barrier is rendered
highly insoluble by the formation of glutamyl-lysyl isodipeptide bonds between
envelope proteins, catalyzed by transglutaminases.1 Several different proteins
contribute to construction of the cornified cell envelope, including involucrin,
and the family of small proline-rich proteins (SPR1) including cornifin or
SPR1 and pancornulins. Other envelope proteins include SKALP/elafin and
keratolinin/cystatin. Some precursors of the cornified envelope are delivered
by granules: small, smooth, sulfur-rich L granules contain the cysteine-rich
protein loricrin, and accumulate in the stratum granulosum.2 Loricrin is the
major component of the cornified envelope. Profilaggrin in F granules may
make a minor contribution to the envelope. Membrane-associated proteins
yi
-•
Fig. 1.28
Granular cell layer: note the keratohyalin and membrane coating granules (arrowed).
the cell membrane. They fuse with the plasma membrane, dispersing their
contents into the intercellular space. Polar lipids from the lamellar granules
are remodeled into neutral lipids in the intercellular space between corneo-
cytes, thereby contributing to the barrier.
Within the granular layer of the epidermis, the main keratinocyte pro-
teins are keratin and filaggrin, which together contribute approximately
80–90% of the mass of the epidermis and are ultrastructurally represented
by the keratohyalin granules (Fig. 1.29). Filaggrin is initially synthesized as
profilaggrin, a ≈500-kDa highly phosphorylated, histidine-rich polypeptide.
During the post-translational processing of profilaggrin, the individual filag-
grin polypeptides, each ≈35 kD, are proteolytically released. These are then
dephosphorylated, a process that assists keratin filament aggregation and
explains the origin of the name ‘filaggrin’ (filament aggregating ­protein) (Fig.
1.30). Typically, there are 10 highly homologous filaggrin units, although the
number of filaggrin repeat units is variable and genetically determined, with
,, H

that contribute to the cornified envelope include the plakin family members,
periplakin, envoplakin, epiplakin, desmoplakin as well as plectin. Formation »

of the cornified cell envelope is triggered by a rise in intracellular calcium

levels.3 This leads to cross-link formation between plakins and involucrin
catalyzed by transglutaminases. Other desmosomal proteins are then also ft/
cross-linked, forming a scaffold along the entire inner surface of the plasma * *•*> 4 Lti
<>
membrane. Ceramides from the secreted contents of lamellar bodies are then if
esterified onto glutamine residues of the scaffold proteins. The cornified cell r». r«
envelope is reinforced by the addition of a variable amount of SPRs, repe- «

tin, trichohyalin, cystostatin α, elafin and LEP/XP-5 (skin-specific protein). /ÿ

Although most desmosomal components are degraded, keratin intermediate .V1
filaments (mostly K1, K10 and K2e) may be cross-linked to desmoplakin and
»,
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envoplakin remnants.
In the upper stratum spinosum and stratum granulosum lipid is synthe- •v
sized and packaged into lamellated membrane-bound organelles known as AJS «.
membrane-coating granules, lamellar granules or Odland bodies (Fig. 1.28).4 <; r<+
O *ÿ
it • 4/

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They are found adjacent to the cell membrane with alternating thick and 1* i•
Fig. 1.29
thin dense lines separated by lighter lamellae of equal width, consistent with
packing of flattened discs within a membrane boundary. These granules con-
tain phospholipids, glycolipids and free sterols and move towards the plasma
membrane as the cells move through the granular layer where they cluster at
mmg0H•t Stratum corneum:
keratohyalin granules are
present just beneath the
keratin lamellae.
 Skin immunity 9

Epidermal barrier: Keratohyalin granules composed of profilaggrin Micro-organisms

mechanical strength;
prevent water loss;
restrict allergen penetration oft
o
External allergens
Stratum corneum
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Stratum Filaggrin deaminated Fig. 1.32
corneum and degraded o Innate immunity in the
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Inflammatory cells
skin: the physical barrier is
complemented by an innate
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targets bacteria, viruses
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Constitutive anti-microbial peptides (psoriasin) skin. These peptides
include constitutive and
Inducible anti-microbial peptides

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(β-defensins, RNASE7, LL-37) inducible substances
against a broad range of
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Dermal-
epidermal
junction Profilaggrin cleaved into Keratinocyte Langerhans cell
10-12 filaggrin peptides Melanocyte
Fig. 1.30
Function of filaggrin in human skin: this is the major component of keratohyalin
granules. In the granular layer profilaggrin is cleaved into filaggrin peptides
subsequent deamination and degradation provides the skin with mechanical
strength and restricts transepidermal water loss. Filaggrin also prevents allergen
penetration. In the absence of filaggrin, for example caused by common mutations
in the filaggrin gene, external allergens may penetrate the epidermis and encounter
Langerhans cells. This may lead to the development of atopic dermatitis as well as
other atopic manifestations and systemic allergies.
duplications of filaggrin repeat units 8 and/or 10 in some individuals. Fewer
filaggrin repeats leads to dryer skin. Loss-of-function mutations in filaggrin
are very common, occurring in up to 10% of the European population. These
mutations lead to reduced or absent keratohyalin granules, and are the cause
of ichthyosis vulgaris as well as constituting a major risk factor for atopic
dermatitis (Fig. 1.31).5
Skin immunity
Skin possesses both innate and adaptive immune responses to defend against
microbial pathogens and thereby prevent infection. One of the primary mech-
anisms is the synthesis, expression and release of antimicrobial peptides (Fig.
1.32).1 There are more than 20 antimicrobial peptides in the skin, includ-
ing cathelicidins, β-defensins, substance P, RANTES, RNase 2, 3, and 7, and
S100A7. Many of these peptides have antimicrobial action against bacteria,
viruses, and fungi. In the stratum corneum there is an effective chemical bar-
rier maintained by the expression of S100A7 (psoriasin).2 This antimicro-
bial substance is very effective at killing Escherichia coli. Subjacent to this
in the skin there is another class of antimicrobial peptides, such as RNASE7,
which is effective against a broad spectrum of microorganisms, especially
enterococci.3 Below this in the living layers of the skin are other antimicro-
bial peptides including the β-defensins.4 The antimicrobial activity of most
peptides occurs as a result of unique structural characteristics that enable
them to disrupt the microbial cell membrane while leaving human cell mem-
branes intact. The antimicrobial peptides can have immunostimulatory and
immunomodulatory capacities as well as being chemotactic for distinct sub-
populations of leukocytes and other inflammatory cells.5 Some peptides have
additional roles in signaling host responses through chemotactic, angiogenic,
growth factor and immunosuppressive activity. These peptides are known as
alarmins.6 Alarmins may also stimulate parts of the host defense system, such
as barrier repair and recruitment of inflammatory cells.
Skin immunity is also provided by a distinct population of antigen present-
ing cells in the epidermis known as Langerhans cells (Fig. 1.33). These are
­dendritic cells that were first described by Langerhans, who demonstrated their
existence in human epidermis by staining with gold chloride. Without stimula-
tion, Langerhans cells exhibit a unique motion termed ‘Dendrite Surveillance
Extension And Retraction Cycling Habitude (dSEARCH)’.7 This is charac-
terized by rhythmic extension and retraction of dendritic processes between
intercellular spaces. When exposed to antigen, there is greater dSEARCH
motion and also direct cell-to-cell contact between adjacent Langerhans
cells which function as intraepidermal macrophages, phagocytosing antigens
among keratinocytes. Langerhans cells then leave the epidermis and migrate
via lymphatics to regional lymph nodes. In the paracortical region of lymph
nodes the Langerhans cell expresses protein on its surface to present to a T
lymphocyte that can then undergo clonal proliferation. Langerhans cells, in
combination with macrophages and dermal dendrocytes, represent the skin's
mononuclear phagocyte system.8 By electron microscopy, Langerhans cells
have a lobulated nucleus, a relatively clear cytoplasm and well-developed
endoplasmic reticulum, Golgi complex and lysosomes. They also possess
characteristic granules which are rod or racquet-shaped (Fig. 1.34). These
‘Birbeck’ granules represent subdomains of the endosomal recycling compart-
ment and form at sites where the protein Langerin accumulates.
Besides antigen detection and the processing role by epidermal Langerhans
cells, cutaneous immune surveillance is also carried out in the dermis by an
array of macrophages, T cells and dendritic cells. These immune sentinel and
effector cells can provide rapid and efficient immunologic back-up to restore
tissue homeostasis if the epidermis is breached. The dermis contains a very

May cause Are the cause of Are a major risk factor Are associated with atopic
hyperlinearity of the palms ichthyosis vulgaris for atopic dermatitis dermatitis persisting into adulthood

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10% of the people in some populations.
10 The structure and function of skin

large number of resident T cells. Indeed, there are approximately 2 × 1010

resident T cells, which is twice the number of T cells in the circulating blood.
:\ Dermal dendritic cells may also have potent antigen-presenting capacities

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mode, a migratory mode or a tissue resident phagocytic mode.9

Melanocytes
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choroid and iris of the eye. In skin, melanocytes are located in the basal keratino-
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cyte layer. The ratio of melanocytes to basal cells ranges from approximately 1:4
on the cheek to 1:10 on the limbs. They appear as vacuolated cells in hematoxylin
and eosin stained sections (Fig. 1.35). Ultrastructurally, melanocytes have pale
; : •>. •
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Fig. 1.33 anocytes is the production of melanin, a ­pigment that varies in color from yel-
Langerhans cells express S-100 protein: note the conspicuous dendritic processes. low to brown or black and accounts for the various skin colors within and

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 Melanocytes 11

'V* Melanin is transferred from melanocytes in melanosomes to neighboring

keratinocytes in the epidermis and into the growing shaft in hair follicles and
_r '..v
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can be identified by silver techniques such as the Masson-Fontana reaction
ry
(Fig. 1.38). Transport occurs along the dendritic processes of the melanocytes
1§3 rrs,
and the melanosomes are engulfed as membrane-bound (lysosomal) single
7 or compound melanosomes by a group of adjacent largely basally located
i -;
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;4Pl Si WJS umbrella-like distribution over the outer aspect of the nucleus (Fig. 1.39).

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phages), melanoma cells and, occasionally, Langerhans cells, the other type of
"VC- Sara epidermal dendritic cell. Macromelanosomes (giant melanosomes) measure
several microns in diameter and therefore are readily visible in hematoxylin
S3 -
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skin, in lentigines, dysplastic nevi, Spitz nevi, in the café-au-lait macules of
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neurofibromatosis and in albinism. A key protein involved in melanosome
9
assembly is NCKX5, encoded by the gene SLC24A5.4 Loss of expression of
Fig. 1.36 this gene in mice results in marked changes in skin color with loss of pigment.
Normal melanocyte: it has abundant pale cytoplasm and scattered solitary
melanosomes. Note the absence of tonofibrils and desmosomes.

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Normal epidermis: this section of black skin has been stained by the Masson–
Fontana reaction for melanin. Note the heavy pigmentation, which is present in
Fig. 1.37 both melanocytes and keratinocytes.
Melanosome: note the typical striated internal structure.

c,
among races. Melanin protects the mitotically active basal epidermal cells from
the injurious effects of ultraviolet light, which accounts for individuals with —
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less pigmentation (fair-haired and light-skinned) having a much greater risk of
sunburn and developing cutaneous malignancies (squamous cell and basal cell
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carcinomas, and melanoma). The mechanism involves absorbing or scatter- V* ®

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ing ultraviolet radiation and/or its photoproducts. Other functions of melanin l > -i ® i A'
include control of vitamin D3 synthesis and local thermoregulation. , .©5? # ' W
In skin and hair, two forms of melanin pigment are produced; eumelanin
and pheomelanin. Eumelanin is a brown or black pigment and is synthe-
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cysteine; it predominates in Caucasian skin.
Melanocytes also possess melanocyte-specific receptors including melano- •* * > *
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cortin-1 (MC1R) and melatonin receptors.1 The activation or the inhibition V\

of melanocyte-specific receptors can augment normal melanocyte function,
skin color, and photoprotection. Moreover, receptor polymorphisms are > -e-
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known to underlie red hair phenotypes.2 Hair graying reflects abnormalities
in melanocyte signaling. Notably, Notch transcription factor signaling in mel- Fig. 1.39
anocytes is essential for the maintenance of proper hair pigmentation, includ- Melanin pigment: actinically damaged skin. Note that the melanin pigment is
ing ­regeneration of the melanocyte population during hair follicle cycling.3 located in a ‘cap’ overlying the keratinocyte nuclei.
12 The structure and function of skin

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(troma-1 antibody). By courtesy of J.P. Lacour, MD, and J.P. Ortonne, MD, University
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Mature melanosomes of eumelanin are ellipsoidal in shape, while pheomela-

nin-producing melanosomes are spherical.
Merkel cells
Merkel cells are postmitotic cells scattered throughout the epidermis of ver-
tebrates and constitute 0.2–0.5% of epidermal cells.1 Merkel cells represent
part of the affector limb in cutaneous slowly adapting type-1 (SA1) mechano-
receptors and are therefore particularly concerned with touch sensation. They
are located amongst basal keratinocytes and are mainly found in hairy skin,
tactile areas of glabrous skin, taste buds, the anal canal, labial ­epithelium
and eccrine sweat glands. In glabrous skin, the density of Merkel cells is ≈50
per mm2. Sun-exposed skin may contain twice as many Merkel cells as non-
sun-exposed skin.2 Numerous Merkel cells can be found in actinic keratoses.3
Merkel cells cannot be recognized in conventional hematoxylin and eosin
stained sections. Rather, immunocytochemistry, particularly using antikeratin
antibodies, or electron microscopy, is necessary for their identification (Figs
1.41 and 1.42).
Ultrastructurally, Merkel cells appear oval with a long axis of ≈15 μm ori-
entated parallel to the basement membrane (Fig. 1.43). They also have a large
bilobed nucleus and clear cytoplasm which reflects a relative scarcity of intra-
cellular organelles. Merkel cells contain numerous neurosecretory granules,
each 50 nm to 160 nm across; these are found opposing the junctions with
the sensory nerve ending (Fig. 1.44). Merkel cells contain keratin filaments,
particularly keratin filament types 8, 18, 19, and 20, which are characteris-
tic of simple epithelium and fetal epidermis. Immunocytochemically, Merkel
cells also express neuropeptides including synaptophysin, vasoactive intes-
tinal peptide (VIP) and calcitonin gene-related polypeptide (CGRP).4,5 They
contain neuron-specific proteins including neuron-specific enolase (NSE) and
protein gene product (PGP) 9.5.6 In addition, Merkel cells express desmo-
somal proteins, membranous neural cell adhesion molecule and nerve growth
factor receptor.7–9 Merkel cells show a positive uranaffin reaction.10 Merkel
cells form close connections with sensory nerve endings and secrete or express
a number of these peptides.11 The close contact between Merkel cells and
nerve fibers represents a Merkel cell–neurite complex, but there is no clear
evidence of synaptic transmission, although numerous vesicles can be identi-
fied in neurons apposed to Merkel cells.12
V
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Fig. 1.42
Merkel cell: positive labeling for CAM 5.2 identifies Merkel cells in this obliquely
sectioned epidermal ridge.
Human skin contains an extensive neural network that contains cholin-
ergic and adrenergic nerves and myelinated and unmyelinated sensory fibers.
Moreover, the skin also contains several transducers involved in the percep-
tion of touch, pressure, and vibration, including Ruffini organs surrounding
hair follicles, Meissner's corpuscles, Vater–Pacini corpuscles located in the
deep layer of the dermis, and nerve endings which pass through the epider-
mal basement membrane. Some of these contain Merkel cells which form the
Merkel cell–neurite complex, while others are free nerve endings. The cell
bodies for all these neurons reside in the dorsal root ganglion. The Merkel
cell–neurite complexes are thought to serve as mechanoreceptors and to be
responsible for the sensation of touch. They are clustered near unmyelinated
sensory nerve endings, where they group and form ‘touch spots’ at the bottom
of rete ridges. These complexes are also known as hair discs, touch domes,
touch corpuscles, or Iggo discs. The complex is innervated by a single, slowly
adapting type 1 nerve fiber. In hairy skin, Merkel cells also cluster in the
rete ridges and in the outer root sheath of the hair follicle where the arrector
pili muscles attach. The function of Merkel cells in hair follicles is unclear,
although they may be involved in the induction of new anagen cycles.
There are two hypotheses for the origin of Merkel cells: one possibility is
that they differentiate from epidermal keratinocyte-like cells and the other
 Intercellular junctions 13

Intercellular junctions
Desmosomes are the major intercellular adhesion complexes in the epider-
mis. They anchor keratin intermediate filaments to the cell membrane and
link adjacent keratinocytes (Fig. 1.45). Desmosomes are found in the epider-
at1** mis, myocardium, meninges and cortex of lymph nodes. Ultrastructurally,
desmosomes contain plaques of electron-dense material running along
:-r
-
n the cytoplasm parallel to the junctional region, in which three bands can
be distinguished: an electron-dense band next to the plasma membrane, a
-•;
V less dense band, and then a fibrillar area (Fig. 1.46).1 Identical components
• \
§5 are present on opposing cells which are separated by an intercellular space
ft & of 30 nm within which there is an electron-dense midline. There are three
main protein components of desmosomes in the epidermis: the desmosomal

mm
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cadherins, the armadillo family of nuclear and junctional proteins, and the
plakins (Fig. 1.47).2 The transmembranous cadherins comprise mostly het-
erophilic ­associations of desmogleins and desmocollins. There are four main
Kjgajÿ fcl
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These show differentiation-specific expression. For example, Dsg1 and Dsc1
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Fig. 1.44 S&.
M£Zu :*' .
Merkel cell granules: they are membrane bound and measure approximately '•••
150 nm in diameter. By courtesy of A.S. Breathnach, MD (1977) Electron
microscopy of cutaneous nerves and receptors. Journal of Investigative
Dermatology 69, 8–26. Blackwell Publishing Inc., USA. agy*—«i .. Si-

is that they arise from stem cells of neural crest origin that migrated during
£
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embryogenesis, in similar fashion to melanocytes.13 Merkel cell hyperplasia is 'iCJ •1V
a common histological finding and may accompany keratinocyte hyperpro-
liferation as well as being frequently seen in adnexal tumors such as nevus &
sebaceus, trichoblastomas, trichoepitheliomas, and nodular hidradenomas.14
*•
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Merkel cell hyperplasia is associated with hyperplasia of nerve endings that
occurs in neurofibromas, neurilemomas, nodular prurigo, or neurodermati-
tis. It is not clear whether Merkel cell carcinoma originates from Merkel cells
JP
Fig. 1.46
or their precursors but the latter may be more likely given that many dermal Mid-prickle cell layer of normal epidermis showing the stratified nature of the
Merkel cell carcinomas do not connect with the epidermis. desmosome.
14 The structure and function of skin
Autosomal dominant Autosomal recessive
fi®-
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I i'lylfi Il5
Ectodermal dysplasia -
K r*

Plakophilin 1
Skin fragility syndrome
T

Arrhythmogenic right Arrhythmogenic right

IlYSsI

Plakophilin 2
_

ventricular cardiomyopathy ventricular cardiomyopathy

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Woolly hair, keratoderma, Woolly hair, keratoderma,

cardiomyopathy +/- cardiomyopathy
.Vr? *
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Arrhythmogenic right
.*

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Desmoplakin
ventricular cardiomyopathy
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Striate palmoplantar Lethal acantholytic

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epidermolysis bullosa
4

keratoderma
r

Arrhythmogenic right
Plakoglobin Naxos disease
Desmoglein Plakoglobin Desmoplakin ventricular cardiomyopathy
Desmocollin Plakophilin Keratin Striate palmoplantar
Desmoglein 1
keratoderma
Fig. 1.47
Protein composition of a desmosome junction between adjacent keratinocytes. The Arrhythmogenic right Arrhythmogenic right
Desmoglein 2
keratin filament network of two keratinocytes is linked by a series of desmosomal ventricular cardiomyopathy ventricular cardiomyopathy
plaque proteins and transmembranous molecules to create a structural and
signaling bridge between the cells. Localized recessive
Desmoglein 4
hypotrichosis
Recessive monilethrix
are found predominantly in the superficial layers of the epidermis whereas
Hypotrichosis with
Dsg3 and Dsc3 show greater expression in basal keratinocytes. The intra- Desmocollin 3
scalp vesicles
cellular parts of the cadherins interact with the keratin filament network
Arrhythmogenic right
via the desmosomal plaque proteins, mainly desmoplakin, plakoglobin and Desmocollin 2
ventricular cardiomyopathy
plakophilin.1
Clues to the biologic function of these desmosomal components have arisen Hypotrichosis simplex Corneodesmosin
from various inherited and acquired human diseases.3,4 Naturally occurring
Fig. 1.48
human mutations have been reported in ten different desmosome genes with
Genetic disorders of desmosomes: autosomal dominant or autosomal recessive
variable skin, hair and heart abnormalities and several desmosomal proteins mutations in ten different structural components of desmosomes may give rise to
serve as autoantigens in immunobullous blistering skin diseases such as pem- specific diseases that can affect skin, hair or heart or combinations thereof.
phigus (Figs 1.48 and 1.49).5 Antibodies to multiple desmosomal proteins
may develop in diseases such as paraneoplastic pemphigus through the phe-
nomenon of epitope spreading.6 Cleavage of the extracellular domain of Dsg1 Immunobullous diseases
has also been demonstrated as the basis of staphylococcal scalded skin syn-
drome and bullous impetigo.7 Desmoglein 3 Pemphigus vulgaris
Adherens junctions are recognized ultrastructurally as electron-dense trans-
Pemphigus foliaceus
membrane structures, with two opposing membranes separated by approxi- Desmoglein 1
mately 20 nm, that form links with the actin skeleton.8 They are 0.2–0.5 μm Endemic pemphigus
in diameter and can be found as isolated cell junctions or in association with Desmocollin 3 Atypical pemphigus
tight junctions and desmosomes. Adherens junctions are expressed early in
skin development and contribute to epithelial assembly, adhesion, barrier for- Atypical pemphigus
Desmocollin 1
mation, cell motility and changes in cell shape. They may also spatially co-
IgA pemphigus
ordinate signaling molecules and polarity cues as well as serving as docking (sub-corneal type)
sites for vesicle release. Adherens junctions contain two basic adhesive units:
the nectin-afadin complex and the classical cadherin complex.9,10 The nectins Fig. 1.49
form a structural link to the actin cytoskeleton via afadin (also known as Immunobullous diseases of desmosomes: intraepidermal blistering can arise
AF-6) and may be important in the initial formation of adherens junctions. through autoantibody disruption of four separate desmosomal proteins which leads
The cadherins form a complex with the catenins (α-, β-, and p120 catenin) to different clinical variants of pemphigus.
and help mediate adhesion and signaling. Cell signaling via β-catenin can acti-
vate several pathways linked to morphogenesis and cell fate determination. connexons (homotypic or heterotypic) to form a gap junction. To date, 13
Inherited gene mutations of the adherens junction proteins plakoglobin different human connexins have been described. The formation and stabil-
and P-cadherin have been reported. Plakoglobin mutations result in Naxos ity of gap junctions can be regulated by protein kinase C, Src kinase, cal-
disease (woolly hair, keratoderma, cardiomyopathy).3 P-cadherin mutations cium concentration, calmodulin, adenosine 3′,5′-cyclic monophosphate
underlie autosomal recessive hypotrichosis with juvenile macular dystrophy (cAMP) and local pH.14 The connexins are classified into three groups (α,
as well as ectodermal dysplasia-ectrodactyly-macular dystrophy (EEM) syn- β and γ) according to their gene structure, overall gene homology and spe-
drome, in which there is hypotrichosis, macular degeneration, hypodontia cific sequence motifs.15 Apart from the connexins, vertebrates also contain
and limb defects, including ectrodactyly, syndactyly and camptodactyly.11,12 another class of gap junction proteins, the pannexins, which are related to the
Gap junctions represent clusters of intercellular channels, known as innexins found in nonchordate animals. The function of gap junctions is to
­connexons, which form connections between the cytoplasm of adjacent allow sharing of low molecular mass metabolites (<1000 Da) and exchange of
­keratinocytes (and other cells).13 Formation of a connexon involves ­assembly ions between neighboring cells. Gap junction communication is essential for
of six connexin subunits within the Golgi network. This complex is then cell ­synchronization, differentiation, cell growth and metabolic coordination
transported to the plasma membrane where connexons associate with other of avascular organs, including epidermis.14
 Pilosebaceous units 15
Deafness with unusual Deafness with ­endocuticle, exocuticle and ‘a’ layer.1 Around the cuticle is the inner root
A

hyperkeratosis and oral erosions Clouston-like phenotype sheath (IRS), which is composed of three distinct layers of cells that undergo
/
\

keratinization: the IRS cuticle, the Huxley layer and the outermost Henle
Hystrix-like-ichthyosis Palmoplantar keratoderma layer.2 Differentiation in the IRS involves the development of trichohyalin
A

deafness syndrome with deafness granules, with 8–10 nm filaments orientated in the direction of hair growth.
Keratitis-ichthyosis - The IRS moves up the follicle, forming a support for the hair fiber, and
26 Bart-Pumphrey syndrome degenerates above the sebaceous gland. The outermost layer is the outer root
deafness syndrome
sheath (ORS), which is continuous with the epidermis and expresses epithe-
Non-syndromic deafness Vohwinkel’s syndrome lial keratins, K5/K14, K1/K10 and K6/K16 in the upper ORS and K5/K14/
Non-syndromic deafness 30 Clouston’s syndrome K17 in the deeper ORS.
Normal growth of the hair fiber is 300–400 μm/day. Hair growth is gener-
Erythro-keratoderma ated by the high rate of proliferation of progenitor cells in the follicle bulb.
30.3
variabilis
There are three phases of cyclical hair growth: anagen, when growth occurs;
Peripheral neuropathy and Erythro-keratoderma catagen, a regressing phase; and telogen, a resting phase. The follicle re-enters
31 anagen, and the old hair is replaced by a new one.
hearing impairment variabilis
Immediately above the basal layer in the hair bulb, cells undergo a sec-
Non-syndromic deafness Charcot-Marie ondary pathway of ‘trichocyte’ or hair differentiation, and express a fur-
32
tooth disease (X-linked) ther complex group of keratins, the hard keratins.2 Two families of hair
Atrial fibrillation 40 keratins, types I and II, are present in mammals, which have distinctive
Non-syndromic deafness 43 Oculodentodigital dysplasia amino- and carboxy-terminals with high levels of cysteine residues but
lack the extended glycine residues of epidermal keratins. The proteins dif-
Zonular pulverulent
46
fer from epithelial keratins in position on two-dimensional gels but form
cataract-3 acidic and basic groups. There are four major proteins in each family and
Zonular pulverulent
50 several minor proteins, Ha 1–4 and Hb 1–4. Recent cloning of the hair ker-
cataract -1
atin genes, which cluster on chromosomes 12 and 17, has shown an even
Fig. 1.50 greater number of hair keratin genes, HaKRT1–6 (including 3.1 and 3.2)
Genetic disorders of connexins: nine different human connexin molecules are and HbKRT1–6.
associated with different inherited diseases. Mutations in the four low molecular Mutations in hair keratin genes have been found to cause autosomal domi-
weight connexins shown at the top of the diagram are associated with a spectrum nant forms of the human disease monilethrix. More common hair variants,
of skin pathology, as highlighted.
such as curly hair, may be explained by dynamic changes during hair growth.3
Curvature of curly hair is programmed from the very basal area of the follicle
and the bending process is linked to a lack of axial symmetry in the lower
Inherited abnormalities in genes encoding four different connexins (Cx26, part of the bulb, affecting the connective tissue sheath, ORS, IRS and the hair
30, 30.3 and 31) have been detected in several forms of keratoderma and/or shaft cuticle.
hearing loss (Fig. 1.50). Nondermatologic disorders can also arise from muta- Sebaceous glands usually develop as lateral protrusions from the outer
tions in some higher molecular weight connexins (Cx32, 40, 43, 46 and 50). root sheath of hair follicles, but at certain sites, such as the eyelids, lips, are-
Tight junctions contribute to skin barrier integrity and maintaining cell olae, nipples and labia minora, they appear to arise independently and drain
polarity, although in simple epithelia they are major regulators of perme- directly onto the skin's surface (Figs 1.51 and 1.52). They are widespread in
ability.8 An important function is to regulate the paracellular flux of water- distribution, being found everywhere on the body except on the palms and
­soluble molecules between adjacent cells.16 The main structural proteins of soles. They are particularly abundant on the face and scalp, in the midline
tight junctions are the claudins, of which there are approximately 24 sub- of the back and about the perineum, and are concentrated around the ori-
types, as well as the IgG-like family of junctional adhesion molecules (JAMs) fices of the body (Fig. 1.53). Those of the eyelid are known as the glands
and the occludin group of proteins. The principal claudins in the epidermis
are claudin 1 and 4. These transmembranous proteins can bind to the intrac-
ellular zonula occudens proteins ZO-1, ZO-2, ZO-3 which interact with the
actin cytoskeleton.8,17

v,
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Clinically, abnormalities in tight junction proteins can result in skin, kid-
ney, ear and liver disease. Inherited gene mutations in claudin 1 have been

\
reported in one pedigree with diffuse ichthyosis, hypotrichosis, scarring
­alopecia and sclerosing cholangitis.18

ti>) ' 5 if
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Pilosebaceous units

t
r
There are four classes of pilosebaceous unit: terminal on the scalp and beard;
apopilosebaceous in axilla and groin; vellus on the majority of skin; and
sebaceous on the chest, back and face. The dermal papilla is located at the
base of the hair follicle and is associated with a rich extracellular matrix.
Around the papilla are germinative (matrix) cells that have a very high rate
of division, and give rise to spindle-shaped central cortex cells of the hair
fiber, and the single outer layer of flattened overlapping cuticle cells. A cen-
tral medulla is seen in some hairs, with regularly stacked condensed cells
interspersed with air spaces or low-density cores. The cortical cells are filled
with keratin intermediate filaments orientated along the long axis of the Fig. 1.51
cell, interspersed with a dense interfilamentous protein matrix. The cuticu- Sebaceous glands: on the inner aspect of the labia these appear as tiny yellow
lar cells are morphologically distinct, with flattened outward-facing cells, papules (Fordyce spots). By courtesy of S.M. Neill, MD, Institute of Dermatology,
with three layers inside the cuticle of condensed, flattened protein granules: London, UK.
16 The structure and function of skin

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Normal vulva: sebaceous glands are conspicuous, but arise independently of a hair Nose: multiple sebaceous glands are evident.
follicle and open directly onto the surface epithelium.

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Fig. 1.53
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shows gradual accumulation of variably sized, nonmembrane-bound, lipid Fig. 1.56
inclusions in differentiating cells. Numerous mitochondria, ribosomes and Sebaceous duct: this is lined by keratinizing stratified squamous epithelium; it is
membrane-bound vesicles may also be evident. As the cells mature before continuous with the external root sheath.
 Eccrine glands 17

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vascularized coiled secretory gland, a coiled dermal duct, a straight dermal
duct, and a coiled intraepidermal duct (the acrosyringium) (Fig. 1.59). The
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Propionibacterium acnes (triglyceride hydrolysis) within the pilosebaceous Fig. 1.59

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canal and Staphylococcus epidermidis (cholesterol ester formation) on the
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epidermal lipids.
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Human sweat glands are generally divided into two types: eccrine and apo- are evident in the upper
crine.1 The eccrine gland is the primary gland responsible for thermoregula- field. The epithelium of
tory sweating in humans.2 Eccrine sweat glands are distributed over nearly the duct is more darkly
the entire body surface. The number of sweat glands in humans varies greatly, B stained than that of the
ranging from 1.6 to 4.0 million. - . glandular component.
18 The structure and function of skin

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(see below). Sometimes the secretory lobules show striking clear cell change
due to glycogen accumulation (Fig. 1.62). The myoepithelial cells contract
in response to cholinergic stimuli. They have spindled cell morphology and
are distributed in a spiral, parallel array along the long axis of the secretory
tubule. On the basis of their expression of keratin filaments, they appear to
be of ectodermal rather than mesenchymal derivation. They do not label for
s vimentin. Myoepithelial cells therefore develop from the epithelial cells of the
tip of the secretory coil and not, as might be expected, from adjacent mesen-
chymal cells. The dermal duct components consist of a double layer of cuboi-
dal basophilic cells. The duct is not merely a conduit, but has a biologically
active function, modifying the composition of eccrine secretion and, particu-

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larly, the reabsorption of water. The intraepidermal portion of the sweat duct
opens directly onto the surface of the skin. A myoepithelial layer is absent.
The secretory unit is strongly labeled by CAM 5.2 (both cytoplasmic and

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membranous) and Ber-EP4 and there is luminal accentuation (Fig. 1.63). The
ductal component is completely negative. EMA can be detected along the
;* luminal aspect of the secretory unit and outlining the intercellular canaliculi.

I/
It is also present around the luminal border of the duct, and is often present
in large quantities within the lumen. CEA is present in a similar distribution
- H to EMA although secretory labeling tends to be rather focal and somewhat

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dermis or around the interface between the dermis and subcutaneous fat and
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types: large clear pyramidal cells, which appear to be responsible for water
secretion, and smaller, darkly staining mucopolysaccharide-containing cells
(probably secreting a glycoprotein), which are much less commonly seen.
mm
—.>m. HI
Fig. 1.63
:

Between adjacent cells are canaliculi, which open into the lumen of the tubule Eccrine gland: immunohistochemistry.
 Apocrine glands 19

cells can be identified by antibodies to S-100 protein, desmin and smooth 4f &:
muscle actin. The eccrine glands show strong activity for the enzymes
­amylophosphorylase, leucine aminopeptidase, succinic dehydrogenase and
5 a ;

cytochrome oxidase.3 Weak or no activity is seen for NADH ­diaphorase, i Bjpf

esterase and acid phosphatase.
With electron microscopy, the serous cells are characterized by abundant
intracytoplasmic glycogen granules and numerous mitochondria (Figs 1.64,
eÿnit m sragsn **•
V>J
,tcCj
%

1.65). Adjacent cell membranes, which show marked interdigitations, may

'yCyÿA> -55
A?
Eg
separate to form microvilli-lined intercellular canaliculi. The mucous cells T *
contain numerous electron-dense lipid droplets and lysozymes. Myoepithelial fc -V ' '“'v Vv 'V*aÿN
cells are present at the periphery of the secretory coil within the eccrine basal * v>.Aii*J
2£1
lamina (lamina densa) and contain abundant myofilaments with characteris- .'•>
raw * CM y&3m
tic dense bodies. The sweat duct lumen is bordered by conspicuous microvilli -ORB •».ÿ2
.j&FT
Sri
•*!-3
H. > j&t* *
(Fig. 1.66). The cytoplasm contains numerous clear vesicles. Tonofilaments
are characteristically orientated in a circumferential manner deep to the
L;-/
*** & <

plasma membrane, the so-called cuticle of light microscopy. This is particu-

larly well developed in the acrosyringium.
Human perspiration is classified into two types: insensible perspiration
H«Sm$il
A 7 *f B
‘i
and active sweating. Insensible perspiration involves water loss from the
Fig. 1.66
Eccrine gland: (A) lumen of the eccrine dermal duct lined by conspicuous microvilli,
(B) high-power view of eccrine dermal duct showing microvilli and circumferentially

mf ••» r< .*
«ÿ£p|K
w orientated tonofilaments.

;> •'. ' * •>7 . '

MM ik
*:•
*T<w ‘
*

A*
respiratory passages, the skin, and gaseous exchanges in the lungs. Heat,
exercise and carbon dioxide can all induce active sweating in human beings.
112ÿ Active sweating may be classified into two types: thermal and mental/emo-
tional. Thermal sweating plays an important role in keeping the body's tem-
'*m4 perature constant and involves the whole body surface.4 The secretory nerve
'Wl <ÿ*<*•>
fibers innervated in human sweat glands are sympathetic, which appear to be

.
r>4
_ÿ
tT*A .'‘.J-ÿ'K
A*'*
':'.JLI®M '-V® • V*
'
A% cholinergic in character as sweating is produced by pilocarpine and stopped
by atropine.5 Vasoactive intestinal peptide (VIP) coexisting in the cholinergic
nerve fibers has been suggested as a candidate neurotransmitter that may con-
•• 'i '> • trol the blood circulation of the sweat glands. Acetylcholine is the primary
wm*
Mm
*
•
neurotransmitter released from cholinergic sudomotor nerves and binds to
muscarinic receptors on the eccrine sweat gland, although sweating can also
‘

.- * A.iiw:-
. *
f>-
.'1
-.•' J-
-'ÿ

H w *>
occur via exogenous administration of α- or β-adrenergic agonists. The ini-
tial fluid released from the secretory cells is isotonic and similar to plasma
although it is devoid of proteins. As the fluid travels up the duct towards the

-
surface of the skin, sodium and chloride are reabsorbed, resulting in sweat
Fig. 1.64 on the surface being hypotonic relative to plasma.6 When the rate of sweat
Eccrine gland: low-power electron micrograph showing the lumen in the upper-right production increases, however, for example during exercise, ion reabsorption
quadrant, granular mucous-secreting cells and serous cells. mechanisms can be overwhelmed due to the large quantity of sweat secreted
into the duct, resulting in higher ion losses. The sodium content in sweat on
the skin's surface, therefore, is greatly influenced by sweat rate.

*
-•ÿ

$*& '-X>.•*'
•/
»*w
-

M%rSr-:.'jÿm-
.

:?<\
V.
• rÿte
Apocrine glands
Apart from eccrine glands, the skin also contains apocrine sweat glands.1,2
Apocrine glands have a low secretory output, and hence no significant role in
*ÿ

+ÿ&£.'’ÿ'
thermoregulation. Apocrine glands are found predominantly in the anogeni-

-
, J •
v
".. .i
• .

Y'j\v. ' *?<vv *%"

-.,
V - .' :
*+ %
vm tal and axillary regions, but are also located in the external auditory meatus
(ceruminous glands), the eyelid (Moll's gland), and within the areola. They
SK :i -‘} £*•
are derived from the epidermis, and develop as an outgrowth of the follicu-

I. rw * f L-.-V
r» \
viJ lar epithelium. They first appear during the fourth to fifth month of gesta-
tion. Their function in humans is unknown, but in other mammals they are

'Am&f
*vr‘.
•'

mi
at
A
\
Tfc
••*ÿ *.

B k
€

••«
.

'•
P> ’
-
responsible for scent production and have importance in sexual attraction.
As with sebaceous glands, they are smaller in childhood, becoming larger and
functionally active at puberty. The secretions of the ceruminous glands are
believed to lubricate, clean and protect the external ear from bacterial and
fungal infections.
Apocrine glands include two distinct components: a complex secretory
Fig. 1.65 element situated in the lower reticular dermis or subcutaneous fat, and
Eccrine gland: (left) high-power view of clear cell showing conspicuous a tubular duct linking the gland with the pilosebaceous follicle at a site
mitochondria and numerous electron-dense glycogen granules, (right) high-power above the sebaceous duct. Microscopically, the secretory portion comprises
view of secretory granules in a dark cell. an outer discontinuous layer of myoepithelial cells and an inner layer of
20 The structure and function of skin

­cuboidal to columnar eosinophilic cells (Figs 1.67, 1.68). Although a histo-

S'-
'i u
logical artifact, secretory droplets, which appear to be pinched off from the A
•J •% %

»
superficial aspect of the columnar cells (decapitation secretion), can be seen

G
\

on light microscopy. The duct portion is formed by a double layer of cuboi- • t* <
dal epithelium. It is morphologically indistinguishable from the eccrine *
duct. The inner layer of the secretory portion contains a single columnar
>
r*
secretory cell type containing numerous large dense granules located at the \ •
o' F

apical aspect, which contribute to the lipid-rich secretion produced. The

» JMb .

n
jm
/
A
inner layer is also surrounded by a fenestrated layer of myoepithelial cells i
but the lumen may be larger in diameter than that present in eccrine tissue 1

U CS -
V
y
The apocrine excretory duct does not have any known reabsorptive func-
tion and consists of a double layer of cuboidal cells that merge distally with
the epithelium of the hair follicle, resulting in emptying of the secretion into
the hair follicle. • /?*' .
**'•,
N'”<
/«
><s
-. '

fm
. v
-V
% 4 ’
I.
Immunohistochemically, the secretory unit shows very strong labeling
t
4

with the antibody CAM 5.2 (both cytoplasmic and membranous), and there %

V • it «

»» rfl
is luminal accentuation. The apocrine duct is negative (Fig. 1.69). EMA labels ' ’ft
EMA
the cytoplasm of the secretory cells, and is accentuated along the luminal
border. It is also present along the luminal aspect of the apocrine duct. With
CAM 5.2
fJC? . IW
CEA, there is faint, focal staining of the secretory epithelium. The luminal Fig. 1.69
Apocrine gland: immunohistochemistry (CAM 5.2 and EMA).

I • .TJf
c • #
'
£ '.£» aspect of the duct is strongly outlined. Cytoplasmic granules express epider-
* mal growth factor. The myoepithelial cells of the secretory unit are reactive
•
-Ht-ISa!?!
/*,— *« •»
iN-
I ,* • /
•: liV for S-100 protein and smooth muscle actin (Fig. 1.70). The apocrine secre-
••• :WJ tory epithelium strongly expresses the enzymes NADH diaphorase, esterase,

m
L
s- *1 acid phosphatase and β-glucuronidase. There is weak or absent reactivity for
• •*

amylophosphorylase, leucine aminopeptidase, succinic dehydrogenase and

r/i
/

* * jpsi&®' V-t
.
cytochrome oxidase. The apocrine gland also can be stained with cationic

-,
W' colloidal gold at pH 2.0.3

r*
4 * * * Ultrastructure of the apocrine reveals cuboidal to columnar secretory cells
J?
t •*
k containing numerous osmiophilic secretory vacuoles. Mitochondria are pres-
>
. •:• - r ent in large numbers. While some show obvious double cristae, others are so

m
r3S
> •
/• W/C' •; •
.• electron dense that the internal structure is obscured. The Golgi is conspicu-
'i Ml
;ÿ

vi ous. The luminal border is lined by prominent microvilli (Fig. 1.71).

f
« V ‘ The mechanism of apocrine secretion and control of apocrine glands is
-
i
W ' £•• uncertain, but there is adrenergic sympathetic innervation, and secretion is
M •' V
V7.
#>4 »<e»• provoked by external stimuli such as excitement or fear. The unpleasant odor
of apocrine secretion, which is odorless in itself, is due to breakdown prod-
\ •i »
•• •. • • "
.**•' •** ucts produced by cutaneous bacterial flora.
Fig. 1.67 A third type of intermediate sweat gland, the apo-eccrine gland, has
Apocrine gland: this specimen from normal axillary skin shows apocrine secretory also been described in axillary skin but its existence is not universally
lobules in the subcutaneous fat. Ducts are present in the upper right of the field. accepted.

V n.rr.
& f

ifl
\
FK df
•* '
K XV'
1 /* * /
. r>
tk
-•
m
tg
*
<* *
«ÿ>

V
%o
*
V •*
*

-
- 3 •• ?*
'
;

m\
m*
5 ,*
/
/
%

f
•W% • *
y

* /./I
a
K
ws_ '4 J
M ••
« K~

c
*
Ei '*»
% _ V
»
-> »»V ,*E# \ -
I
%
rM ?:"
* i 4
J au
r.
.
«k r*
h-
-
-
-
-
-V •* C7
1 vs ‘ s ' -A**
-**M

J '
*S'
t .t - /
#

•*.. • •k
a

* ;I9P ••
w
m
r 'v «*
« *;• *' #
O
••
N
‘ •;
i # % k
i
m%
«
••; * > . v ;• -i
#
.1 S1OO-protein SMA
_ • * -r"# vV~-
Fig. 1.68
Apocrine gland: lobules are lined by tall columnar cells with intensely eosinophilic
**'
Fig. 1.70
V

cytoplasm. ‘Decapitation secretion’ is conspicuous. Apocrine gland: immunohistochemistry (S-100 protein and SMA).
 Dermal–epidermal junction 21

. c
i Basal keratinocyte
4
•4 *• *ÿ
Keratin filaments
%

r* » *
% s?.

##
r.*-
*ÿ • ©

*
r
# .
i n Hemidesmosomal inner plaque

Hemidesmosomal outer plaque

* 0 i wwv
rrVtÿrfW'r Cell membrane
Sub-basal dense plate
Lamina lucida
Anchoring filaments
* A
Lamina densa

Anchoring fibrils
Fig. 1.71
Apocrine gland: close-up view showing microvilli and decapitation secretion.
Papillary dermis

Dermal–epidermal junction Fig. 1.73

Schematic representation of a hemidesmosome-anchoring filament-anchoring
The interface between the lower part of epidermis and the top layer of dermis
fibril complex at the dermal–epidermal junction. A continuum of adhesive proteins
consists of a complex network of interacting macromolecules that form the extends from the keratin tonofilaments within basal keratinocytes through to
cutaneous basement membrane zone (BMZ) (Figs 1.72, Fig. 1.73).1 Many of dermal collagen. This complex represents the main adhesion unit at the dermal–
these components are glycoproteins and thus the BMZ can be recognized his- epidermal junction.
tologically as staining positive with PAS staining (Fig. 1.74). Ultrastructural
examination of the BMZ by transmission electron microscopy shows two
layers with different optical densities (Fig. 1.75).2 The upper layer, the lam- •V
V
- -
r -
ina lucida, is a low electron density region of 30–40 nm in breadth which is .• K *2
* :* U
directly subjacent to the plasma membranes of basal keratinocytes. Below the
lamina lucida is the lamina densa, an electron-dense region, 30–50 nm across, j
., :u ;>*
which interacts with the extracellular matrix of the upper dermis. Within H H •i
•V c
the cutaneous BMZ distinct adhesion complexes are evident. Extending from
.': , •; ..„ ,
>#*,. 'ItipilL ' i_>- * '
* *•»
Keratins
5 & 14 * rm r
>*1
«
«ÿ' is %

Plectin
I fSLi pv>: £&
"I'-'
230-kDa
i

VPK?ÿ α6β4
BP Ag
. >4L .vV 4

rw»
integrin Type XVII Fig. 1.74

//nil 1IJ
Type IV
collagen Laminin-332
The basement membrane region stains strongly with periodic acid-Schiff.

inside the basal keratinocytes, through the lamina lucida and lamina densa,
collagen and into the superficial dermis are ultrastructurally recognizable attachment
structures. The components of these adhesion units are the hemidesmosomes,
anchoring filaments and anchoring fibrils.3 The importance of these struc-
Type VII tural complexes in securing adhesion of the epidermis to the underlying der-

Pi
&ssa
collagen mis is highlighted by both inherited and acquired subepidermal blistering skin
diseases (Figs 1.76, Fig. 1.77). The precise role of individual proteins in adhe-
sion is demonstrated by the group of inherited skin blistering diseases, epi-
dermolysis bullosa, in which components in the hemidesmosomal structures,
Fig. 1.72 anchoring filaments, or anchoring fibrils are genetically defective or absent.4
The macromolecular components of the dermal–epidermal junction centered on This leads to fragility at the dermal–epidermal junction as a result of minor
a hemidesmosome-anchoring filament-anchoring fibril complex. Protein–protein trauma.
interactions between these molecules secure adhesion between the epidermis and The hemidesmosomes extend from the intracellular compartment of the
the subjacent dermis. basal keratinocytes to the cell membrane adjacent to the lamina lucida in
22 The structure and function of skin

KERATIN
jgg|s ir
5
ANCHORING Keratins
FILAMENTS FIBRILS 5 & 14
L Bullous
i*
MT i Bullous
* pemphigoid

P'S©” Plectin

io|H
-4

J
pemphigoid-like 230-kDa

#C«J V
r J v -. ,r '-v
~
isi
-&i Bullous
fi
α6β4
BP Ag Mucous
4 membrane
pemphigoid
LAMINA LUCIDA r*
pemphigoid-like integrin Type XVII
Mucous
collagen Laminin-332
LAMINA DENSA membrane
pemphigoid
HEMIDESMOSOMES 7 \
T7- . */ A

Fig. 1.75
Transmission electron microscopy of the dermal–epidermal junction. Bar = 200 nm.
EB acquisita Type VII
Bullous SLE 4 collagen

Keratins
EB simplex
5 & 14 Fig. 1.77
Recessive Acquired disorders of hemidesmosomal proteins. Autoantibodies directed against
EB simplex 4 EB simplex
components of the hemidesmosome-anchoring filament-anchoring fibril complex
EB simplex with give rise to specific subepidermal autoimmune blistering diseases.
Plectin
muscular dystrophy 4

J
230-kDa
BP Ag
EB simplex with
pyloric atresia BH
α6β4
Non-Herlitz
4 junctional EB ­structure of laminins contains both globular and rodlike segments which con-
tribute to interactions with other extracellular matrix molecules, as well as
integrin Type XVII
Herlitz & cell attachment and spreading, and cellular differentiation. The critical role
Junctional EB with collagen of laminin 332 in providing integrity to the cutaneous BMZ is evident from
Laminin-332 non-Herlitz
pyloric atresia
junctional EB findings that mutations in any of the three polypeptide subunits (the α3, β3,
or γ2 chains) can result in junctional forms of epidermolysis bullosa.
The major component of the lamina densa is type IV collagen, which in
skin is mainly composed of the α1 and α2 chains.7 Type IV collagen is assem-
bled to form a complex hexagonal arrangement which allows high flexibility
Dominant and to the BMZ and facilitates interactions with other collagenous and noncollag-
Type VII
recessive 4
collagen enous proteins (Fig. 1.79). Other BMZ components at the dermal–­epidermal
dystrophic EB
junction include the glycoprotein nidogen (previously known as entactin)
which interacts with type IV collagen either alone or as part of a laminin-
nidogen complex. Also present are the heparan sulfate proteoglycans, which
are highly negatively charged and hydrophilic and capable of interacting with
Fig. 1.76 a number of basement membrane components and thus contribute to the
Genetic disorders of hemidesmosomal proteins. Mutations in components of the architectural organization of the BMZ.8
hemidesmosome-anchoring filament-anchoring fibril network give rise to specific
Anchoring fibrils are ultrastructurally recognizable fibrillar structures
variants of epidermolysis bullosa (EB).
which extend from the lower part of lamina densa to the upper reticular der-
mis. The main component of anchoring fibrils is type VII collagen (Fig. 1.80).9
Individual type VII collagen molecules are ≈450 nm long and by complexing
the upper portion of the dermal–epidermal basement membrane. The inner
as antiparallel dimmers and aggregating laterally, they forms loops which are
plaques of hemidesmosomes serve as attachment sites for keratin filaments
traversed by interstitial dermal collagens (types I, III and V) to adhere the
while the outer plaques associate with anchoring filaments that traverse the
BMZ to the underlying dermis.10 Type VII collagen is synthesized by both
lamina lucida. Subjacent to the hemidesmosomal outer plaques in the lamina
dermal fibroblasts and epidermal keratinocytes. Also inserting into the lam-
lucida are the sub-basal dense plates which contribute to the structural orga-
ina densa at the dermal–epidermal junction are elastic microfibrils, contain-
nization of the attachment complex. Intracellular hemidesmosomal proteins
ing proteins such as fibrillin. Fibrillin-containing microfibrils may exist as a
include the 230-kD bullous pemphigoid antigen 1 and the 500-kD plectin
fibrillar mantle surrounding an elastin core or be found independently as elas-
protein. Transmembranous hemidesmosomal proteins comprise the 180-kD
tin-free microfibrils. The latter, located beneath the lamina densa, are known
bullous pemphigoid antigen (also known as type XVII collagen), and the α6
as the dermal microfibril bundles (Fig. 1.81)
and β4 integrin molecules.5 The hemidesmosomes are associated with anchor-
ing filaments in the lamina lucida, thread-like structures 3–4 nm in diameter
that span the lamina lucida to the lamina densa. Dermal collagen
Located at the lamina lucida–lamina densa interface are the laminins.
The major laminin within the cutaneous BMZ is laminin 332, previously The major extracellular matrix component in the dermis is collagen.
known as laminin 5 (Fig. 1.78). In addition, laminin 111 (laminin 1), laminin Currently, 29 distinct collagens have been identified in vertebrate tissues
311 (laminin 6), laminin 321 (laminin 7) and laminin 511 (laminin 10) are and each is designated a Roman numeral in the chronological order of its
also integral components of the dermal–epidermal junction.6 The cruciform ­discovery. At least eight different collagens are found in human skin. All collagen
 Dermal collagen 23

α3

41

β3 γ2 #

4f

i % (
* v*
Fig. 1.78
Laminin-332 is a major
r. m i %
adhesion protein at the dermal–
sr i

- % epidermal junction: (A) the

protein is composed of three

i:v a
polypeptide chains: α3, β3, and
γ2; (B) Laminin-322 identified by
immunofluorescence in a sample
o
A B
of split skin.

­molecules ­consist of three subunit polypeptides which can either be iden-

tical in homotrimers or can consist of two or even three genetically differ-
ent polypeptides in heterotrimeric molecules. Since the different subunits
B&£1 LS
Sg*

are all distinct gene products, there are well over 40 different genes in the
human genome that encode the different subunit polypeptides.1 Collagens »•; -N **?«* m
demonstrate considerable tissue specificity and are synthesized by a number > -• -• Kmm I
of different cell types, including dermal fibroblasts, keratinocytes, vascular i •V
V
endothelial cells, and smooth muscle cells. A characteristic feature of col-
lagen is the presence of hydroxyproline and hydroxylysine residues, amino
. y

acids that are post-translationally synthesized by hydroxylation of proline F

and lysine residues, respectively. These hydroxylation reactions take place in
the rough endoplasmic reticulum by prolyl and lysyl hydroxylases, respec- 7
£
tively, enzymes that require ascorbic acid, molecular oxygen and ferrous iron
-< W'

*
as cofactors. The hydroxylation of prolyl residues is necessary for stabili- m
2P*2
zation of the triple-helical conformation at physiologic temperatures, and '•
hydroxylysyl residues are required for formation of stable covalent cross- /
links. In the rough endoplasmic reticulum, trimeric molecules are formed
M I.
a < V

s
***
'

0 v :-
and following the prolyl hydroxylation reactions, triple helices are generated
ME
n,
which are then secreted through Golgi vesicles into the extracellular space.
Here, parts of the noncollagenous peptide extensions are cleaved by specific &
' -a
proteases, and the collagen molecules undergo supramolecular organization. XI \s
To acquire fibrillar strength, the fibers are then covalently linked together by
Jf

-
V
I
specific intra- and intermolecular cross-links. The most common forms of
cross-links in type I collagen are derived from lysine and hydroxylysine resi-
r V
* Kr#;1V**
dues, and in some collagens there are also cysteine-derived disulfide bonds. V.
«*

Fig. 1.80
Normal skin: the anchoring fibrils are composed predominantly of type VII collagen
as shown in this immunogold electron microscopic preparation.
"N

*i'':0ÿ0*
\ÿ
• :ÿ'-"
«.
»•«
‘« H <•

, .> i • jb V
On the basis of their fiber architecture in tissues, collagens can be divided
into different classes. Types I, II, III, V and IX align into large fibrils and
are designated as fibril-forming collagens. Type IV is arranged in an inter-
lacing network within the basement membranes, while type VI is a distinct
.-.: •.WrV microfibril-forming collagen and type VII collagen forms anchoring fibrils.
r
< FACIT collagens (fibril-associated collagens with interrupted triple-heli-
6

Fig. 1.79
•SJ> »
Q
0 ces), include types IX, XII, XIV, XIX, XX, and XXI.2 Many of the FACIT
­collagens ­associate with larger collagen fibers and act as molecular bridges
stabilizing the organization of the extracellular matrices.
Type I collagen, the most abundant form of collagen, is the predomi-
Basement membrane: basement membrane staining with type IV collagen. nant collagen in human dermis, accounting for approximately 80% of total
24 The structure and function of skin

v.
mp tf V

- m -
t
WI
m HpiffW) w .. - .
t
yj

7
/.-ÿ
'
*
f'T*
r*
*df. ..i\>/. i* mI* li\ÿv-- - ™- •ÿ

a
7
. * t
V1 1 i1

I
S '

# Ar 1 *
K* i 'A

m i S?
>•-
"1 *5
KrjPxS-
k/JwT:*
*
£•
fel#
IP> -
•

/ f;
.

p WIA3
,7

?
*
/k .
-<r
H- « %
k
.•SV 5' A
*K;
k*
W
“• A
t* -. jV
* ! * jpP* 1

\iV''
;v.

a
«4l
§
i% * K. r
1 y “ /• ,
Fig. 1.82
Wt *
;
&V
rV
•
Fig. 1.81
'i
Normal skin of forearm:
in the papillary dermis

i J •s'
/ÿ

Normal skin: this view

shows a well-formed
0
r.
the collagen fibers are
fine and sometimes have
. <5*
4 * »
,r
<&
dermal microfibril bundle
(arrowed). L4 2
7A
>a
i
* <V*
f

** *
a vertical orientation.
Masson's trichrome.

c­ ollagen. Type I collagen associates with type III collagen to form broad,
extracellular fibers in the dermis. Mutations in the type I and III collagens or ' V77 '-',v '
in their processing enzymes can result in connective tissue abnormalities seen
in different forms of the Ehlers-Danlos syndrome, and mutations in the type
.“v.:; t -T •

I collagen gene lead to osteogenesis imperfecta.3

J
- ;v -
s

Type III collagen accounts for about 10% of the total collagen in adult der-
mis, although it is the predominant dermal collagen in the fetus. It predomi- •
*>>
nates in vascular connective tissues, the gastrointestinal tract, and the uterus, )

and mutations in the type III collagen gene occur in the vascular type of the
pr- . ? -. 4>--rÿr
Ehlers-Danlos syndrome.
&L* . '
-• &*<
a;-
Type V collagen is present in most connective tissues, including the der-
mis, where it represents less than 5% of the total collagen. Type V collagen is
located on the surface of large collagen fibers in the dermis, and its function
is to regulate their lateral growth. A lack of type V collagen leads to vari-
igltoSS'
?SB®
-
5ÿ
able collagen fiber diameters and an irregular fiber contour in cross-section.
Such fibers are seen in autosomal dominant forms of Ehlers-Danlos syndrome
associated with mutations in the type V collagen gene.
Mature collagen fibers are relatively inert and can exist in tissues under -M, ? 7';
normal physiologic conditions for long periods. However, there is some
continuous turnover of collagen that involves a number of enzymes of
the matrix metalloproteinases (MMP) family. These proteinase families
include the collagenases, gelatinases, stromelysins, matrilysins, and the
membrane-type MMPs.4 The MMPs are synthesized and secreted as inert
Fig. 1.83
*
Normal skin of back: broad bundles of collagen typify the reticular dermis.
Masson's trichrome.

proenzymes which become activated proteolytically by removal of the

approximately 64 nm (Fig. 1.84). The cross-striations are seen because of
propeptide. The MMPs are zinc metalloenzymes and require calcium for
the longitudinal overlap of individual collagen molecules, which occurs dur-
their activity. The MMPs also have specific small molecular weight pep-
ing assembly of the mature fibril. Fibrous long-spacing collagen is a vari-
tide inhibitors, known as tissue inhibitors of metalloproteinases (TIMPs).
ant with a periodicity of 90–120 nm (Fig. 1.85). It is characteristically seen
These proteins stoichiometrically complex with MMPs to prevent colla-
in peripheral nerve and central nervous system tumors. Collagen bundles
gen degradation. In normal human skin, a number of MMPs are syn-
exhibit anisotropy and are therefore birefringent when viewed with polar-
thesized and secreted by fibroblasts and keratinocytes. The expression of
ized light (Fig. 1.86).
these enzymes is enhanced in various pathologic states, including inva-
sion and metastasis of cutaneous malignancies, as well as during dermal
wound healing. Dermal elastic tissue
Within the papillary dermis, collagen fibers are fine and often verti-
cally orientated whereas reticular dermal collagen consists of broad, thick The elastic fiber network provides resilience and elasticity to the skin.1 Elastic
bundles generally arranged parallel to the surface epithelium (Figs 1.82, fibers are a relatively minor component in normal sun-protected adult skin, com-
1.83). When longitudinal sections of collagen are examined by transmis- prising less than 2–4% of the total dry weight of the dermis. The ­configuration
sion electron microscopy they show cross-striations with a periodicity of of elastic fibers in the reticular dermis consists of horizontally orientated fibers
 Dermal elastic tissue 25

.....
wan*!*''"’*" •; which interconnect (Fig. 1.87).2 Extending from these into the papillary ­dermis

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elastin (elaunin fibers) (Fig. 1.88).3 Elastic fibers have two principal compo-
P\33S*

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BfiVr nents: elastin, which is a connective tissue protein that forms the core of the
>'W mature fibers, and the elastin-associated microfibrils which consist of a family
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tin core that makes up over 90% of the elastic fiber and which is surrounded
V •
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that about one-third of the total amino residues consist of glycine but the pri-
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residues. The lysine residues in tropoelastin are critical for the formation of
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Fig. 1.84 specific cross-links is oxidative deamination of three lysine residues to form
Collagen: it is characterized by cross-striations with a periodicity of 64 nm.

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Fibrous long-spacing collagen: compare with the adjacent conventional collagen Reticular dermis: the elastic fibers are long and fairly thick and tend to run parallel to
fibers. There is a very different periodicity. the surface epithelium.

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Fig. 1.86 Fig. 1.88

Collagen of the reticular dermis: note the birefringence when viewed with polarized Papillary dermis: the elastic fibers are delicate and orientated perpendicular to the
light. Masson's trichrome. epithelial surface. Weigert–van Gieson stain.
26 The structure and function of skin

• Y: : • w ,
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Fig. 1.89 Ground substance: an eccrine gland from the sole of the foot shows an abundance
Elastic fiber: this consists of microfibrils embedded in an electron-dense matrix of glycosaminoglycans.
called elastin.

aldehydes, known as allysines. These aldehydes, with additional lysine, fuse
to form a stable desmosine compound which covalently links two of the tro-
poelastin polypeptides. Addition of desmosines to other parts of the molecule
progressively converts tropoelastin molecules into an insoluble fiber struc-
ture. The oxidative deamination of lysyl residues to corresponding aldehydes
is catalyzed by a group of enzymes, lysyl oxidases, which require copper for
their activity. Thus, copper deficiency can lead to reduced lysyl oxydase activ-
ity and synthesis of elastic fibers that are not stabilized by sufficient amounts
of desmosines. In such a situation, the individual tropoelastin polypeptides
remain soluble and susceptible to non-specific proteolysis, and the elastin-rich
tissues are fragile. The metabolic turnover of elastin is slow, but is increased
in some forms of cutis laxa and cutaneous aging. Elastic fibers are degraded
by elastases and metalloelastases.
The elastin-associated microfibrils consist of tubular structures of ≈10–
12 nm in diameter. These proteins include fibrillin, the latent transforming
growth factor-β binding family of proteins, and the fibulins. Other compo-
nents comprise the families of microfibril-associated glycoproteins and micro-
fibril-associated proteins (MFAP), the emilins and certain lysyl oxidases. The
importance of the fibrillin is illustrated by mutations resulting in Marfan
syndrome with skeletal abnormalities, aortic dilatation, subluxation of the
ocular lens, and cutaneous hyperextensibility.5 Likewise, the significance of
certain fibulins is evident from mutations resulting in cutis laxa, manifesting
with loose and sagging skin and loss of elastic recoil.
Ground substance
Proteoglycans form a number of subfamilies defined by a core protein to which
polymers of unbranched disaccharide units, glycosaminoglycans (GAGs), are
linked.1 The core proteins can be intracellular, reside on the cell surface, or
be part of the extracellular matrix and the GAGs are highly charged polyan-
ionic molecules that vary greatly in size. For example, dermal fibroblasts can
synthesize versican which consists of a core protein with attachment sites for
12 to 15 GAG side chains. The GAGs in versican are primarily chondroitin
sulfate or dermatan sulfate, but versican can also bind hyaluronic acid, result-
ing in formation of large aggregates. Proteoglycan/GAG complexes have mul-
tiple functions. For example, the proteoglycans containing heparan sulfate
and dermatan sulfate have the ability to bind extracellular matrix compo-
nents, including various collagens.2 In addition, these proteoglycans bind
several growth factors, cytokines, cell adhesion molecules, and growth fac-
tor binding proteins, thereby influencing the bioactivity of these molecules.
They can also serve as antiproteases. In addition to binding to a number
of extracellular molecules, proteoglycans also play a role in the adhesion of
cells to the extracellular matrix. For example, syndecan-4, which is selectively
enriched in dermal fibroblasts, facilitates the adherence of cells in conjunc-
tion with other extracellular matrix binding molecules, such as the integrins.3
Proteoglycans also interact with other extracellular matrix molecules besides
collagen; notably, chondroitin sulfate and dermatan sulfate bind fibronectin
and laminin. The largest extracellular GAG, hyaluronic acid, plays an impor-
tant role in providing physical and chemical properties to the skin, mediated
in part by its hydrophilicity and viscosity in dilute solutions. Of particular
note, hyaluronic acid has an expansive water-binding capacity, providing
hydration to normal skin. Indeed, water makes up ≈60% of the weight of
normal human skin in vivo. Other properties attributed to large proteogly-
cans complexes, such as those formed with the versican or basement mem-
brane proteoglycans, include their ability to serve as ionic filters, regulate salt
and water balance, and provide an elastic cushion.1
Except when present in very large amounts, ground substance cannot be
easily detected by routine hematoxylin and eosin staining (Fig. 1.90). Cationic
dyes, such as Alcian blue at appropriate pH and electrolyte concentration, are
usually necessary for its demonstration.
Fibroblast biology
The main cell responsible for the synthesis of collagens, elastic tissue and
proteoglycan/glycosaminoglycan macromolecules in the dermis is the fibro-
blast.1 In the mid-dermis of postnatal skin, the number of fibroblasts ranges
from 2100 to 4100 per mm3, and the cells have a limited replicative capacity
ranging from 50–100 cell divisions. Fibroblasts also play a significant role
in epithelial–mesenchymal interactions, secreting various growth factors and
cytokines that have a direct effect on epidermal proliferation, differentiation
and formation of extracellular matrix. The term fibroblast refers to a fully
differentiated, biosynthetically active cell, while the term fibrocyte refers to
an inactive cell.
Myofibroblasts are a specialized form of fibroblast found in granulation
tissue and are involved in wound contraction. They are functionally distinct
from other fibroblasts with ultrastructural, biochemical and physical fea-
tures of smooth muscle cells. Moreover, myofibroblasts are characterized
by the presence of intracellular bundles of α smooth muscle actin, which is
the actin isoform expressed by smooth muscle cells. Currently it is thought
that the evolution of myofibroblasts involves a preceding form known as
the protomyofibroblast, although the latter do not always become the fully
differentiated myofibroblast. In contrast to myofibroblasts, protomyofibro-
blasts have stress fibers but no α smooth muscle actin filaments. A bio-
synthetically active fibroblast has an abundant cytoplasm, well-developed
rough endoplasmic reticulum, and prominent ribosomes attached to the
membrane surfaces.

Fibroblasts from different anatomical sites all have similar morphology
but fibroblasts in different sites have their own gene-expression profiles and
characteristic phenotypes, synthesizing extracellular matrix proteins and
cytokines in a site-specific manner.2
Dermal fibroblasts have numerous functions, not only in synthesizing and
depositing extracellular matrix components, but also in proliferation and migra-
tion in response to chemotactic, mitogenic and modulatory cytokines, and also
autocrine and paracrine interactions. Autocrine activity includes the trans-
forming growth factor (TGF)-β-induced synthesis and secretion of connective
tissue growth factor which promotes collagen synthesis as well as fibroblast
proliferation. Paracrine activity affects keratinocyte growth and differentiation,
specifically through fibroblast secretion of keratinocyte growth factor (KGF),
granulocyte-macrophage colony-stimulating factor, interleukin (IL)-6 and fibro-
blast growth factor (FGF)-10. Fibroblasts also contribute to basement membrane
formation partly by producing type IV collagen, type VII collagen, laminins and
nidogen, but also through the secretion of cytokines, such as TGF-β, that stimu-
late keratinocytes to produce basement membrane components.
Neovascularization and lymphangiogenesis are also important processes for
the maintenance of normal skin homeostasis and wound healing, for which
fibroblasts have an important paracrine role. Members of the vascular endothe-
lial growth factor (VEGF) family include VEGF-A, -B, -C, and -D, which are
produced by normal human fibroblasts and are important in regulating vascu-
lar and lymphatic endothelial cell proliferation through specific receptors.
There is, however, considerable heterogeneity within fibroblast popula-
tions. For example, fibroblasts isolated from the papillary dermis compared
to the reticular dermis have higher rate of synthesis of type III collagen and
there can be as much as 30-fold differences in the level of fibronectin expres-
sion within individual cells. Fibroblasts from the papillary dermis appear
smaller, grow faster and have a longer replicative lifespan.3 When co-cultured
with keratinocytes, papillary dermal fibroblasts produce a more differentiated
and organized epidermis with complete formation of the dermal–epidermal
junction. Papillary dermal fibroblasts also produce more granulocyte–mac-
rophage colony-stimulating factor (GM-CSF) and relatively less keratinocyte
growth factor (KGF) than reticular dermal fibroblasts. In addition, there are
differences in the synthesis of some extracellular matrix components, such
as decorin. While fibroblasts demonstrate certain variability in their gene
expression profiles they are considered fully differentiated cells with relatively
little plasticity. Recent observations, however, suggest that fibroblasts can be
induced to become pluripotent stem cells (iPS), essentially indistinguishable
from the embryonic stem cells, by transduction of cultured fibroblasts with
four transcription factors, Oct4, Sox2, Klf4, and c-myc.4
Cutaneous blood vessels and lymphatics
The skin receives a rich blood supply from perforating vessels within the skele-
tal muscle and subcutaneous fat.1 Most of the blood flow is directed toward the
more metabolically active constituents of the skin, namely the epidermis, hair
papillae and the adnexal structures. While the dermal papillae are richly vascu-
larized, no capillaries actually enter the epidermis, which receives its nutrition
by diffusion. The subcutaneous vessels give rise to two vascular plexuses linked
by intercommunicating vessels: the deep vascular plexus lies in the region of the
interface between the dermis and subcutaneous fat, and the superficial vascu-
lar plexus lies in the superficial aspects of the reticular dermis and supplies the
papillary dermis with a candelabra-like capillary loop system (Fig. 1.91). Each
loop consists of an ascending arterial limb and a descending venous limb. The
vessels of the dermal papillae comprise terminal arterioles, arterial and venous
capillaries, and postcapillary venules, with the last predominating. Within the
deep vascular plexus are small muscular arteries, which give rise to the arteri-
oles that supply the superficial vascular plexus (Fig. 1.92).
The histology of these plexuses is similar, the difference being one of size
rather than structure (arterioles have a diameter of less than 0.3 mm).2 From
the lumen outwards the arteriole consists of a very thin intima resting against a
conspicuous internal elastic lamina. Next to this is the media, consisting of two
layers of smooth muscle, which constitutes the bulk of the vessel. The adven-
titia surrounding the media is composed of loose connective tissue. In small
muscular arteries (but not arterioles), the adventitia often contains elastic fibers
Cutaneous blood vessels and lymphatics 27
Epidermis
Papillary dermis
Superficial
vascular plexus
Reticular dermis
Deep
vascular plexus
Subcutaneous fat Fig. 1.91
Relationship of the
superficial and deep
vascular plexuses.
constituting the external elastic lamina. Small arterioles have an endothelium
surrounded by a single layer of smooth muscle. Capillaries consist of a single
layer of endothelial cells, but may have adjacent pericytes, which have less
well-developed dense bodies and fewer filaments than smooth muscle cells.
Endothelial cells and pericytes form tight junctions. Venous capillaries have
numerous pericytes and a multilayered basement membrane in contrast to
arterial vessels where the basement membrane is solitary and homogeneous.
Each dermal papilla is supplied by a single capillary loop. Endothelial cells
contain vimentin filaments, Weibel-Palade bodies measuring approximately
0.1 × 3.0 μm (containing factor VIII) and numerous pinocytotic vesicles (Figs
1.93, 1.94). Postcapillary venules are larger, but have the same basic struc-
ture as capillaries. Their wall is devoid of smooth muscle. The small muscu-
lar venules into which the postcapillary venules drain have an intima made
up of flattened endothelial cells surrounded by a smooth muscle layer one or
two cells thick. They are therefore similar to small arterioles, but with much
wider lumina. Veins are composed of an endothelium surrounded by a muscle
coat several layers thick. Typically, an internal elastic lamina is poorly repre-
sented. There is usually a thick connective tissue adventitia, but elastic fibers
are absent; only very large muscular veins have elastic tissue (Fig. 1.95).
Also present in the dermis are veil cells, which surround all the microves-
sels and separate them from the adjacent connective tissue. Veil cells are long,
thin cells with an attenuated cytoplasm, and they more closely resemble fibro-
blasts than pericytes. They do not have a basement membrane investment and
are located outside the vessel wall.
The capillary loop in the dermal papilla has an ascending arterial compo-
nent and an intrapapillary segment, which is characterized by a hairpin turn
and a descending venous capillary segment. Capillary loops run perpendicular
to the skin surface, except in the nail where they have a parallel orientation.
The dermis is richly supplied with arteriovenous anastomoses. Specialized
shunts (glomus bodies), found primarily in the dermis of the fingertips, con-
sist of an arterial segment (Sucquet-Hoyer canal), which connects directly
to the venous limb (Fig. 1.96). The canal is surrounded by several layers of
modified smooth muscle cells (glomus cells) with a particularly rich nerve
supply. Glomus bodies function as sphincters, allowing the capillaries of the
superficial dermis to be bypassed, therefore increasing the venous return from
the extremities.
Cutaneous blood flow (under hypothalamic control) is of extreme impor-
tance in thermoregulation. Mediated by the autonomic nervous system, heat
loss can be increased or decreased by varying the blood flow to the superficial
vascular plexuses. If the environmental temperature exceeds that of the body,
then the blood flow to the papillary dermis increases. A concomitant increase
in eccrine sweat gland secretion, evaporation of which cools the outer parts
of the body, lowers the temperature of the circulating blood and maintains a
stable core temperature. Temperature control therefore depends on a delicate
interplay between both vascular and sweat gland functions.
28 The structure and function of skin

>•
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rw ft > «, 'ÿ> |A'' Fig. 1.92
r
,\ “-6ÿ5 /dJt *•*£< Small muscular artery from the deep vascular plexus from
the lower leg of an elderly man with endarteritis (intimal
aV5' / T thickening): note the thick muscle coat and conspicuous

f - -hr:j- •/" V 1
'P"'
r<
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internal elastic lamina, the latter accentuated by the
Weigert–van Gieson reaction. (A) Hematoxylin and eosin;
A
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SWSW58E gSS; trunks are very thick and muscular and can be confused with an artery
A
ga&v. Wf,. IV (Fig. 1.98). The absence of an internal elastic lamina readily allows their
ft*
distinction. Vascular endothelial cells may be identified by the monoclo-
* nal antibody CD31 or by an anti-von Willebrand factor antibody. Vascular
endothelial growth factor receptor 3 (VEGFR-3) has not lived up to its
r .
SOiraE., V
promise to be a useful lymphatic endothelial cell marker.5,6 Lymphatic vessel
endothelial hyaluronan receptor 1 (LYVE-1), Prox-1 and podoplanin may
E be more useful.7
f, . •

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Nervous system of the skin
\ The skin may be innervated with around one million afferent nerve fibers.
i

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.

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The cutaneous nerves contain axons with cell bodies in the dorsal root gan-
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glia. Their diameters range from 0.2 to 20.0 μm. The main nerve trunks enter-
;•ÿ «
-, - ing the subdermal fatty tissue each divide into smaller bundles. Groups of
? myelinated fibers fan out in a horizontal plane to form a branching network
-ÿT -
from which fibers ascend, usually accompanying blood vessels, to form a
Fig. 1.93 web of interlacing nerves in the superficial dermis. The cutaneous nerves sup-
Normal dermal capillary: note the lining of endothelial cells surrounded by a pericyte ply the skin appendages and form prominent plexuses around the hair bulbs
cell process and adjacent basal lamina. The lumen contains erythrocytes (E). and the papillary dermis. The afferent receptors consist of free nerve endings,
nerve endings in relation to hair, and encapsulated nerve endings. Free nerve
endings, of both myelinated and nonmyelinated types and with a low conduc-
The dermis also contains an extensive lymphatic system, which is closely tion speed, are mainly responsible for the appreciation of temperature, itch
associated with the vascular plexuses.3 Although largely disregarded except and pain. Hair follicles are supplied by an intricate network of myelinated
for their role in tumor spread, lymphatics are of major importance in fibers, some of which ramify as free nerve endings in the periadnexal fibrous
removing the debris of daily wear and tear including fluid, cells and macro- tissue sheath, while others enter the epidermis to terminate as expansions
molecules (Fig. 1.97). They also represent the primary disposal mechanism in intimate association with Merkel cells in the external root sheath. The
for contaminating microorganisms. Lymphatics have been shown to supply hair disc is a complex structure consisting of basally situated Merkel cells
the major route for epidermal Langerhans cells to reach the regional lymph and an associated myelinated peripheral nerve fiber. Despite the name, it has
node following antigen stimulation. Under normal circumstances these deli- an inconstant association with hair follicles. Hair discs are slowly adapting
cate vessels are collapsed and are difficult to detect. They are supported by mechanoreceptors. Throughout their course the axons of cutaneous nerves
delicate elastic tissue scaffolding and consist of a large thin-walled collapsed are enveloped in Schwann cells but, as they track peripherally, an increas-
vessel lined by attenuated endothelium and characterized by the presence of ing number lack myelin sheaths. Most end in the dermis; some penetrate the
multiple valves. Their presence is much more obvious in obstructive situ- basement membrane, but do not travel far into the epidermis.
ations (e.g., lymphedema or due to the presence of metastases). Dermal Sensory endings are of two main kinds: corpuscular, which embrace non-
lymphatics are loosely aggregated into a superficial and deep plexus, which nervous elements; and ‘free’, which do not. Corpuscular endings can, in turn,
drain into muscularized lymphatic trunks.4 In the lower limbs the lymphatic be subdivided into encapsulated receptors, of which a range occurs in the
 Nervous system of the skin 29

A B

Fig. 1.94
(A) Small dermal arteriole: the lumen is compressed to a narrow slitlike space; (B) high-power view of typical Weibel–Palade bodies. These are characteristic of blood vessel
endothelium.

A B

Fig. 1.95
Companion vein to Figure 1.92: note the wide diameter of the lumen in comparison to the relatively thin muscle coat. There is a little elastic tissue but no discernible internal
elastic lamina. (A) Hematoxylin and eosin; (B) Weigert–van Gieson.

dermis, and nonencapsulated, exemplified by Merkel's ‘touch spot’, which
is epidermal.
The most striking of the encapsulated receptors is the Pacinian corpuscle.
It is an ovoid structure about 1 mm in length, which is lamellated in cross-
section like an onion, and is innervated by a myelinated sensory axon, which
loses its sheath as it traverses the core (Fig. 1.99). Pacinian corpuscles are
responsible for the appreciation of deep pressure and vibration and are found
predominantly in the subcutaneous fat of the palms and soles, dorsal surfaces
of the digits, around the genitalia, and in ligaments and joint capsules.
The Golgi-Mazzoni corpuscle found in the subcutaneous tissue of the
human finger is similarly laminate but of much simpler organization. Another
classical receptor is the Krause end bulb, an encapsulated swelling on myeli-
nated fibers situated in the superficial layers of the dermis.
Meissner's corpuscles are characteristic of the papillary ridges of glabrous
skin in primates. They have a thick, lamellated capsule, 20–40 μm in diameter
and up to 150 μm long (Fig. 1.100).1 Meissner's corpuscles are involved in the
appreciation of touch sensation (rapidly adapting mechanoreceptors) and are
found predominantly in the dermal papillae of the hands and feet, the lips,
and on the front of the forearm. They comprise a perineural-derived lamel-
lated capsule surrounding a core of cells and nerve fibers, and are supplied by
myelinated and nonmyelinated nerve fibers. They make intimate contact with
the basal keratinocytes. Meissner's corpuscles have a multiple nerve supply
and each nerve may also supply multiple corpuscles. Of somewhat different
structure are the terminals first described by Ruffini in human digits, in which
several expanded endings branch from a single, myelinated afferent fiber. The
endings are directly related to collagen fibrils. ‘Free nerve-endings’, which
30 The structure and function of skin

Fig. 1.96 Fig. 1.99

Glomus body: note the arterial and venous limbs connected by a vascular channel Pacinian corpuscle: note the characteristic lamellar internal structure.
rich in glomus cells.

Fig. 1.97
Lymphatics: these exceedingly thin-walled channels are normally not visible in the
dermis. They become readily apparent, however, when obstructed, as in this patient
with lymphedema.

Fig. 1.100
Meissner's corpuscle within a dermal papilla: with hematoxylin and eosin staining it
appears as perpendicularly orientated lamellae of Schwann cells.

appear to be derived from nonmyelinated fibers, occur in the superficial der-

mis and in the overlying epidermis.2 Those in the dermis are arranged in a
tuftlike manner and have thus been designated penicillate nerve endings.

Fig. 1.98
Skin of lower leg: muscular lymphatic trunks can be readily mistaken for arteries.
An internal elastic lamina is characteristically absent.
Subcutaneous fat
Fat is a major component of the human body. In nonobese males, 10–12% of
body weight is fat, while in females the figure is 15–20%. Eighty per cent of fat
is under the skin; the rest surrounds internal organs. Fat comprises white and
brown adipose tissue, the latter being more common in infants and children
and is characterized by different mitochondrial properties and increased heat
production.1 Historically, fat has been thought to provide insulation, mechani-
cal cushioning and an energy store but recent data suggest that it also has an
 Subcutaneous fat 31

endocrine function, communicating with the brain via secreted molecules such ­ ediastinum. The brown coloration is due to the high cytochrome con-
m
as leptin to alter energy turnover in the body.2 Adipocytes also have important tent. The brown fat cytoplasm contains numerous, somewhat pleomorphic,
signaling roles in osteogenesis and angiogenesis. Indeed, multipotent stem cells mitochondria. Endoplasmic reticulum and a Golgi apparatus are not usually
have been identified in human fat which are capable of developing into adi- visible. The adipocytes have a bubbly appearance with the nucleus located
pocytes, osteoblasts, myoblasts and chondroblasts. Biological clues to genes, towards the center of the cell (Fig. 1.103).
proteins, hormones and other molecules that influence fat deposition and
distribution are gradually being realized, from both research on rare inher-
ited disorders (such as the lipodystrophies or obesity syndromes) as well as
­population studies on more common forms of obesity.3
The subcutaneous fat is divided into lobules by vascular fibrous septa, and
its cells are characterized by the presence of a large single globule of lipid,
which compresses the cytoplasm and nucleus against the plasma membrane
(Fig. 1.101). The adipocyte is large, measuring up to 100 μm in diameter. The
cytoplasm contains numerous mitochondria. Smooth endoplasmic reticulum
is prominent and a Golgi is often conspicuous. Processing for routine histo-
logical preparation dissolves the lipid, but the use of special stains on fro-
zen sections will reveal its presence (Fig. 1.102). The subcutaneous fat may
­contain large numbers of mast cells.
Deposits of brown fat may be seen in the newborn and occasionally
in adults, particularly in the interscapular region, the back, thorax and

Fig. 1.102
Adult fat in frozen section stained by the Sudan IV technique.

Fig. 1.101
The lipid contents of fat cells are dissolved during processing using conventional
(paraffin-embedding) techniques. The cells therefore appear empty and have Fig. 1.103
peripheral compressed nuclei. Typical brown fat showing pink granular cytoplasm.
Chapter
Specialized techniques in
2 dermatopathology
Pratistadevi K. Ramdial, Boris C. Bastian, John Goodlad, John A. McGrath and
Alexander Lazar
See
www.expertconsult.com
for references and
additional material

Specimen fixation, grossing/put-through, Immunofluorescence 35 Polymerase chain reaction (PCR) 43

processing, embedding and
Electron microscopy 37 Diagnosis of lymphomas 43
sectioning 32
PCR analysis of cutaneous lymphoid infiltrates 44
Diagnosis of inherited skin diseases 37
Routine and ‘special’ stains 33 TCR gene rearrangement in cutaneous
Molecular techniques 39 lymphoproliferations 44
Immunohistochemical techniques 34 IG gene rearrangement in cutaneous
Chromosomal karyotyping 39
Immunohistochemical techniques and Allelic imbalance 39 lymphoproliferations 45
trouble shooting 34 Fluorescence in situ hybridization (FISH) 39
Comparative genomic hybridization (CGH) 42

Specimen fixation, grossing/ put-through,
processing, embedding and sectioning
The aim of fixation in dermatopathology is to maintain clear and consistent
morphological features and to preserve tissue in an optimal state suitable for
a range of staining and ancillary histopathological techniques.1,2 Most fixa-
tion methods employed during tissue processing depend on chemical fixa-
tion of tissue in liquid fixatives.3 Tissue fixation may also be accomplished
by physical (heat, microwave, freeze-drying and freeze substitution) and/or
chemical (coagulant and cross-linking) methods.4 The most commonly used
fixative is 10% neutral-buffered formalin solution. The quality of fixation is
affected by:
• the size of the specimen,
• duration and temperature of fixation,
• pH,
• concentration,
• osmolality,
• ionic composition of fixatives and additives contained in the fixative.5
Formalin fixation occurs at an approximate rate of 1 mm per hour.4,6,7
The volume of the fixative should be at least 10 times the volume of the
specimen.7 Large specimens, such as tumors, may require sectioning into
5-mm thick slices, covering with fixative soaked gauze or cloth and fixation
overnight.5,7
Diagnostic dermatological biopsies may be:
• small incisional (shave, core, punch),
• excisional specimens.8
Prior to put-through, excisional specimens that require an appraisal of
margins should be inked. If localization sutures have been inserted by sur-
geons then four-quadrant, four-color painting or two-color painted halves
(Fig. 2.1) may be appropriate. Shave biopsies are used to sample or remove
lesions, and if of appropriate size, may be divided into sections, bisected or
trisected and embedded on edge. Edge embedding is critical in a shave exci-
sion of a lesion such as a small melanoma so that the width and depth of
invasion can then be quantified.8,9 The main purpose of core or punch biop-
sies, which generally measure 2–8 mm in diameter, is to sample large lesions.
Biopsies larger than 4 mm in size should be bisected eccentrically and the
specimens embedded with the cut surfaces down. The eccentric sectioning
ensures that the lesion is not missed. Biopsies less than 4 mm are put through
in toto.9,10
Tissue processing refers to a series of steps that effect the removal of
extractable water from biopsies to ensure sections of optimal diagnostic qual-
ity.9 These include fixation, dehydration, clearing, infiltration and embedding
in a support matrix. Use of manual and automated tissue processing achieves
this goal, including:
• carousel-type processors,
• self-contained vacuum tissue processors,
• microwave tissue processing.
In most laboratories, overnight processing runs are the norm. 9
However, microwave-assisted tissue processing facilitates shorter pro-
cessing times of one to two hours. Dehydrating reagents promote the
removal of unbound water and aqueous fixatives from the tissue.
Clearing reagents serve as an intermediary between the dehydrating and
infiltrating solutions, being miscible with both. Paraffin is the most pop-
ular infiltration and embedding medium, being suitable for the major-
ity of routine and special stains. The important principle to be adhered
to during embedding of skin biopsies is that the orientation of the skin
sample should offer the least resistance to the blade during microtomy.
Skin biopsies are usually cut in a plane at right angles to the epidermis
so that the epidermal surface is sectioned last, minimizing its compres-
sion and distortion.
Suboptimally processed tissue may result in incomplete tissue sections and
expansion or disintegration of sections in the water bath. Incorrectly embed-
ded tissue may result in poorly orientated incomplete sections. Faulty micro-
tome mechanisms, loose, dull or damaged blades and inaccurate clearance
angles may be the causes for:
• thick and thin sections,
• folds (Fig. 2.2),
• holes (Fig. 2.3),
• scores (Fig. 2.4),
• chatter.10
The presence of calcified areas and suture in skin tissue and nicks in the
blade may result in chatter or splitting of sections at right angles to the knife
edge.
 Routine and ‘special’ stains 33

A B C D

Fig. 2.1
Gross representation of basal cell carcinoma: (A) with two-color painting of the
inferior surface (B). A 2-mm thick gross sections demonstrating the black and
blue painting at put through (C) and in paraffin blocks (D). By courtesy of Dr. J.
Deonarain, Department of Anatomical Pathology, National Health Laboratory
Service, Durban, South Africa.

Fig. 2.3
Technical artifact: holes in
tissue sections because
tissue sections were cut
too thin.

Fig. 2.2
Technical artifact: folds in tissue sections because of poor water bath floating
technique.

Routine and ‘special’ stains

With the advent of immunohistochemistry, special stains are less commonly
employed, but can still play an important role in highlighting certain tissue
characteristics or for detection of infectious organisms.
Diagnostic sections are usually stained with hematoxylin and eosin (H&E),
the most widely used routine stain.1 The hematoxylin component stains the
nuclei blue-black and the eosin stains the cytoplasmic compartment and con-
nective tissue in variable shades and intensity of pink, orange and red. The
periodic acid-Schiff (PAS) technique is used widely to demonstrate: Fig. 2.4
Technical artifact: score
• glycogen, in tissue section because
• starch, of a damaged microtome
• sialomucin, blade.
• neutral mucin,
• basement membranes,
• α1-antitrypsin, charides are not. Mucicarmine demonstrates acidic epithelial mucins.2 It is
• reticulin, useful for the diagnosis of adenocarcinomas and the mucoid C. neoformans
• Russell bodies of plasma cells, capsule. Alcian blue highlights acidic mucopolysaccharides, staining the muci-
• fungi.2 nous components of dermal mucinoses, granuloma annulare, scleredema of
The PAS technique is therefore employed to demonstrate basement mem- Bushke, lupus erythematosus and metastatic adenocarcinomas. Alcian blue
brane thickening in lupus erythematosus, porphyria cutanea tarda and in demonstrates heterogeneity of staining that is pH based: sialomucins are
some tumors. Glycogen is digested by diastase, while neutral mucopolysac- demonstrated at pH 2.5 and sulfamucins at pH 1.0.3
34 Specialized techniques in dermatopathology

Table 2.1
The more commonly used histochemical stains
Stain Component Outcome
A. Routine
Hematoxylin- Cells, connective Nuclei: blue
eosin tissue Cytoplasm: pink/red
Extracellular matrix:
red/pink
B. Carbohydrates &
glycoconjugates
Periodic acid-Schiff Neutral mucins, glycogen Magenta
PAS-diastase Glycogen, Resistant to
proteoglycans, HA diastase
resistant sialomucin digestion
Alcian blue, pH 2.5 Labile sialomucin Blue
Alcian blue, pH 1.0 Sulfomucin, resistant Blue
sialomucin
Mucicarmine Sialomucin, sulfomucin Pink
Colloidal iron Sialomucin, sulfomucin Blue
Fig. 2.5 HA, proteoglycans
Special stains: Warthin-Starry silver stain demonstrating Donovan bodies. High iron diamine Proteoglycans, Blue
sulfomucin
Toluidine blue Sulfomucin Blue
Hyaluronidase HA Sensitive to HA
While colloidal iron, initially described by Hale for the identification of
acid mucopolysaccharides, is as sensitive as Alcian blue for this purpose, C. Connective tissue
its specificity and selectivity are debatable and background staining may be fibers
problematic.4 However, reduction of pH of the colloidal iron solution and Masson trichrome Collagen Blue or green
Muscle, nerve Red
inclusion of acetic acid washes may reduce this artifact.3–5 The high iron
Verhöeff-van Gieson Elastic fibers Black
diamine stain, in contrast to colloidal iron, stains highly acidic sulfamu- Pinkus acid orcein Elastic Dark brown
cins but does not stain sialomucins or hyaluronic acid.5–7 Connective tissue Silver nitrate Reticulum fibers Black
stains highlight collagen, elastic and reticulin fibers. The trichrome stain, a
D. Infective stains
combination of three dyes, is employed for the differential demonstration
Ziehl Neelsen Acid fast bacilli Red
of muscle, collagen fibers, fibrin and erythrocytes.8 Elastic fibers may stain
Fite-Faraco (weakly) acid fast bacilli Red
with eosin, phloxine, Congo red and PAS stains but are demonstrated well Periodic acid-Schiff Fungi, parasites Magenta
with the Verhöeff method in the diagnosis of scleroderma, anetoderma and Mucicarmine Cryptococcus sp Red
pseudoxanthoma elasticum. Silver stains are useful to demonstrate reticulin Giemsa Leishmania sp, Red
fibers, melanin and the identification of infective agents. While methenamine Donovan bodies Metachromatically
silver and Gomori Grocott methenamine silver stains highlight fungi and purple
bacteria, Warthin-Starry, Dieterle and Steiner silver stains are particularly Methenamine silver Fungi, bacteria Black
useful in the demonstration of spirochetes, B. henselae and Donovan bodies Grocott Fungi Black
(Fig. 2.5). Masson-Fontana silver staining is pivotal to the staining of the methenamine
silver
cell wall of C. neoformans, especially in the identification of capsule-deficient
Warthin Starry silver Spirochetes, bacteria Black
C. neoformans. The role of the more commonly used special stains is sum-
Dieterle and Spirochetes, bacteria Black
marized in Table 2.1. Steiner silver
E. Other
Immunohistochemical techniques Perl's potassium Hemosiderin Blue
ferrocyanide
Since the first practical application of antibodies using the peroxidase labeled Oil red O Lipids Red
antibody method on paraffin-embedded tissues in 1968, immunohistochemis- Scarlet Red Lipids Red
Von Kossa Phosphate (often as Black
try (IHC) has emerged as a powerful supplementary investigation to histomor-
calcium phosphate) Black
phologic assessment.1–3 IHC has widespread dermatopathologic diagnostic,
Alizarin red S Calcium Orange-Red
prognostic, therapeutic and pathogenetic applications, not only in a range of Alkaline Congo Red Amyloid Apple green
neoplastic (Table 2.2), immunobullous and infective disease, but also in the birefringence
distinction between reactive and neoplastic disorders.4–14 Immunohistologic Chloro-acetate Myeloid series Red granules
techniques can be performed manually or in automated platforms. While esterase
automation allows enhanced quality and reproducibility of staining, detailed,
exact IHC protocols are critical in the many laboratories that still perform Key: HA, hyaluronic acid

manual IHC, to achieve optimal, reproducible results.

Immunohistochemical techniques and
trouble shooting
In many centers, IHC is now the most commonly utilized ancillary test for
clinical tissue samples.
Historically, the introduction of enzymes as labels in IHC overcame dif-
ficulties associated with immunofluorescence, including the inability to
assess histomorphology with the latter.1 The peroxidase-antiperoxidase
(PAP) technique, was replaced by alkaline phosphatase-antialkaline phos-
phatase (APAAP) techniques and avidin-biotin labeling.1,2 Although the
­streptavidin-biotin labeling system gained popularity, the endogenous biotin-
associated background staining under certain circumstances has resulted in
increasing use of labeled polymer-based detection systems, suitable for man-
ual and automated IHC platforms (Fig. 2.6).3
The direct conjugation of the primary antibody to the label formed the
principle of the initial, traditional direct technique, in which the labeled

Table 2.2
Some diagnostic immunohistochemical applications for cutaneous tumors4–13
Stain Application
Epidermal and appendageal neoplasms
AE1/AE3 Pan-keratin. Confirms epithelial lineage
CAM 5.2 CKs 8,18. Confirm epithelial lineage. Useful to confirm
glandular neoplasms
MNF 116 CKs 5, 6, 8, 17, 19. Useful in diagnosis of SCC with
single cell infiltration
BerEP4 Positive in BCC. Negative in SCC.
CK 7 Confirmation of mammary and extra-mammary Paget's
disease
p63 Distinguish primary cutaneous spindle SCC from
mesenchymal spindle cell tumors & primary
cutaneous adnexal from metastatic adenocarcinomas
CD10 Trichoepithelioma: positive in stroma and papillae,
negative in epithelium. BCC: positive in epithelium,
negative in stroma.
bcl2 Positive in BCC, negative in SCC.
Vascular proliferations
CD31 High specificity and good sensitivity for endothelial tumors
CD34 High sensitivity but low specificity for endothelial tumors
Fli-1 Nuclear staining of endothelial tumors
GLUT 1 Positive in endothelial cells of all juvenile hemangiomas.
Usually negative in congenital hemangiomas
(rapidly involuting congenital hemangioma and non-
involuting congenital hemangioma)
Melanocytic tumors
S-100 protein Most widely used melanocytic marker. It is highly sensitive
but not as specific as other melanocytic markers
HMB 45 Good specificity but relatively low sensitivity.Tends to
be negative in spindle cell melanoma. Also positive in
PEComa.
Melan A/Mart 1 Similar specificity to HMB45. Tends to be negative in
spindle cell melanomas.
Ki-67 Higher proliferation index in melanoma (13–35%)
than in nevi (<5%). Useful in the evaluation of some
melanocytic tumors, mainly nevoid melanoma
Neuroectodermal and neural tumors
S-100 protein Positive in neuroectodermal, neuronal, nerve sheath,
chondroid tumors, some sweat gland tumors and
myoepithelioma
NSE Merkel cell carcinoma
CK 20 Merkel cell carcinoma
Neurofilament Merkel cell carcinoma
Chromogranin Merkel cell carcinoma
Synaptophysin Merkel cell carcinoma
TTF1 Negative in most Merkel cell carcinoma
Myogenic/myofibroblastic differentiation
MSA Tumors of muscle origin
Desmin Tumors of muscle origin (smooth muscle and skeletal
muscle, rarely and focally in myofibroblastic tumors)
Myogenin Positive in rhabdomyosarcoma
SMA Positive in smooth muscle tumors, glomus tumor,
myopericytoma, dermatomyofibroma
BCC, basal cell carcinoma; SCC, squamous cell carcinoma; SMA, anti-smooth muscle
actin; MSA, muscle specific actin; CK, cytokeratin.
a­ ntibody reacted directly with the tissue antigen.1 In the two-step indirect
technique, labeled secondary antibody directed against the immunoglobulin
of the animal in which the primary antibody was raised was used to visual-
ize an unlabeled primary antibody.4 The labeled streptavidin-biotin (LSAB)
method is a three-step technique. An unconjugated primary monoclonal
or polyclonal antibody, attached to the tissue antigen forms the first layer,
­creating an antigen-antibody complex. The second layer is formed by a bioti-
nylated secondary antibody raised against the same species of the primary
Immunofluorescence 35
animal.1 The secondary antibody binds to the primary antibody with the
biotinylated end being available for binding to a third layer. This layer may
bind either to enzyme-labeled streptavidin or to a complex of enzyme-labeled
biotin and streptavidin. The enzyme may be horseradish peroxidase or alka-
line phosphatase. An appropriate chromogen is used for detection. In the per-
oxidase method, peroxidase-oriented chromogens such as diaminobenzidine
or 3-amino-9 ethylcarbazole are appropriate. Indole reagents (red), naphthol
fast red (red) or NBT / BCIP (blue) are the chromogens used in the alkaline
phosphatase-streptavidin method.1,4
The presence of endogenous biotin and resultant background staining led
to the introduction of the increasingly popular polymer-based immunohis-
tochemical methods. In the new direct Enhanced Polymer One Step (EPOS)
technique, approximately 70 enzyme molecules and 10 primary antibodies
are conjugated to a dextran ‘backbone’. While the entire IHC procedure is
completed in one step, the method is limited to highly select manufacturer-
specific primary antibodies. Other newer polymer detection systems with a
dextran backbone to which multiple enzyme molecules may attach are avail-
able for manual and automated IHC. These quick, reliable and reproducible
techniques are also characterized by greater sensitivity. Single-, dual-, and
triple-color staining with different chromogens is possible.1,2,4,5
Background staining is a common difficulty that has multiple predispos-
ing causes.6 While monoclonal antibodies reduce non-specific background
staining, not only must antibody concentrates and prediluted preparations be
optimized for usage at the correct dilution in different laboratories (Figs
2.7 and 2.8), diluent pH is also critical in ensuring the absence of antibody
degeneration and resultant background staining. Avidin-biotin detection sys-
tems and horseradish peroxidase systems may require biotin blocking and
endogenous peroxidase quenching steps to decrease unnecessary background
staining. Polymer-based detection systems can effectively eliminate biotin-
induced false-positive staining. While antigen retrieval techniques are criti-
cal for antigen unmasking, optimal results require control of the pH and
temperature of retrieval solutions and controlled enzymatic digestion (Fig.
2.9).7–10 The latter causes excessive background staining when sections are
exposed to increased digestion time, inappropriate high temperature and
inadequate rinsing, causing protein diffusion into or deposition in skin sec-
tions and b­ ackground staining.
Chromogen entrapment, precipitation and contaminants may lead to false-
positive interpretation of an IHC test. Depletion of peroxidase or alkaline
phosphatase chromogenic activity, a consequence of the breakdown of chro-
mogens because of the sensitivity to light and heat, results in a background
blush. A  similar effect is seen when there is inadequate chromogen rinsing
or prolonged chromogen time. Filtering of the chromogen is effective in pre-
venting chromogen precipitation. Chatter, tears, folds and wrinkles and poor
adhesion of sections to slides causes entrapment and suboptimal rinsing of
chromogen (Fig. 2.10). Skin sections with a thick stratum corneum, dermal
calcification, or sclerosis may be prone to these artifacts, requiring meticulous
microtomy to prevent its occurrence. The handling of water baths, tissue sec-
tions and slides with ungloved hands may cause contamination of sections
with squames.1
False-negative immunostaining may also compromise IHC interpreta-
tion. Incomplete deparaffinization causes suboptimal or incomplete staining
because of incomplete tissue penetration by the antibody. Overdigestion of
tissue sections by proteolytic enzymes can destroy the tissue sections with
attendant loss of antigen for antibody binding. Other causes of false-negative
immunostaining include:
• incorrect temperature of reagents, including retrieval solutions,
• expired antibodies,
• inappropriate dilutions,
• suboptimal storage of antibodies .1,3
Immunofluorescence
Immunofluorescent techniques have the potential to define antigen-antibody
interactions at a subcellular level.1 This interaction requires the irreversible
binding of a readily identifiable label for its recognition.1,2 Fluorochromes
such as rhodamine or fluorescein are labels that can absorb radiation in the
36 Specialized techniques in dermatopathology

P Antigen

Biotin
B
P Peroxidase
P B B P

P B P Primary
P
Antibody

Secondary
Antibody
P
Secondary Antibody on
a polymer backbone Fig. 2.6
Immunohistochemical techniques:
(A) direct, (B) indirect (C)
streptavidin biotin (D) polymer
chain. By courtesy of Dr. J.
Ag Ag Ag Ag Ag Deonarain, Department of
Direct method Indirect method Avidin-biotin method Polymer chain two step direct method Anatomical Pathology, National
Health Laboratory Service, Durban,
A B C D South Africa.

Fig. 2.7 Fig. 2.9

Technical artifact: poor tissue fixation resulting in incomplete sections, Technical artifact p53 stain: wrinkling and background staining of tissue sections
fragmentation and suboptimal AE1/AE3 stained section. because of erroneously high temperature heat-assisted microwave antigen retrieval
exposure of sections in EDTA buffer (pH 8.0).

Fig. 2.8 Fig. 2.10

Technical artifact: suboptimal antibody concentration of CD3 antibody resulting in Technical artifact: HHV8 stained sections demonstrating chromogen entrapment in
background staining. stratum corneum.
 Diagnosis of inherited skin diseases 37

form of ultraviolet or visible light.1–5 Direct and indirect immunofluorescence
(IMF) techniques demonstrate a range of tissue antigens of dermatopatho-
logic importance, including the diagnosis of infectious and autoimmune blis-
tering disorders.3 In the direct IMF technique, antibody is conjugated directly
with a fluorochrome and is used to detect an antigen in a tissue section using
ultraviolet light microscopy.1–3 In the indirect IMF technique, patient serum
(containing the antibodies) interacts with a tissue section containing the anti-
gen. Antibody to a human immunoglobulin, conjugated to a fluorochrome, is
applied thereafter.1–7 The successful demonstration of the antigen requires the
antigen to remain sufficiently insoluble in situ. Skin biopsies for direct immu-
nofluorescence can be transported fresh on saline-soaked gauze in a container
on ice, or in a transport medium such as Michel medium.8 The transport
medium must be maintained at a pH of 7.0 to 7.2.1,3,5 The main uses for IMF
in dermatopathology are in the interpretation of the autoimmune blistering
diseases, lupus erythematosus, and vasculitis.6,7 In general, immunofluores-
cence has the following advantages over immunohistochemistry:
• more sensitive detection of antigen.
• use of special fixation that preserves ‘difficult’ antigens.
between the dermatopathologist and molecular laboratory is absolutely criti-
cal for efficient use of molecular techniques.
Analysis of the inherited skin blistering disorder known collectively as epi-
dermolysis bullosa (EB) discussed in detail in Chapter 4 demonstrates the
complex, multifaceted approach to diagnosis required in such cases. EB has
been shown to result from mutations in genes encoding at least 11 different
structural proteins at or close to the dermal–epidermal junction (Fig. 2.11).1
Clinically, the different types of EB are characterized by widely differing
prognoses, from death in early infancy to blistering that may become milder
in later life.2 The clinical presentation in neonates, however, can be confusing
to dermatologists and pediatricians because of the overlapping features (Fig.
2.12). In these circumstances, skin biopsy, usually a superficial shave biopsy
since the key region is the dermal–epidermal junction, can provide critical
Keratins
5 & 14
EB simplex

Electron microscopy EB simplex

with muscular Plectin
Electron microscopy is less utilized than in the past. Immunohistochemical 230-kDa
dystrophy
BP Ag
approaches are preferred in those instances where they are a reasonable
Non-Herlitz
substitute. junctional EB
Junctional
Transmission electron microscopy offers better resolution than light α6β4
EB with Type XVII
microscopy.1 To optimize this, tissue has to be embedded in extremely rigid integrin Herlitz &
pyloric atresia collagen
material to allow sectioning at 80 nm. In most circumstances, hydrophobic Laminin-332 non-Herlitz
epoxy resins are preferred. When a specimen is removed for ultrastructural junctional EB
examination, it must be fixed in a suitable fixative immediately. The volume
of the fixative should be 10 times the sample size. The final specimen size is
1 mm2.1 Fixation is affected by:
• pH,
Dominant and
• osmolarity, recessive
Type VII
• ionic composition of buffer, dystrophic EB
collagen
• fixative concentration,
• temperature,
• duration of fixation.
Primary fixation in an aldehyde, usually gluteraldehyde, and secondary
Fig. 2.11
fixation in osmium tetroxide are standard procedures. Advances in immu-
Basement membrane region: protein components at the dermal–epidermal junction
nohistochemistry have decreased the dependence on electron microscopy for and the subtypes of EB that result from mutations in the genes encoding these
ultrastructural confirmation of cell lineage. Notwithstanding, dermatologic proteins.
ultrastructural investigations are important in the diagnosis of:
• undifferentiated tumors,
• immunobullous disease,
• cerebral autosomal dominant arteriopathy with subcortical infarcts and
leucoencephalopathy (CADSIL),
• amyloidosis,
• metabolic storage diseases.2–7
Intercellular junctions, Weibel-Palade bodies, melanosomes, and premelano-
somes may help in the diagnosis of carcinomas, endothelial tumors, and mel-
anocytic tumors, respectively.3 In CADSIL, extracellular, electron-dense granular B
material is present in an indentation in vascular smooth muscle cells.5,6 Amyloid
is identifiable as randomly arranged, extracellular, nonbranching fibrils of inde-
terminate length and 7–10 nm diameter.7 Transmission electron microscopy
remains a valuable tool in the ongoing evaluation of the structure of normal and
pathological human cell and tissue components and infective agents.8–10

Diagnosis of inherited skin diseases

An efficient approach to genetic testing often relies on initial traditional his-
tologic characterization of skin biopsies.
Recent advances in molecular genetics and gene sequencing have led to
many inherited skin diseases being diagnosed or confirmed by clinical molec-
ular biologists rather than dermatopathologists. Analysis of skin biopsies still
remains vital for the accurate diagnosis of several genodermatoses, and often
provides a guide for subsequent molecular analyses. Examination of the skin
biopsy informs the selection of additional molecular testing. Communication
A C
Fig. 2.12
Epidermolysis bullosa: clinical appearances of neonates with different forms of
inherited EB. All three cases have similar blisters and erosions but their respective
prognoses differ considerably; (A) Severe, generalized recessive dystrophic EB; (B)
Dowling-Meara EB simplex; (C) Herlitz junctional EB. Skin biopsy is fundamental to
establishing the subtype of severe forms of EB.
38 Specialized techniques in dermatopathology
Fig. 2.13
Optimal skin biopsy for diagnosing EB: following local anesthesia, the normal-
appearing skin is gently rubbed, and then a superficial shave biopsy is taken. The
skin sample can then be subdivided for immunolabeling of frozen sections as well
as being processed for transmission electron microscopy.
diagnostic and prognostic information. Typically, nonblistered skin from any
body site is sampled. Just before the biopsy is taken, the skin is rubbed gently
in an attempt to induce fresh microsplits at the dermal–epidermal junction, to
facilitate the microscopic subtyping of EB (Fig. 2.13).
The most informative investigation is immunolabeling of the der-
mal–epidermal junction using a panel of basement membrane anti-
bodies. Skin biopsies can be transported in Michel's medium to a
diagnostic laboratory at ambient temperature: this fixative is extremely
useful since basement membrane zone immunoreactivity is main-
tained for at least 6 months. 3 For the immunolabeling, frozen skin
sections are used rather than formalin-fixed paraffin-embedded mate-
rial because the antigenic epitopes of several transmembranous pro-
teins may be lost in routine skin processing. The basement membrane
Fig. 2.14
Antigen mapping to diagnose the subtype of inherited EB: this picture shows
immunolabeling of rubbed skin from an individual with EB (case illustrated in
Fig. 2.12a) with an anti-type IV collagen antibody. Rubbing the skin induces microsplits
at the dermal–epidermal junction (asterisk). The type IV collagen reactivity maps to the
roof of the dermal–epidermal junction (arrows). This indicates a sub-lamina densa plane
of cleavage and establishes a diagnosis of dystrophic EB. (Bar = 25 μm.)
A B
Fig. 2.15
Specific antibody probes to subtype inherited EB: (A) immunostaining of normal
control skin with an antibody to type VII collagen shows bright linear labeling at the
dermal–epidermal junction; (B) in contrast, the complete absence of labeling in skin
from an individual with EB (case illustrated in Fig. 2.12a) indicates a diagnosis of severe,
generalized recessive dystrophic EB. (Bar = 50 μm.)
antibodies can be used either to determine the level of cleavage in the
skin (antigen mapping) or to see if there is a reduction or absence of
immunostaining for a particular antigen.4 Figure 2.14 , for example,
demonstrates labeling using an antibody against type IV collagen in skin
from the neonate illustrated in Figure 2.12a . In this example, labeling
maps to the roof of the split. This indicates that the lamina densa is in
the blister roof and that there is a sublamina densa plane of blister for-
mation. These findings support a diagnosis of dystrophic EB. This diag-
nosis can be refined by immunolabeling with an antibody to type VII
collagen, as shown in ( Fig. 2.15 ). In normal skin there is bright, linear
labeling at the dermal–epidermal junction; however, in the skin from the
neonate shown in Figure 2.12a , there is a complete absence of type VII
collagen immunoreactivity. All other antibodies show normal ­reactivity
Fig. 2.16
Transmission electron microscopy of skin in Dowling-Meara EB simplex (case
illustrated in Fig. 2.12b): within the basal keratinocyte cytoplasm the keratin
filaments are condensed and form clumps and there is cytolysis that occurs just
above the dermal–epidermal junction. (Bar = 1 μm.)
 Molecular techniques 39

at the dermal–epidermal junction. These findings therefore establish a

diagnosis of severe, generalized recessive dystrophic EB. Reduced or Molecular techniques
absent immunolabeling with specific basement membrane antibodies is
an extremely useful and rapid means of diagnosing recessive forms of Chromosomal karyotyping
EB. For example, skin from the neonate shown in Figure 2.12c demon-
This technique can be used as an initial screen to demonstrate gross chromo-
strated a lack of reactivity against laminin-332 but normal immunos-
somal aberrations associated with certain tumors. Most skin tumors are small
taining for all other antibodies. These findings establish a diagnosis of
and thus tissue is generally not set aside for karyotype analysis.
Herlitz junctional EB.
Chromosomal karyotyping is the historical gold standard for detecting
The development of a panel of basement membrane antibodies, most of
chromosomal aberrations in neoplastic tissue (Fig. 2.17). Fresh tumor tissue is
which are commercially available, has led to decreased emphasis on transmis-
required to grow the cells and the cytogenetic preparations and interpretation
sion electron microscopy as a diagnostic tool in EB.5 Ultrastructural analysis,
require skilled personnel. Nonetheless, this technique provides an open, unbi-
however, can be useful in confirming the plane of cleavage and in establish-
ased look at all of the chromosomes of a particular tumor. Total chromosomal
ing the diagnosis of certain dominant forms of EB. Skin from the neonate
gains and losses and also translocations between chromosomes can be demon-
illustrated in Figure 2.12b, for example, shows normal intensity basement
strated. Some of these chromosomal translocations are virtually diagnostic of
membrane zone reactivity for all diagnostic probes but transmission electron
certain tumors, particularly soft tissue and hematopoietic tumors.1 Other chro-
microscopy (Fig. 2.16) identifies discrete clumps of tonofilament and basal
mosomal changes can be suggestive of certain tumor types. While most trans-
keratinocyte cytolysis, characteristic of the Dowling-Meara variant of EB
locations are now confirmed by the other molecular methods described below,
simplex. For recessive forms of EB, however, immunolabeling of basement
traditional chromosomal karyotyping retains a role as an initial examination
membrane proteins has become the most important diagnostic approach.6,7
of the chromosomal complement of a neoplasm and an important tool for dis-
Reduced or absent staining for a particular protein provides a rapid diagnosis
covery of new chromosomal aberrations.2 Indeed, over time, the discovery of
as well as a means of identifying the encoding gene (or genes) in which the
chromosomal translocations within specific tumor types is proportional to the
underlying pathogenic mutations are present. Thus the skin biopsy findings,
number of cases karyotyped.3 Additional methodologies discussed below such
both histologic and immunohistochemical, provide a direct guide to molecu-
as spectral karyotyping (SKY) or multiplexed fluorescence in situ hybridiza-
lar screening tests, most of which are PCR-based, as discussed below. This
tion (mFISH) can aid in the interpretation of complex karyotypes.
molecular information can then be used for genetic counseling, carrier screen-
ing, and DNA-based prenatal testing, if indicated.
While the details of the initial analysis change in the diagnostic work-
Allelic imbalance
up of various inherited skin diseases, in many cases, preliminary histologic Gains or losses of specific regions of DNA, often containing particular genes
and other testing is performed in an attempt to determine which molecular of interest, can provide diagnostic insight.
diagnostic test is most relevant. This is important, as such testing is difficult An allele is a variant of a particular genetic locus or region of DNA such
and expensive and thus selection of which gene to examine is important for as a gene. Detection of allelic imbalance or loss of heterozygosity (LOH) is a
­efficient diagnostic work-up. method that can detect the presence of deletions or gains of specific alleles in

Fig. 2.17
Genetics of clear cell sarcoma: (A) this complicated karyotype shows derivative chromosomes 12 (blue box) and 22 (orange box). While recurrent translocation-associated
karyotypes are initially simple, they can become more complex with tumor progression. (B) The mechanism of chromosomal translocation involves breaks in chromosomes
12 and 22 that recombine to produce novel derivative chromosomes 12 and 22. The active fusion gene (EWSR1-ATF1) is produced on der(22). The fusion genes can be
produced by a variety of breakpoints within the introns of the involved genes making multiple exon combinations (C). This complicates the design of PCR-based detection
methods, as does substitution of the CREB1 gene for ATF1 on occasion.
40 Specialized techniques in dermatopathology

paraffin-embedded material.4 This usually corresponds to regions of a particu-

lar gene(s) of interest. For this approach, PCR is used to amplify small genomic
fragments that carry common polymorphisms and thus have a high likelihood
of being present in two different variants (alleles) in an individual. Ideally, these
variants are of different size so that they can easily be detected on an electro-
phoretic gel; DNA sequencing can be used if this is not possible. Only if two
different alleles in the normal tissue of a patient are present is this technique
informative. Imbalance (loss of one allele) is implied if one detects only one
of the alleles in the tumor tissue. More detailed analysis can distinguish those
which are true losses. Sites of recurrent losses are typically areas that harbor
tumor suppressor genes. This method can detect losses that would not be dem-
onstrated in a traditional chromosomal karyotype analysis and can be readily
adapted to formalin-fixed, paraffin-embedded (FFPE) tissue. The limitations of
LOH analysis include that it is sensitive to contamination by normal (stromal)
cells that can make it difficult to decide whether an allele is lost. Another draw-
back is its inability to determine whether the imbalance is caused by the loss of
one marker or by a copy number increase of the other marker.

Fluorescence in situ hybridization (FISH)

FISH uses specific probes to determine the number of copies of a specific
region of DNA that are present or whether a particular locus has been rear-
ranged as part of a chromosomal translocation.
FISH utilizes fluorescently labeled probes that are complementary to and
thus specifically hybridize a specific region of genomic DNA, allowing it to
be visualized.5,6 The labeled probe and the target genomic DNA, which can be
metaphase spreads, interphase nuclei (Fig. 2.18), or nuclei in ­formalin-fixed,
paraffin-embedded tissue sections (Fig. 2.19), are denatured and brought
into contact for several hours to days. Given appropriate hybridization con- Fig. 2.18
ditions, the labeled probes will anneal with the corresponding sequence Four-color FISH to two interface nuclei and metaphase chromosomes: the upper
portion shows two interface nuclei with the hybridization signals for the four
in the target DNA. This is easiest if probes are targeted to chromosomal
colors detectable as discrete spots. In the metaphase spread underneath, the
regions that are rich in repetitive sequences such as the centromeres. In these
hybridization signals can be seen to map to chromosome 6p (purple), 6 centromere
regions the probe can hybridize multiple times, resulting in hybridization (light blue), 6q (yellow), and chromosome 11q13 (green).
signals that are large and easy to detect. However, these regions typically do
not contain any functional genes, and while increases in chromosome copy
number can be recognized, no direct information on the copy number of a
specific cancer gene or locus can be obtained. Human cancers, including
melanoma, frequently have aberrations that involve only fragments of the
chromosome. The detection of these types of aberrations requires probes
targeted to unique, i.e., non-repetitive, sequences of DNA. Unique sequence
probes give smaller hybridization signals and can be more difficult to detect.
However, by using larger probe sizes of 100–300 kb, detection of unique
sequences is possible in paraffin sections (see Fig. 2.17). The advantage of
FISH is that it can detect cells with aberrations in the presence of signifi-
cant numbers of normal cells, provided that the neoplastic cells can be mor-
phologically identified in the hybridized section. Combinations of FISH and
immunofluorescence have been developed to assist in the identification of
the target cell population, but the compromises that have to be made to
accommodate antigen preservation by maintaining acceptable hybridization
Fig. 2.19
efficiency restrict its application for routine use in paraffin-embedded tissue. FISH to tissue sections of a melanoma (left panel) and nevus (right panel): the
Detection of heterozygous deletions is more difficult with FISH in tissue sec- panels show 400-fold magnifications of two nests of melanocytes with the nuclei
tions, because truncation of nuclei in tissue sections cut at normal thickness stained in blue. The green probe for chromosome 11q13 shows amplification in the
results in random loss of hybridization signals. Similarly, increased ploidy of melanoma as evident by a marked copy number increase compared to the purple
the neoplastic tumor cell population can simulate a gain of the target locus. signals representing chromosome 6p. By contrast, the melanocytes of the nevus in
These problems can be compensated by simultaneously hybridizing multiple, the right panel do not show significant differences for these two loci.
differentially labeled, probes to several loci in the genome and by analyzing a
larger number of cells. Comparing a probed locus to a centromeric probe on the flanking probes are fluorescently labeled in two different colors such as
the same chromosome in an alternate color can also compensate for cell ane- green and red, and when they are in close proximity in an intact chromo-
uploidy. A common example of this technique is comparison of the hybrid- some, the spectral overlap leads to two yellow signals, one for each normal
ization signals for the HER2 locus on 17q with centromere 17. This allows chromosome. In a cell with a rearrangement of a gene such as EWSR1 at
one to detect and distinguish both increased copy number of chromosome 22q12 in clear cell sarcoma, nuclei are seen with one intact chromosome 22
17 and specific amplification of the HER2 locus. with EWSR1 producing a yellow signal. In addition, the centromeric probe is
FISH using probes that flank a potential breakpoint associated with a chro- retained on the derivative (rearranged) 22 chromosome while the telomeric
mosomal translocation can be used to demonstrate rearrangement of that probe is transferred to the recipient chromosome (12 in the case of clear cell
locus (Fig. 2.20). This can be diagnostically helpful in certain hematopoi- sarcoma) leading to separate red and green signals in the nucleus. This method
etic malignancies with recurrent translocations, e.g., large cell anaplastic lym- only indicates that a locus is rearranged, not the identity of the chromosomal
phoma and some soft tissue tumors that can involve the skin.7,8 In this method, partner and gene. Thus caution must be used in interpretation as different
 Molecular techniques 41

der(22) d(22)
22 22
d(12)
12 R
der(12) 22
Y Y

Probe Y G
22
R
R
EWSR1 ATF1
Active breakpoint
ATF1 I

Probes Probe
G Y G
Y Y G
R EWSR1 ATF1 EWSR1 G
(q12) Silent breakpoint
R Y

A B

Fig. 2.20
Break-apart fluorescent in situ hybridization (FISH) technique: the 12;22 translocation associated with clear cell sarcoma is depicted; (A) when the EWSR1 locus is intact, the
probes hybridize to the centromeric (red) and telomeric (green) regions flanking the gene. The spectral overlap of the two signals in juxtaposition produce a yellow signal.
Thus in cell lacking rearrangement of this locus, two yellow signals are present, representing the two copies of chromosome 22 lacking rearrangement (right); (B) When
rearrangement occurs, such as the balanced translocation with chromosome 12 depicted here, the centromeric probe (red) is retained by the derivative chromosome
22 while the green probe is transferred to the derivative chromosome 12. Thus in the nuclei one yellow signal indicates the intact chromosome 22 while the derivative 12
and 22 chromosomes segregate freely as single green and red signals, respectively (right).

Desmoplastic small
round cell tumor

WT1 NR4A3(TEC) Extraskeletal myxoid

11p13 9q22 chondrosarcoma

Myxoid CHOP/DDIT3 EWSR1

posarcoma 12q13 22q12

Angiomatoid
ATF1 ETS family Ewing
fibrous / PNET
12q13 FLI1 11q24 sarcoma
histiocytoma
ERG 21q22
FUS/TLS
FEV 2q36
Clear cell sarcoma 16p11 Acute myeloid leukemia
(EWSR1-ATF1) CREB1
ETV1 7p22 Fig. 2.21
ETV4 17q12 (FUS-ERG) Multiple translocations involve EWSR1 and the
(EWSR1-CREB1) 2q32
ZSG 22q12 Ewing homologous gene, FUS: both EWSR1 and FUS
(FUS-ATF1) CREB3L2 / PNET
7q33 sarcoma can often substitute for one another and both are
involved in balanced translocations with multiple
CREB3L1 genes resulting in a variety of neoplasms. Since
11p11 FISH only indicates that a single locus, such as
EWSR1, is re-arranged and nothing about the fusion
partner, results must be interpreted carefully within
the clinical and morphologic context of a tested
Low grade
case. Sometimes techniques such as RT-PCR must
fibromyxoid sarcoma
be used to verify the fusion partner.

translocations seen in different ­neoplasms can be associated with the same

probed locus. For instance, EWSR1 is rearranged in clear cell sarcoma, Ewing
sarcoma, extraskeletal myxoid chondrosarcoma, angiomatoid fibrous histio-
cytoma, and some cases of myxoid liposarcoma (Fig. 2.21). Careful correla-
tion with the clinical and histologic features can help avoid confusion in these
situations.
The disadvantage of FISH is that it can only look at a few loci at a time,
and that analysis is time-consuming because signals in a large number of
nuclei have to be counted. The latter restriction has been partially overcome
by the development of computer-based counting algorithms.9
In situ hybridization can also employ chromogenic probes such that
light microscopy can be used to visualize signals (termed CISH). This
method is useful for detecting amplification of a genetic locus and tech-
nically can be utilized in a break-apart probe strategy to detect trans-
locations, but in practice this latter application can be very difficult to
42 Specialized techniques in dermatopathology

interpret. Probably the most common use for CISH is in direct detection
of nucleic acids associated with infections in cells such as human papil-
lomavirus (HPV) or Epstein-Barr virus. In HPV, this technique can be use
to type the virus and determine whether it is high risk (e.g., 16 and 18)
or low risk (6 and 11). In this application, ISH is used to demonstrate the
presence of viral DNA that is not present in a cell until infection occurs.
Modifications of this technique can be used to detect messenger RNA in
tissue sections as well.
In situ hybridization, fluorescent or chromogenic, is best used to
demonstrate:
• amplification of a specific gene,
• rearrangement of a specific gene,
• presence of ‘foreign’ (infection-related) DNA or RNA.

Comparative genomic hybridization (CGH)

Comparative genomic hybridization can be used to demonstrate gains and
losses of DNA through the entire genome of a tumor sample. While this is
mainly a research tool at this time, its application has lead to important dis-
coveries that have been translated into focused genetic tests.
CGH demonstrates for the entire genome:
• regions of chromosomal loss (often containing tumor suppressor genes),
• regions of chromosomal gains (often containing oncogenes),
• overall patterns of gains and losses (rather than just a few focused
regions).
As originally described, CGH detects and maps DNA sequence copy num- Fig. 2.22
ber variation throughout the entire genome onto a cytogenetic map supplied Comparative genomic hybridization (CGH) on a metaphase chromosome spread
by metaphase chromosomes (Fig. 2.22).10 CGH can be regarded as a varia- (upper panels) and a microarray (lower panels): the regions of the chromosomes
tion of FISH in which the entire genome of a sample such as DNA from a skin (upper panel) that appear red are affected by deletions, whereas the regions that
tumor is used as a hybridization probe. The tumor is freed from contaminat- appear green are affected by gains or amplifications (bright green). Yellow indicates
ing normal cells by manual dissection, the DNA extracted, and labeled with a an area with normal DNA complement-no gain or loss. The lower panel on the right
fluorochrome (green, for example). In addition, a reference probe of normal shows a DNA microarray with approximately 2500 targets printed as triplicates
genomic DNA from a healthy donor is labeled with a different fluorochrome spots. Triplets that appear green indicate gains whereas those that appear red
indicate loss. The array targets are not printed in order of their genomic position
(red, for example). Equal amounts of the green- and red-labeled DNA are
which can help control for technical variations. The precise genomic location of
mixed and hybridized onto a substrate, which represents the entire human the DNA copy number changes detected by the measurement only becomes
genome. Originally, these were metaphase spreads of normal human chro- apparent after plotting the average ratios of red to green fluorescence intensities
mosomes prepared from lymphocytes of a healthy donor that represented a corresponding to their genomic position as illustrated in Figure 2.23
cytogenetic map. More recently, this substrate has been replaced by manu-
factured microarrays composed of nucleotide probes that are printed at high
density on a solid surface.11 Depending on the number and lengths of these
nucleotide probes, the entire genome can be represented on an array. By using
smaller probes, higher resolution of genetic gains and losses can be achieved.
During the hybridization, the red- and green-labeled DNA populations com-
pete for binding to corresponding regional microarray targets. For each
array target (or region of a chromosome in the original protocol) the ratio
of red and green fluorescence intensity ratio is determined. A ratio of 1 indi-
cates a balanced situation at this locus, i.e., no gain or loss in the tumor (see
Fig. 2.23). In the presence of deletions in the tumor genome, less green probe
will be available to hybridize to the corresponding targets, which will result
in a decreased green to red fluorescence intensity ratio (< 1). In the presence
Fig. 2.23
of increased copies, the corresponding targets still show a green to red fluo-
DNA copy number changes as detected by array CGH of an acral melanoma: the
rescence intensity ratio greater than 1. The ratio of red and green fluores- graph shows the log2 of the ratio of the fluorescence intensity ratios of tumor
cence intensity can be used to quantify the copy number change. A ratio of to reference DNA plotted according to their genomic position on the x-axis. The
1 indicates normal copy number, a ratio < 1 indicates a loss, and a ratio > 1 numbers at the top and at the bottom indicate the chromosomes. A log2 ratio of
indicates a gain. Gains with a high ratio that only affect portions of a chro- zero corresponds to normal copy number. As can be seen, multiple contiguous
mosomal arm are called amplifications. They arise from multiple independent chromosomal regions showed losses and gains. The arrow corresponds to an
events (chromosomal breakage and fusions) that accumulate under positive amplification of chromosome 11q13 interval containing the gene that encodes
selection, typically because the genomic region present in the amplicon con- cyclin D1.
tained an oncogene, i.e., a gene that provided a growth advantage to the
tumor cells with increased copies of the gene. analysis of solid tumors. Compared to conventional cytogenetic analysis,
The full experimental protocol for CGH is slightly more complex than CGH does not require culture of cells for karyotypic analysis, which brings
outlined above. A third, unlabeled DNA population is needed to ascertain the major advantage that CGH can be performed on archival tissue. It is
that repetitive regions that are scattered throughout the genome do not cross- important to note that the DNA copy number measurement obtained with
hybridize and interfere with the measurement. This blocking DNA is highly CGH represents an average of the entire cell population from which the DNA
enriched for repetitive regions and suppresses unwanted cross-hybridization was extracted. For this reason, only the copy number alterations present in
between repetitive regions in the labeled DNA populations and the chro- a substantial portion of the cells are detected by the method. Depending on
mosomes which serve as substrate. CGH has revolutionized the cytogenetic the type of aberration – amplifications can be detected most easily – the copy

number change needs to be present in about 30% to 50% of the cells in
order to be identifiable. Alterations affecting only a minority of cells remain
undetected. A further limitation is that CGH only detects genomic aberra-
tions that result in DNA copy number changes. Balanced translocations and
point mutations are not detected. Copy number neutral rearrangements that
arise through chromosomal recombination and LOH (see above) are also not
detectable by CGH. More recent implementations that use oligonucleotides
to determine single nucleotide polymorphisms (SNPs) allow the genome-wide
simultaneous assessment of DNA copy number and LOH in unfixed tumor
tissue.12,13 However, these methods are still being optimized to allow broad
applicability to routinely fixed tissue.
Polymerase chain reaction (PCR)
In the diagnostic setting, PCR is used primarily to acquire sufficient DNA for
analysis by sequencing or other methods, primarily to demonstrate a muta-
tion or other genetic change or the presence of a specific gene or messenger
RNA.
PCR is an extremely flexible technique and can be adapted to:
• detect mutations (base pair substitutions, insertions and deletions) in
genes,
• demonstrate novel fusion transcripts (gene fusions),
• demonstrate clonality,
• demonstrate loss of heterozygosity (loss of one allele),
• detect DNA or RNA associated with infectious organisms,
• detect the levels of expression of messenger RNA.
The ability to specifically amplify and detect any segment of DNA in the
human genome has opened many diagnostic doors. In this technique, a pair
of short sequences of DNA (called primers) that hybridize to two sequences
of genomic DNA (or RNA reverse transcribed to DNA) are designed to
amplify a specific region of DNA. Using a DNA polymerase that is stable
at high temperatures, a series of annealing, extending, and melting/denatur-
ing cycles amplifies the DNA between the two probes. This technique can be
used on nucleic acids extracted from formalin-fixed, paraffin-embedded tis-
sue, although probes must be designed to amplify shorter segments of DNA
since the starting material has been cross-linked and fragmented from the
formalin treatment. A variety of techniques based on PCR can be used to
amplify DNA and then determine its sequence. Direct sequencing of genomic
DNA allows detection of point mutations in cancer, such as BRAF or NRAS
in melanoma.14 Generally, one can detect a mutation in 1 in 5 cells with this
technique. More sensitive techniques such as pyrosequencing can reduce this
to 1 in 10 or 20 cells by analysis for a precise mutation. Finally, allele-­specific
PCR can be used to detect a known point mutation in as little as 1 in 50
or 100 cells. This technique has applications such as detecting KIT D816V
mutation in mastocytosis in skin where the neoplastic cells may be sparse
relative to the surrounding normal tissue.15 Insertions and deletions in genes
can also be detected, usually by Sanger sequencing.8
Reverse transcribing RNA to DNA can allow specific detection of fusion
genes produced by chromosomal translocations such as seen in clear cell
sarcoma or dermatofibrosarcoma protuberans.16,17 This technique is partic-
ularly valuable as there is no amplification product in the absence of tumor
as the translocations are not seen in normal tissue or other tumors (see
Fig. 2.24). Because the two genes involved in a translocation event may
have breaks at multiple introns (the noncoding region of DNA between the
protein encoding exon segments), multiple primer pairs may be necessary to
detect all of the possible translocation types. Also, since multiple genes can
be involved, for instance clear cell sarcoma can contain either an EWSR1-
ATF1 or EWSR1-CREB1 fusion, additional primer sets will be required for
detection of these as well (see Fig. 17.11c).18,19 In hematopoietic malignan-
cies, detection of fusion transcripts can be used to detect minimal residual
disease in the peripheral blood or marrow to measure tumor DNA as a sur-
rogate of tumor load to assess response to therapy or allow early detection
of recurrence. This approach may be applied to solid tumors in the future.
PCR can be used to detect normal genes as well. An instance of this in der-
matopathology was the attempt to detect melanocyte-specific RNA (reverse
transcribed to DNA) in sentinel lymph nodes that might have been missed by
histology and immunohistochemical screening.20–22 Ultimately, this technique
Diagnosis of lymphomas 43
Primer Primer Primer Primer
EWSR1 ATF1
EWSR1 / ATF1 Fusion
No Amplification Amplification
1 2
Type 2
EWSR1-ATF1
fusion amplicon
Fig. 2.24
Use of reverse transcription-polymerase chain reaction (RT-PCR) to detect fusion
transcripts: this technique uses reverse transcription to convert RNA to cDNA that
can then be amplified by PCR. This step is necessary as the breakpoints in the
usually large intronic regions of genomic DNA within a gene are essentially random,
making it extremely difficult to amplify such large regions to identify the breakpoints
using genomic DNA as the template. When the gene is transcribed to RNA, the
introns are removed during splicing and introns are directly juxtaposed
(Fig. 2.11c) allowing more ready detection of the novel juxtaposition of exons from
two different genes. When primers are designed for the exons of each of the two
genes involved in a translocation, amplification only occurs of the cDNA of the fusion
transcript as these introns would not be adjacent in normal tissue. This product
will have a specific size and can be detected on a gel, but direct DNA sequencing
or other methods should be used to confirm its identity. Amplification of normal
housekeeping gene transcripts are used to ensure the quality of the cDNA.
was not valuable, at least in part because of the presence of nodal nevi which
would also be detected by this technique. While widely used in the research
arena, other diagnostic approaches based on detection of gene expression will
likely evolve with time.
It is often advantageous to have multiple methodologies for detecting vari-
ous molecular defects, as they are used in different situations and provide
slightly different information. Figure 2.25 depicts this for the translocation
present in clear cell sarcoma.
Diagnosis of lymphomas
The diagnosis and subclassification of lymphomas has transformed dramati-
cally in the last three decades. Prior to this, the classifications in general use
were based purely on the morphological features of the neoplastic lympho-
cytes.1,2 However, modern classification systems also utilize all available immu-
nophenotypic, genetic, and clinical information to group cases together for
the purposes of treatment and prognostication.3–7 Immunohistochemical and
molecular techniques therefore form an integral part of the diagnostic process,
and are routinely employed in the assessment of suspect cutaneous lymphop-
roliferations in order to discriminate reactive from neoplastic processes, and
to subclassify the latter once identified. A battery of antibodies and molecular
techniques are now available to the practicing pathologist. 8–14
This section focuses specifically on amplications of the polymerase chain
reaction (PCR) to diagnostic hematopathology, the molecular technique in
most common usage, for the detection of antigen receptor gene rearrange-
ment. The relevant immunophenotypic and genetic features of specific
lymphoma subtypes are detailed in Chapter 29. In addition, FISH-based tech-
niques can also be used to demonstrate translocation associated primarily
with B-cell lymphomas.
44 Specialized techniques in dermatopathology

Fig. 2.25
Multiple modalities for detection of recurrent translocations. Traditional karyotypes use metaphase chromosomes spreads to detect translocations and other structural
genetic aberrations using banding (staining) techniques. FISH uses less condensed interphase chromosomes to detect rearrangements or amplifications. RT-PCR can detect
the precise exons involved in a fusion RNA transcript. Each is a valid method for demonstrating chromosomal translocations, but each has applicability to different sample
types and provides different information.

PCR analysis of cutaneous lymphoid

infiltrates
The diagnosis of cutaneous lymphoma relies on a constellation of morpho-
logic, immunophenotypic, and clinical features, and may be difficult, par- * *
ticularly in the early stages. Molecular genetic findings are increasingly
incorporated into the diagnostic process. Often, their role is confirmatory,
demonstrating clonality in a lesion already thought to be lymphomatous on
the basis of pathological findings. However, in a significant proportion of
cases, a definitive diagnosis cannot be reached with certainty on the basis of
histology and immunophenotype. In such instances, the results of molecular
clonality studies may provide sufficient additional information for a diagno-
* *
sis to be assigned and/or to guide patient management. However, PCR analy-
sis of skin biopsies is subject to the same limitations and pitfalls as described
above. Therefore, the results of such studies must always be interpreted with
caution and only following close discussions between the pathologist, molec-
ular biologist, and clinician.

TCR gene rearrangement in cutaneous

lymphoproliferations
Unlike the testing of solid tumors, PCR-based testing of lymphoid infiltrates
can take advantage of TCR receptor gene rearrangements to establish clonal-
ity, although this does not always equate to malignancy.
Clonality studies may be useful in identifying the early stages of myco-
sis fungoides or other cutaneous T-cell lymphomas. Dominant clones can
be demonstrated in the early lesions of mycosis fungoides and in cases of
cutaneous T-cell lymphoma which could not otherwise be identified using
conventional morphology (Fig. 2.26).1–6 They have also been said to facil-
itate discrimination between mycosis fungoides and inflammatory derma-
toses, and simulators of mycosis fungoides such as actinic reticuloid.3–8 PCR
is also useful in identifying the underlying disease in erythroderma when it is
due to cutaneous T-cell lymphoma, rather than inflammatory processes such
as eczema, contact dermatitis, drug reactions, pityriasis rubra pilaris, pso-
A B
riasis, and pemphigus foliaceus.5,9–12 In addition, there are certain variants
and malignant mimics of cutaneous T-cell lymphoma, in which absence of a Fig. 2.26
clonal TCR gene rearrangement helps confirm the diagnosis. These include Mycosis fungoides: TCR gene rearrangement (photo of gel). Red astrixes indicate
extranodal NK/T-cell lymphoma of nasal type, CD4+/CD56+ hematodermic dominant clonal T-cell gene rearrangement shown as discrete bands rather than a
neoplasm and leukemia cutis. smear demonstrating numerous clones and non-rearranged receptors.
 Diagnosis of lymphomas 45

However, clonality does not always equate with a diagnosis of malignant

lymphoma. Monoclonal TCR gene rearrangements have been demonstrated Constant Variable Disulphide Heavy Light
domain domain chain chain
in otherwise typically benign dermatoses. These include: bonds

• discoid lupus erythematosus,

• lichen planus,
• lichen sclerosus.13–15
Bona fide T-cell clones may also be found in examples of cutaneous T-cell
pseudolymphoma, particularly those associated with reversible hypersensitivity
drug reactions, and in some instances the same clone has been demonstrated
in biopsies from the same patient taken at different sites.15–19 There is also a
group of disorders which generally run a benign clinical course, but can be
associated with progression to cutaneous T-cell lymphoma, usually mycosis
fungoides but occasionally cutaneous anaplastic large cell lymphoma or some
other form of cutaneous T-cell lymphoma. These include:
• pigmented purpuric dermatosis,
• pityriasis lichenoides chronica,
• pityriasis lichenoides et varioliformis acuta, Fig. 2.27
Structure of Ig. The two
• lymphomatoid papulosis.20–34 epitope binding sites are
A variable, but often high, incidence of monoclonality is found when series of formed primarily by the
these conditions are analyzed by PCR for the TCRG and/or TCRB gene, and the two variable domains.
same clone is usually found in follow-up biopsies when lymphoma ensues.18,25,32–39
Another similar group comprises cutaneous T-cell lymphoproliferative dis- cases using PCR techniques designed to detect IG gene rearrangements as part
orders that are currently thought to represent very indolent or prelymphoma- of the routine diagnostic work-up (Figs 2.27 and 2.28).1–4 However, even
tous forms of recognized subtypes of cutaneous T-cell lymphomas including: using BIOMED-2 protocols, there may be a significant false-negative rate.
• large plaque parapsoriasis,15,19,40 This is particularly the case if the only primers used are for the framework
• idiopathic follicular mucinosis,15,41 regions on the IG heavy chain gene, one study detecting clonality in only 67%
• syringolymphoid hyperplasia with alopecia,42–44 of primary cutaneous B-cell lymphomas.4 This is likely to be due to the rela-
• hypopigmented mycosis fungoides.45 tively high proportion of lymphomas of germinal center, or postgerminal cen-
These are thought to be related to variants of mycosis fungoides. Idiopathic ter origin encountered in the skin, since these are associated with high levels
erythroderma has similarities to Sezary syndrome46 and atypical lymphocytic of somatic hypermutation. Detection levels increase when assays targeting IG
lobular panniculitis to subcutaneous panniculitis-like T-cell lymphoma.47,48 light chains, including the Kde, are introduced.2
These entities are typically monoclonal and share many characteristics with Clonality assays are not a reliable way of differentiating B-cutaneous lym-
the lymphomas to which they are putatively related. However, they lack full phoid hyperplasia from cutaneous B-cell lymphoma. Monoclonal immuno-
morphologic and/or phenotypic evidence of lymphoma, and although most globulin gene rearrangements have been demonstrated in lesions designated
run a recalcitrant course resistant to topical therapy, and some progress to B-cutaneous hyperplasia (or synonyms thereof), even when less sensitive
overt malignant lymphoma, most have an innocuous clinical outcome. Southern blotting techniques have been used.5–9 However, in series quoting
It has been proposed that the following be encompassed under the rubric high levels of monoclonal B-CLH, relatively few cases progress to overt lym-
of ‘cutaneous T-cell lymphoid dyscrasia’49: phoma.5,7,8 These lesions may therefore be analogous to the cutaneous T-cell
• idiopathic pigmented purpuric dermatosis, dyscrasias described above, in that they may run a protracted but ultimately
• pityriasis lichenoides, benign clinical course, only rarely progressing to overt malignancy.
• large plaque parapsoriasis,
• idiopathic follicular mucinosis,
• syringolymphoid hyperplasia with alopecia,
• hypopigmented mycosis fungoides,
• idiopathic clonal erythroderma,
• atypical lymphocytic lobular panniculitis.
The concept is similar to that of monoclonal gammopathy of uncertain sig-
nificance, already well established for plasma cell dyscrasias.46 ‘Cutaneous T-cell
lymphoid dyscrasia’ is used to convey the limited but real malignant potential
of these monoclonal and oligoclonal lymphoproliferations, and is preferred by
the authors to terms such as ‘premycotic’, because evolution to overt cutaneous
T-cell lymphoma is uncommon. It is hypothesized that T-cell clones develop as
a result of chronic antigenic stimulation. Acquisition of genetic abnormalities
by an expanded clone results in an ability for autonomous growth. This is ini-
tially held in check by the host immune cells, and only when these are overcome
does the fully malignant clone emerge. Entities that occasionally harbor clonal
populations of T cells, but have no malignant potential (such as drug-induced
pseudolymphoma), are excluded from this category.

IG gene rearrangement in cutaneous

lymphoproliferations
Fig. 2.28
A number of variant gene rearrangements often involve the promoters of
B-cell lymphoma: Ig gene rearrangement
immunoglobulin genes to drive the expression of oncogene critical to lym- (photo of gel). The upper bands arrowed in
phomagenesis. The current World Health Organization (WHO) classification lanes two and three indicate non-rearranged
scheme relies on these molecular results for precise classification. IG with the astrix in lane two indicates a
The clonal nature of cutaneous B-cell infiltrates in both primary and sec- polyclonal IG population. The lower band in
ondary cutaneous B-cell lymphomas can be confirmed in a high percentage of lane three shows a dominant IG clone.
Chapter

3 Disorders of keratinization
Dieter Metze
See
www.expertconsult.com
for references and
additional material

Ichthyosis 46 Lichen spinulosus 66 Marginal papular acrokeratoderma 82

Ichthyosis vulgaris 46 Phrynoderma 67 Huriez syndrome 82
X-linked recessive ichthyosis 49 Keratosis pilaris 67 Vohwinkel's syndrome 83
Syndromes with steroid sulfatase Keratosis pilaris atrophicans 68 Loricrin keratoderma 84
deficiency 50 Clouston's syndrome 84
Acquired ichthyosis-like conditions 69
Multiple sulfatase deficiency 50 Olmsted syndrome 85
Pityriasis rotunda 70
Refsum syndrome 50 Papillon-Lefèvre syndrome 86
Autosomal recessive lamellar ichthyoses 51 Erythrokeratodermas 71 Naxos syndrome 87
Harlequin ichthyosis 54 Erythrokeratoderma variabilis 71 McGrath syndrome 87
Autosomal dominant lamellar ichthyosis 55 Progressive symmetric erythrokeratodermia 73 Pachyonychia congenita type I 88
Congenital bullous ichthyosiform Keratitis-ichthyosis-deafness Pachyonychia congenita type II 88
erythroderma 55 syndrome 73 Tyrosinemia type II 89
Ichthyosis bullosa of Siemens 58 Hystrix-like ichthyosis with deafness 74 Carvajal Huerta syndrome 89
Linear epidermolytic epidermal nevus 59 Howell-Evans syndrome 90
Palmoplantar keratoderma 75 Schöpf-Schulz-Passarge syndrome 91
Epidermolytic acanthoma 59
Keratosis palmoplantaris diffusa
Focal epidermolytic hyperkeratosis 60
Vörner-Unna-Thost 76 Acquired palmoplantar keratoderma and
Peeling skin syndrome 60
Epidermolytic hyperkeratosis with polycyclic internal malignancy 91
Ichthyosis hystrix Curth-Macklin 60
psoriasiform plaques 77 Keratoderma climactericum 91
Congenital reticular ichthyosiform
Diffuse nonepidermolytic palmoplantar Clavus 91
erythroderma 61
keratoderma 77 Callus 91
Comèl-Netherton's syndrome 61
Progressive palmoplantar keratoderma 78 Acrokeratosis verruciformis of Hopf 91
Sjögren-Larsson syndrome 63
Keratolytic winter erythema 78 Porokeratosis 92
Conradi-Hünermann-Happle syndrome 65
Mal de Meleda 79 Hyperkeratosis lenticularis perstans 95
Other congenital ichthyotic Keratosis palmoplantaris areata Granular parakeratosis 96
syndromes 65 et striata 80 Circumscribed palmar or plantar
Follicular ichthyosis 66 Keratosis palmoplantaris nummularis 80 hypokeratosis 96
Ichthyosis follicularis with alopecia and Punctate palmoplantar keratoderma 81
photophobia 66 Keratosis punctata of the palmar creases 81

• Congenital ichthyoses present with collodion membrane or ichthyosiform

Ichthyosis
The term ichthyosis (Gr. ichthys, fish) is applied to a number of heterogenous
genetic disorders characterized by permanent and generalized abnormal kera-
tinization.1,2 The clinical features range from mild involvement, often passed
off as ‘dry skin’ (xerosis), through to severe widespread scaly lesions causing
much discomfort and social embarrassment (Fig. 3.1). The scales are often
shed as clusters rather than as single cells as is the norm.1 The pathogenesis of
the ichthyoses is very complex but ultimately depends upon two distinct final
common pathways: one relates to retention of corneocytes (e.g., ichthyosis
vulgaris, recessive X-linked ichthyosis), the other involves epidermal hyper-
proliferation (e.g., congenital ichthyosiform erythroderma, bullous ichthyo-
sis, Sjögren-Larsson syndrome and Refsum's disease).3
Ichthyotic skin disorders are classified into the following groups3a
(Tables 3.1, 3.2):
• Noncongenital ichthyoses develop 4 weeks after birth and spare flexures,
palms and soles.
erythroderma at birth or manifest within 4 weeks.
• Variants in which the skin lesions are but one facet of a more sinister
systemic illness (syndromic ichthyosis).
The development of a diffuse ichthyosis-like scaling during life should not
be confused with ichthyotic skin disorders. These acquired ichthyosis-like
(ichthyosiform) skin conditions can be caused by different underlying dis-
eases (see below). 4
Ichthyosis vulgaris
Clinical features
This relatively common disorder (incidence of 1:250 to 1:1000 births) has
an autosomal dominant mode of inheritance.1,2 It may present initially as
keratosis pilaris (follicular hyperkeratosis) on the arms, buttocks and thighs.
The disease is usually fairly mild and becomes apparent within the first few
months or years of life. It affects the sexes equally and presents as dryness
 Ichthyosis 47

Fig. 3.1
(A, B) Severe generalized ichthyosis: this was an
A B incidental finding at postmortem. Ichthyosis can be very
disfiguring and a considerable social disadvantage.

Table 3.1
Non-congenital ichthyoses
Isolated (nonsyndromic
ichthyosis)
Autosomal dominant ichthyosis
vulgaris
Recessive X-linked ichthyosis
With associated symptoms
(syndromic ichthyosis)
Syndromes with steroid sulfatase
deficiency
Multiple sulfatase deficiency
Refsum's disease
those on the face and scalp. The rims of the ears are often scaly.3 There is sea-
sonal variation, with improvement of the condition in the summer months,
particularly in humid climates.2 The palms and soles show increased palmar
and plantar markings in contradistinction to sex-linked ichthyosis and may
also show mild hyperkeratosis.3 An association with keratosis punctata of
the palms and soles has also been documented.4 Chapping of the hands and
feet can be a problem.5 There is no evidence of hair, nail, or teeth involve-
ment. There is an increased incidence of atopic disorders.5 Serum lipids are
normal.3

Table 3.2 Pathogenesis and histological features

Congenital ichthyoses Ichthyosis vulgaris is characterized by deficiency of profilaggrin, a major con-
stituent of the keratohyalin granules.6,7 Flaky tail mice, which represent an ani-
Isolated (nonsyndromic With associated symptoms
mal model of ichthyosis vulgaris, produce defective profilaggrin with resultant
ichthyosis) (syndromic ichthyosis)
absence of filaggrin.8 Ultrastructurally, the keratohyalin granules are reduced,
Autosomal recessive lamellar Comèl-Netherton's syndrome
spongy or crumbly and associated with decreased amounts of filaggrin.9 The
ichthyoses (nonbullous congenital Sjögren-Larsson syndrome
clinical severity of ichthyosis vulgaris correlates with the reduction of keratohy-
ichthyosiform erythroderma)
alin granules, which reflects a defective epidermal synthesis of filaggrin. Using
Harlequin ichthyosis Conradi-Hünermann-Happle fluorescein-labeled filaggrin antibodies demonstrates the severity of the defect
syndrome (chondrodysplasia (H. Traupe and V. Oji, unpublished observation). Filaggrin aggregates keratin
puncta type 2)
intermediate filaments in the lower stratum corneum and is subsequently prote-
Autosomal dominant lamellar Ichthyosis prematurity syndrome olyzed to form free amino acids including urocanic and pyrrolidone carboxylic
ichthyosis acids critical as water-binding compounds in the stratum corneum.
Bullous congenital ichthyosiform Gaucher syndrome, Type 2 Linkage analysis of the epidermal differentiation complex on chromosome
erythroderma Dorfman-Chanarin syndrome 1q21 has identified mutations in the gene encoding filaggrin. Parents with one
Ichthyosis bullosa of Siemens Trichothiodystrophy heterozygous filaggrin mutation may be asymptomatic, whereas affected off-
spring with two mutations often show classic ichthyosis vulgaris.10 Since the
Peeling skin syndrome Ichthyosis follicularis with atrichia filaggrin gene is a major susceptibility gene for atopic dermatitis, ­mutations
ichthyosis hystrix Curth-Macklin and photophobia
have also been shown in atopic dermatitis.11
Congenital reticular ichthyosiform Ichthyosis vulgaris is characterized by mild to moderate orthohyperkera-
erythroderma tosis associated with a hyperplastic, atrophic or normal epidermis. The key
feature is a thin or absent granular cell layer (Fig. 3.3).12,13 Regional vari-
ation in the thickness and/or presence of the granular cell layer may be a
(xerosis) and slight to moderate fine scaling, particularly involving the exten- ­feature and therefore it is best to take the biopsy from a site of maximal scal-
sor surfaces of arms and legs and characteristically sparing the flexures (Fig. ing. The lesions of keratosis pilaris show dilated follicles containing large
3.2). The light-gray scales vary in quality from thick adherent shiny plates keratin plugs. In the upper dermis a mild perivascular lymphocytic infiltrate
to simply dusty accumulations which, when scratched, leave a mark just as may be present. When ichthyosis vulgaris is associated with atopic dermatitis,
when one touches a dusty surface. The truncal lesions tend to be thicker than ­parakeratosis and other signs of a spongiotic dermatitis can be found.
48 Disorders of keratinization

Differential diagnosis
The histologic differential diagnosis includes other diseases character-
ized by orthohyperkeratosis and a reduced or absent stratum granulosum
(Table 3.3)

Table 3.3
Histologic patterns in ichthyotic skin disorders

Orthohyperkeratosis & stratum granulosum reduced or absent

Fig. 3.2
Ichthyosis vulgaris:
abdominal involvement
is most noticeable in this
patient. Sparing of the
flexures is characteristic
of this variant of
ichthyosis. By courtesy
of W.A.D. Griffiths, MD,
Institute of Dermatology,
London, UK.
A Differential diagnosis:
B Annular epidermolytic ichthyosis
Fig. 3.3
(A, B) Ichthyosis vulgaris: there is hyperkeratosis. The granular cell layer is absent.
Ichthyosis vulgaris (w/o atopic dermatitis)
Acquired ichthyosis-like condition
Refsum syndrome
Dorfman syndrome
Trichothiodystrophy syndrome
Conradi-Hünermann-Happle syndrome
Orthohyperkeratosis & stratum granulosum well developed
XR-ichthyosis
AR-lamellar ichthyosis
Harlequin ichthyosis
Acquired ichthyosis-like condition
(Lichen simplex chonicus)
Hyperkeratosis with ortho- and parakeratosis and stratum granulosum
prominent
AD-lamellar ichthyosis
Sjögren-Larsson syndrome
Harlequin ichthyosis
Inflammatory skin disease
Epidermolytic hyperkeratosis
Bullous ichthyotic erythroderma Brocq
Annular epidermolytic ichthyosis
Ichthyosis bullosa Siemens
Epidermal nevi
Epidermolytic acanthoma/leukoplakia
Epidermolytic palmoplantar keratoses
Incidental finding
Perinuclear vacuoles and binucleated keratinocytes
With parakeratosis:
Congenital reticular
Ichthyosiform erythroderma
With orthokeratosis:
Ichthyosis hystrix Curth-Macklin
Epidermolytic ichthyoses (Keratin clumps !)
Follicular hyperkeratosis
Keratosis pilaris, lichen spinulosus, phrynoderma
Keratosis pilaris atrophicans
Ichthyosis vulgaris with follicular keratosis
Lamellar ichthyosis
Sjögren-Larsson syndrome
Ichthyosis follicularis with alopecia and photophobia
Congenital atrichia
HID-, KID syndrome
Hereditary mucoepithelial dysplasia
Pachyonychia congenita
Ectodermal dysplasias
Darier's disease
Pityriasis rubra pilaris
Psoriasis-like features
Psoriasis vulgaris
Dermatophytosis
Comèl-Netherton's syndrome
CHILD syndrome
Papillon-Lefèvre syndrome
 Ichthyosis 49

X-linked recessive ichthyosis

Clinical features
Also known as steroid sulfatase deficiency and ichthyosis nigricans, this
X-linked, recessively inherited disorder has an incidence of 1:6000 male
births.1–3 The disease is exceedingly rarely expressed in females.4 Cutaneous
lesions tend to be more conspicuous and severe than in the autosomal dom-
inant variant.2 The scales are large and dark and are seen particularly on
the trunk, the extensor surface of the extremities, the scalp, the preauricular
region, and the neck (Figs 3.4–3.7).2 Mild Involvement of the flexures is also
present (Fig. 3.8).1 However, differentiation from ichthyosis vulgaris can be
difficult as some patients present with fine, light scales and the flexures may
be spared. The palms and soles are usually unaffected and keratosis pilaris is
not a feature. Involvement of the trunk and neck often gives the skin a dirty
appearance. Lesions may improve or disappear in warm weather.2 The hair,
nails, and teeth are not affected.
Corneal opacities due to comma-shaped deposits in the posterior capsule
of Descemet's membrane or corneal stroma, visible with slit-lamp exami-
nation (Fig 3.9), are characteristic and may be detected in female carriers.5 Fig. 3.5
Inadequate cervical dilatation may lead to prolonged delivery of affected Sex-linked ichthyosis: the scale is coarser than that seen in ichthyosis vulgaris.
male newborns. Undescended testes and hypogonadism can be a feature in By courtesy of the Institute of Dermatology, London, UK.
as many as 25% of affected patients.6–8 Rarely, testicular cancer has been
documented.6

Pathogenesis and histological features

The disease is associated with a deficiency of the microsomal enzyme, ste-
roid sulfatase/STS (sterol sulfate sulfohydrolase/arylsulphatase C).9 This is a
membrane-bound enzyme, which hydrolyses the 3-β-sulfate esters of choles-
terol and the sulfated steroid hormones.10 Absence of this enzyme is associ-
ated with persistence of the sulfate moiety on a number of sulfated steroid
hormones and cholesterol sulfate.3
X-linked recessive ichthyosis is characterized by a raised serum choles-
terol sulfate.10 The corneocytes contain excess cholesterol 3-sulfate and
diminished free sterol.11 Steroid sulfatase deficiency possibly results there-
fore in persistence of the lipid contents of the membrane-coating granules
and hence increased or persistent adhesion between adjacent keratin plates
in the stratum corneum. Beyond that, increased amounts of cholesterol sul-
fate may inhibit the epidermal serine protease activity, which results in reten-
tion of corneodesmosomes leading to less shedding of scales and retention
hyperkeratosis. Steroid sulfatase deficiency can be detected using the patient's

Fig. 3.6
Sex-linked ichthyosis: the scales are large and disfiguring. By courtesy of
R.A. Marsden, MD, St George's Hospital, London, UK.

­ eripheral leukocytes and cultured skin fibroblasts. Diagnosis may also be

p
affected by lipoprotein electrophoresis, which shows increased mobility of
low density and very low density beta-lipoproteins in addition to the steroid
sulfatase deficiency.12,13
The gene locus for recessive X-linked ichthyosis is within the Xp22.3
region of the X chromosome.14–16 Recently, indirect genotypic analysis using
polymorphic DNA markers closely linked to the STS gene has been shown
to be a reliable method of detection of the carrier status.14,17 Complete dele-
tions of structural STS gene have been reported in 90% of patients with
X-linked ichthyosis;14,16–19 the other 10% show partial deletions or point
mutations.1 Carrier status can also be confirmed by fluorescent in situ
hybridization (FISH) analysis.19 Recently, rapid diagnosis and differentia-
tion from ichthyosis vulgaris using polymerase chain reaction (PCR) has
been documented.20 Other important genes are located close to the steroid
sulfatase gene.
Fig. 3.4 Lesions show non-specific features of compact hyperkeratosis and slight
Sex-linked ichthyosis: there is severe involvement. Note the large, dark confluent acanthosis associated with a granular cell layer, which may be normal
scales. or increased in thickness (Fig. 3.10).21,22 Keratohyalin granules show no
50 Disorders of keratinization

Fig. 3.7
Sex-linked ichthyosis:
in this example the
scales appear dirty. This
can be an extremely
embarrassing condition.
By courtesy of the
Institute of Dermatology,
London, UK.

Fig. 3.9
(A) Sex-linked ichthyosis: characteristic linear opacities at the level of Descemet's
membrane. Slit-lamp photograph. (B) Same lesion viewed by specular microscopy.
By courtesy of R.J. Buckley, MD, Moorfield's Eye Hospital, London, UK.

Syndromes with steroid sulfatase

deficiency
A number of other important genes are located close to the steroid sulfatase gene.
If a deletion is larger, it may include some of these genes, producing a contigu-
ous gene syndrome.1 Two closely linked genes are those for Kallmann syndrome
(hypogonadotropic hypogonadism and anosmia) and X-linked recessive chon-
drodysplasia punctata.2 Possible linkage to a gene for hypertrophic pyloric steno-
sis has also been described.2 Thus patients may present with the skin changes of
X-linked recessive ichthyosis but with a whole spectrum of other problems.2
Fig. 3.8
Sex-linked ichthyosis: Multiple sulfatase deficiency
involvement of the
flexures is sometimes a
Multiple sulfatase deficiency is a severe neuropediatric disorder inherited as an
feature of this variant. By autosomal recessive. Patients develop normally for the first several years and
courtesy of the Institute then begin to show striking loss of mental capacity and motor ­abilities. They
of Dermatology, London, usually die before puberty. The ichthyosis is typically mild and the least of
UK. their problems. In multiple sulfatase deficiency patients the ­ichthyosis is simi-
lar to but usually less severe than in X-linked recessive ­ichthyosis. Therefore,
ichthyosis in a child with unexplained neurological symptoms should always
prompt measurement of steroid sulfatase levels.1
abnormality. Follicular plugging is not a feature. Paradoxically, biopsies of
thicker scales can show massive orthohyperkeratosis with reduction of the
granular layer and a thin epidermis, causing confusion with ichthyosis vul-
Refsum syndrome
garis. A discrete lymphocytic perivascular inflammatory cell infiltrate may
be evident. Clinical features
Ultrastructural features include a high number of transitional cells and an Refsum syndrome (hereditary motor and sensory neuropathy type 4, here-
abnormal persistence of desmosomal disks in the horny layer while keratohy- dopathica atactica polyneuritiformis, phytanic acid deficiency) is a rare type
alin granules are normal. An increased melanosome transfer accounts for the of an autosomal recessive syndromic ichthyosis.1 The skin changes appear
dark appareance of the scales.23 in childhood and are similar to those seen in ichthyosis vulgaris including
 Ichthyosis 51

The more severe noneyrthrodermic phenotype of lamellar ichthyosis has an

estimated prevalence of 1:200 000–300 000. The infant is often born encased
in a thick ‘collodion’ plate-like shell of keratin (Figs 3.11, 3.12), and while
the term ‘collodion baby’ is most often applied to cases of lamellar ichthyosis,
similar appearances are sometimes found in a number of other disorders such
as autosomal dominant lamellar ichthyosis, Netherton's syndrome, Sjögren-
Larsson syndrome, trichothiodystrophy, and infantile cerebral Gaucher
syndrome.3,4 Hence, colloidon baby is a clinical description but not a dis-
ease. Within a few days the shell is shed to reveal a mild ­erythroderma with

Fig. 3.11
Autosomal recessive
lamellar ichthyosis: the
collodion membrane
is best seen on the
forehead. There is scaling
and erythema on the
trunk. By courtesy of
B
R.A. Marsden, MD,
St George's Hospital,
Fig. 3.10 London, UK.
(A, B) Sex-linked ichthyosis: there is hyperkeratosis and mild acanthosis. The
granular cell layer is normal.

hyperlinear palms. Due to lipid storage, melanocytic nevi may show a yellow
hue. Associated symptoms include loss of vision from retinitis pigmentosa,
in which night blindness is often the first problem, anosmia, cardiac arrhyth-
mias, and a whole spectrum of neurological problems including bilateral
sensorineural deafness, cerebellar ataxia, and peripheral polyneuropathies.2

Pathogenesis and histological features

Refsum syndrome is generally caused by a mutation in a gene encoding
perioxisomal phytanol-CoA hydroxylase, although it can also be caused by
­specific ­mutations in the peroxisomal receptor gene PEX7.3,4 Peroxisomes are
involved in the metabolism of bile acid and cholesterol biosynthesis. Elevated
levels of ­phytanic acid in plasma and tissue are diagnostic. Low-phytol diet
is mandatory.5
Routine histology of a skin biopsy does not differ from ichthyosis vulgaris.
When a biopsy is fixed in alcohol and a Sudan stain performed, lipid drop-
lets are found in the keratinocytes, in particular in biopsies from melanocytic
nevi. The same inclusions can be shown by ultrastructural examination.6 Fig. 3.12
Autosomal recessive
lamellar ichthyosis: note
Autosomal recessive lamellar ichthyoses the erythema. The skin
is shiny, taut, and shows
Clinical features fissuring around the
anterior aspect of the
Autosomal recessive lamellar ichthyoses include a group of mostly mono- ankle. By courtesy of D.
genetic disorders presenting at birth with generalized hyperkeratosis and Atherton, MD, Children's
­scaling (ichthyosis congenita). The clinical presentation varies considerably Hospital at Great Ormond
in ­severity and clinical course.1–5 Street, London, UK.
52 Disorders of keratinization
g­ eneralized scaling (Fig. 3.13). In nonerythrodermic phenotype of lamellar
ichthyosis the scales are large, dark and platelike and cover the entire body
including the palms, soles, scalp, and flexures.5–8 Fissuring of the hands and
feet occurs and the skin around the joints may become verrucous. There is
often associated difficulty with sweating, and hyperpyrexia may be a feature.7
There is nail dystrophy, hair involvement (scarring alopecia), severe ectro-
pion (up to 80% of patients) and eclabium are characteristic (Fig. 3.14). The
ectropion is of the cicatricial type and develops as a consequence of exces-
sive dryness and associated contracture of the anterior lamella of the eye-
lid. Complications include corneal ulceration, vascularization, and corneal
­scarring with eventual ­blindness.9 Primary conjunctival lesions have also been
Fig. 3.13
Autosomal recessive
lamellar ichthyosis:
note the widespread
and prominent large
dark brown scales. By
courtesy of D. Atherton,
MD, Children's Hospital
at Great Ormond Street,
London, UK.
Fig. 3.14
Autosomal recessive
lamellar ichthyosis: in
this infant, there is gross
ectropion and eclabion.
By courtesy of D. Atherton,
MD, Children's Hospital
at Great Ormond Street,
London, UK.
described including ichthyosis, keratinization, hyper- and parakeratosis, and
papilla development. The teeth are not affected.3
In contrast, other individuals show a more pronounced erythroderma
with fine, white scaling (non-bullous congenital ichthyosiform erythroderma,
NCIE). A collodion membrane is often present at birth.1 After shedding, the
infant typically presents with an intense generalized erythroderma.2 While
platelike scales may be seen on the extensor surfaces of the legs, the scalp,
face, upper extremities and trunk are covered with fine white scaling (Figs
3.15–3.20).8 Mild ectropion and eclabium may be complications and palmo-
plantar keratoderma is often more severe than in noneyrthrodermic forms of
AR-lamellar ichthyosis.3 Exceptionally, congenital ichthyosiform erythroderma
has been associated with retinitis pigmentosa.10 There is an increased risk of
developing skin cancer including basal and squamous cell carcinoma.11
Fig. 3.15
Nonbullous congenital
ichthyosiform
erythroderma: there is
intense erythema and fine
scaling is also present.
The scalp hair is sparse
and the eyebrows are
absent. By courtesy of
D. Atherton, MD, Children's
Hospital at Great Ormond
Street, London, UK.
Fig. 3.16
Nonbullous congenital ichthyosiform erythroderma: there is marked erythema with
severe scaling. Blistering is not seen in this variant of ichthyosis. By courtesy of
D. Atherton, MD, Children's Hospital at Great Ormond Street, London, UK.

Fig. 3.17
Nonbullous congenital ichthyosiform erythroderma: there is intensive erythema and
fine scaling. By courtesy of the Institute of Dermatology, London, UK.
Fig. 3.18
Nonbullous congenital ichthyosiform erythroderma: there is generalized platelike
scaling. By courtesy of the Institute of Dermatology, London, UK.
Pathogenesis and histological features
The most common cause of lamellar ichthyosis is transglutaminase-1 deficiency
which accounts for 30–40% of cases. Mutations in the ­transglutaminase-1gene
result in markedly diminished or lost enzyme activity and/or protein. In some
cases, this enzyme is present but there is little detectable activity, and in other
clinically similar cases, transglutaminase-1 levels appear to be normal.12–17
Since conventional enzyme assays and mutational analyses are tedious, an
assay for the rapid screening of transglutaminase-1 activity using covalent
incorporation of biotinylated substrate peptides into skin cryostat sections
has been developed.18 Coupled with immunohistochemical assays using
transglutaminase-1 antibodies, this allows rapid identification of those cases
caused by alterations in this enzyme.18
Ichthyosis 53
Fig. 3.19
Nonbullous congenital ichthyosiform erythroderma: the scales are large, thick and
white. By courtesy of the Institute of Dermatology, London, UK.
Fig. 3.20
Nonbullous congenital ichthyosiform erythroderma: there is severe palmar
involvement and constriction bands are evident. By courtesy of the Institute of
Dermatology, London, UK.
Other variants of transglutaminase mutations are characterized by dis-
tinct clinical features. In self-healing collodion baby the ­transglutaminase-1
mutation is pressure-sensitive so that while in utero the enzyme cannot
function properly, it resumes normal function after birth. About 10% of
collodion babies fall into this group.19 In bathing suit ichthyosis (BSI) the
mutation in transglutaminase-1 appears to be temperature sensitive so that
the face and extremities are almost completely spared apart from skin areas
overlaying blood vesssls. Digital thermography has validated a striking cor-
relation between warmer body areas and the presence of ­scaling, suggesting
a decisive influence of the skin temperature. In situ TGase testing in skin
of BSI patients has also demonstrated a marked decrease of enzyme activity
when the temperature is increased from 25 to 37 degrees Celsius.20
The second most common mutation in lamellar ichthyosis can be found
in the binding cassette protein.21,22 Missense mutations cause lamellar ich-
thyosis while deletions are responsible for the far more dramatic harlequin
fetus.23 Mutations in either transglutaminase-1 or the lipoxygenases are most
often responsible for the nonbullous congenital ichthyosiform erythroderma
phenotype. The ichthyin mutation also usually produces nonbullous con-
genital ichthyosiform erythroderma (Table 3.4).24–28 Attempts to refine the
classification of non erythrodermic and erythrodermic phenotypes by the use
54 Disorders of keratinization

Table 3.4
Types of autosomal recessive lamellar ichthyosis (LI)

Type Locus Gene Protein Defect

LI 1 14q11 TGM1 Transglutaminase-1 Impaired cross-linking of proteins and
lipids to the cornified cell envelope
LI 2 2q34 ABCA12 ATP binding cassette Abnormal lamellar body function and
lipid trafficking
LI 3 / LI 4 19p12-q12 FLJ39501 Cytochrome P450 family protein Epidermal lipid metabolism
LI 5 17p13 ALOX12B 12R-lipoxygenase Epidermal lipid metabolism
ALOXE3 Lipoxygenase-3
LI 6 5q33 ICHYN Ichthyin Transmembrane protein

of clinical, biochemical, and ultrastructural observations have so far failed to
yield a consistent scheme.29–31 This difficulty is illustrated by the fact that the
same transglutaminase-1 mutation can give rise to different phenotypes.31
Histologically, the epidermis in autosomal recessive lamellar ichthyosis
shows marked hyperkeratosis (which may be extreme in the collodion baby)
and mild acanthosis with a normal or thickened granular cell layer (Fig. 3.21).
The hyperkeratosis is much less marked in erythrodermic than in noneryth-
rodermic forms. Epidermal papillomatosis associated with a psoriasiform
appearance has also been documented. A perivascular lymphocytic infiltrate
is occasionally a feature.4 Dilatation and tortuosity of the dermal capillaries is
sometimes evident. Follicular hyperkeratosis may occasionally be seen.
Ultrastructural studies show a variety of features including defective devel-
opment of the cornified cell envelopes and electron-dense debris adjacent to
the plasma membranes, cholesterol clefts, lipid vacuoles, increased numbers
of small and dysmorphic lamellar bodies, elongated membrane structures,
or membrane packages.32–34 Prenatal diagnosis of lamellar ichthyosis can be
achieved by fetoscopy and biopsy.35
Harlequin ichthyosis
Clinical features
Harlequin ichthyosis (harlequin fetus, ichthyosis fetalis, ichthyosis congenita
gravis) is an extreme and rapidly fatal subtype, where babies are born with
a fissured ‘armor-plated’ skin (Fig. 3.22).1–4 Ectropion and eclabium are fre-
quent complications, and the ears and nose are often malformed.2 Harlequin
fetus has a very high mortality due to respiratory and feeding difficulties
accompanied by excessive fluid loss.3 Sometimes, treatment by retinoids and
intensive care is successful. Long-term survivors, following shedding of the
scales, develop a severe erythroderma reminiscent of nonbullous ichthyosi-
form erythroderma.5 Fortunately, antenatal diagnosis is possible.6,7

Pathogenesis and histological features

This very rare form of ichthyosis is due to an apparently dramatic loss of
function of the lamellar bodies, which results from nonsense mutations in
the ABCA12 gene. Less severe missense mutations cause a variant of lamellar
ichthyosis. This indicates that a severely truncated protein is the molecular
cause of Harlequin ichthyosis.8 The ATP-binding cassette (ABC) transporter
A
family encompasses a variety of membrane proteins involved in the energy-
dependent transport across membranes. In the epidermis, ABCA12 may have
an important function for the lamellar bodies, through exocytosis traffic of
lipids or proteases across the apical keratinocyte membrane.
The lesions are characterized by massive hyperkeratosis (sometimes
with lipid deposits) associated with a normal or absent granular cell layer
(Fig. 3.23). The hair follicles are usually affected first, during the second tri-
mester.2,7 Parakeratosis may also sometimes be evident.9 Acanthosis is often
marked and papillomatosis is sometimes a feature. A sparse mixed inflamma-
tory cell infiltrate can be present in the superficial dermis.7
Ultrastructurally, the harlequin fetus has recently been shown to be associated
with deficient or morphologically abnormal lamellar bodies ­(including concen­
trically lamellated forms) and deficient intercellular lipid lamellae within the
stratum corneum.1,2,9 Small vesicles, devoid of internal lamellation, may be pres-
ent in the granular cell layer (and retained in the stratum corneum), but show no
association with the keratinocyte cell membranes as is typical of normal lamel-
lar bodies.1,9 Recent immunohistochemical evidence suggests that these vesicles
­represent abnormal lamellar bodies characterized by an inability to discharge
B their lipid contents into the intercellular space. Keratin and filaggrin expression
have also been shown to be defective.2 In the harlequin fetus, the keratinocytes
Fig. 3.21 may display the hyperproliferative keratins K6 and K16 and show an inability to
Autosomal recessive lamellar ichthyosis: (A) there is very marked hyperkeratosis convert profilaggrin to filaggrin.2 The results of ultrastructural and ­biochemical
and the epidermis shows papillomatosis; (B) high-power view. analyses suggest that the harlequin fetus is a heterogeneous condition.

A B
Fig. 3.23
Harlequin ichthyosis: there is massive hyperkeratosis associated with a
conspicuous granular cell layer and a papillomatous epithelium. The dilated spaces
in the stratum corneum represent dilated ostial of eccrine ducts. By courtesy of
M.M. Black, MD, Institute of Dermatology, London, UK.
Autosomal dominant lamellar ichthyosis
Clinical features
Autosomal dominant lamellar ichthyosis is characterized by generalized scal-
ing with palmoplantar keratoderma.1 Patients may present as a collodion
baby. They are later covered by diffuse dark-gray scales that involve all areas
of the body but are most prominent on the extensor surfaces. Backs of the
hands and feet are characterized by lichenification. There may be massive
plantar hyperkeratosis with thick, yellow scales. The palms are usually only
minimally involved and show accentuated markings.1
Pathogenesis and histological features
This disorder appears to be genetically and clinically heterogeneous and of
variable penetrance. Its genetic defect has not been identified. Biochemically,
an abnormal lipid profile has been detected in the scales.2
Ichthyosis 55
Fig. 3.22
(A, B) Harlequin ichthyosis: the most extreme form
of congenital ichthyosis. There is an exceedingly high
mortality. The scales are very thick and are often referred to
as armor-plating.
Histologically, there is an acanthosis, papillomatosis, and compact ortho-
hyperkeratosis with focal parakeratosis that, paradoxically, is associated with
a thickened stratum granulosum (Fig. 3.24).2
Electron microscopy shows a high number of transitional cells and a
spongy appearance of the keratohyaline granules.2
Differential diagnosis
The differential diagnosis includes lichen simplex chronicus which, however,
differs by the presence of inflammatory changes and fibrosis of the papillary
dermis (see Table 3.3).
Congenital bullous ichthyosiform
erythroderma
Clinical features
Congenital bullous ichthyosiform erythroderma (also known as epidermo-
lytic hyperkeratosis, bullous ichthyosis, bullous ichthyosiform erythroderma of
Brocq) is a very rare disease (incidence of 1:300 000 births) and, although some-
times inherited by an autosomal dominant mode, it more often appears to arise
by spontaneous mutation. At birth the infant may show marked hyperkerato-
sis, erythroderma, or even present as a collodion baby. Although the scales are
soon lost, leaving a generalized moist, tender erythroderma, re-epithelialization
leads to further scale production followed by the development of widespread
blistering (Fig. 3.25) which heals without scarring. As the patient becomes
older, the erythema and blistering become less apparent and, later, the disease is
complicated by the development of verrucous hyperkeratosis, especially in the
flexures (Figs 3.26–3.31). In some cases, the scales have been said to assume
a porcupine quill-like appearance (ichthyosis hystrix) and scalp involvement
may simulate tinea capitis.1 The nape, axilla, groin, and flexural folds are sites
of predilection. Occasional blisters still arise, often in summertime and at sites
of pressure. In patients with keratin 1 but not with keratin 10 mutations, pal-
moplantar keratoderma is often present. Nail dystrophy may sometimes be a
feature. The patients suffer from an offensive body odor. Congenital bullous
ichthyosiform erythroderma is associated with considerable morbidity and sig-
nificant mortality due to sepsis, fluid loss, and electrolyte imbalance.1
A nevoid variant in which the lesions follow Blaschko's lines is also rec-
ognized.2 In the past, such lesions may have been mistaken for epidermal
nevi showing epidermolytic hyperkeratosis. Due to the possibility of gonadal
mutations, children of affected patients with the nevoid variant may develop
generalized congenital bullous ichthyosiform erythroderma
56 Disorders of keratinization

Fig. 3.26
Congenital bullous
ichthyosiform
erythroderma:
Hyperkeratosis and scales
follow re-epithelialization
of widespread blistering.

Fig 3.24
(A, B) Autosomal dominant lamellar ichthyosis: in this example there is marked
compact hyperkeratosis. The granular cell layer is prominent and there is focal
parakeratosis.

Fig. 3.27
Congenital bullous
ichthyosiform
erythroderma: adult
showing very generalized
scaling, particularly
severe on the legs. By
courtesy of the Institute
of Dermatology, London,
UK.

Pathogenesis and histological features

Fig. 3.25
Congenital bullous ichthyosiform erythroderma: close-up view of an infant showing
intense erythema and blistering. By courtesy of M. Liang, MD, The Children's
Hospital, Boston, USA.
An annular variant has also been described. Patients may have mild eryth-
roderma and blisters at birth, but the characteristic feature is the presence of
many annular gray hyperkeratotic plaques with a peripheral erythematous
border. 3,4
There is considerable evidence in the recent literature confirming that con-
genital bullous ichthyosiform erythroderma represents a genetic disorder of
keratin expression associated with hyperproliferation of the epidermis.5,6 In
the skin, basal keratinocytes predominantly express keratin 5 and 14, while
suprabasal cells switch to the expression of keratin 1 and 10. Keratin mono-
mers form obligate heterodimers in pairs of acidic (type I) and basic (type
II) keratins, which assemble into keratin intermediate filaments building a
cytoskeleton for the structural stability and flexibility of epidermal cells.
Transgenic mouse studies using a truncated human keratin 10 gene have
been shown to result in the pathobiological and biochemical phenotype of
epidermolytic hyperkeratosis.7 Epidermolytic hyperkeratosis shows linkage
 Ichthyosis 57

Fig. 3.28
Congenital bullous Fig. 3.30
ichthyosiform Congenital bullous
erythroderma: same ichthyosiform
patient as Figure erythroderma: blistering
3.27, showing elbow may sometimes be seen
involvement. By courtesy in adulthood. By courtesy
of the Institute of of the Institute of
Dermatology, London, UK. Dermatology, London, UK.

Fig. 3.29
Congenital bullous ichthyosiform erythroderma: the hands are particularly affected.
By courtesy of the Institute of Dermatology, London, UK.
to the keratin gene cluster either on chromosome 12q11–13 (type II keratin)
or chromosome 17q21-q22 (type I keratin).8–10 Direct sequencing of keratin
1 and 10 genes has identified point mutations in a number of affected fami-
lies.11–17 Most mutations are missense and clustered at the ends of the central
helical rod domains. Keratin 1 mutations are associated with severe pal-
moplantar hyperkeratosis while keratin 10 mutations are not because kera-
tin 10 is physiologically substituted by keratin 9 on palmoplantar skin.15
Mutations in the keratin 1 or 10 gene exhibiting mosaicism explain the
nevoid variant of congenital bullous ichthyosiform erythroderma.18,19 The
annular variant shows minor mutations in keratin 1 or 10 genes on distinct
keratin domains.4
The histological features are known as epidermolytic hyperkeratosis or
granular degeneration and are very striking.20,21 Suprabasal keratinocytes
appear vacuolated and typically contain distinct eosinophilic intracytoplas-
mic inclusions. The cell borders are ill defined and intraepidermal blister
Fig. 3.31
Congenital bullous
ichthyosiform
erythroderma: adult
showing very severe
verrucous flexural scaling.
By courtesy of R.A.J.
Eady, MD, Institute of
Dermatology, London, UK.
formation may be present. There is massive orthohyperkeratosis, papillo-
matosis, and acanthosis. The granular cell layer is prominent and contains
coarse and irregular keratoyhaline granules (Fig. 3.32).
By immunohistochemistry, epidermolytic hyperkeratosis shows a normal
distribution pattern of keratins 5/14 and 1/10, but in addition there is over-
expression of keratin 14 in the suprabasal epithelium accompanied by quite
marked labeling of the upper epithelial layers by keratin 16, as would be
expected in a hyperproliferative state.5,22
Ultrastructural studies have shown that the intracytoplasmic inclusions
seen on light microscopy are composed of abnormally aggregated keratin
58 Disorders of keratinization

Fig. 3.33
Congenital bullous
ichthyosiform
erythroderma: striking
perinuclear keratin
clumping is evident.
By courtesy of R.A.J.
Eady, MD, Institute of
Dermatology, London,
A UK.

Ichthyosis bullosa of Siemens

Clinical features
Ichthyosis bullosa of Siemens is inherited as an autosomal dominant. The
condition, which is milder than congenital bullous ichthyosiform eryth-
roderma, presents at birth with blistering subsequently replaced by dark
­lichenified hyperkeratosis of the limbs, predominantly affecting the ­flexures
and shins (Fig. 3.34).1,2 The skin remains fragile and blisters on mild trauma,
­giving rise to characteristic superficial peeling with a molting-like ­appearance
(Mauserung phenomenon) (Fig. 3.35).2,3 Symptoms usually improve with
age. Erythroderma is typically absent. Rarely, pustulation and ­hypertrichosis
may be additional features.3,4 There is considerable clinical overlap between
­ichthyosis bullosa of Siemens and congenital bullous ichthyosiform
­erythroderma, and their distinction can best be achieved by molecular genetic
B analysis.

Fig. 3.32
Congenital bullous ichthyosiform erythroderma: (A) there is massive hyperkeratosis
and acanthosis. The epidermis shows conspicuous superficial vacuolation which has
resulted in vesiculation, (B) there is intracellular edema, and irregular eosinophilic
granules (representing dense abnormal aggregates of keratin filaments) are present
in the superficial layers of the epidermis.

filaments. Since large areas of the cytoplasm lack a regular keratin skeleton,
the suprabasal keratinocytes appear vacuolated and contain irregular kera-
toyhaline granules. Impairment of desmosome-keratin complexes accounts
for the fragility of the epidermis (Fig. 3.33).18 These ultrastructural changes
may form the basis of prenatal diagnosis including amniotic fluid squame
analysis.20,21
Immunoelectron microscopy has identified that the keratin clumps are
composed of keratins 1 and 10.22

Differential diagnosis
Epidermolytic hyperkeratosis is a histopathologic pattern that is seen in
many conditions including ichthyosis bullosa of Siemens, epidermal nevus,
epidermolytic keratoderma, epidermolytic acanthoma, and epidermolytic
leukoplakia (see Table 3.3). It may also represent an incidental finding in
seborrheic keratosis, actinic keratosis, in situ squamous cell carcinoma, inva-
sive squamous cell carcinoma, melanocytic nevi, and epidermal and pilar Fig. 3.34
Bullous ichthyosis
cysts.23 Epidermolytic hyperkeratosis may also be seen in normal and par-
Siemens: flexural
ticularly actinically damaged skin. In such incidental lesions, the changes are hyperkeratosis with early
limited to the epidermis overlying just one or two dermal papillae in contrast blister formation.
to the much more extensive involvement of the other conditions mentioned By courtesy of W.A.D.
above. Therefore, accurate clinical information is necessary to avoid diagnos- Griffiths, MD, Institute of
tic confusion. Dermatology, London, UK.
 Ichthyosis 59

Fig. 3.35
Bullous ichthyosis Siemens: marked hyperkeratosis is present over the knees.
By courtesy of W.A.D. Griffiths, MD, Institute of Dermatology, London, UK.

Pathogenesis and histological features

Bullous ichthyosis is associated with a point mutation in the keratin 2e gene
on chromosome 12q11-q13.4–9 Since this keratin is not expressed on volar
skin, palmoplantar keratoderma does not develop.
Histologically and by electron microscopy, the features are indistinguish-
able from congenital bullous ichthyosiform erythroderma except that they
are milder and the vacuolation of the keratinocytes and cytoplasmic inclu-
sions are restricted to the more superficial prickle and granular cell layers
as opposed to involving almost the entire epidermis as is typical of the latter
condition. Subcorneal separation may be evident.10
B

Linear epidermolytic epidermal nevus Fig. 3.36

Linear verrucous epidermal nevi occasionally show the features of epi- Linear epidermolytic epidermal nevus: (A) low-power view showing massive
dermolytic hyperkeratosis (Fig 3.36). Some patients with such a lesion, hyperkeratosis and papillomatosis (B) high-power view showing epidermolytic
hyperkeratosis.
although by no means all, in reality suffer from the nevoid variant of con-
genital bullous ichthyosiform erythroderma.1–4 It is therefore important that
patients with apparent epidermolytic epidermal nevi are offered genetic
counseling.

Epidermolytic acanthoma
Clinical features
Isolated epidermolytic acanthoma (also termed disseminated epidermolytic
acanthoma) is an acquired lesion that presents as a verrucous papule or
plaque approximately 1.0 cm in diameter and sometimes resembles a viral
wart, nevus or seborrheic keratosis.1–3 Lesions may present at any site, but
the scrotum, head, neck, and leg are particularly affected.2,3 Although usually
solitary, occasional patients may present with multiple localized or dissemi-
nated lesions.4–8 Variants affecting the mucosae of the oral cavity and female
genital tract have also been documented.9,10 Caucasians and the Japanese are
predominantly affected.3

Pathogenesis and histological features Fig. 3.37

Although not proven, it has been suggested that epidermolytic acanthoma
develops as a consequence of keratin 1 and 10 gene mutation.3
The lesion is characterized by hyperkeratosis, parakeratosis, acanthosis,
and papillomatosis (Fig. 3.37).1,2 The upper prickle cell and granular cell lay-
ers show features of epidermolytic hyperkeratosis (i.e., marked vacuolation
of the keratinocytes with eosinophilic keratin inclusions) (Fig. 3.38).
Epidermolytic acanthoma: the lesion is papillomatous with massive hyperkeratosis.
There is a superficial perivascular chronic inflammatory cell infiltrate.
Epidermolytic acanthoma displays diminished expression of keratins
1 and 10 and increased expression of the hyperproliferative keratins 6
and 16.3
60 Disorders of keratinization

Fig. 3.38 Fig. 3.39

Epidermolytic acanthoma: there is superficial cytoplasmic vacuolation and Peeling skin syndrome: Erythematous lesions show peeling of the skin leaving
eosinophilic inclusions are conspicuous. superficially denuded red patches. By courtesy of H.Traupe MD and V.Oji MD,
Department of Dermatology, Munster, Germany.
Differential diagnosis
Identical histological changes are seen in congenital bullous ichthyosiform
erythroderma, linear epidermolytic epidermal nevus, epidermolytic palmo-
plantar keratoderma, and in focal epidermolytic hyperkeratosis (see Table
3.3). Clinical information is usually necessary to avoid diagnostic confusion.

Focal epidermolytic hyperkeratosis

Focal epidermolytic hyperkeratosis (incidental epidermolytic hyperkeratosis)
represents a non-specific finding of epidermolytic hyperkeratosis in the epi-
dermis overlying or adjacent to an unrelated lesion. It is very common and
has been described, for example, in seborrheic keratoses, overlying scars and
fibrous histiocytoma, in banal and dysplastic nevi, actinic keratosis, squamous
cell carcinoma in situ, and melanoma. It may also be seen in normal skin. 1–5

Peeling skin syndrome

Clinical features
Peeling skin syndrome (familial continual skin peeling, keratolysis exfoliativa Fig. 3.40
congenitale) is characterized by a spontaneous, lifelong peeling of the stratum Peeling skin syndrome:
corneum without bleeding or pain.1–6 The mode of inheritance is autosomal The skin of the backs
of hand and feet shows
recessive.1 Three types can be distinguished:
reddish scaly patches. By
• In type A a generalized continued shedding or peeling of the entire skin courtesy of H.Traupe MD
without signs of inflammation or other symptoms is present from birth and V Oji MD, Department
or develops during childhood (Fig. 3.39).2 of Dermatology, Munster,
• Type B appears, resembles and is characterized by isolated erythematous Germany
lesions which then peel, leaving burning superficially denuded red
patches with a peripheral collarette.3 Only recently a mutation of
corneodesmosin has been identified.3a
• In type C (acral peeling skin syndrome), involvement is confined to the backs Ichthyosis hystrix Curth-Macklin
of the hand and feet (Fig. 3.40).4,5 A homozygous missense mutation in the
gene of transglutaminase-5 has been identified in two unrelated families.6 Clinical features
‘Ichthyosis hystrix’ is a descriptive name for cornification disorders with spiny
Histological features and dark hyperkeratosis. Ichthyosis hystrix Curth-Macklin is characterised
• In type A, histology shows a plane of separation either within the lower by generalized verrucous plaques, involving the entire trunk, the flexural sur-
part of an otherwise normal horny layer or above the granular cell faces of the extremities and the palms and soles. The autosomal dominant
layer. Ultrastructural analysis reveals an intracellular splitting within the disorder sometimes resembles bullous ichthyosiform erythroderma, but there
corneocytes.2 is no clinical or histological evidence for blistering. 1–3
• In type B, the epidermis is psoriasiform with an absent or reduced
granular cell layer and marked parakeratosis. The split occurs at the level Pathogenesis and histological features
of the granular cell layer.3 Recent evidence suggests that in ichthyosis hystrix Curth-Macklin a mutation
• In type C peeling skin syndrome, the horny layer is detached from the in a keratin gene affecting the variable tail domain (V2) of keratin 1 results
stratum granulosum (Fig. 3.41).4,5 in a failure in keratin intermediate filament bundling and retraction of the
 Ichthyosis 61

Fig. 3.41
Peeling skin syndrome: the biopsy is taken from the edge of the lesion. Note that
the stratum corneum is clearly separated from the underlying epidermis.

cytoskeleton from the nucleus.2 This is the first in vivo evidence for the crucial
role of a keratin tail domain in supramolecular keratin intermediate filament
organization and barrier formation.2
Histologically, the epidermis is acanthotic and orthohyperkeratotic. The
suprabasal keratinocytes are vacuolated and a few of them appear ­binucleated.
In contrast to epidermolytic hyperkeratosis, eosinophilic intracytoplasmic
inclusions are not present.4
The significant ultrastructural observation in ichthyosis hystrix Curth-
Macklin is the presence of perinuclear concentric shells of tonofilaments. In
contrast to keratin mutations of the rod domain in epidermolytic hyperkera-
tosis, aggregations and clumping of keratin filaments are absent.4

Congenital reticular ichthyosiform B

erythroderma
Clinical features
Congenital reticular ichthyosiform erythroderma is a rare inherited disorder
of keratinization.1 Since only sporadic cases have been recognized, the mode of
inheritance is unknown. Most of the patients have been female. The patients
are born with congenital ichthyosiform erythroderma. During ­childhood the
integument clears gradually so that enlarging patches of normal skin appear
to be enclosed by erythrokeratotic and hyperpigmented areas in a reticular
arrangement. Because of this clinical appearance the genodermatosis has also
been termed ichthyosis ‘en confettis’ or, more precisely, ichthyosis variegata.2–8
Associated features are hypertrichosis, and palmoplantar hyperkerato-
sis, and, in single cases, hypogonadism, growth retardation, hepatomegaly,
­keratoacanthoma or squamous cell carcinoma.1,5,7
Pathogenesis and histological features
Histologically, the epidermis is pale staining and there is psoriasiform hyper-
plasia. The horny layer is thickened and parakeratotic. The parakeratotic
corneocytes have enlarged nuclei. The keratinocytes of the upper layers show
prominent perinuclear vacuolation and contain few keratohyalin granules.
Their cell borders are well defined and intracytoplasmic eosinophilic granules
are absent. Some of the vacuolated keratinocytes are binucleate (Fig. 3.42).
The dermal vessels are dilated, and there is a sparse perivascular inflamma-
tory cell infiltrate with scattered melanophages.
While keratin 2e is missing, the other epidermal keratins are regularly
expressed. At the ultrastructural level the arrangement of the keratin skeleton
is highly disturbed. Immuno-electron microscopy reveals complete absence
of keratin filaments in the perinuclear cytoplasm.1–3 The number of transi-
tional cells is increased and nick end labeling (TUNEL) for DNA fragmenta-
tion shows strong labeling of the parakeratotic corneocytes consistent with
Fig. 3.42
Ichthyosis variegata: (A) there is hyperkeratosis and well-developed psoriasiform
hyperplasia; (B) there is parakeratosis with prominent nuclei. Note the cytoplasmic
vacuolation. Eosinophilic intracytoplasmic inclusions are absent.
an apoptotic mode of cell death.9 Uptake and processing of melanosomes is
irregular. The basic genetic defect in congenital reticular ichthyosiform eryth-
roderma is due to dominant mutations is keratin 10 that causes mislocalisa-
tion to the nucleolus and disruption of the keratin filament network.9,10
Differential diagnosis
The absence of keratin clumping clearly distinguishes congenital reticular
ichthyosiform erythroderma from keratinization disorders characterized by
epidermolytic hyperkeratosis. Ichthyosis hystrix Curth-Macklin shares the
intraepidermal formation of binucleate, vacuolated keratinocytes but lacks
parakeratosis and shows formation of perinuclear shells of tonofibrils (see
Table 3.3).
Comèl-Netherton's syndrome
Clinical features
Comèl-Netherton's syndrome (Netherton's syndrome, ichthyosis linearis cir-
cumflexa) is a rare genodermatosis inherited as an autosomal recessive. It
is characterized by the triad of congenital ichthyosiform erythroderma, hair
shaft anomalies, and a severe atopic diathesis with high IgE blood levels and
eosinophilia.1 It is believed to affect approximately 1:200 000 of the pop-
ulation.2 Generally, the congenital ichthyosiform erythroderma gradually
evolves into a milder ichthyosis linearis circumflexa which is characterized
by an erythematous, scaly rash predominantly affecting the trunk and limbs.3
62 Disorders of keratinization
It is composed of polycyclic, migratory, annular and serpiginous lesions
with characteristic two parallel lines of scale at the periphery, the so-called
­double-edged scale (Figs 3.43–3.45). In infancy, erythema and scaling may
be widespread, but later the face is often predominantly affected (particularly
marked around the mouth and eyes), along with the perineum,4 and as such
the eruption can be mistaken for acrodermatitis enteropathica (Fig. 3.46).1
Later the scalp, face, and eyebrows may show a yellowish scaling.5 Ichthyosis
linearis circumflexa is typically nonpruritic,5 and the nails and teeth are not
involved.3 Rarely, infants may also show palmoplantar hyperkeratosis.6
Comèl-Netherton's syndrome is often misdiagnosed as seborrheic dermatitis,
atopic dermatitis, and psoriasis vulgaris.
Trichorrhexis invaginata (due to a transient and repeated defect of ker-
atinization, with resultant hair shaft intussusception)7 presents clinically as
coarse and lusterless hair, which is short, brittle, and fragile (Fig. 3.46). Pili
torti and trichorrhexis may also be evident (Fig. 3.47).5
Fig. 3.43
Comèl-Netherton's syndrome: ichthyosis linearis circumflexa. Note the serpiginous
lesions with characteristic double border. By courtesy of M. Judge, MD, Institute
of Dermatology, London, UK.
Fig. 3.44
Comèl-Netherton's syndrome: (A) hyperkeratotic lesions
may sometimes be prominent; (B) note the focal loss of the A B
polycyclic pattern.
Patients with Netherton's syndrome may in addition suffer from life
threatening neonatal dehydration with hypernatremia, failure to thrive, and
recurrent skin infections often caused by Staphylococcus aureus,4,8,9 amino-
aciduria,5 mental retardation,5,7 and immune defects.1,5 An impaired epider-
mal barrier is a potential risk for increased and even toxic absorption of
topical medications.
Pathogenesis and histological features
Netherton's syndrome results from mutations in the SPINK5 gene which
has been localized to 5q32.10,11 Nonsense, frameshift deletions and inser-
tions and splice site defects resulting in premature termination codons and
Fig. 3.45
Comèl-Netherton's
syndrome: there is
prominent involvement of
the trunk and limbs.

A B
Fig. 3.47
Comèl-Netherton's
syndrome: bamboo hair
(trichorrhexis invaginata).
By courtesy of M.
Judge, MD, Institute of
Dermatology, London,
UK.
a defective serine protease inhibitor, i.e., Lympho-Epithelial Kazal Type
Inhibitor (LEKTI), have been identified.11–13 The lack of LEKTI consequently
leads to a hyperactivity of the proteases involved in the desquamation pro-
cess or inflammatory response (kallikreins) and accounts for the ichthyotic
and inflammatory skin phenotype, which is associated with an extremely
impaired epidermal barrier.
For diagnostic features, the biopsy must be taken from skin just preced-
ing the lesion's scaly margin (Fig. 3.48).14,15 In this region the epidermis may
show psoriasiform hyperplasia with associated spongiosis. There is a thick
adherent parakeratotic scale. Small, dark, round or oval granules can be iden-
tified within the stratum granulosum. These are diastase-resistant, PAS and
Ichthyosis 63
Fig. 3.46
Comèl-Netherton's syndrome: (A) there is profound
erythema with scaling; (B) the hair is dull and appears short
and thin. The eyebrows are deficient. (A) By courtesy of M.
Judge, MD, Institute of Dermatology, London, UK,
(B) By courtesy of A. Griffiths, MD, Institute of
Dermatology, London, UK.
Sudan black positive and are thought to represent an influx of serum exu-
dates resulting from the accompanying dermal inflammation.4 Similar ‘inclu-
sions’ have been described in psoriasis and atopic eczema16 and as such they
are not specific. Rarely, the parakeratotic scale may be associated with the
presence of Munro microabscesses.6 Biopsies from the center of the lesion
shows the features of atopic dermatitis.
Electron microscopy reveals reduced numbers of lamellar bodies in kera-
tinocytes and the presence of lysosomal inclusion bodies with intercellular
amorphous deposits in the horny layer.14,16
Immunohistochemistry can demonstrate the absence of LEKTI antigen
and is highly specific.17
Differential diagnosis
The histologic distinction from psoriasis vulgaris may be histologically
extremely difficult (if not impossible) in the absence of clinical information.
Other genodermatoses, dermatophytosis, and inflammatory skin diseases
with a psoriasiform-like pattern must be differentiated (see Table 3.3). Atopic
dermatitis is another important differential diagnosis.
Sjögren-Larsson syndrome
Clinical features
This autosomal recessive inherited disorder combines the features of ichthyo-
sis, spastic bi- or quadriplegia and mental retardation.1–5 It is rare, with an
incidence of 0.4 per 100 000 of the population.4 Although the disease may
be encountered worldwide, the prevalence is particularly high in Northern
Sweden.2
The ichthyosis, which develops in the first year of life with a diffuse scal-
ing, affects the entire body with the exception of the central face and is typi-
cally intensely pruritic (Fig. 3.49).3,5 Later, the skin has a brownish-yellow
color and shows a cobblestone-like lichenification.4 Hyperkeratosis around
the umbilicus is said to be characteristic.5 Erythroderma is not a feature and
the hair, nails, and sweat glands are unaffected.3,4 The diagnosis should be
especially considered in preterm babies with congenital ichthyosis.5
The spasticity, which presents in early childhood, predominantly affects
the legs and is often associated with contractures. The majority of patients are
wheelchair bound.4 Kyphoscoliosis may also be present.3 Mental retardation
is typically present but is not invariable.1 Epilepsy is sometimes a feature.3
64 Disorders of keratinization

Visual acuity is often impaired and photophobia is a frequent complaint.

Macular degeneration associated with crystal deposition is characteristic
(Fig. 3.50).6

Pathogenesis and histological features

Sjögren-Larsson syndrome results from deficiency of microsomal fatty alde-
hyde dehydrogenase (FALDH).7 The gene has been mapped to 17p11.2 and
multiple mutations including missense mutations, deletions, and insertions
have been identified.8–10 The abnormal level of free fatty alcohols in cultured
fibroblasts, direct testing of FALDH activity, or the presence of LTB4 metabo-
lites in urine can provide biochemical screening and/or confirmation of the
clinical diagnosis, prior to molecular mutation analysis of the FALDH gene.5
Epidermal hyperproliferation has been demonstrated in Sjögren-Larsson
syndrome.11
Histologically, there is papillomatosis, acanthosis, and basket-weave hyperk-
eratosis with scattered mild parakeratosis and occasional follicular hyperkeratosis
(Fig. 3.51).12 The granular cell layer may be slightly thickened. A light lymphohis-
tiocytic infiltrate is sometimes present around the superficial dermal vasculature.
Ultrastructurally, there are lamellar inclusions in the prickle and granular
cell layers.12 Lipid inclusions are not a feature.
A

Fig. 3.48
Comèl-Netherton's syndrome: (A) scanning view showing a detached Fig. 3.50
thickened stratum corneum and psoriasiform hyperplasia; (B) note the marked Sjögren-Larsson syndrome: characteristic macular crystals. By courtesy of
parakeratosis. M. Willemsen, MD, University Medical Center, Nijmegen, Belgium.

Fig. 3.49 Fig. 3.51

Sjögren-Larsson syndrome: there is severe scaling and the skin has a yellowish- Sjögren-Larsson syndrome: there is hyperkeratosis, hypergranulosis and mild
brown color. By courtesy of M. Willemsen, MD, University Medical Center, papillomatosis. A light superficial perivascular lymphocytic infiltrate is present. By
Nijmegen, Belgium. courtesy of M. Willemsen, MD, University Medical Center, Nijmegen, Belgium.
 Other congenital ichthyotic syndromes 65

Conradi-Hünermann-Happle syndrome
Clinical features
Conradi-Hünermann-Happle syndrome is an X-linked dominant congeni-
tal ichthyosis with associated chondrodysplasia punctata. It is lethal in the
majority of male embryos. Chondrodysplasia punctata is defined as a ­stippled
calcification of the epiphyses. There are several forms but only the type
2 variant presents with severe ichthyosiform erythroderma. Later the
­erythema clears and a whorled scaling following the lines of Blaschko ­persists
(Fig. 3.52).1,2
Associated symptoms are scarring alopecia, follicular atrophoderma,
localized hypo-and/or hyperpigmentation, sectorial cataracts, and skeletal
­dysplasia, which leads to asymmetric shortening of the long bones or severe
kyphoscoliosis. Due to the individual differences in X-inactivation, ­expression
of the disease is rather variable even within families.1,2

Pathogenesis and histological features Fig. 3.53

Biochemical analyses using gas chromatography-mass spectrometry show Conradi-Hönermann-Happle syndrome: there is hyperkeratosis and acanthosis.
elevated plasma levels of 8-dehydrocholesterol and 8(9)-cholesterol, result-
ing from a block of a key enzyme in sterol metabolism, namely the 8–7 ste-
rol isomerase. This enzyme is encoded by the emopamil-binding protein
gene, which shows heterozygous mutations in Conradi-Hünermann-Happle
syndrome.3
The histologic features resemble those of ichthyosis vulgaris (Fig. 3.53).
There is hyperplasia of the epidermis, orthohyperkeratosis, a reduced stra-
tum granulosum, and dilated hair infundibula with follicular plugs. As a
pathognomonic finding in newborns, von-Kossa staining demonstrates cal-
cium deposits in the corneocytes which allows for discrimination of other
ichthyoses that share the feature of a reduced stratum granulosum (Fig. 3.54)
(see Table 3.3). At a later age the calcification is difficult to detect histologi-
cally but electron microscopy may reveal cytoplasmic vacuoles and electron-
dense calcium crystals in the granular cell layer.4

Other congenital ichthyotic syndromes

A
Many syndromes can be associated with congenital ichthyosis. In ichthyosis
prematurity syndrome there is associated polyhydramnios and the premature
neonates may suffer from transient asphyxia. The infants have a thick cheesy

Fig. 3.52
Conradi-Hünermann-
Happle syndrome:
Scaly erythema follow
the whorled lines of
Blaschko. By coutesy of
H Traupe MD, Dept of
Dermatology, Munster,
Germany.
Fig. 3.54
Conradi-Hönermann-Happle syndrome: (A) the granular cell layer is absent. Note
the basophilic deposits within the thickened stratum corneum, (B) the basophilic
deposits represent calcium as seen in this von Kossa preparation.
membrane which desquamates and then the skin improves within some weeks.
The skin shows compact orthohyperkeratosis and acanthosis. At ultrastruc-
tural level, characteristic masses of lipid membranes in lentiform paranuclear
swellings of granular and horn cells can be demonstrated which has lead to
the designation ichthyosis congenita type 4.1 A novel locus for the ichthyosis
prematurity syndrome has been assigned to chromosome 9q33–34.2
66 Disorders of keratinization

Type II or infantile cerebral Gaucher syndrome presents as a collodion

baby. The diagnosis of this fetal metabolic disease can be made by measure-
ment of glucocerebrosidase activity in peripheral blood leukocytes or in
extracts of cultured skin fibroblasts.3
Dorfman-Chanarin syndrome is a triglyceride storage disease with
impaired long-chain fatty acid oxidation resulting in cataract, hepatospleno-
megaly, neurosensorial deafness, myopathy or developmental delay. At birth,
generalized white scaling and a variable degree of erythema are present. The
skin findings resemble congenital ichthyosiform erythroderma although the
stratum granulosum may be thinned. Intracellular lipid vacuoles can be pres-
ent in circulating neutrophils, as well as in a variety of other cells including
keratinocytes. Thus a skin biopsy fixed in alcohol may be useful. Lipid vac-
uoles may also be found in the obligate carrier parents. Refsum syndrome
patients also have epidermal lipid vacuoles, but in Dorfman-Chanarin syn-
drome patients, the phytanic acid levels are normal.4
Trichothiodystrophy represents a heterogeneous group of autosomal
recessive disorders that share brittle hair and an abnormally low hair shaft
sulfur content (decrease of cysteine). Trichoschisis and alternating light and A
dark banding by polarizing microscopy are typical findings.5 At least two
subtypes of trichothiodystrophy are associated with congenital ichthyo-
sis: the acronym IBIDS (‘Tay syndrome’) refers to the clinical findings of
­ichthyosis (e.g., collodion membrane), brittle hair, intellectual impairment,
decreased fertility, and short stature. Other features are microcephaly, dys-
plasia of nails, failure to thrive, ‘progeria’-like symptoms, cataracts, and
photosensitivity (» PIBIDS).6 Half of all trichothiodystrophy patients show
an abnormal nucleotide excision repair of UV-damaged DNA.7 Histology of
the ichthyotic skin shows acanthosis with orthohyperkeratosis and a reduced
stratum granulosum.

Follicular ichthyosis
Clinical features
Follicular ichthyosis (ichthyosis follicularis) is a poorly documented ­condition
in which patients present with horny, follicular lesions which, although
­usually generalized, show a predilection for the head and neck (Fig. 3.55).1,2 B
In the report by Hazell and Marks, associated clinical findings included
pseudoacanthosis nigricans affecting the axillae, comedones on the cheeks Fig. 3.55
and ­fingers, and dental malocclusion.2 Literature subsequent to these two Follicular ichthyosis: (A) there are bilateral follicular lesions; (B) the follicles are plugged
papers has focused on the association of ichthyosis follicularis with alopecia with thornlike scale. By courtesy of the Institute of Dermatology, London, UK.
and photophobia (see below).3

Pathogenesis and histological features Pathogenesis and histological features

Follicular ichthyosis (ichthyosis follicularis) is an umbrella term or histologic
pattern that is present in many conditions and is defined by follicular ortho-
hyperkeratosis with or without hypergranulosis in the infundibulum.
For differential diagnosis see Table 3.3.
Ichthyosis follicularis with alopecia and
photophobia
Clinical features
Ichthyosis follicularis with alopecia (atrichia) and photophobia (IFAP syn-
drome) is an exceedingly rare disorder characterized by the presence of
non-inflammatory thorn-like (filiform) follicular hyperkeratosis that often
improves during the first year of life (Fig. 3.56). Other features are ichthyosi-
form dry skin, generalized complete nonscarring alopecia (with absence of
eyelashes and eyebrows), and severe photophobia.1–6 Ocular findings may
include corneal deformity and opacity with surface vascularization.6 Angular
cheilitis, keratotic psoriasiform plaques on the extensor surfaces of the
extremities, and nail dystrophy with chronic infection may also be present.2,6
Additional findings including hypohidrosis, recurrent respiratory infections,
skeletal abnormalities, cryptorchidism or progressive deteriorating neuro-
logic symptoms such as generalized seizures and cerebellar symptoms have
been reported.5
The mode of inheritance and pathogenesis of this disorder is unknown
although autosomal dominant and X-linked recessive forms have been
described. The complete IFAP phenotype seems to be only observed in male
patients. It is therefore thought to be of X-linked recessive inheritance. Female
carriers may present with linear ‘lesions of Blaschko’ showing circumscribed
hairless, anhidrotic or ichthyotic areas of skin 2,5,6
The follicular lesions are characterized by projecting hyperkeratotic plugs
showing focal parakeratosis and associated hypergranulosis.7 Hair follicles
are atrophic and lack hair shafts and sebaceous glands (Figs 3.57, 3.58).1
Sweat glands are normal but hyperkeratosis of the acrosyringia may occlude
the openings of sweat ducts.5
The psoriasiform plaques show hyperkeratosis with parakeratosis, acan-
thosis, spongiosis, and a bandlike upper dermal lymphohistiocytic infiltrate.7
Differential diagnosis
Other forms of atrichia and follicular keratosis should be considered (see
Table 3.3).
Lichen spinulosus
Clinical features
Lichen spinulosus is a rare dermatosis of unknown etiology which par-
ticularly affects the extensor surfaces of the arms and legs, back, chest,

B infundibula and a perivascular and perifollicular lymphohistiocytic infiltrate.1
Fig. 3.56
Ichthyosis follicularis with alopecia and photophobia: (A) the skin is dry and
ichthyosiform, (B) on the scalp a non-scarring alopecia with follicular hyperkeratosis
is characteristic. By courtesy of H Traupe MD, Dept of Dermatology, Munster,
Germany.
Fig. 3.57
Ichthyosis follicularis with alopecia and photophobia: there is marked follicular
atrophy. Note the small arrector pili muscles.
Other congenital ichthyotic syndromes 67
Fig. 3.58
Ichthyosis follicularis with alopecia and photophobia: there is hyperkeratosis
centered on an acrosyringium.
buttocks, face, and neck.1 Occasionally, lesions are generalized. Lesions pres-
ent in the second and third decades as round to oval, 2–6-cm flesh-colored
and sometimes pruritic, symmetric plaques composed of multiple 1–3-mm
thorny, grouped follicular papules which protrude above the surface of the
skin.1–3 The texture has been likened to a nutmeg grater. Males are affected
more often than females. There is no racial predilection.2 Other than a cos-
metic nuisance, the condition is of no clinical significance. Lichen spinulosus
has been described in association with Crohn's disease, human immunodefi-
ciency virus (HIV) infection, and as an adverse drug reaction.4–7
Histological features
Lichen spinulosus is characterized by keratotic plugging of dilated follicular
Sebaceous glands may be atrophic or absent. Perforating folliculitis-like fea-
tures can be superimposed.
Differential diagnosis
There is considerable histological overlap with keratosis pilaris and the follic-
ular lesions of pityriasis rubra pilaris. The distinction is best made clinically.
Phrynoderma
Clinical features
Phrynoderma (toad skin) most often develops as a consequence of vitamin A
deficiency.1–4 Other proposed etiological factors include deficiencies of the vita-
min B complex, riboflavin, vitamin C, vitamin E, and essential fatty acids.4 In
Western countries most cases develop as a result of malabsorption.4,5 Patients
present with xerosis, hyperpigmentation and multiple 2–6-mm, red-brown,
dome-shaped papules with a central folliculocentric crater filled with lami-
nated keratinous debris.1,4 The elbows and knees are predominantly affected
but lesions may extend to involve the thighs, upper arms and buttocks.1
Histological features
The papules consist of a cystically dilated follicular infundibulum filled with
keratinous debris.4
Keratosis pilaris
Clinical features
This fairly common condition, which has an autosomal dominant mode of
inheritance, is probably a follicular variant of ichthyosis and, indeed, fre-
quently accompanies ichthyosis vulgaris.1–3 The age at presentation is most
68 Disorders of keratinization

A
A

Fig. 3.59
Keratosis pilaris:
(A) typical follicular
papules and pustules on
the thigh; (B) note the
conspicuous plugged
follicles. (A) By courtesy
Fig. 3.60
of R.A. Marsden, MD,
Keratosis pilaris: (A) there
St George's Hospital,
is follicular dilatation and
London, UK, (B) By
plugging; (B) note the
B courtesy of the Institute of
B atrophy of the infundibular
Dermatology, London, UK.
epithelium.

often in the first two decades with a peak during adolescence.2 Up to 40%
of adults may be affected.2 There is no racial predilection. There is an appar-
ent increased incidence in females and lesions present as pruritic small fol-
licular keratoses, sometimes containing small distorted hairs. They are most
often found on the lateral aspects of the arms and thighs, although the face,
trunk, and buttocks may also be affected (Fig. 3.59).2 Seasonal variation,
with lesions being much more severe in winter, is often documented.2 There is
an increased incidence of atopy.2
Although keratosis pilaris most often presents as an isolated phenom-
enon, occasionally it may develop in association with systemic disease
including Hodgkin's lymphoma, vitamins B12 and C deficiency, hypo-
thyroidism, Cushing's disease, and treatment with adrenocorticotropic
hormone.3,4,5
Histological features
Keratosis pilaris is characterized by follicular dilatation and keratin plugs,
which may contain a single or several distorted hair shafts (Fig. 3.60).4 A
mild, non-specific chronic inflammatory cell infiltrate surrounds the dermal
blood vessels and sometimes involves the hair follicles themselves.
Keratosis pilaris atrophicans
Clinical features
Keratosis pilaris atrophicans combines the features of follicular hyper-
keratosis and scarring.1 Although some authors believe this to represent a
­single ­disease entity, others prefer to subdivideit into a number of categories
­including ulerythema ophryogenes, atrophoderma vermiculata, and keratosis
­follicularis spinulosa decalvans.2 Evidence of different modes of inheritance,
clinical differences, and variable associations supports the latter.2
Ulerythema ophryogenes (keratosis pilaris atrophicans facei, KPAF) pres-
ents at birth or in early infancy with follicular papules and surrounding ery-
thema followed by atrophic scarring affecting the lateral aspect of the eyebrows
(Fig. 3.61).3–5 The cheeks, forehead, temples, and neck may also be involved
(Fig. 3.62). Later on, the entire eyebrow may be lost. Keratosis pilaris affect-
ing the extensor aspects of the arms and thighs is also sometimes present.3 The
condition is believed to be inherited as an autosomal dominant.
It may be associated with a number of other inherited disorders including
Noonan's syndrome, woolly hair, cardiofaciocutaneous syndrome, Cornelia de
Lange syndrome, Rubinstein-Taybi syndrome, and partial monosomy 18.3,6–12

Fig. 3.61
Ulerythema ophryogenes: there is intense erythema with loss of follicles. The
eyebrow is a commonly affected site. By courtesy of the Institute of Dermatology,
London, UK.
Fig. 3.62
Ulerythema ophryogenes:
the cheek is also
frequently involved. By
courtesy of the Institute
of Dermatology, London,
UK.
The association with Noonan's syndrome is of particular importance since
such patients suffer from potentially life-threatening congenital pulmonary
stenosis. Ulerythema ophryogenes is also associated with atopy.13
Atrophoderma vermiculata (ulerythema acneiforme, atrophoderma ver-
miculatum, atrophoderma reticulata, acne vermoulante, folliculitis ulery-
thema reticulata, folliculitis ulerythematosa, honeycomb atrophy) is an
exceedingly rare form of atrophic keratosis pilaris thought to be inherited as
an autosomal dominant. Patients present with follicular keratoses and pit-
ted depressions separated by normal skin (worm-eaten appearance) affect-
ing the cheeks, ears, and forehead (honeycomb atrophy).2,14–17 The disorder
presents in patients after 5 years of age.2 Unilateral nevoid variants following
Blaschko's lines have been documented.15–17
Keratosis follicularis spinulosa decalvans is characterized by diffuse
atrophic keratosis pilaris associated with scarring alopecia affecting the
scalp.18–20 Other conditions sometimes present include atopy, palmoplantar
Acquired ichthyosis-like conditions 69
Fig. 3.63
Keratosis pilaris atrophicans: (A) low-power view showing gross follicular
hyperkeratosis and dilatation of the ostium; (B) high-power view. Note the
perifollicular fibrosis.
hyperkeratosis, photophobia, and punctate keratitis.18 In some patients it
is inherited as an X-linked recessive disorder which has been mapped to
Xp21.13-p22.2.21,22 X-linked dominant and autosomal dominant variants
have also been proposed.19
Pathogenesis and histological features
The pathogenesis of keratosis pilaris atrophicans is unknown although it
involves blockage of the follicular ostium by a keratinous plug.
All variants of keratosis pilaris atrophicans are characterized by follicular
hyperkeratosis with ostial dilatation, atrophy of the sebaceous gland, and a
scanty perifollicular or perivascular lymphohistiocytic infiltrate. Comedones
and milia may be found. There is a variable perifollicular fibrosis that extends
into the reticular dermis (Fig. 3.63).3,11,12,16
Acquired ichthyosis-like conditions
Acquired ichthyosis-like or ichthyosiform conditions refer to patients who
develop diffuse ichthyosis-like scaling during their life (Table 3.5). The adult
onset renders the term acquired ichthyosis inappropriate. It is an important
paraneoplastic manifestation of a number of malignancies: Hodgkin's lym-
phoma is most often encountered, but non-Hodgkin's lymphoma including
mycosis fungoides and a range of carcinomas have all been associated.1–8
Ichthyosiform skin changes may also accompany malnutrition, HIV and
other infectious diseases, sarcoidosis, collagenoses, celiac disease and other
70 Disorders of keratinization

Table 3.5
Acquired ichthyosis-like conditions

Etiology Diseases
Dry skin None
Paraneoplastic Hodgkin and non-Hodgkin lymphoma
Kaposi sarcoma
Various carcinomas
Infections Leprosy
Tuberculosis
HIV/AIDS
Malnutrition Pellagra
Vitamin A deficiency
Drugs Lipid-lowering agents (statins)
Nicotinic acid
Allopurinol
Cimetidine
Lithium A
Retinoids
Gastrointestinal diseases Crohn's disease
Celiac disease
Gastrectomy
Endocrinopathies Hyperparathyroidism
Hypothyroidism
Miscellaneous Renal insufficiency
Sarcoidosis
Graft-versus-host disease
Dermatomyositis and systemic lupus
erythematosus
Down's syndrome

gastrointestinal diseases, renal insufficiency, hypothyroidism, and graft-

­versus-host disease.4,9–15 Ichthyosiform skin changes following administra-
tion of lipid-lowering agents and other various drugs or kava consumption
has been documented.13,14 Dry skin, especially in blacks, leads to the develop- B
ment of lamellar scales on the legs and trunk. The features of acquired ich-
thyosis-like skin conditions most often resemble those of ichthyosis vulgaris Fig. 3.64
both clinically and histologically (Figs 3.64–3.67). Acquired ichthyosis: (A) cutaneous manifestations most often resemble ichthyosis
Clinical differential diagnosis includes xerosis cutis which lacks thick vulgaris; (B) close-up view of the scale. By courtesy of the Institute of Dermatology,
scales, develops at later age, and can be easily treated by fatty emolients. London, UK.

Pityriasis rotunda
Clinical features
Also known as pityriasis circinata, this acquired disorder of keratinization
was originally described in the Japanese.1 It is also not uncommon in South
Africans (Bantu) and West Indian blacks,2,3 but has only rarely been reported in
Caucasians with the exception of a subpopulation of Italians in Sardinia.4–7 Fig. 3.65
Patients present with persistent, very sharply defined, circular or oval areas Acquired ichthyosis:
of hyper- or hypopigmentation associated with a fine scale (Fig. 3.68). Lesions, there is intense erythema
which are usually multiple and frequently numerous, are characteristically non- and scaling. This patient
inflammatory and asymptomatic. Often, they are confluent. They measure 0.5– also suffered from graft-
28 cm in diameter and are particularly located on the trunk and limbs. The sex versus-host disease.
incidence is equal. Lesions are sometimes associated with gradual remission By courtesy of B. Solky,
during the summer months and relapse in winter.6 The maximum incidence is MD, Department of
Dermatology, Brigham
in the third to fifth decades. There is often a family history of ichthyosis vul-
and Women's Hospital
garis.8 It may occasionally be associated with a familial incidence.8,9 and Harvard Medical
Pityriasis rotunda sometimes appears to be a cutaneous marker of severe inter- School, Boston, USA.
nal disease including tuberculosis,1 cancer (particularly hepatoma),10,11 leukemia,12 cir-
rhosis,6 ovarian and uterine disease,13 undernutrition, and favism.8 Pityriasis rotunda
might best be regarded as an acquired circumscribed variant of ichthyosis.12 Increased pigmentation of the basal keratinocytes may be evident. A mild
perivascular chronic inflammatory cell infiltrate is sometimes present in the
Histological features superficial dermis. A superficial fungal infection, for example tinea (pityr-
The histological features are subtle and comprise hyperkeratosis with a dimin- iasis) versicolor, should always be excluded by a PAS reaction or silver
ished or absent granular cell layer and loss of the epidermal ridge pattern. stain.14
 Erythrokeratodermas 71

Fig 3.66
Acquired ichthyosis: this patient developed ichthyosis in a background of mycosis Fig. 3.68
fungoides. Low-power view showing marked focally compact hyperkeratosis and Pityriasis rotunda: characteristic lesion showing circumscription, scaling, and
acanthosis. hyperpigmentation. By courtesy of R.A. Marsden, MD, St George's Hospital,
London, UK.

transmembrane proteins that form gap junctions and are involved in epider-
mal differentiation.The KID/HID syndrome and Vohwinkel's syndrome are
associated with sensorineural hearing loss. In others, the genetic defect has
yet to be identified.2

Fig 3.67
Acquired ichthyosis: high-power view to emphasize the atypical lymphocyte population
and atypia. Note the well-developed retraction artifact so typical of this condition.
Erythrokeratodermas
‘Erythrokeratoderma’ or ‘erythrokeratodermia’ refers to a group of geno-
dermatoses characterized by localized erythematous lesions, hyperkeratotic
plaques, and, infrequently, a mild palmoplantar keratosis.1 Many of these
diseases represent connexin mutations (Table 3.6). Connexin genes code for
Table 3.6
Diseases with connexin mutations
Erythrokeratoderma variabilis
Clinical features
This rare ichthyosiform dermatosis generally has an autosomal dominant
mode of inheritance although an autosomal recessive variant has recently
been described.1–5 Lesions usually present soon after birth or during the first
year of life and are of two types, typically present simultaneously:
• Type 1 lesions are symmetrically distributed, discrete figurate, and
often bizarre patches of erythema, which vary in size, shape, number,
and location over periods of hours and days (Fig. 3.69).3 These are
sometimes temperature or stress related.1,6
• Type 2 lesions are well-defined, fixed geographical, reddish-yellow-
brown greasy, hyperkeratotic plaques arising either within the
erythematous lesions or, more often, independently (Fig. 3.70). Lesions
are usually asymptomatic although occasionally mild pruritus or burning
sensations are a feature.4
The condition particularly affects the face, buttocks, and extensor surfaces
of the extremities.7 While cold weather in winter and emotional ­problems
may sometimes exacerbate the condition, the symptoms often improve in the
summer months.4 Erythrokeratoderma variabilis is occasionally ­associated
with high estrogen levels and symptoms may worsen with estrogen-contain-
ing oral contraceptive therapy.1,2,4 Hypertrichosis (of vellus hairs) and mild

Disease Inheritance Locus Gene Protein

Erythrokeratoderma variabilis AD or AR 1q35.1 GJB3 Connexin 31
AD 1q35.1 GJB4 Connexin 30.3
Erythrokeratoderma variabilis with AD 1q35.1 GJB4 Connexin 30.3
erythema gyratum repens-like lesions
Keratitis-ichthyosis-deafness syndrome/Hystrix-like- AD 13q11-12 GJB2 Connexin 26
ichthyosis deafness syndrome (KID/HID Syndrome)
Oculodentodigital dysplasia AD 6q22-24 GJA1 Connexin 43
Vohwinkel keratoderma AD 13q11-12 GJB2 Connexin 26
Hidrotic ectodermal dysplasia of Clouston AD 13q11-12 GJB6 Connexin 30
72 Disorders of keratinization
Fig. 3.69
Erythrokeratoderma variabilis: annular and serpiginous erythematous lesions
showing scaling and the characteristic trailing edge. By courtesy of R.A. Marsden,
MD, St George's Hospital, London, UK.
Fig. 3.70
Erythrokeratoderma
variabilis: in these lesions
there is more pronounced
scaling.
­ eratoderma of the palms and soles may additionally be evident.3,6 The
k with pyknotic nuclei reminiscent of the grains of Darier have been described
mucous membranes, hair, teeth, and nails are unaffected and there are no
associated systemic manifestations.4
Pathogenesis and histological features
Connexin genes code for proteins that form intercellular channels called gap
junctions that allow for transport and signaling between neighboring cells
in the epidermis. In the skin, Cx31 and Cx30.3 are expressed in the stra-
tum granulosum of the epidermis with a suggested role in late keratinocyte
differentiation.8
Initially linked to the RH1 locus on 1p, erythrokeratoderma variabilis
has been mapped to 1p34-p35, which includes the connexion genes GJB3
and GJB4.7,8 However, erythrokeratoderma variabilis appears to be hetero-
geneous since not all individuals that have been clinically diagnosed with
Fig. 3.71
Erythrokeratoderma variabilis: (A) low-power view showing hyperkeratosis,
acanthosis with an undulating skin surface and a very light superficial perivascular
chronic inflammatory cell infiltrate; (B) high-power view showing marked
parakeratosis overlying a thickened orthokeratotic stratum corneum. Note the
presence of a granular cell layer.
erythrokeratoderma variabilis harbor Cx31 or Cx30.3 mutations.8–11 A subset
of patients with connexin 30.3 mutations manifest with a unique clinical
feature, namely transient erythematous patches with a peculiar, circinate or
gyrate border reminiscent of erythema gyratum repens, i.e., erythrokerato-
derma with erythema gyratum repens-like lesions.12
The histopathological features of this disease are not specific, consisting of
orthohyperkeratosis, variable parakeratosis, irregular acanthosis, and papil-
lomatosis with an undulating skin surface (Fig. 3.71).3,13 Dyskeratotic cells
in one case.6 The granular cell layer appears normal. A perivascular lympho-
histiocytic inflammatory cell infiltrate may be present in the superficial der-
mis. Pilosebaceous follicles and sweat glands are normal.13
Connexin immunohistochemistry discloses an irregular distribution of the
epidermal gap junction proteins.14
Ultrastructural observation have shown an increased number of gap junc-
tions, some of which display four layers, suggesting a loosened connection of
the keratinocyte plasma membrane through the gap junctions.15 Other studies
have revealed markedly diminished numbers of Odland bodies in the granu-
lar cell layer.6,14 Conspicuous nonmyelinated nerve fibers and Schwann cells
have been described in the papillary dermis.6,14 These, however, are not con-
sistent findings.16 Nuclear encirclement by condensed keratin filaments and
keratohyalin has also been recorded.16

Differential diagnosis
Progressive symmetrical erythrokeratoderma is characterized by symmetrical
distribution and a more fixed or very slow progression of erythema and scaly
plaques. Since mutations in the the loricrin gene have been identified (loricrin ker-
atoderma), this condition should no longer be grouped as a connexin disorder.
Progressive symmetric erythrokeratodermia
Clinical features
Also known as erythrokeratodermia progressiva symmetrica or Gottron's
syndrome, this condition is inherited as an autosomal dominant with incom-
plete penetrance, although sporadic cases may also be encountered.1,2 It usu-
ally presents in the first year of life with fixed, symmetrical, and sometimes
pruritic, erythematous scaly plaques on the extensor surfaces including
the elbows, knees, buttocks, dorsal surfaces of the feet and hands, and head
(Fig. 3.72).1–5 The face, chest, and abdomen are typically unaffected.2 The
plaques gradually extend during the first few years and then become static.3
Additional features include palmoplantar keratoderma and pseudoainhum
(constriction bands on the fingers and toes). The sex incidence is equal.2 There
is clinical overlap with erythrokeratoderma variabilis and indeed patients
may present with features of both diseases. However, progressive symmetric
erythrokeratoderma lacks transient migratory erythema.1
Pathogenesis and histological features
A mutation in the loricrin gene on chromosome 1q21 has been identified in
one family with progressive symmetric erythrokeratoderma.6 Similar muta-
tions have been reported in the ichthyotic variant of Vohwinkels's syndrome.
As a result, more definitive genotype-phenotype correlation within the con-
nexin gene disorders or other causative genes will have to be established to
define symmetrical progressive erythrokeratoderma as a separate entity.
Histologically, there is marked basket-weave hyperkeratosis with focal
parakeratosis, hypergranulosis, and psoriasiform hyperplasia.2,3 Paranuclear
vacuolation may be evident in the granular cell layer.3,7 A perivascular lym-
phocytic infiltrate is present in the superficial dermis.5
Ultrastructurally, characteristic loricrin-rich intranuclear granules are seen
in the granular cell layer.6 Lamellar granules are increased in number and lipid
droplets may be evident in the cornified cells.3 Immunohistochemically, the
cornified cell envelopes show greatly reduced staining for loricrin.6 Swollen
Fig. 3.72
Progressive symmetric
erythrokeratodermia:
Erythematous scaly
plaques gradually appear
on the extensor surfaces
on the extremities and
then persist.
Erythrokeratodermas 73
mitochondria in the granular cell layer are said to be a helpful ultrastructural
diagnostic pointer.3–5,7
Differential diagnosis
Progressive symmetric erythrokeratodermia can be distinguished from pso-
riasis by the absence of suprapapillary plate thinning, neutrophil infiltration,
and Munro microabscesses.2 In addition, the parakeratosis tends to be very
focal and hypergranulosis is usually present.
Keratitis-ichthyosis-deafness syndrome
Clinical features
Keratitis-ichthyosis-deafness syndrome (KID syndrome, palmoplantar ectoder-
mal dysplasia type XVI) is a very rare genodermatosis. Spontaneous mutations,
autosomal dominant, and autosomal recessive modes of inheritance have all
been documented.1–4 There is an equal sex incidence.5 It may present at birth
as a ‘vernix-like’ covering, which soon progresses to a dry, scaling erythema,
particularly affecting the face (especially the cheeks) and extremities, including
the palms and soles.1,3,4,6,7 The skin may be thickened and leathery.7,8 Later the
lesions become verrucous and hyperkeratotic, brownish-yellow, sharply circum-
scribed plaques (Fig. 3.73).1 Circumoral furrows may lead to a progeria-like
appearance.9 Follicular keratoses sometimes develop on the head and extremi-
ties and a ‘prickly’ spiculated appearance on the backs of the hands is occasion-
ally evident.3,4,8 Palmar and plantar involvement with accentuation of the skin
markings has been likened to heavily grained leather.10 There does, however,
appear to be some variation in presentation.1 Some patients have therefore been
described as being normal at birth, developing dry, scaly skin in later childhood,
while others have been reported as ‘red and wizened at birth’.11,12
Inflammation of the cornea with photophobia is usual and a vascularizing
keratitis leads to severe visual impairment.8 The end result is destruction of
the cornea by a pannus of vascular or fibrous tissue (keratoconus).1
Deafness is of the congenital neurosensory type, but is occasionally due to
recurrent otitis media; conduction defects may also be present.1,7,8 It is often
total and frequently present at birth although not usually recognized until
sometime later in early childhood.8
Ectodermal dysplasia is variably present and features include alope-
cia (either partial or complete, including eyebrows and eyelashes), small
Fig. 3.73
KID syndrome: there is
marked scaling of the
scalp with alopecia. Note
the facial erythema and
dark plaques on the
cheeks. By courtesy
of R.J.G. Rycroft, MD,
St John's Dermatology
Centre, London, UK.
74 Disorders of keratinization

malformed teeth with increased caries, scrotal tongue, leukokeratosis, and a

variety of dystrophic nail changes including fragility, hyperkeratosis, dyspla-
sia, leukonychia, and aplasia.1,4,8
Additional features that may be detected include increased susceptibility to
superficial and systemic chronic infections (bacterial and fungal), neuromus-
cular disease, retraction of the Achilles tendon, hypohidrosis, heat intolerance,
and growth deficiency.1,3,8,13–15 The reason for the increased risk of cutaneous
infection is unknown. While an abnormality of immunity has been proposed,
it is felt more likely that colonization of greatly increased and degenerate
keratin is the more important etiological factor.16 No consistent abnormal-
ity of immune function has so far been reported.3,11,14 Mental retardation is a
rare feature, which may be seen in patients with the autosomal recessive vari-
ant.1 Liver disease including cirrhosis has been present in autosomal recessive
patients.1,2 Squamous carcinoma of the tongue and skin (sometimes multiple)
are important complications (Fig. 3.74).3,13,17–19

Pathogenesis and histological features

KID syndrome, at least in some families, has been shown to be associated Fig. 3.75
with mutations in the connexin 26 gene.20,21 KID syndrome: scanning
The histological appearances of the skin lesions are non-specific and view showing basket-
include basket-weave hyperkeratosis with occasional foci of parakerato- weave hyperkeratosis. In
sis, acanthosis, and papillomatosis (Figs 3.75, 3.76).8 Some authors have this example the eccrine
observed prominence and vacuolization of the stratum granulosum.22,23 sweat glands are normal.
Follicular plugging is commonly present and occasionally the orifices of the
eccrine ducts are similarly affected.5,11 A superficial perivascular lymphohistiocytic
infiltrate is sometimes evident.8 Eccrine sweat glands may be diminished in num-
ber and atrophic, with thickened, hyalinized basement membranes and absent or
atrophic hair follicles are seen in the areas of alopecia.3,8,22 Electron microscopic
studies of the epidermis have revealed no significant abnormalities.7,15
A recently reported autopsied case has described both ocular and aural
changes:16
• Ocular changes were limited to the cornea and conjunctiva. Dyskeratosis
and atrophy of the corneal surface epithelium accompanied by
neovascularization and mild chronic inflammation of the substantia
propria were evident. The bulbar conjunctiva showed epithelial
atrophy, dyskeratosis, and mild chronic inflammation. Late changes are
characterized by the development of an inflammatory and vascular pannus.8
• Aural changes related not only to epithelial maturation abnormalities
of the external auditory meatus and tympanic membrane, but also to
cochleal maldevelopment.16 The essential features of the former included

Fig. 3.76
KID syndrome: high-power view emphasizing the basket-weave keratin overlying a
zone of compact keratin. There is focal parakeratosis. There is vacuolization of the
granular cell layer.

parakeratosis of the squamous epithelium overlying the tympanic

membrane. Immaturity and parakeratosis of the ridge pattern of the
epithelium covering the bony aspect of the external auditory meatus may
also be present. Changes of the internal ear included maldevelopment of
the cochlea and absence of the tectorial membrane and organ of Corti,
accompanied by reduction in the number of nerve fibers and spiral
ganglion nerve cells.16 These features are very much in keeping with
sensorineural deafness of cochleal origin.
The liver changes include micronodular cirrhosis, cholestasis, Kupffer cell
hyperplasia, abundant Mallory's hyaline and marked copper storage.1

Hystrix-like ichthyosis with deafness

Fig. 3.74
KID syndrome: squamous
carcinoma on the knee.
Tumors may be multiple.
By courtesy of M. Judge,
MD, Institute of
Dermatology, London,
UK.
Clinical features
Hystrix-like ichthyosis-deafnesss (HID) syndrome (ichthyosis hystrix type
Rheydt) presents with spiky and cobblestone-like hyperkeratosis.1,2 There
are many similarities with keratitis-ichthyosis-deafness syndrome. However,
HID patients show multiple red patches shortly after birth, which develop
into ichthyotic erythroderma. In contrast to the KID syndrome, patients with
 Palmoplantar keratoderma 75

HID show a more widespread involvement of the trunk but less palmoplan-
tar hyperkeratosis. Keratitis of the eyes is less prominent in HID patients, but
they also suffer from neurosensorial deafness, proneness to mycotic/bacterial
skin infections, and skin cancer.2
Pathogenesis and histological features
Both HID and KID syndromes are associated with an identical connexin
26 missense mutation.3 Therefore they may represent a spectrum of pheno-
typic variability instead of separate entities.3
Histologically, there is orthohyperkeratosis with foci of parakeratosis,
acanthosis, and the nuclei are surrounded by empty spaces reminiscent of
a bird's eye. At the ultrastructural level, keratinocytes show reduction of
tonofibrils and abnormal membrane-bound granules containing mucous sub-
stances that are discharged into the intercellular spaces.4 The absence of these
features in KID syndrome may result from sampling errors, with some skin
areas being more severely affected than others.3
Palmoplantar keratoderma
The palmoplantar keratodermas (PPKs) consist of a large heterogeneous
group of localized cornification disorders characterized by hyperkeratosis
of the palms and soles. Ichthyotic skin disorders and erythrokeratoderma
may also show palmoplantar hyperkeratosis but mainly affect other body
areas. PKKs are classified on the basis of mode of inheritance, distribution of
lesions, additional clinical features, and associated abnormalities.1–5 Many of
these genodermatoses have a late onset. At least 30 subtypes are recognized
and subdivided into two broad subtypes, one in which lesions are restricted
to the skin (Table 3.7) and the other in which there is a much broader spec-
trum of ectodermal defects affecting skin, mucosae, nails, hair, teeth and neu-
rological abnormalities (Table 3.8).4,5 Where more than a single ectodermal
structure is involved Stevens et al. coined the term ‘palmoplantar ectodermal
dysplasia’ to emphasize the generalized nature of the disorder and identified
a total of 19 subtypes.6

Table 3.7
Isolated palmoplantar keratodermas (PPK)
Palmoplantar keratoderma Inh. Locus Protein Disease
Diffuse AD 17q12-q21 Keratin 9 Epidermolytic palmoplantar keratoderma (Vörner-Unna-Thost)
12q11-13 Keratin 1 Epidermolytic PPK Vörner-Unna-Thost, Epidermolytic hyperkeratosis
with polycyclic psoriasiform plaques
12q11-13 Keratin1 Progressive palmoplantar keratoderma (Greither) and other
nonepidermolytic palmoplantar keratoderma
8p22-23 unknown Keratolytic winter erythema
AR 8qter SLURP1 Mal de Meleda
12q11-13 unknown Gamborg-Nielson palmoplantar keratoderma
Circumscribed AD 18q12.1-12.2 Desmoglein1 Keratosis palmoplantaris areata et striata (type 1–3)
6q24 Desmoplakin
12q Keratin1
unknown unknown Keratosis palmoplantaris nummularis (hereditary painful callosities)
Punctate AD 8q24 unknown Punctate palmoplantar keratoderma (Buschke-Fischer-Brauer)
unknown unknown Marginal papular acrokeratoderma

Table 3.8
Palmoplantar keratodermas (PPK) with associated symptoms

Palmoplantar
keratoderma Disease Inh Locus Protein Symptoms
Diffuse Huriez syndrome AD 4q23 ? Sclerodactyly, nail dystrophy, squamous cell
carcinomas in atrophic areas
Vohwinkel syndrome 13q11-12 Connexin 26 Mutilating keratoderma, sensorineural deafness
Loricrin keratoderma 1q21 Loricrin Associated ichthyosis
Clouston syndrome 13q12 Connexin 30 Diffuse palmoplantar keratoderma, alopecia, nail
dystrophies
Olmsted [1927] syndrome ? ? ? Diffuse mutilating palmoplantar, periorificial
keratoses, ectodermal dysplasia
Papillon-Lefèvre AR 11q14 Cathepsin C Diffuse palmoplantar keratosis with severe
syndrome periodontitis
Naxos syndrome 17q21 Plakoglobin Wooly hair, cardiomegaly, tachycardia
McGrath syndrome 1q32 Plakophilin 1 Painful diffuse palmoplantar keratosis, Skin
fragility, dystrophic nails, sparse hairs
Circumscribed Pachyonychia congenita 1 AD 12q13 Keratin 6A Thickened nails, focal palmoplantar keratoderma,
Jadassohn-Lewandowsky 17q12-q21 Keratin 16 folliculare hyperkeratosis, leukokeratosis
Pachyonychia congenita 2 12q13 Keratin 6B Thickened nails, focal palmoplantar keratoderma,
Jackson-Lawler 17q12-q21 Keratin 17 cysts, natal teeth
Howel-Evans syndrome 17q24 ? Association with carcinoma of esophagus
Tyrosinemia II AR 16q22.1-q22.3 Tyrosine ­ Focal, often painful palmoplantar keratoderma
(Richner-Hanart amino-transferase
syndrome)
Carvajal-Huerta syndrome 6p24 Desmoplakin Epidermolytic PPK, wooly hair, arrhythmogenic
left cardiomyopathy
Punctate Schöpf-Schulz-Passarge ? ? ? PPK with lid cysts, hypodontia and hypotrichosis
syndrome
76 Disorders of keratinization

Table 3.9
Histologic patterns of PPK

Epidermolytic hyperkeratosis Epidermolytic palmoplantar

keratoderma (Vörner-Unna-Thost)
Keratosis palmoplantaris
nummularis
PKK with polycyclic psoriasiform
plaques
Carvajal-Huerta syndrome
Hyperkeratosis overlying depressed Keratosis palmoplantaris punctata
area of the epidermis
Paranuclear eosinophilic globular Pachyonychia congenital
inclusions Tyrosinemia type II
(Richner-Hanhart)
Orthohyperkeratosis and, Other forms of PKK
inconsistently,
focal parakeratosis, epidermal
hyperplasia, discrete perivascular
inflammation Fig. 3.77
Diffuse palmoplantar
keratoderma Vörner-
Unna-Thost: there is
There are three major clinical categories: diffuse, circumscribed, and punctu- hyperkeratosis affecting
ate (Tables 3.7 and 3.8).4,5 Histologically, there are four main histologic patterns the entire sole of the foot.
that are characterized by epidermolytic hyperkeratosis, orthohyperkeratosis By courtesy of W.A.D.
with hypergranulosis and acanthosis, hyperkeratosis ­overlaying depressed areas Griffiths, MD, Institute of
Dermatology, London, UK.
of the epidermis, and paranuclear eosinophilic inclusions (Table 3.9). In many
subtypes, the underlying molecular defect has been ­identified and can be related
to structural proteins (keratins), cornified envelope (loricrin, transglutaminase),
cohesion (plakophilin, desmoplakin, desmoglein1), cell-to-cell communication
(connexins), and transmembrane signal transduction (cathepsin C).7

Keratosis palmoplantaris diffusa

Vörner-Unna-Thost
Clinical features
Keratosis palmoplantaris diffusa Vörner-Unna-Thost is an epidermolytic pal-
moplantar keratoderma (PPK) and represents the most common form of pal-
moplantar keratoderma with an incidence of 1:100 000. Reinvestigation of
the original family with Unna-Thost PPK showed that epidermolytic forms
existed within the family as has been described by Vörner. Therfore, it is not
justified to separate Vörner disease from Unna-Thost disease.1
The condition is inherited as an autosomal dominant and usually presents
in the first months or else when the patients start running.1–6 Patients pres-
ent with symmetrical, well-demarcated yellowish, smooth and waxy plaques
covering the palms and soles, and, to some extend, the ventral surface of
fingers and toes (Figs 3.77, 3.78). The lesions reach the lateral aspects of
hands and feet but not beyond. The periphery is bordered by an erythematous
margin (Fig. 3.79).2 Painful blisters are not uncommon. Hyperhidrosis and
maceration may be present and facilitate dermatophytosis.3,6 Rarely, associ-
ated knuckle pads or clubbed digits have been documented.7 Identification
of the epidermolytic form of PPK has therapeutic consequences since lesions
become inflammatory and erosive with systemic retinoid therapy.
Pathogenesis and histological features
Epidermolytic palmoplantar keratoderma was initially mapped to17q12-q21, the
locus of the type I acidic keratin cluster where different point mutations of keratin
9 were identified.8 Epidermolytic palmoplantar keratoderma, however, has also
been reported to be associated with keratin 1 mutations that map to 12q11–13,
the site of the keratin II genes.9,10 Keratin 1 and 9 are the major structural keratins
in the suprabasal keratinocytes of palmoplantar epidermis. Mutations in keratin
9 are associated with more severe manifestations than mutations in keratin 1.
Most of the keratin mutations affect the central regions of the protein,
which are important for filament assembly and stability of the keratin skel-
eton. As a consequence, tonofilament clumping causes cellular degeneration
and disruption, e.g., epidermolytic palmoplantar keratoderma. Mutations in
Fig. 3.78
Diffuse palmoplantar keratoderma Vörner-Unna-Thost: in this patient the palms
of the hands were also affected. By courtesy of W.A.D. Griffiths, MD, Institute of
Dermatology, London, UK.
the rod domain are associated with only mild focal signs of epidermolytic
hyperkeratosis in the spinous layer of palmoplantar epidermis.11
Epidermolytic palmoplantar keratoderma is not associated with malig-
nancy. Patients in one large kindred showed a high incidence of breast and
ovarian cancer.10 It is now believed that this represented a coincidental co-
segregation of a keratin 9 mutation with a BRCA1 mutation on 17q21.2
Histologically, there is a massive orthohyperkeratosis, hypergranulosis,
papillomatosis, and acanthosis accompanied by features of epidermolytic
hyperkeratosis in the prickle and the granular cell layers with unstained,
vacuolated cytoplasm, intracytoplasmic eosinophilic granules, and coarse
keratohyalin granules (Figs 3.80, 3.81). A superficial dermal perivascular
lymphohistiocytic infiltrate may sometimes be present. Epidermal spongiosis
and vesiculation may indicate mycotic superinfection.
Electron microscopy shows aggregations of keratin filaments and keratin
clumps that accounts for the intracytoplasmic eosinophilic granules seen by
light microscopy. Large areas of the cytoplasm that are devoid of a keratin
 Palmoplantar keratoderma 77

Fig. 3.79 Fig. 3.81

Diffuse palmoplantar keratoderma Vörner-Unna-Thost: the border of the lesion is Diffuse palmoplantar keratoderma Vörner-Unna-Thost: high-power view
marked by a linear zone of erythema. By courtesy of W.A.D. Griffiths, MD, Institute demonstrating the features of epidermolytic hyperkeratosis.
of Dermatology, London.

Histological features
Histopathologic examination of the psoriasiform plaques demonstrates the
characteristic features of epidermolytic hyperkeratosis. Sequencing of the ker-
atin 1 gene in affected family members reveals a mutation within the highly
conserved helix termination motif of the helix 2B segment.1

Diffuse nonepidermolytic palmoplantar

keratoderma
Clinical features
Diffuse nonepidermolytic palmoplantar keratoderma is a heterogenous, ill-
defined group of conditions. It includes an autosomal recessive disorder with
a high incidence in Sweden and characterized by a thick, horny layer sharply
demarcated from the normal skin and knuckle pads on the dorsal aspect of
the finger joints.1 Symptoms usually present in the first 3 years of life.1 Many
patients suffer from increased sweating and, therefore, maceration is com-
Fig. 3.80 mon. There is a greatly increased risk of dermatophyte infections.1 Patients
Diffuse palmoplantar with this variant may also show axillary and groin involvement, subungual
keratoderma Vörner- hyperkeratosis, onychodystrophy, and central facial lesions.2 Another non-
Unna-Thost: scanning epidermolytic variant of diffuse PPK is Mal de Meleda (see below).
view showing massive Although diffuse palmoplantar keratoderma was originally believed
hyperkeratosis, to be associated with esophageal carcinoma (Howell-Evans syndrome),
papillomatosis, and
­re-examination of the affected kindreds disclosed that the keratoderma would
acanthosis.
better be classified as focal (see focal nonepidermolytic palmoplantar kera-
toderma with esophageal squamous carcinoma).3 There are, however, rare
instances of diffuse palmoplantar keratoderma associated with cutaneous
skeleton explain the vacuolar change. Keratohyalin granules cluster in a ran- squamous cell carcinoma, for example Huriez syndrome (palmoplantar kera-
dom fashion around the keratin aggragates. toderma with sclerodactyly) and Schöpf-Schulz-Passarge syndrome (palmo-
plantar keratoderma with squamous carcinoma arising in the areas affected
Epidermolytic hyperkeratosis with polycyclic by keratoderma).4,5
Acquired diffuse palmoplantar keratoderma may also be associated with
psoriasiform plaques malignancy.6

Clinical features Pathogenesis and histological features

Epidermolytic hyperkeratosis with polycyclic psoriasiform plaques is a
unique palmoplantar keratoderma with an autosomal dominant inheri-
tance.1 Clinically, affected individuals manifest transient blistering at birth
followed by chronic diffuse palmoplantar keratoderma. Intermittent flares
of fixed polycylic erythematous psoriasiform plaques which characteristi-
cally deteriorate and then improve are seen although there is marked indi-
vidual variation in both the severity and duration of lesions, ranging from
weeks to months.1
Diffuse nonepidermolytic palmoplantar keratoderma has been mapped to 12q11–
13, the site of the keratin II genes.7,8 The disease mutation described by Kimonis
and coworkers was the first to be identified in a keratin chain variable end region.9
The fact that epidermolysis was not present suggests that the amino-terminal
domain of keratins may be involved in supramolecular interactions of keratin fila-
ments rather than stability.9 There is, however, genetic heterogeneity.10
This disorder is characterized by marked hyperkeratosis, hypergranulosis,
acanthosis, and an exaggerated epidermal ridge pattern (Fig. 3.82). A chronic
78 Disorders of keratinization

Fig. 3.82
Diffuse nonepidermolytic
palmoplantar
keratoderma: there is
massive hyperkeratosis,
hypergranulosis, and
acanthosis.

inflammatory cell infiltrate is sometimes evident in the superficial dermis. The

presence of spongiosis and vesiculation should suggest a concomitant der-
matophyte infection and prompt evaluation of a PAS or silver stained section
(Figs 3.83, 3.84).11 In the diffuse recessive variant, the hyperkeratosis is even
more marked than in the dominant form and the epidermis shows prominent
psoriasiform hyperplasia.1

Progressive palmoplantar keratoderma B

Clinical features Fig. 3.83

Progressive palamoplantar keratoderma, (syn: Greither syndrome, keratosis Diffuse nonepidermolytic palmoplantar keratoderma: (A) in this example, there
palmoplantaris diffusa transgrediens et progrediens) is an autosomal dom- is massive hyperkeratosis with an undulating growth pattern. Intra-epidermal
inantly inherited disease. In childhood, a diffuse symmetric palmoplantar vesiculation is apparent, (B) high-power view.
keratoderma with small pits or fissures and hyperhidrosis develops that pro-
gressively extends to the back of the hands and feet, the region of the Achilles
tendon, ankles, knees or elbows where patchy hyperkeratosis develops. In the
middle of life amelioration occurs (Figs 3.85, 3.86).1

Pathogenesis and histological features

The previously reported cases of Greither's syndrome showed phenotypic
variability suggestive of different underlying gene defects. At least some cases
of Greither's syndrome are caused by keratin mutations.2
Histopathology shows acanthosis with focal orthohyperkeratosis located
on delled areas of the epidermis (Fig. 3.87). There are generally no features
of epidermolytic hyperkeratosis with the exception of a case where a keratin
mutation was detected.3

Keratolytic winter erythema

Clinical features
Keratolytic winter erythema (synonyms: erythrokeratolysis hiemalis,
Oudtshoorn disease) is an autosomal dominant disorder first described in
South Africa.1 Sporadic cases have been reported from other countries.2,3 The
disorder manifests at an early age and is characterized by recurring cycles of
erythema involving the palms and soles, followed by mild hyperkeratosis and
nonpruritic and nonpainful peeling. In severe cases the limbs and trunk are Fig. 3.84
affected with gyrate scaling erythemas. Most remarkably, the onset of symp- Diffuse nonepidermolytic palmoplantar keratoderma: fungal hyphae are apparent in
toms occurs during cold weather.2 the thickened stratum corneum (PAS stain).
 Palmoplantar keratoderma 79

Fig. 3.85
Progressive palmoplantar
keratoderma: (A) diffuse
hyperkeratosis with fissures
progressively extends to the
back of the hands and feet
A B and (B) affects the region of
the Achilles tendon.

Fig. 3.86 Fig. 3.87

Progressive palmoplantar Progressive palmoplantar keratoderma: massive hyperkeratosis with a central small
keratoderma: Patchy dell (arrowed).
hyperkeratosis develops
on the knees.

Pathogenesis and histological features
The disorder has been mapped to chromosome 8p22–23 with some genetic
heterogeneity, but a causative gene has not yet been identified.4,5
The epidermis is acanthotic with a thickened stratum granulosum.
At the advancing edge spongiosis and vesicle formation can be observed.
More centrally, the stratum granulosum becomes pale staining and
pyknotic. Concommitantly, parakeratotic layers form on top. In the
horny layer a cleft appears that contains remnants of parakeratotic cells.1
A superficial perivascular lymphocytic infiltrate has been reported by
some authors.3
Mal de Meleda
Clinical features
Mal de Meleda is inherited as an autosomal recessive with a high prevalence
in Meleda in the Adriatic Sea. The diffuse keratoderma progresses onto the
dorsal aspects of the fingers and toes (keratosis palmoplantaris transgre-
diens et progrediens Meleda). Further features are inflammatory borders,
severe hyperhidrosis, maceration, and unpleasant smell. In addition, con-
stricting bands (pseudoainhum), brachydactyly, nail dystrophy, lesions on
knees and elbows, the perioral region and even oral leukokeratosis can be
observed.1,2
80 Disorders of keratinization

Pathogenesis and histological features

Mutations have been identified in the ARS component B gene on chromo-
some 8, encoding a protein named SLURP1.3–6 It is postulated that SLURP1
interacts with neuronal acetylcholine receptors present in keratinocytes and
sweat glands. Since SLURP1 may act as a secreted epidermal neuromodula-
tor essential for both epidermal homeostasis and inhibition of TNF-alpha
release by macrophages during wound healing, this may explain both the
hyperproliferative as well as the inflammatory clinical phenotype of Mal de
Meleda.3–6
Histology shows orthohyperkeratosis with focal parakeratosis, acanthosis
without epidermolytic changes, and a superficial perivascular lymphocytic
infiltrate

Keratosis palmoplantaris areata et striata

Clinical features
Keratosis palmoplantaris areata et striata (striate palmoplantar keratoderma,
Brünauer-Fuchs-Siemens syndrome, acral keratoderma) is an autosomal dom-
Fig. 3.88
inant disorder characterized by linear bands of keratoderma affecting the pal-
Keratosis palmoplantaris areata et striata: linear hyperkeratotic bands are present
mar aspects of the palms and fingers (Fig. 3.88) accompanied by island-like best seen along the ulnar border of the palm. By courtesy of the Institute of
areas of hyperkeratosis on the soles of the feet.1,2 Lesions typically present Dermatology, London, UK.
in adolescence or early adulthood and are exacerbated by manual labor. A
background palmar hyperkeratosis may be present and fissuring can also be
seen.3 Abnormalities of the nails (ridging and cuticle hyperkeratosis), teeth,
described.6 The granular/filamentous material represents condensed kera-
and hair (wooly hair) may also sometimes be encountered.3,4 There are no
tin filaments. Premature expression of involucrin and filaggrin has been
systemic associations.
found.9 In one family, immunohistochemistry demonstrated diminished
lesional desmoplakin staining.6 Electron microscopy displays diminished
Pathogenesis and histological features
numbers of small and/or rudimentary desmosomes accompanied by keratin
Striate palmoplantar keratoderma is a heterogeneous condition. A transi- filament aggregates and enlarged malformed keratohyalin granules.6,8,9
tion mutation in desmoglein 1, mapped to chromosome 18q12.1, has been
identified in one family.5–7 In another, a transition mutation in desmoplakin,
mapped to chromosome 6p21, was identified, and in a third type, mutation
Keratosis palmoplantaris nummularis
of keratin 1 with partial loss of the glycine loops in the V3 domain has been
reported.3,8 Clinical features
Histologically, striate palmoplantar keratoderma is characterized by In keratosis palmoplantaris nummularis (hereditary painful callosities)
massive hyperkeratosis, hypergranulosis, and acanthosis (Fig. 3.89). patients present with nummular keratotic lesions overlaying plantar pres-
Dark-staining granular and filamentous material within the prickle cell sure points. Keratoses develop when children start to walk. Pain is the major
layer accompanied by slight separation of the keratinocytes has also been complaint.1

Fig. 3.89
Keratosis palmoplantaris areata et striata: (A) there
A B is massive hyperkeratosis with hypergranulosis and
acanthosis; (B) high-power view.
 Palmoplantar keratoderma 81

Pathogenesis and histological features

The gene defect has not been identified as yet.
Histology shows epidermolytic hyperkeratosis similar to epidermolytic
palmoplantar keratoderma of Vörner-Unna-Thost.1

Punctate palmoplantar keratoderma

Clinical features
Punctate palmoplantar keratoderma (keratosis punctata palmaris et plan-
taris, keratoderma hereditarium dissipatum palmare et plantare, Buschke-
Fischer-Brauer disease, Davis-Colley disease) is characterized by an autosomal
dominant mode of inheritance.1–4 There is an increased incidence in blacks.2
Sometimes, lesions are associated with excessive manual labor.2 In an estab-
lished case, the patient has numerous discrete yellow-brown, small (1–3 mm),
depressed keratotic lesions on the palms and soles and also on the ventral
aspects of the fingers and toes (Figs 3.90, 3.91).5 If the keratin plug is dis-
lodged, a deeply depressed pit remains. Lesions are usually asymptomatic,
but occasionally pain, tenderness or burning are features.2,5
Fig. 3.91
There are occasional reports of punctate palmoplantar keratoderma asso-
Punctate palmoplantar keratoderma: close-up of lesions shown in Figure 3.90.
ciated with internal malignancies including carcinomas of the colon, kidney,
By courtesy of the Institute of Dermatology, London, UK.
breast, and pancreas and Hodgkin's lymphoma.6,7
Punctate keratoderma-like lesions affecting the palms and the soles have
been described as a complication of dioxin exposure.8

Pathogenesis and histological features

The pathogenesis is unknown. A locus has been genetically mapped on chro-
mosome 15q22-q24. The keratin gene clusters have been excluded by linkage
analysis.9
Histologically marked hyperkeratosis is seen overlying areas of epithelial
depression (Fig. 3.92).

Keratosis punctata of the palmar creases

Clinical features
Keratosis punctata of the palmar creases (keratotic pits of the palmar creases)
is a variant of punctate keratoderma in which the lesions are confined to
the palmar and digital creases.1–5 The soles of the feet and heels may also be

Fig. 3.92
Punctate palmoplantar keratoderma: there is massive hyperkeratosis overlying a
dell to the right of center.

involved.3,6 The sexes are equally affected and the disease is predominantly
seen in young to middle-aged adults.7 Although very rare in white patients,
it is common in black adults.3,5,8,9 The development of lesions appears to be
trauma related in many patients since outdoor workers are particularly affected
and the condition improves during a vacation. Although in the majority of
patients the condition appears to be a sporadic occurrence, in some reports an
autosomal dominant mode of inheritance has been documented.2,4
Lesions are small (1–3 mm) depressed yellowish keratotic plugs which are
usually asymptomatic but sometimes may be painful. They are localized to the
flexor creases and when removed leave a cone-shaped depression (Fig. 3.93).
Although usually seen as an incidental finding, on occasions they have been asso-
ciated with ichthyosis vulgaris.4,7 There are also reports of keratosis punctata of
Fig. 3.90 the palmar creases developing in patients with Dupuytren's contracture, derma-
Punctate palmoplantar titis herpetiformis with psoriasis, striate keratoderma, and knuckle pads.7,10
keratoderma:
discrete yellow foci Histological features
of hyperkeratosis are
present over the weight- The lesions are characterized by a hyperkeratotic plug, sometimes with foci of
bearing surfaces. By parakeratosis below which are deep cone-shaped depressions sometimes cen-
courtesy of the Institute tered on the acrosyringium.4 The adjacent epidermis shows acanthosis with
of Dermatology, London, hypergranulosis and in some cases a perivascular lymphohistiocytic infiltrate
UK. is present in the superficial dermis.
82 Disorders of keratinization
Fig. 3.93
Keratosis punctata of the palmar creases: minute punctate lesions are localized
solely to the palmar creases. There is often a history of manual labor.
By courtesy of the Institute of Dermatology, London, UK.
Marginal papular acrokeratoderma
Clinical features
Marginal papular acrokeratoderma refers to a complex, confusing, and
overlapping group of disorders which includes acrokeratoelastoidosis
of Costa, focal acral hyperkeratosis, mosaic acral keratosis, degenerate
collagenous plaques of the hands, digital papular calcific elastosis, and
keratoelastoidosis marginalis of the hands.1 All present with frequently
crateriform, keratotic papules along the borders of the hands and feet
(Fig. 3.94).1 Although usually discrete, in some patients the papules may
coalesce into plaques.
Acrokeratoelastoidosis presents in childhood and adolescence with yel-
lowish, warty, and crateriform keratotic or pearly papules predominantly
affecting the sides of the hands, wrists, fingers, and feet.2–5 There is no racial
predilection and the sexes are affected equally. Patients may also develop cir-
cumscribed keratodermatous knuckle padlike lesions, palmoplantar hyperk-
eratosis, and hyperhidrosis (Fig. 3.95).1,3 Sporadic and autosomal dominant
variants have been described. The disorder may be linked to chromosome 2.6
Repeated trauma is believed to be of etiological importance.
Fig. 3.94
Marginal papular acrokeratoderma: there is a linear band of scaling along the border
of the foot. By courtesy of the Institute of Dermatology, London, UK.
Fig. 3.95
Acrokeratoelastoidosis: knuckle pads are conspicuous in this patient. By courtesy of
the Institute of Dermatology, London, UK.
Focal acral hyperkeratosis is clinically identical to acrokeratoelastoidosis,
patients presenting with keratotic papules along the sides of the hands, fingers, and
feet.7,8 It has also been designated acrokeratoelastoidosis without elastorrhexis.9
Other reported cases have been mistakenly documented as acrokeratoel­astoidosis.10
Females are affected more often than males. Although originally thought to be a
­disorder of black children, more recently it has been described in whites.11
Mosaic acral keratosis is similar if not identical to focal acral hyper­
keratosis, being characterized by keratotic papules distributed in a mosaic
or ­jigsaw-puzzle pattern along dorsal aspects of the feet and adjacent lower
legs.12 Hyperkeratosis may be seen on the palms and soles.1 Only females,
predominantly black, are affected.1
Degenerative collagenous plaques of the hands affect the sun-damaged
skin of the elderly and present as symmetrical yellowish, keratotic or smooth
papules and plaques affecting the thumb, first web, and side of the index
­finger.4,13–18 The ulnar border of the hand and volar aspect of the wrist may
also be involved. Keratoelastoidosis marginalis of the hands is a similar
­condition described in Australians in which keratotic papules develop at sites
of trauma along the index finger and thumb.19 The skin is typically grossly
sun damaged. Calcified variants of degenerative collagenous plaques are
known as digital papular calcific elastosis.20,21
Histological features
Acrokeratoelastoidosis is characterized by massive orthohyperkeratosis over-
lying a crateriform dell lined by acanthotic epidermis. Hypergranulosis may
be present. The dermis shows fragmentation and loss of the elastic tissue
(elastorrhexis) (Fig. 3.96). Collagen may be disorganized or appear homog-
enized and pale staining.2,3
Focal acral hyperkeratosis and mosaic acral keratosis are histologically
identical with the exception that the elastic tissue appears normal.7–12
Degenerative collagenous plaques of the hands are characterized by a
dense zone of thickened and distorted collagen with fragmentation of elastic
fibers and overlying hyperkeratosis and acanthosis.4,13–18 The papillary dermis
is spared. Calcification is sometimes a feature (digital papular calcific elasto-
sis).19–21 Telangiectatic vessels may also be seen and increased dermal mucin
has been described.19
Huriez syndrome
Clinical features
In Huriez syndrome (keratosis palmoplantaris diffuse with sclerodactyly, scle-
rothylosis) patients present with a diffuse mild palmoplantar keratoderma,
scleroatrophic skin of the limbs, hypohidrosis, hypoplasia, and dystrophy of
the nails (Fig. 3.97).1 Aggressive squamous cell carcinoma may develop in the

A B
A B
Fig. 3.97
Huriez syndrome: (A) the leading features are sklerodactyly, hypotrophic and dystrophic nails, (B) there is mid palmar keratosis.
affected skin in approximately 15% of the cases. It has an early onset with a
high risk of metastasis in the third to fourth decades.1
Pathogenesis and histologic features
The genetic cause of this autosomal dominant condition is still unknown.
Histology shows a mild acanthosis, orthohyperkeratosis and well developed
granular layer (Fig. 3.98). Most interestingly, immunohistochemical and ultra-
structural studies revealed an absence of Langerhans cells in involved skin.2
Vohwinkel's syndrome
Clinical features
Vohwinkel's syndrome (keratoderma hereditarium mutilans, keratosis pal-
moplantaris mutilans, mutilating palmoplantar keratoderma, palmoplantar
Palmoplantar keratoderma 83
Fig 3.96
Acrokeratoelastoidosis:
(A) there is marked
hyperkeratosis; (B) there is
diminution of the dermal
elastic tissue.
ectodermal dysplasia type VII) is a rare keratoderma which is usually inher-
ited as an autosomal dominant although a recessive variant has also been
described.1–3 Onset is in infancy or early childhood.2 Caucasians are pre-
dominantly affected and there is a predilection for females.3 The clini-
cal features include palmoplantar keratoderma with a yellowish papular
and honeycomb-like appearance and hyperhidrosis. Other characteristics
are starfish-like keratoses affecting the dorsal surfaces of the hands, feet,
wrists, forearms, elbows. and knees (Figs 3.99 and 3.100).3 Flexion con-
tractures and circumferential hyperkeratotic constriction bands (pseudoain-
hum) affecting the interphalangeal joints associated with autoamputation
are also present.2,3 Additional features include alopecia, nail dystrophy, and
onychogryphosis.2 In the classical variant, sensorineural deafness is an inte-
gral feature.1,4,5 The ichthyosis-associated variant of Vohwinkel is a com-
pletely different entity (see Loricrin keratoderma or Camisa variant form of
Vohwinkel's syndrome).6–9
84 Disorders of keratinization
Fig. 3.98
Huriez syndrome. There are mild acanthosis, orthohyperkeratosis and well
developed granular layer.
Fig. 3.99
Vohwinkel's syndrome: there is marked palmoplantar keratoderma. By courtesy of
W.A.D. Griffiths, MD, Institute of Dermatology, London, UK.
Pathogenesis and histological features
Classical, deafness-associated Vohwinkel's syndrome is due to mutations in
the connexin 26 gene.8
Histologically, the keratoderma is characterized by hyperkeratosis, hyper-
granulosis, and acanthosis.3
Loricrin keratoderma
Clinical features
Loricrin keratoderma (Camisa variant form of Vohwinkel's syndrome,
Vohwinkel keratoderma with ichthyosis) is inherited in an autosomal dom-
inant fashion and characterized by a diffuse palmoplantar keratoderma
that is very similar to that of Vohwinkels' syndrome including the honey-
comb-like appearance (Fig. 3.101).1 In contrast, however, the palmoplantar
­keratoderma is less mutilating, and warty papules and starfish-like keratosis
are absent. A concomitant ichthyosis with generalized fine scaling is a con-
stant feature and often presents congenitally prior to the development of the
palmoplantar keratoderma.2 The patients also do not suffer from the deafness
seen in Vohwinkel's keratoderma.
Fig. 3.100
Vohwinkel’s syndrome: in
this example there is very
disfiguring keratoderma,
hence the alternative title,
keratoderma hereditarium
mutilans. By courtesy
of W.A.D. Griffiths, MD,
Institute of Dermatology,
London, UK.
Pathogenesis and histologic features
Mutations on chromosome 1q21 that result in aberrant, elongated C-terminal
domains of one loricrin allele may lead to an abnormal loricrin expression, and
impairment of cross-linking to itself and other cornified envelope ­proteins.3–5
Loricrin keratoderma and some cases of progressive symmetrical erythro-
keratoderma may share the mutation and light and ultrastructural ­features.6
Therefore some authors have proposed that the loricrin keratoderma should
include cases of what has been termed either (Vohwinkel's) keratoderma with
ichthyosis and progressive symmetrical erythrokeratoderma.7
As with progressive symmetrical erythrokeratoderma acanthosis, a promi-
nent stratum granulosum and parakeratosis is present in loricrin keratoderma
(Figs 3.102, 3.103).
Electron microscopy characteristically reveals formation of a well-formed
transitional layer, intranuclear granules in the upper stratum granulosum, and
a thin cornified envelope.4 Immunoreactivity for loricrin can be detected in
the nuclei of the stratum granulosum and of the parakeratotic cells.4 Mutant
loricrin in the nucleus is thought to impair the function of profilaggrin to
mediate nuclear dissolution in the course of apoptosis which represents an
integral part of keratinocyte terminal differentiation.6
Clouston's syndrome
Clinical features
Clouston's syndrome (hidrotic ectodermal dysplasia, palmoplantar ectoder-
mal dysplasia type X) is an uncommon disorder with an autosomal dominant
mode of inheritance. Nail dystrophy is often predominant, but hair defects
and palmoplantar keratoderma are also found (Fig. 3.104).1–7 Rare manifesta-
tions include sensorineural deafness, ocular abnormalities, skin hyperpigmen-
tation, polydactyly, syndactyly, mental retardation, epilepsy, and dwarfism.5,6
Changes in the nails are variable, but usually they are short and thickened
with longitudinal striations, often with discoloration, and may have grooves,
pits and ridges.5,6 Development of paronychia is a frequent complication.
Scalp alopecia (from hair thinning to complete baldness) is the rule, and facial,
axillary, and pubic hair is usually sparse or totally absent.6 The patients have a
normal facies and no involvement of the dentition or abnormal sweating.
Although hidrotic ectodermal dysplasia has been documented predomi-
nantly in French Canadian families, kindreds have been described in French,
Scottish-Irish, and Indians.4,7–10

A B
Fig. 3.102
Loricrin keratoderma: there is hyperkeratosis and mild acanthosis.
Pathogenesis and histological features
The gene responsible for this condition has been mapped to 13q11–
12.1.11–14 Hidrotic ectodermal dysplasia results from a connexin 30
mutation.15–18
The palmoplantar keratoderma is typified by hyperkeratosis, thickening
of the granular cell layer, and acanthosis.5,7 Elsewhere, eccrine sweat glands
are normal, but hair and sebaceous glands are greatly reduced in number and
apocrine glands completely absent.8
Olmsted syndrome
Clinical features
Olmsted syndrome is exceedingly rare and combines the features of mutilat-
ing palmoplantar keratoderma with periorificial plaques. Approximately 20
cases have been documented.1–5 It is usually associated with sporadic occur-
rence although X-linked dominant transmission has been suggested at least in
Palmoplantar keratoderma 85
Fig. 3.101
Loricrin keratoderma:
(A) there is a generalized fine
scaling and (B) palmoplantar
keratoderma with a yellowish
popular and honeycomb-like
appearance less mutilating
than in classical Vohwinkel's
syndrome.
Fig. 3.103
Loricrin keratoderma: the stratum granulosum is prominent. Scattered cells (on
the right side of the field) show perinuclear vacuolization and the parakeratotic
keratinocytes in the lower horny layer represent transitional cells.
one family.6 There is no racial predilection. There is a striking predominance
in males (5:1).
The keratoderma is present at birth or begins in early infancy and when
fully developed presents as bilateral and symmetrical massively thickened,
yellow, macerated, keratotic plaques covering the whole of the sole and palm
and often extending to the lateral and even the dorsal surface of the hands
and feet (Fig. 3.105).3,4 The heels and forearms may also be affected. The
border of the plaque is sharply defined and surrounded by a pruritic ery-
thematous border. Lesions are often fissured and extremely painful, mak-
ing walking exceedingly difficult or impossible.3,4 Blistering has occasionally
been described.5 Flexion contractures, ainhum-like constriction bands, and
autoamputation are common complications. Superinfection with bacteria
and fungi, particularly Candida albicans, contributes to the problems and as
a result lesions are frequently very malodorous. Squamous carcinoma is an
occasional complication.7,8
86 Disorders of keratinization
Fig. 3.104
Clouston's syndrome: there is nail dystrophy accompanied by hyperkeratosis of the
fingertips, thereby accentuating the epidermal surface ridges.
By courtesy of D. Atherton, MD, the Children's Hospital at Great Ormond Street,
London, UK.
Fig. 3.105
Olmsted syndrome: in this variant, the lesions are very disfiguring. Constriction
bands and autoamputation are important complications. By courtesy of W.A.D.
Griffiths, MD, Institute of Dermatology, London, UK.
Affected children also develop erythematous keratotic papules and plaques
around the body orifices including the mouth, nares, ears, and anus.3,4 The eye-
lids, umbilical region, inguinal region, and gluteal cleft can also be involved.
Additional features include scarring alopecia, keratosis pilaris, and nail
dystrophy including ridging, transverse striae, thickening, curvature, subun-
gual keratosis, and infection.3,4 Hyperkeratotic linear streaks may develop in
the axillae and cubital fossae. Growth retardation, laxity of the large joints,
and corneal involvement are occasional manifestations.3,4
Histological features
The plaques are characterized by massive hyperkeratosis, often with foci of
vertically orientated parakeratosis.2–5 There is hypergranulosis with large
coarse granules under the former whereas the granular cell layer is absent
beneath the areas of parakeratosis. The epidermis is acanthotic and shows
psoriasiform hyperplasia or papillomatosis and there is edema and increased
vascularity of the superficial dermis where a lymphohistiocytic infiltrate is
also seen.
The plaques show increased mitotic activity, increased Ki-67 expres-
sion and increased argyrophilic nucleolar organizer regions (AgNORS).4,9
Keratinization is abnormal with aberrant expression of keratins 5, 10 and
14, filaggrin, and involucrin.4,5 It has, however, been proposed that the kera-
tin abnormalities might be a result of isotretinoin and etretinate therapy.10
Papillon-Lefèvre syndrome
Clinical features
Palmoplantar keratoderma with periodontopathia (palmoplantar kerato-
derma with periodontopathia, palmoplantar ectodermal dysplasia type IV)
is rare and has an autosomal recessive mode of inheritance.1 The incidence
is 1–4 per million of the population.2 There is an equal sex incidence and
onset is usually in the first decade. It is characterized by symmetrical and
marked palmoplantar keratoderma sometimes affecting the dorsal aspects of
the hands and feet (Fig. 3.106).3 Hyperhidrosis may also be present, associ-
ated with gingivitis and marked periodontosis involving both deciduous and
permanent teeth.4,5 Periodontosis is unrelated to oral hygiene and results in
loss of attachment of teeth to the periodontal ligament (Fig. 3.107) and atro-
phy of the alveolar processes (maxillar and mandibular) with eventual loss
of teeth. The periodontal ligament, which is a dense fibrous band, attaches
the tooth to the alveolar bone and carries the blood vessels, lymphatics, and
nerves.6 Psoriasiform lesions may be evident on the knees and elbows and
Fig. 3.106
Papillon-Lefèvre
syndrome: (A) there is
marked hyperkeratosis
affecting the soles of the
feet; (B) in this patient,
the dorsal aspects of
the hands, particularly
the knuckles are also
affected. By courtesy
of W.A.D. Griffiths, MD,
B Institute of Dermatology,
London, UK.

Fig. 3.107
Papillon-Lefèvre syndrome: gingival inflammation and swelling with the particularly
characteristic irregular positioning of the teeth which, as a result of destruction of
supporting tissues, have shifted under the forces of mastication. This patient is
a 12-year-old child, but the severity of the periodontal destruction is what might
be expected in a person aged 60 years. By courtesy of R.A. Cawson, MD, Guy's
Hospital, London, UK.
onychogryphosis has been documented (Fig. 3.108).3 The adnexae are not
usually affected. Presentation is usually in the early years of life (2–4 years
of age).
There is sometimes associated calcification of the falx cerebri and chor-
oid plexus.6 Other features, which may sometimes be present, include deaf-
ness, deformity of the terminal phalanx, follicular hyperkeratosis, and mental
retardation. Patients show an increased risk of infection, particularly furun-
culosis; this has been associated with defective neutrophil chemotaxis and
phagocytosis and impaired B- and T-cell mitogenic responses.7
Pathogenesis and histological features
Papillon-Lefèvre syndrome has been mapped to 11q14–21.8 The disease
is associated with missense and nonsense mutations, deletions, and inser-
tions in the gene for the lysosomal cysteine protease cathepsin C (dipeptidyl
aminopeptidase I).9–12 In homozygous patients, loss of cathepsin C activ-
ity results in impaired activation of bone marrow myeloid and macrophage
Fig. 3.108
Papillon-Lefèvre syndrome: a scaly psoriasiform plaque is present over the elbow.
By courtesy of W.A.D. Griffiths, MD, Institute of Dermatology, London, UK.
Palmoplantar keratoderma 87
Fig. 3.109
Papillon-Lefèvre
syndrome: there
is hyperkeratosis,
hypergranulosis and
acanthosis.
granule serine proteases with resultant defective bacterial phagocytosis.11,12
The cathepsin C gene is also expressed in squamous epithelium of the palms,
soles, knees, and the oral keratinized gingiva.9 At this site, its function is
unknown.
The histopathological features of the palmoplantar lesions show marked
hyperkeratosis with acanthosis and a thickened granular cell layer (Fig.
3.109).3 Parakeratosis and epidermal psoriasiform hyperplasia have also
been described.7 The elbow and knee lesions show epidermal psoriasiform
hyperplasia with parakeratosis, elongation of the dermal papillae, and dilata-
tion of the superficial dermal vasculature.3
Naxos syndrome
Clinical features
Naxos syndrome (keratosis palmoplantaris with arrhythmogenic cardiomy-
opathy) is an autosomal recessive inherited disease defined by palmoplan-
tar keratoderma, curly hair, and other ectodermal features associated with
dilatative cardiomyopathy leading to arrhythmogenic episodes.1,2 It was first
reported in families on the Greek island of Naxos.1
Pathogenesis and histological features
A deletion in the plakoglobin gene which results in a frameshift mutation in
plakoglobin, an important component of desmosomes, has been identified in
Naxos syndrome.3 Histology shows compact hyperkeratosis, hypergranulo-
sis, and acanthosis.2
McGrath syndrome
Clinical features
McGrath syndrome (skin fragility and hypohidrotic ectodermal dysplasia) is
inherited in an autosomal recessive mode and is characterized by a diffuse,
sometimes verruciform palmoplantar keratoderma, trauma-induced skin
­fragility, and congenital ectodermal dysplasia affecting nails, hair, and sweat
glands.1 In some cases plantar hyperkeratosis is painful and there is disabling
cracking. The nails are thickened and markedly dystrophic. The integument
shows fragility, with trauma-induced blisters and crusting on pressure points.
Hairs are noted to be short and sparse. Sweating may be reduced.
88 Disorders of keratinization

Pathogenesis and histologic features described.11 The follicular lesions show plugging of the ostia with surround-
ing hyperkeratosis, parakeratosis, and acanthosis (Fig. 3.114).6 A mononu-
The disease has been shown to be associated with mutations in the
clear perivascular chronic inflammatory cell infiltrate may be present in the
­ lakophilin-1 gene (PKP1) leading to complete ablation of plakophilin 1
p
superficial dermis. The oral lesions are indistinguishable from those of the
which is responsible for recruitment of desmosomal proteins to the plasma
white sponge nevus, consisting of parakeratosis, acanthosis, and epithelial
membrane and keratin interaction.1,2
vacuolation (Fig. 3.115). No evidence of dysplasia is seen.
Light microscopy of the skin shows thickening of the epidermis and exten-
sive widening of keratinocyte intercellular spaces, extending from the first
suprabasal layer upward. There is complete absence of cutaneous immunos- Pachyonychia congenita type II
taining for plakophilin-1. Electron microscopy reveals loss of keratinocyte–
keratinocyte adhesion. Desmosomes, particularly in the lower suprabasal
layers, are small and reduced in number. The inner and outer desmosomal
Clinical features
plaques are poorly developed.3 Pachyonychia congenita type II (palmoplantar ectodermal dysplasia type
II, Jackson-Lawler syndrome, Jackson-Sertoli syndrome) is inherited as an
autosomal dominant. It is characterized by limited and usually mild focal
Pachyonychia congenita type I
Clinical features
Focal (nonepidermolytic) palmoplantar keratoderma with oral hyperkera-
tosis (Jadassohn-Lewandowsky syndrome, focal palmoplantar keratoderma
with oral hyperkeratosis, palmoplantar ectodermal dysplasia type I) is usu-
ally associated with an autosomal dominant mode of inheritance although an
autosomal recessive variant has been described.1,2 It has a high incidence in
Croatia and Slovenia and also appears to be more commonly seen in Jews.3,4
Clinical features may be present at birth or appear within the first 6 months
of life.1,5 The sex incidence is equal.
The features include massive hyperkeratosis of the distal nail beds of the
fingers and toes, resulting in elevation and apparent thickening of the nail
plate (Fig. 3.110). Also present are palmoplantar keratoderma, hyperhidro-
sis and follicular keratosis, xerosis, and verrucous lesions, which most often
arise on the elbows, knees, and lower legs (Fig. 3.111). Patients also develop
alopecia and nail bed infections.1,5,6 Erythema and blistering of the soles of the
feet, and to a lesser extent on the palms of the hands, are sometimes present;
leukokeratosis oris is almost invariably evident (Fig. 3.112).1,6,7 Laryngeal
involvement has also been documented.8 Fig. 3.111
Pachyonychia congenita
Pathogenesis and histological features type 1: discrete, yellow,
hyperkeratotic plaques on
This variant of focal palmoplantar keratoderma is heterogeneous. Mutations
the soles of the feet are
have been described in keratin K16 and K6a genes.9–14 a common manifestation.
The nail beds show massive hyperkeratosis.1 The palmoplantar lesions By courtesy of R.A.
are characterized by hyperkeratosis, hypergranulosis, and acanthosis (Fig. Marsden, MD, St
3.113).1 Round to oval darkly staining perinuclear inclusions represent- George's Hospital,
ing densely aggregated keratin filaments in the prickle cell layer have been London, UK.

A B

Fig. 3.110
Pachyonychia congenita type 1: (A) there is gross nail deformity with transverse arching of the distal portion. Although the nail plate appears to be thickened, most of the
changes are, in fact, due to massive hyperkeratosis of the nail bed, resulting in elevation and bending of the nail plate; (B) in this view, the subungual hyperkeratosis is more
obvious. (A) By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK, (B) By courtesy of W.A.D. Griffiths, MD, Institute of Dermatology, London, UK.

Fig. 3.112
Pachyonychia congenita type 1: leukoplakia of the buccal mucosa is a frequent
accompanying feature. By courtesy of R.A. Marsden, MD, St George's Hospital,
London, UK.
Fig. 3.113
Pachyonychia congenita
type 1: volar skin showing
massive hyperkeratosis,
hypergranulosis, and
acanthosis.
palmoplantar keratoderma over pressure areas, subungual hyperkeratosis,
epidermal cysts, steatocystoma multiplex, abnormal eyebrows and body
hair (pili torti), natal teeth, angular cheilosis, and hoarseness.1,2 Plantar
lesions may be delayed until late childhood. In contrast to pachyonychia
congenita type I, patients do not develop leukokeratosis oris. This palmo-
plantar ectodermal dysplasia has no known association with malignancy.
Pathogenesis and histological features
Pachyonychia congenita type II results from mutations in keratin 17 and ker-
atin 6b genes.3–7 Interestingly, mutations in keratin 17 may also result in ste-
atocystoma multiplex in isolation.3
Histologically, the subungual changes and keratoderma are similar to
those described in the type I variant, although milder. The epidermoid cysts
and steatocystomata show typical features.
Palmoplantar keratoderma 89
Fig. 3.114
Pachyonychia congenita
type 1: follicular lesion
showing keratin plugging
of the ostium with
adjacent hyperkeratosis
and associated
acanthosis.
Tyrosinemia type II
Clinical features
Tyrosinemia type II (Richner-Hanhart syndrome, tyrosine aminotransferase
deficiency, keratosis palmoplantaris with corneal dystrophy) is an oculocu-
taneous syndrome characterized by herpetiform corneal ulcers that develop
during the first months of life. Later painful punctuate, sometimes striated
and circumscribed hyperkeratoses of digits, palms, and soles evolve, often
accompanied by hyperhidrosis. Aberrant keratotic plaques have been sporad-
ically observed on the elbows, knees, and even the tongue. Other symptoms
include severe mental and somatic retardation.1
Pathogenesis and histological features
Tyrosinemia type II is caused by autosomal recessively inherited deficiency
of hepatic tyrosine aminotransferase. Point mutations in the tyrosine amin-
otransferase gene have been identified which map to the long arm of chro-
mosome 16. 2,3 Diagnosis can be confirmed by identifying tyrosinemia and
phenylacetic acidemia with excessive levels of P-hydroxyphenylactic acid in
the urine. Clinical and biochemical improvement may be achieved by a low
phenylalanine-low tyrosine diet.1
Histologically the epidermis is acanthotic, the granular layer is thickened,
and the keratinocytes contain eosinophilic globular inclusions. 4
Electron microscopy demonstrates an increased synthesis of tonofibrils
and keratohyalin, large numbers of microtubules, and unusually tight pack-
ing of tonofibrillar masses, which contain tubular channels or inclusions
of microtubules.4 Presumably, excessive amounts of intracellular tyrosine
enhance cross-links between aggregated tonofilaments leading to a globular
appearance.4
Carvajal-Huerta syndrome
Clinical features
The Carvajal-Huerta syndrome is an autosomal recessively inherited dis-
ease with palmoplantar keratoderma, woolly hair, and dilated cardiomy-
opathy.1,2 The patients are born with woolly hair. Around the first year,
palmoplantar keratoderma and other keratotic signs appear. The clinical
symptoms of Carvajal-Huerta syndrome resemble those of Naxos disease
90 Disorders of keratinization

At the ultrastructural level, loosening of intercellular connections, disrup-

tion of desmosome–keratin intermediate filament interactions, and rudimen-
tary desmosomal structures can be demonstrated.2

Howell-Evans syndrome
Clinical features
The combination of autosomal dominant focal nonepidermolytic palmoplan-
tar keratoderma with esophageal squamous carcinoma was first recognized
in 1958 and subsequently termed the Howell-Evans syndrome.1–5 Although
initially regarded as a diffuse keratoderma, a subsequent clinical re-evalu-
ation determined that the lesions were focal, sparing nontraumatized areas
(Fig. 3.116).4 The condition typically presents between 6 and 15 years of
age. The patients develop painful hyperkeratoses on the pressure areas,
which ­disappear with prolonged bed rest.5 Palmar involvement may be seen

A
B

Fig. 3.115
Pachyonychia congenita type 1: (A) scanning view of oral mucosa showing
massive acanthosis with large blunt rete ridges; (B) high-power view showing focal
parakeratosis and vacuolization of superficial keratinocytes. A single dyskeratotic
cell is evident (arrowed).

but the PPK in the former is of a striated and not diffuse type. The first car-
diac abnormalities are exclusively electrocardiographic and occur in asymp-
tomatic patients. In these patients, dilatation of the left ventricle, together
with alterations in muscle contractility, may lead to congestive heart failure
and death.

Pathogenesis and histological features

Mutations in the gene on chromosome 6p24 encoding desmoplakin have
been found.3 Desmoplakin is a major constituent of desmosomes and as such
is crucial for the rigidity and strength of the epidermis and cardiac tissue.
Biopsies of skin lesions show features of epidermolytic hyperkeratosis.1
Immunohistochemistry confirms perinuclear localization of keratin in the
suprabasal keratinocytes. This suggests collapse of the intermediate filament
network as a response to the failure of desmoplakin to attach the intermediate
filaments to the desmosomes.
B
Fig. 3.116
Howell-Evans syndrome: (A) focal autosomal dominant palmoplantar keratoderma
is associated with an increased risk of esophageal squamous carcinoma; (B) in
this patient, the palms were also severely affected. By courtesy of the Institute of
Dermatology, London, UK.

in ­manual workers. This syndrome, also termed palmoplantar ectodermal
dysplasia type III, includes keratosis pilaris particularly affecting the upper
arms and thighs, multiple epithelial cysts, and gray-white buccal mucosal
hyperkeratosis (This last feature typically predates the onset of keratoderma
and may therefore represent a clinical diagnostic clue of early involvement in
family members of a pedigree.).5–9 Nails are unaffected.6 In the largest kin-
dred reported to date, 28% developed esophageal squamous carcinoma (89
affected members) of whom 84% died of their tumor.4
Pathogenesis and histological features
The condition has been mapped to 17q23-qter region (TEC locus) distal to
the keratin gene cluster, thereby excluding a keratin gene mutation.10–12
The cutaneous lesions are characterized by hyperkeratosis, hypergranulo-
sis, and acanthosis. Features of epidermolytic hyperkeratosis are absent.
The buccal mucosal lesions are characterized by parakeratosis, acantho-
sis, and spongiosis accompanied by cytoplasmic vacuolation of the prickle
cell layer.4
Schöpf-Schulz-Passarge syndrome
Clinical features
The Schöpf-Schulz-Passarge syndrome (palmoplantar keratoderma with eye-
lid cysts, hypodontia, and hypotrichosis) is probably inherited in an auto-
somal recessive pattern.1 Patients have a relatively mild, diffuse erythematous
keratoderma association with hypodontia, hypotrichosis, nail dystrophies,
and late-onset eyelid cysts.
Histological features
The eyelid lesions represent apocrine hidrocystomas. Multiple eccrine syrin-
gofibroadenomas and squamous cell carcinomas may arise on the acral sur-
faces in older patients.1,2 The underlying defect remains unknown.3
Acquired palmoplantar keratoderma and
internal malignancy
Acquired diffuse palmoplantar keratoderma may represent a paraneoplas-
tic phenomenon associated with a number of internal malignancies includ-
ing carcinoma of the bronchus, esophagus, stomach, urinary bladder, and
myeloma (Fig. 3.117).1–6 There are also reports of acquired filiform (filiform
palmoplantar keratoderma) and punctate (punctate porokeratotic kerato-
derma) variants associated with a range of visceral cancers including breast,
kidney, colon, and lung.7,8
Fig. 3.117
Acquired palmoplantar
keratoderma: acquired
disease may be a
manifestation of
underlying malignancy. By
courtesy of the Institute
of Dermatology, London,
UK.
Acquired palmoplantar keratoderma and internal malignancy 91
Keratoderma climactericum
Clinical features
Keratoderma climactericum (Haxthausen's disease, climacteric kerato-
derma) is an acquired disorder which is restricted to menopausal women.1,2
Lesions present on the weight-bearing surfaces of the sole of the foot as ery-
thematous hyperkeratotic and fissured plaques and then spread to involve
the rest of the plantar skin (Fig. 3.118). Patients are often overweight.
Palmar involvement is sometimes seen with lesions affecting the area
between the thenar and hypothenar eminences.2 Similar lesions have been
documented in younger women who have undergone bilateral oophorec-
tomy.3 The condition is distinguished from congenital palmoplantar kerato-
derma by its late onset.
Histological features
The plantar skin shows massive hyperkeratosis, hypergranulosis, acanthosis,
and spongiosis with lymphocytic exocytosis.2 A superficial perivascular der-
mal lymphohistiocytic infiltrate is present and vertically orientated dermal
collagen associated with atypical myofibroblasts is often seen.2
Clavus
Clavi (corns) are extremely common painful keratotic lesions that develop
on the dorsal or lateral aspect of the toes, often as a consequence of ill-fitting
shoes. Histologically, they are characterized by a deep keratin-filled depres-
sion often associated with atrophy of the underlying epidermis (Fig. 3.119).
They are distinguished from plantar warts by the absence of koilocytes and
irregular keratohyalin granules.
Callus
In contrast to a clavus, a callus is a nonpainful localized focus of hyperkerato-
sis usually arising on the ball of the foot or heel from pressure or foot defor-
mity. Palmar lesions arise as a consequence of chronic rubbing. Histologically,
they are similar to a clavus, consisting of a keratin-filled epidermal dell with
hypergranulosis. Parakeratosis is often present.
Acrokeratosis verruciformis of Hopf
Clinical features
This is an exceedingly rare dermatosis with an autosomal dominant mode of
inheritance.1–3 The disease presents in infancy or early childhood as dry, rough,
brownish or skin-colored verrucoid, keratotic papules, located particularly on
Fig. 3.118
Keratoderma climactericum: there is massive hyperkeratosis with fissuring over the
heels. By courtesy of the Institute of Dermatology, London, UK.
92 Disorders of keratinization
Fig. 3.119
Clavus: massive
hyperkeratosis overlies an
epidermal depression.
the backs of the hands (Fig. 3.120) and feet, and on the knees and elbows.4
Keratotic punctate pits are found on the palms and soles. Lesions, which are
clinically and histologically indistinguishable, may occasionally be seen in
Darier's disease.5–7 Exceptionally, a similar association with Hailey-Hailey dis-
ease has been documented and there is a report of acrokeratosis verruciformis
presenting in a patient with nevoid basal cell carcinoma syndrome.8,9 Nail
involvement, including longitudinal splitting, striations and subungual hyper-
keratosis may also be seen.10
Pathogenesis and histological features
Loss of function of the sarco- (endo-) plasmic reticulum Ca2+ ATPase2
mutant in acrokeratosis verruciformis provides evidence that acrokeratosis
verruciformis and Darier's disease are allelic disorders.11 However, identifica-
tion of mutations in genes other than ATP2A2 suggests genetic heterogeneity
of acrokeratosis verruciformis.12
The lesions are acanthotic with a prominent granular cell layer, typically
showing a ‘church spire’ appearance (Fig. 3.121). There is usually moderate
to marked hyperkeratosis. Parakeratosis is not a feature. Step sections some-
times reveal acantholytic dyskeratosis in those cases associated with Darier's
disease.
Differential diagnosis
Acrokeratosis verruciformis-like features may occasionally be seen in lin-
ear epidermal nevi.13 There is also considerable histological overlap with
stuccokeratosis.
Porokeratosis
Clinical features
Porokeratosis is a not uncommon pathological process. It consists of a pig-
mented or reddish atrophic center bordered by a peripheral grooved keratotic
ridge, from the center of which a keratotic core (cornoid lamella) projects
at an obtuse angle.1 There are six major categories: classical, localized, lin-
ear, punctate, disseminated superficial porokeratosis (DSP), and disseminated
superficial actinic porokeratosis (DSAP), all of which may be inherited as an
autosomal dominant, but sporadic cases also occur.
• In the classical variant described by Mibelli, patients develop one or
several plaquelike lesions on the extremities (Fig. 3.122). It usually
Fig. 3.120
Acrokeratosis
verruciformis: numerous
brown flat-topped
papules are symmetrically
distributed over the dorsal
aspects of the hands.
By courtesy of
R.A. Marsden, MD,
St George's Hospital,
London, UK.
Fig. 3.121
Acrokeratosis verruciformis: there is hyperkeratosis and church-spire papillomatosis.
presents in adulthood as persistent lesions that are highly resistant to
therapy.
• Localized porokeratosis usually consists of a single large lesion.
• Disseminated superficial actinic porokeratosis, the most common variant,
is characterized by numerous small, dry, shallow lesions arising on
the sun-damaged skin of adults (Figs 3.123 and 3.124).2 It may also
complicate PUVA therapy and develop in the immunosuppressed.3–5 It
presents in the third and fourth decades and, despite its relationship
to sunlight, rarely affects the face. The legs, forearms, back, upper
arms, and thighs are most commonly affected, in decreasing order of
frequency.6
• Disseminated superficial (nonactinic) porokeratosis (porokeratosis
palmoplantaris et disseminata) is characterized by asymptomatic lesions
with a tendency to involve the trunk, genitalia, palms, and soles. An
intensely itchy eruptive variant of this has recently been described.7
• In linear porokeratosis, the lesion is clinically reminiscent of an epidermal
nevus affecting the extremities and usually presents in infancy or early

A B
Fig. 3.123
Disseminated superficial
actinic porokeratosis:
there are numerous small,
reddish or brownish
keratotic macules on sun
damaged skin.
childhood (Fig. 3.125).8 A zosteriform variant has also been described
which generally affects children and shows a predilection for the lower
limbs, upper limbs, and trunk.9
• In punctate porokeratosis (porokeratosis palmoplantaris punctata, spiny
keratoderma) tiny spines develop on palms and soles in the second or
third decade. Some argue that the typical ultrastructural changes of
porokeratosis of Mibelli are not present. It must be distinguished from
other forms of punctate keratoderma.6
Porokeratosis may involve the mucous membranes, cause nail dystrophy,
and result in patchy alopecia. It is associated with a slightly increased risk of
cutaneous neoplasia. Lesions of porokeratosis may therefore be complicated
by the development of Bowen's disease, and basal cell and squamous cell
Acquired palmoplantar keratoderma and internal malignancy 93
Fig. 3.122
Porokeratosis of Mibelli: (A) these lesions have an
extensive and linear distribution; (B) the lesions are
erythematous, atrophic and scaly, with sharply defined and
slightly raised margins By courtesy of M.M. Black, MD,
Institute of Dermatology, London, UK.
Fig. 3.124
Disseminated superficial actinic porokeratosis: in this variant, the lesions are small
and discrete. Note the characteristic raised edge. By courtesy of the Institute of
Dermatology, London, UK.
carcinoma.1,8,10–15 The reported incidence has varied from 6.8% to 11.6%.10,13,14
In some instances there is a probable causal relationship with previous treat-
ment with radiotherapy.10 Tumors usually develop many years after the onset
of the disease, are frequently multiple, and arise most often on large or coalesc-
ing lesions.8,10,16 They are most often found on the trunk and extremities.8
Pathogenesis and histological features
The pathogenesis of porokeratosis is unknown. The presence of localized
dysplastic features was suggested by Reed and Leone to indicate that the
disease represented a focal, expanding clone of abnormal keratinocytes asso-
ciated with the development of a cornoid lamella.17 The more recent literature
appears to support this claim.
Porokeratotic lesions have been shown to be associated with abnormal
epidermal DNA ploides in association with increased DNA indices, midway
between normal skin and Bowen's disease.18,19 Uninvolved skin, however, is
usually diploid.8 Chromosomal abnormalities have been identified within
94 Disorders of keratinization
cultured keratinocytes and fibroblasts derived from patients suffering from
both the localized and Mibelli variants.8,10,20,21 These findings have since been
confirmed in both cultured fibroblasts from normal untreated skin and lym-
phocytes, and it has been shown that chromosome 3 is preferentially affected.22
Mutations in the proximal segment of the short arm of chromosome 3 have
been associated with a wide variety of malignancies.22 Ionizing radiation, ultra-
violet light including sun tanning beds, and PUVA may be associated with the
development of new skin lesions in porokeratosis.23 The first may be of par-
ticular relevance to the development of malignancy in these lesions.14,24
Cultured fibroblasts from porokeratosis patients have been shown to be
hypersensitive to the lethal effects of X-radiation, but not ultraviolet radia-
tion.21,22 This has been shown to be associated with chromosomal instability
in approximately 50% of patients.20 While it has been proposed that this may
result from abnormal DNA repair mechanisms (see xeroderma pigmentosa)
the evidence necessary to support such a hypothesis is not yet available.21
Porokeratosis of Mibelli, disseminated superficial porokeratosis, and
disseminated superficial actinic porokeratosis may also develop against a
background of solid organ transplantation or blood transfusion, possibly
Fig. 3.125
Linear porokeratosis: in
this variant, the lesion
has a linear, nevoid
distribution.
A B
Fig. 3.126
Porokeratosis of Mibelli: (A) there is hyperkeratosis with two well-developed cornoid lamellae. Note the epidermal depression at their bases. (B) The cornoid lamella can be
seen to be composed of an angulated tier of parakeratosis.
causally related to hepatitis C infection, Crohn's disease, renal failure, and
hemodialysis.25–29
p53 and pRb proteins are overexpressed within keratinocytes immedi-
ately beneath and adjacent to the cornoid lamellae; mdm-2 and p21waf-1 are
reduced.30–33 This imbalance in cell cycle control mechanisms offers a poten-
tial explanation for the development of malignancy in porokeratosis although
to date p53 mutation has not been identified.32,34
Recently, a gene for disseminated superficial actinic porokeratosis has been
mapped to chromosome 12q23.2–24.1 in a large Chinese family.35
The biopsy must be taken through the peripheral grooved ridge. If the long
axis of the specimen does not transact the border, the diagnostic features will be
missed. These consist of a keratin-filled epidermal invagination with an angu-
lated parakeratotic tier, the cornoid lamella (Fig. 3.126). Despite its name,
the lesions of porokeratosis are rarely related to the ‘pore’ of the eccrine duct.
While they may involve the follicle, their most common origin is from nonad-
nexal epithelium. The corneocytes of the cornoid lamella contain characteristic
PAS-positive granules. The epithelium deep to the tier is vacuolated and devoid
of a granular cell layer (Fig. 3.127). Dyskeratotic cells may be present and
Fig. 3.127
Porokeratosis of Mibelli:
the epidermis at the base
of the cornoid lamella
is vacuolated and the
granular cell layer absent.
 Acquired palmoplantar keratoderma and internal malignancy 95

Fig. 3.128
Disseminated superficial actinic porokeratosis: in this example, the cornoid lamella
has arisen overlying an acrosyringium. The epidermis towards the center on the
lesion appears atrophic and the papillary dermis contains ectatic blood vessels.

epithelial dysplasia, ranging from mild changes through to carcinoma in situ, A

is occasionally a feature. Liquefactive degeneration of the basal cell layer of the
epithelium is sometimes present and occasionally there are conspicuous cytoid
bodies. The adjacent epithelium towards the center is often atrophic, but may
be of normal thickness or even acanthotic. In the dermis, a non-specific chronic
inflammatory cell infiltrate and telangiectatic vessels are sometimes seen. The
typical features are best seen in the Mibelli variant. The changes tend to be less
pronounced in the other subtypes (Fig. 3.128). In the actinic variant there is
often solar elastosis and atrophy of the adjacent epidermis.6

Differential diagnosis
With the appropriate clinical information, the histopathological changes
of porokeratosis are diagnostic. Cornoid lamella formation, however, does
occur as a non-specific finding in a variety of conditions including psoriasis
vulgaris, seborrheic, solar keratosis, verruca vulgaris, and squamous cell and
basal cell carcinomas.36 Cornoid lamellae are also features of verrucous epi-
dermal nevus and porokeratotic eccrine nevus.37,38 They are also not uncom-
mon in normal, and particularly actinically damaged, skin. PAS-positive
B
structures in the cornoid lamella may be a useful marker for porokeratosis
although this has not been authors experience.39 Fig. 3.129
Flegel's disease: (A) there are characteristic disseminated erythematous scaly
lesions; (B) the lower legs are commonly affected. Lesions are small, multiple
Hyperkeratosis lenticularis perstans and covered by a well-developed scale. By courtesy of M. Price, MD, Institute of
Dermatology, London, UK.

Clinical features
Hyperkeratosis lenticularis perstans (Flegel's disease) is a not uncommon der-
matosis that is sometimes mistaken for Kyrle's disease.1–5 It has an equal sex
incidence and patients present most often in their fourth or fifth decade. It is
characterized by a very protracted course, many patients having lesions for
decades. Patients present with large numbers of 1–5-mm discrete, gray, gray-
brown or red-brown, circular scaly papules (Fig. 3.129). Initial lesions often
arise on the dorsum of the foot. Other sites of predilection include the lower
legs, upper arms, and pinnae. The buttocks, trunk, and dorsal aspects of the
hands may also be affected, and punctate keratoses have been described on
the palms and soles. The lesions are either asymptomatic or mildly pruritic.
Characteristically, removal of the scale is associated with pinpoint bleeding,
a feature that distinguishes this disorder from stucco keratoses. Other than
an isolated report of an increased incidence of both basal cell and squamous
carcinomas, there is no particular associated disease process (compare
with Kyrle's disease).6 Although most cases appear to be sporadic, there is
some ­evidence to support an autosomal dominant mode of inheritance in a
­proportion of cases.
Pathogenesis and histological features
Flegel's disease is of unknown etiology and pathogenesis and is characterized
by focal areas of abnormal hyperkeratinization.7–10 Early lesions are not diag-
nostic, showing merely lamellar hyperkeratosis, focal parakeratosis, and an
essentially normal epidermis. In an established lesion, in addition to hyper-
keratosis and occasional parakeratosis, there is epidermal atrophy with an
inconspicuous or absent granular cell layer (Figs 3.130, 3.131). The lower
layers of the epithelium may show intercellular edema and occasional foci of
basal cell degeneration. Cytoid bodies are sometimes evident. Typically, the
papillary dermis is edematous and a chronic inflammatory cell infiltrate is
often present, adopting a perivascular or lichenoid distribution. Pigmentary
incontinence is not usually a feature.
The lymphocytes are an admixture of CD4+ T-helper cells and, less fre-
quently CD8+ T-suppressor cells.8,9 Sézary-like forms have been described.
Langerhans cells are highly reduced.9 In the atrophic areas, differentiation
96 Disorders of keratinization
B The etiology is unknown. It has been suggested that the condition develops
Fig. 3.130
Flegel's disease: (A) scanning view of an established lesion showing focal
hyperkeratosis, parakeratosis, and a superficial bandlike chronic inflammatory
cell infiltrate; (B) there is hyperkeratosis, focal epidermal atrophy and basal cell
liquefactive degeneration. Note the cytoid bodies
markers such as cytokeratin 1 and 10, filaggrin, and loricrin are absent.
Ultrastructurally, the most commonly documented changes have been
­rudimentary keratohyalin granules, absence, vacuolation or abnormally
lamellated membrane coating (Odland) bodies, failure to form a compact
keratin, and cornified envelope in the corneocytes.8,9
Differential diagnosis
Clinically, Flegel's disease differs from Kyrle's disease by the absence of
­keratin-filled penetrating plugs and the frequent presence of palmar and plan-
tar lesions, which are not seen in Kyrle's disease. Flegel's disease is sometimes
confused with stuccokeratoses, but these do not affect the trunk, palms, and
soles and the lesions may be readily removed without bleeding. Histologically,
stucco keratoses are characterized by orthohyperkeratosis and ‘church spire’
papillomatosis. Although there may be histological overlap with other condi-
tions showing lichenoid features, the striking keratotic tier with parakeratosis
and absent granular cell layer are useful diagnostic pointers.
Granular parakeratosis
Clinical features
Granular parakeratosis is a distinctive acquired disorder of keratinization
originally reported in 1991.1–4 The condition most often affects the axillae
but it has also been described involving other intertriginous areas including
submammary and intermammary skin, groins, vulva, perianal region and,
Fig. 3.131
Flegel's disease: high-power view showing spongiosis with microvesiculation,
cytoid bodies, and a predominantly lymphocytic infiltrate.
less commonly, in nonintertriginous skin including the lower back, buttocks,
and flanks.5–8 Women are affected more commonly than males. The disease
mainly affects the middle aged to elderly; children are rarely involved.8–10
It presents as pruritic or burning erythematous, hyperpigmented, and
hyperkeratotic patches, papules, or plaques (Fig. 3.132). Fissures and a
­‘cobblestone’ appearance may be seen. The condition has been documented
to respond to retinoids and to calcipotriene and ammonium lactate.11,12
Pathogenesis and histological features
as a result of a contact reaction to an antiperspirant or as a result of exces-
sive use of other topical products including creams, shampoos, and soaps.1–6,8
However, this does not explain the involvement of areas distant from the
axilla. The molecular mechanism proposed to explain the disease consists of
a failure to transform profilaggrin to filaggrin with the resultant failure in
degradation of keratohyalin granules.1,7
The histological appearances typically consist of a massive hyperkerato-
sis with parakeratosis and retention of keratohyalin granules in the stratum
corneum (Fig. 3.133). The underlying epidermis may show mild acanthosis
or even some degree of thinning. Hair infundibula are occasionally affected.
Necrotic areas with invasion of neutrophils or perforation of the epidermis
are rarely found. The superficial dermis contains a sparse perivascular lym-
phocytic infiltrate.1–7
Differential diagnosis
Apart from representing a dermatosis, granular parakeratosis is a diagnos-
tic feature in solitary keratosis, i.e., granular parakeratotic acanthoma.13
Granular parakeratosis can be also found as an incidental finding in many
diseases, e.g., dermatophytosis, molluscum contagiosum, dermatomyositis,
solar keratosis, squamous cell carcinoma, keratoacanthoma, lymphomatoid
papulosis, and basal cell carcinoma (Fig. 3.134).14 As such, granular parak-
eratosis can best be considered as a histologic pattern similar to focal acan-
tholytic dyskeratosis or epidermolytic hyperkeratosis.14
Circumscribed palmar or plantar
hypokeratosis
Clinical features
Circumscribed palmar or plantar hypokeratosis is a recently described
entity that is characterized by the development of well-circumscribed,
 Acquired palmoplantar keratoderma and internal malignancy 97

Fig. 3.132
Granular parakeratosis: (A)
in the axilla of a middle-
aged woman erythematous,
hyperpigmented and
hyperkeratotic papules
develop in a reticulated
A B fashion, (B) a few of them
are erosive.

A B

Fig. 3.133
Granular parakeratosis: (A) there is marked thickening of the horny layer with parakeratosis, (B) high-power view showing retention of the keratohyalin granules.

depressed, ­erythematous lesions on the thenar and hypothenar regions of
the palms or the medial side of the soles (Fig. 3.135).1 The lesions some-
times have an arcuate or polycyclic outline, a slightly scaling border, range
in diameter from a few millimeters up to 3 centimeters, and are symp-
tomless. All patients were middle aged or elderly with a predominance of
women.2
Pathogenesis and histological features
The pathogenesis of circumscribed palmar or plantar hypokeratosis is a mat-
ter of debate. While some authors favor the interpretation of an epidermal
malformation in view of persistence over years, others dispute this because
of the continuous growth of some lesions, and suggest a trauma or a human
papillomavirus type 4 as a causative.1–5
Histologically, the lesional depression relates to a sharply circumscribed
loss of the cornified layer above an otherwise normal epidermis (Fig. 3.136).1–7
Other authors observed a thin layer of parakeratosis in the hypokeratotic
zone and some psoriasiform hyperplasia of the epidermis with expression of
the hyperprolifertaive keratin 16.6,7
Additional features are hyperplasia of sweat ducts, and tortuous and elongated
capillaries in the papillary dermis; still, an inflammatory cell infiltrate is lacking.5
Ultrastructurally, breakage of the corneocytes within their cytoplasm
­suggests enhanced corneocyte fragility.7
98 Disorders of keratinization

Fig. 3.134
Granular parakeratosis:
(A) this example arose
against a background of
A B lymphomatoid papulosis;
(B) high-power view.

Fig. 3.136
Circumscribed palmar or plantar hypokeratosis: (A) scanning view from the edge of
a lesion, (B) note the focal thinning of the stratum corneum.

Fig. 3.135
Circumscribed palmar or plantar hypokeratosis: (A) on the thenar a well-
circumscribed, depressed, erythematous lesion is present, (B) a closer view reveals
a scaly border.
 Inherited and autoimmune Chapter

See
www.expertconsult.com
for references and
additional material
subepidermal blistering diseases
4
Split skin immunofluorescence 100 Lichen planus pemphigoides 131 Dermatitis herpetiformis 144
Immunoperoxidase antigen mapping 101 Mucous membrane pemphigoid (cicatricial Linear IgA disease 147
pemphigoid) 133
Epidermolysis bullosa 101
Epidermolysis bullosa acquisita (dermolytic
Bullous pemphigoid 117
pemphigoid) 137
Pemphigoid gestationis 127
Bullous systemic lupus erythematosus 142

Blisters, which are clinically subdivided into vesicles (L. vesicula, dim. of
­vesica, bladder) and bullae (L. bubble), are defined as accumulations of fluid
either within or below the epidermis and mucous membranes. Although
somewhat arbitrary, the term ‘vesicle’ is applied to lesions less than 0.5 cm in
diameter and ‘bulla’ to those greater than 0.5 cm. Subepidermal blisters, i.e.,
those that develop at the epidermal or mucosal basement membrane region,
include inherited variants and acquired (often autoimmune mediated)
­conditions. The former are usually classified as noninflammatory (cell-poor)
­blisters whereas the latter are commonly inflammatory (cell-rich) in nature
(Fig. 4.1).
Subepidermal blisters may develop within the lower epidermis, the lamina
lucida (e.g., bullous pemphigoid) or deep to the lamina densa (e.g.,
­epidermolysis bullosa acquisita) (Fig. 4.2). In addition to clinical observa-
tions, the precise diagnosis of a blistering disorder requires careful histologi-
cal and immunofluorescence correlation. When possible, the last should
include indirect studies and, in particular, NaCl-split skin should be used as
substrate as a mechanism of localizing the site of epidermodermal ­separation.1
If a sample has not been taken for indirect immunofluorescence, immunoper-
oxidase antigen mapping on paraffin-embedded material may on occasions
be of value at least as a screening procedure. Although the results of electron
microscopic investigations and, in particular, molecular studies have formed
the basis of the current classification of subepidermal bullous dermatoses,
such techniques are usually not essential to the everyday investigation of a
patient with an acquired blistering disorder.
The mechanisms involved in the development of a subepidermal blister are
variable. They include inherited mutational defects of basement membrane
proteins, i.e., epidermolysis bullosa, acquired autoimmune bullous diseases
such as bullous pemphigoid, cellular immunity-mediated disorders (e.g.,
­erythema multiforme and toxic epidermal necrolysis), metabolic ­diseases
including porphyria cutanea tarda, and profound subepidermal edema such
as may be seen in bullous arthropod bite reactions and dermal acute
­inflammatory processes (e.g., Sweet's disease).

Fig. 4.1
Classification of subepidermal
blisters: lesions may be
A B subdivided into (A) cell-poor
and (B) cell-rich variants.
100 Inherited and autoimmune subepidermal blistering diseases

Intact skin
K5, K14 (IF)
Epidermis

300K>IFAR LL
LD
Plectin BP230

a6
HD
CM Dermis
BP180 b4

LL
NaCL split skin
Laminin-5
LD Epidermis

AF

AP Artificial
blister cavity

Fig. 4.2
Basement membrane constituents: blisters can be classified into those that develop LD
within the lamina lucida (LL) and those that arise below the lamina densa (LD). (AF,
anchoring fibrils; AP, anchoring plaque; CM, cell membrane.) Dermis Fig. 4.3
Split skin immunofluorescence.

In this chapter, only those conditions in which subepidermal blister forma-

tion represents an inherited or autoimmune primary event are considered.
Other conditions, which may be associated with subepidermal blistering, are
dealt with in more appropriate chapters.
Split skin immunofluorescence
This technique represents a modification of indirect immunofluorescence
(IMF) where normal skin is split through the lamina lucida of the basement
membrane region to produce an artificial blister cavity (with the lamina densa
lining the floor) for use as substrate. Artificial separation can be achieved by
the suction technique (in vivo) or by immersion of normal skin in 1 M NaCl
for 48 hours at 4°C (Fig. 4.3). In general, the latter technique is preferred.2 As
such a split is invariably through the lamina lucida region ­(confirmed by
­electron microscopy or immunofluorescence) (Figs 4.4, 4.5), the technique
enables precise localization of a circulating basement membrane zone anti-
body to either the floor or the roof of the artificial blister cavity. In bullous
pemphigoid, pemphigoid gestationis, and the majority of cases of mucous
membrane pemphigoid, linear immunofluorescence is found along the roof of
the artificial blister whereas in diseases characterized by a sublamina densa
split (e.g., epidermolysis bullosa acquisita, antilaminin mucous membrane
­pemphigoid, anti-p105 pemphigoid, anti-p200 pemphigoid, and bullous der-
matosis of bullous lupus erythematosus), the immunofluorescent signal is
found along the floor of the blister (see references 3 and 4 for a review)
(Fig. 4.6). In some diseases, positive immunofluorescence may be found on
either the roof or the floor or even at both sites simultaneously (e.g., ­linear IgA
disease and some variants of mucous membrane pemphigoid). Such variable
labeling reflects the antigen heterogeneity in a number of bullous dermatoses.

A B

Fig. 4.4
(A, B) Split skin immunofluorescence: the split is through the lamina lucida, the lamina densa lining the floor of the artificial blister cavity.

Fig. 4.5
Split skin immunofluorescence: type IV collagen lines the floor of the split skin
artificial blister which therefore forms within the lamina lucida. By courtesy of B.
Bhogal, FIMLS, Institute of Dermatology, London, UK.
Fig. 4.6
Split skin immunofluorescence: (left) linear IgG at the basement membrane;
(middle) in epidermolysis bullosa acquisita (EBA), the antibody binds to the floor of
the blister cavity; (right) in bullous pemphigoid (BP), the antibody binds to the roof
of the blister. By courtesy of B. Bhogal, FIMLS, Institute of Dermatology, London,
UK.
Immunoperoxidase antigen mapping
As an alternative to split skin immunofluorescence, paraffin-embedded
sections of lesional skin have been proposed in a direct immunoperoxidase
antigen mapping technique to identify the level of the epidermodermal
separation.5–8This procedure localizes known basement membrane region
constituents such as keratins 5/14, laminin, and type IV collagen to the roof
or floor of the blister cavity. The site of blister formation can therefore be
characterized as intrabasal, within the lamina lucida or deep to the lamina
densa. For example, in epidermolysis bullosa simplex variants, all of these
immunoreactants are present along the floor of the blister cavity. In bullous
pemphigoid, keratin is present along the roof of the blister while laminin and
type IV collagen are found along the floor (Fig. 4.7). In dystrophic epidermolysis
bullosa, epidermolysis bullosa acquisita, and bullous systemic lupus
erythematosus, all three immunoreactants are present in the roof of the blister
(Fig. 4.8). However, in many hereditary and acquired blistering diseases
the relevant antibodies against the target antigens do not work well in
paraffin-embedded material and false-positive and false-negative results are
common, making this method unreliable for use in routine diagnosis. For
example, antigen mapping of the group of hereditary subepidermal blistering
diseases is done exclusively on frozen sections with excellent results.
Epidermolysis bullosa 101
Fig. 4.7
Paraffin-embedded immunoperoxidase antigen mapping: in bullous pemphigoid,
type IV collagen is present along the floor of the blister.
Fig. 4.8
Paraffin-embedded immunoperoxidase antigen mapping: in epidermolysis bullosa
acquisita, type IV collagen is present along the roof of the blister cavity.
Epidermolysis bullosa
Epidermolysis bullosa (EB) refers to a heterogeneous group of diseases in
which the skin and sometimes the mucous membranes blister easily in
response to mild trauma, hence the alternative title ‘mechanobullous derma-
tosis’, which has sometimes been applied.1 All are rare conditions; the estimated
incidence for the group as a whole is in the order of 1:20 000. Apart from the
acquired autoimmune variant (epidermolysis bullosa acquisita), they are all
autosomal inherited disorders.
EB was initially described as a defined entity in 1886.2 This group of con-
ditions has been classified in several ways over the years. The three major
types were defined in a groundbreaking electron microscopy study in 1962.3
In 1988, the contemporary classification and subtyping of the major variants
commenced with the first consensus meeting of the Steering Committee of
the National EB Registry (established in 1986) held in conjunction with the
American Academy of Dermatology.4,5 At that time, 23 seemingly clinically
distinct variants were recognized (Table 4.1).5 In the following decade, a
second consensus conference was held.6 As a result of the considerably
increased number of cases available for study, a much greater degree of clinical
overlap between the various subtypes was recognized. For this reason and
because of a much better understanding of the molecular basis for many of
102 Inherited and autoimmune subepidermal blistering diseases

Table 4.1 Table 4.2

First consensus conference (1988): classification of subepidermal blisters Second consensus conference (1999): classification of epidermolysis bullosa
EB simplex
Major EB Protein/gene
Localized Major EB type subtype systems involved
EB simplex of hands and feet (Weber-Cockayne variant)
EBS (‘epidermolytic EBS-WC K5, K14
EB simplex with anodontia/hypodontia (Kallin syndrome)
EB’) EBS-K K5, K14
Generalized EBS-DM K5, K14
EB simplex, Koebner variant EBS-MD Plectin
EB simplex herpetiformis (Dowling-Meara variant)
Junctional EB JEB-H Laminin-5*
EB simplex with mottled or reticulate hyperpigmentation with or without
HEB-nH Laminin-5; type XVII collagen
punctate keratoderma
EB simplex superficialis JEB-PA† α6β4 integrin‡
EB simplex, Ogna variant DEB (‘dermolytic EB’) DDEB Type VII collagen
Autosomal recessive EB simplex (letalis) with or without neuromuscular RDEB-HS Type VII collagen
disease RDEB-nHS Type VII collagen
EB simplex, Mendes da Costa variant
Reproduced with permission from Fine, J.D. et al (1991) Pediatrician, 18, Reproduced from Fine et al (2000) J Am Acad Dermatol, 42, 1051–1066 from American
175–187. Academy of Dermatology.
DDEB, dominant dystrophic EB; DEB, dystrophic EB; RDEB, recessive DDEB, dominant dystrophic EB; EBS-DM, EBS Dowling-Meara; EBS-K, EBS, Koebner;
EBS-MD, EBS with muscular dystrophy; EBS-WC, EBS, Weber-Cockayne; JEB-H,
dystrophic EB.
junctional EB, Herlitz; JEB-nH, junctional EB, non-Herlitz; JEB-PA, junctional EB with
Junctional EB pyloric atresia; RDEB-HS, recessive dystrophic EB, Hallopeau-Siemens; RDEB-nHS,
Localized recessive dystrophic EB, non-Hallopeau-Siemens.
*Laminim-5 is a macromolecule composed of three distinct (α3, β3, γ2) laminin chains;
Junctional EB, inversa
mutations in any of the encoding genes result in a junctional EB phenotype.
Junctional EB, acral/minimus †Some cases of EB associated with pyloric atresia may have intraepidermal cleavage
Junctional EB, progressiva variant or both intralamina lucida and intraepidermal clefts.
Generalized ‡α β integrin is a heterodimeric protein; mutations in either gene have been
6 4

Junctional EB, gravis variant (Herlitz variant)
Junctional EB, mitis variant (non-Herlitz variant; EB atrophicans
generalisata mitis; generalized atrophic benign EB)
Cicatricial junctional EB
Dystrophic EB
Localized
RDEB, inversa
DDEB, minimus
DDEB, pretibial
RDEB, centripetalis
Generalized
Autosomal dominant forms of DEB
DDEB, Pasini variant
DDEB, Cockayne-Touraine variant transient bullous dermolysis
of the newborn
Autosomal recessive forms of DEB
RDEB, gravis (Hallopeau-Siemens variant)
RDEB, mitis
the variants of EB, a considerably simplified classification system was rec-
ommended at that time (Table 4.2).7,8 Most recently, at the Third International
Consensus Meeting on Diagnosis and Classification of EB, the classification
scheme was further revised and this current proposed scheme forms the
framework for the discussion in this chapter (Tables 4.3, 4.4).9 Research
over the past two decades has generated a wealth of literature ­specifically
addressing the molecular basis of the various subtypes of EB. As a result, it
is now possible to subgroup EB on the basis of the level of ­separation within
the ­basement membrane region as well as on specific molecular findings.
Though molecular classification now drives our understanding of this dis-
ease group, knowledge of the traditional clinical subtypes can be helpful in
explaining the disease course to patients, despite the often overlapping
­spectrum of manifestations.
Traditionally, EB has been classified into three major groups based on
­clinical differences, antigen mapping, and electron microscopic observations:
• simplex (epidermolytic; in which the level of split is within the basal
keratinocyte),
• junctional (lucidolytic; where the level of split is within the lamina
lucida),
• dystrophic (dermolytic; where the level of split is deep to the lamina
densa).
associated with the JEB-PA syndrome.
In 1999, a fourth category – hemidesmosomal EB (where the level of split
is within the hemidesmosome) – was added.10 This provisional category has
now been removed and Kindler syndrome now constitutes a fourth major cat-
egory. The most recent classification, which takes into account the current
precise molecular data which is now known for virtually all of the subtypes
of this disease, is particularly valuable when considering the pathological
basis of EB and forms the basis for this account. There have been some
changes in nomenclature based on an attempt to produce names that are
more accurately descriptive of the diseases and concordant with current
molecular classification of this disease.
Mutations of sundry types in a variety of genes encoding plakophilin-1
(PKP1), desmoplakin (DSP), keratins 5 and 14 (KRT5, KRT14), plectin
(PLEC1), BP180, α6 and β4 integrin subunits (ITGA6, ITGB4), laminin-5
(now termed laminin-332 and encoded by LAMA3, LAMB3, LAMC2), types
XVII and VII collagen (COL17A1, COL7A1) and kindling-1 (KIND1) cur-
rently account for the different subtypes of EB (a more detailed account of
these basement membrane proteins is given in Chapter 1).10–12
Molecular studies including Western blot and ­immunoprecipitation,
­however, are not always available for every case of EB, particularly at
­presentation, and therefore initially at least the patient may well be
­provisionally subclassified on the basis of:
• clinical variation,
• presence or absence of extracutaneous manifestations,
• mode of inheritance,
• immunoepitope mapping and/or electron microscopy.
Clinical evaluation of a patient with suspected EB should include the age
of onset and nature and distribution of the cutaneous lesions and whether or
not scarring and contractures are present. In addition, the family pedigree
should be studied and the patient investigated for the presence or absence of
extracutaneous involvement (eyes, oropharynx, larynx, gastrointestinal and
genitourinary tracts, and musculoskeletal system) and other specific lesions
(including enamel hypoplasia, anodontia or hypodontia, pyloric atresia, and
muscular dystrophy) that might point towards a particular variant.4,5
Four major subtypes of EB are now recognized: simplex, junctional,
­dystrophic and Kindler Syndrome: 4–7,9
• EB simplex (historically also known as the epidermolytic variant) is
characterized by the level of separation within the epidermis, usually as a
 Epidermolysis bullosa 103

Table 4.3
Third consensus conference (2007): classification of epidermolysis bullosa

Major EB type Major EB subtype Protein involved

EBS Suprabasal
Lethal acantholytic EB Desmoplakin
Plakophilin deficiency Plakophilin-1
EBS superficialis (EBSS) ?
Basal
EBS, localized (EBS-loc)+ K5, K14
EBS, Dowling-Meara (EBS-DM) K5, K14
EBS, other generalized (EBS, gen-nonDM; EBS, gen-nDM)^ K5, K14
EBS with mottled pigmentation (EBS-MP) K5
EBS with muscular dystrophy (EBS-MD) Plectin
EBS with pyloric atresia (EBS-PA) Plectin, α6β4 integrin‡
EBS, autosomal recessive (EBS-AR) K14
EBS, Ogna (EBS-Og) Plectin
EBS, migratory circinate (EBS-migr) K5
Junctional EB JEB, Herlitz (JEB-H) Laminin-332 (laminin-5)*
JEB, other (JEB-O)
JEB, non-Herlitz, generalized (JEB-nH gen)$ Laminin-332; type XVII collagen (BP180)
JEB, non-Herlitz, localized (JEB-nH loc) Type XVII collagen
JEB with pyloric atresia (JEB-PA)† α6β4 integrin‡
JEB, inversa (JEB-I) Laminin-332
JEB, late onset (JEB-lo)# ?
LOC syndrome (laryngo-onycho-cutaneous syndrome) Laminin-332 α3 chain
DEB (‘dermolytic EB’) Dominant dystrophic EB (DDEB)
DDEB, generalized (DDEB-gen) Type VII collagen
DDEB, acral (DDEB-ac) Type VII collagen
DDEB, pretibial (DDEB-Pt) Type VII collagen
DDEB, pruriginosa (DDEB-Pr) Type VII collagen
DDEB, bullous dermolysis of the newborn (DDEB-BDN) Type VII collagen
Recessive dystrophic EB (RDEB)
RDEB, severe generalized (RDEB-sev gen)@ Type VII collagen
RDEB, generalized other (RDEB-O) Type VII collagen
RDEB, inversa (RDEB-I) Type VII collagen
RDEB, pretibial (RDEB-Pt) Type VII collagen
RDEB, pruriginosa (RDEB-Pr) Type VII collagen
RDEB, centripetalis (RDEB-Ce) Type VII collagen
RDEB, bullous dermolysis of the newborn (RDEB-BDN) Type VII collagen
Kindler syndrome Kindlin-1

Adapted from Fine et al (2008) J Am Acad Dermatol, 58, 931–50 from American Academy of Dermatology.
Rare variants are italicized.
+Previously termed EBS, Weber-Cockayne
^Includes cases previously termed EBS-Koebner
‡α β integrin is a heterodimeric protein; mutations in either gene have been associated with both EBS-PA and JEBS-PA. Some cases of EB associated with pyloric atresia may have
6 4
intraepidermal cleavage or both intralamina lucida and intraepidermal clefts.
*Laminin-332 (laminin-5 is a macromolecule composed of three distinct (α3, β3, γ2) laminin chains; mutations in any of the encoding genes result in a junctional EB phenotype.
$Previously termed generalized atrophic benign EB (GABEB).

#Previously termed EB progressiva.

@Previously termed RDEB, Hallopeau-Siemens.

Dominant dystrophic EB; EBS-DM, EBS Dowling-Meara; EBS-K, EBS, Koebner; EBS-MD, EBS with muscular dystrophy; EBS-WC, EBS, Weber–Cockayne; JEB-H, junctional EB, Herlitz;
JEB-nH, junctional EB, non-Herlitz; JEB-PA, junctional EB with pyloric atresia; RDEB-HS, recessive dystrophic EB, Hallopeau-Siemens; RDEB-nHS, recessive dystrophic EB, ­
non-Hallopeau-Siemens.
†Some cases of EB associated with pyloric atresia may have intraepidermal cleavage or both intralamina lucida and intraepidermal clefts.

‡α β integrin is a heterodimeric protein; mutations in either gene have been associated with the JEB-PA syndrome.
6 4

consequence of cytolysis. Traditionally, all variants have been associated
with mutations in the genes encoding keratin 5 or 14.8,9 However, the
most current classification scheme divides this group into suprabasal and
basal forms, and now certain rare variants are known to be associated
with mutations in the genes encoding desmoplakin, plakophilin-1,
plectin, and α6 and β4 integrin subunits.9
• Epidermolysis bullosa with late-onset muscular dystrophy, which had
traditionally been included in the simplex category, is now known to
result from a mutation in the plectin gene and was included in the
provisional hemidesmosomal group of EB as delineated by Pulkkinen and
Uitto in the 1999 classification scheme.10,13 Hemidesmosomal EB was
distinguished by the split through the hemidesmosome. The group
included EB with late-onset muscular dystrophy (previously included in
the simplex group), some examples of generalized atrophic benign EB
(others associated with laminin-332 mutations are included within the
junctional group) and EB with pyloric atresia (previously included in the
junctional group).10,14–16 These three variants of EB develop as a
consequence of mutations of genes encoding the hemidesmosomal
proteins plectin, BP180, and the α6 and β4 integrin subunits
respectively.10 In the newest classification scheme, these are now
included in the suprabasal and basal types of EB simplex (Table 4.4).
The hemidesmosomal group designation is no longer used as the
104 Inherited and autoimmune subepidermal blistering diseases
Table 4.4
Simplified classification of epidermolysis bullosa
Subtype Mutation
Simplex Suprabasal Plakophilin-1; desmoplakin
Basal Keratin 5 or 14; plectin; α6β4 integrin
Junctional Herlitz Laminin-332 (laminin-5)
Non-Herlitz Laminin-332; type XVII collagen;
α6β4 integrin
Dystrophic Dominant Type VII collagen
Recessive Type VII collagen
Kindler syndrome Kindlin-1
consensus conference considered its application to be less useful than the
current scheme. The main reason for this decision is that it is a somewhat
artificial category. It separated non-Herlitz junctional EB into two
categories namely, junctional EB and hemidesmosomal EB, based only on
the presence of mutations in the genes encoding either laminin-332 or
type XVII collagen, respectively. Both conditions have very similar
clinical features and cannot be separated on clinical grounds, making this
distinction confusing for clinicians, patients, and their parents. Thus all
the diseases in the hemidesmosomal category are now reclassified into
either the junctional or simplex types of EB.
• Junctional EB is characterized by the development of cleavage within the
lamina lucida. It results from mutations in one of the three genes
encoding the hetrotrimeric subunits of laminin-332 (laminin-5), α6 and β4
integrin subunits, and type XVII collagen.17 As mentioned above, some of
these cases were deamed in the provisional hemidesmosomal category in
the previous classification scheme (e.g., α6 or β4 integrin subunits with EB
with pyloric atresia).
• Dystrophic EB (also known as the dermolytic variant) is defined by a
split developing immediately below the lamina densa in the region of the
anchoring fibrils. This type is composed of genetically dominant and
recessive subtypes invariably due to type VII collagen gene mutations.18,19
Clinical features
EB simplex (EBS)
Two major types of EB simplex (with 12 subtypes) are now recognized:
• suprabasal,
• basal.
Suprabasal EBS
Three suprabasal subtypes are recognized; all of them are rare variants.
Lethal acantholytic EB
Lethal acantholytic EB has been described in two cases with severely defective
skin and mucosal epithelia.19 The disease was lethal in the neonatal period
due to epidermolysis that was first noted during parturition leading to uncon-
trollable loss of fluid from the skin. Additional defects included universal
alopecia and complete shedding of nails and the presence of neonatal teeth.
Histology revealed clefting of the suprabasal layer producing a tombstone-type
appearance reminiscent of pemphigus vulgaris. Molecular investigation
revealed that the patient had inherited two different nonfunctional copies of
the gene encoding desmoplakin (DSP, a desmosomal protein that links the
transmembrane cadherins to the various proteins of the cytoplasmic interme-
diate filaments), one from each parent, indicating that the disease is autosomal
recessive. The mutations both lead to truncation of the desmoplakin protein
and an inability to act as a linker. Additional cases will be necessary to further
define this syndrome.
Plakophilin deficiency (ectodermal dysplasia-skin fragility syndrome,
McGrath syndrome)
Plakophilin is a required component of desmosomes and an important pro-
tein in ectodermal development. The rare deficiencies in this protein result in
a recently described inherited disease known as ectodermal dysplasia-skin
fragility syndrome. Plakophilin-1 (PKP1) deficiency is an autosomal recessive
disease that is associated with skin fragility and an inflammatory response
resulting in erosions, scale-crust, and progressive palmoplantar keratoderma.
Ectodermal effects such as sparse hair and anhidrosis and astigmatism are
also noted.20 While initially described in a single child, approximately ten
cases with mutations in this gene have now been described.20,21
Epidermolysis bullosa simplex superficialis
This rare form of EB transmitted in an autosomal dominant fashion was first
described in 1989. It specifically differs from the other simplex variants by
the site of epidermal cleavage: variable subcorneal split between the stratum
corneum and granular cell layer or sometimes within the stratum spinosum
rather than intrabasal.22 Patients present at birth or within the first 2 years of
life with erosions and crusts sparing the palms and soles. Atrophic scarring,
nail dystrophy, and milia are additional common features; oral and ocular
epithelia can be affected.23 As well as the cutaneous manifestations, anemia
and gastrointestinal lesions affect a minority of patients. Some cases are asso-
ciated with mutations causing structural dysfunction of type VII collagen.23
The condition may be clinically confused with peeling skin syndrome but in
the latter there are no blisters and peeling is continous and spontaneous.
Basal EBS
Nine subtypes of basal EBS are currently recognized, five of which are very
rare.
EB simplex, localized (Weber-Cockayne; EB simplex of the
hands and feet)
This is the most common form of epidermolysis bullosa and has an ­autosomal
dominant mode of inheritance.4 5 Lesions are limited to the palms and soles
and are usually detected in infancy or the first few years of life (Fig. 4.9).
Occasionally, in patients with mild involvement, blisters and erosions may
not develop until childhood or even early adulthood in association with
strenuous activity. The lesions, which sometimes heal with atrophic scarring,
show seasonal variation, often occurring only in the summer months.
Hyperhidrosis may sometimes be present. Milia, atrophic scarring, and nail
dystrophy are uncommon features.5,7 The teeth are uninvolved and there is no
evidence of any systemic involvement, except perhaps for oral erosions, which
may affect an appreciable number of patients in infancy.7 Ocular lesions are
not a feature. Repeated episodes of secondary infection may occur in some
patients. Postinflammatory hyper- and hypopigmentation may sometimes
be a cosmetic problem.8
EBS, Dowling-Meara (EBS herpetiformis)
This variant, which is the second commonest form of EB simplex, shows clin-
ical features resembling dermatitis herpetiformis and has an autosomal domi-
nant mode of inheritance (Fig. 4.10).7,24–27 Herpetiform grouping of blisters is
characteristic. Lesions are usually present at birth and have a distribution
sometimes mimicking severe dystrophic or junctional disease.7 Some patients
die in early infancy due to infection, fluid loss or electrolyte imbalance.1 Milia
formation is common, but atrophy and scarring are rare.7 Distal flexural
contractures are occasionally present.25 Nail dystrophy is often found and
palmoplantar keratoderma is characteristic. Anodontia and hypodontia have
also been described. Normalization during episodes of high fever is a typical
finding but seasonal variation is not a feature.26 Blistering significantly
improves with advancing years.27 Mutations in keratins 5 and 14 underlie this
disease.28–31 Death as a result of complications of the disease is rare and gener-
ally occurs by age 1 as a result of sepsis or respiratory failure.32
EBS, other generalized (includes Koebner variant)
This group has an autosomal dominant mode of inheritance and includes pri-
marily those cases previously termed Koebner-type and all other generalized
subtypes of EBS.5 In the Koebner variant, blisters are present at birth or
shortly thereafter and, although the entire body may be affected, lesions are
particularly severe on the extremities, where the dorsal surfaces tend to be
involved (Fig. 4.11).5 The blisters usually heal without scarring or atrophy
and milia are very uncommon.5 The eruption often worsens in the summer
months. The nails are rarely dystrophic and teeth abnormalities are typically
 Epidermolysis bullosa 105

A B

Fig. 4.9
EB simplex (Weber-Cockayne): typical lesions affecting (A) the fingers and (B) the toes. The pale color of the latter is due to the marked thickness of the roof of the blister.
By courtesy of the Institute of Dermatology, London, UK.

Fig. 4.11
EB simplex (Koebner):
intact blisters are present
in the axilla and on the
chest. By courtesy of
M.J. Tidman, MD, Guy's
Hospital, London, UK.
Fig. 4.10
EB bullosa simplex:
Dowling-Meara variant involvement.36–38 Blisters and erosions present at birth or soon ­thereafter and
showing characteristic are usually generalized. Patients may also suffer from atrophic ­scarring, milia,
grouping of blisters and
nail dystrophy or anonychia, alopecia, and oral lesions36,37 Severe mucose
erosions. By courtesy
of R.A.J. Eady, MD,
membrane involvement is rare.39 The mortality of this variant is high.6
Institute of Dermatology, Mutations in plectin are associated with these forms of the disease.40–42 Plectin
London, UK. is a large (greater than 500 kD) intermediate filament binding protein that pro-
vides mechanical rigidity to cells by acting as crosslinking adaptor to the
cytoskeleton.43 The PLEC1 gene bears a domain structure similar to BPAG1,
indicating they belong to a common family and may have similar functions.
absent. Although oral lesions may be present in infancy, systemic involvement
A lethal variant of EBS with mutations in plectin at the level of the plakin
is not a feature of this variant.
domain may occur exceptionally and it is associated with aplasia cutis of the
EBS with mottled pigmentation limbs and developmental impairment.42
This autosomal dominant variant was originally described in six members of
EBS with pyloric atresia
a single kindred.33 The cutaneous lesions are similar to the Dowling-Meara
This category was placed in the provisional hemidesmosomal category in the
variant with the addition of mottled or reticulate pigmentation, particularly
prior edition of this book. Cases with pyloric atresia are currently considered
affecting the neck and trunk. Atrophic scarring, milia, and nail dystrophy are
in two groups: EBS discussed here, and another category in junctional EB dis-
uncommon. Punctate keratoderma affecting the palms and warty hyperkera-
cussed below. This is a rare variant of epidermolysis bullosa in which affected
totic lesions involving the hands, elbows, and knees may be additional fea-
infants are at risk of ureterovesical junction obstruction with fibrosis involv-
tures.33–35 Dental caries is also sometimes present and intraoral lesions are
ing the entire urinary tract and aplasia cutis congenita in addition to pyloric
occasionally seen.
atresia (Figs 4.12, 4.13).44–47 Polyhydramnios is also seen. The pyloric atresia
EBS with muscular dystrophy (pseudojunctional EB) may be due to a diaphragm or stenosis (Fig. 4.14). The mortality rate of this
This is an autosomal recessive variant in which patients concomitantly develop variant is very high, up to 78% of affected infants succumbing.46 It appears to
muscular dystrophy or exceptionally myasthenia gravis and even cardiac be the most lethal form in the EBS category. Mutations in both plectin and
106 Inherited and autoimmune subepidermal blistering diseases

Fig. 4.12
EB with pyloric atresia:
stillborn infant with
widespread blistering.
By courtesy of M.J.
Tidman, MD, Institute of
Dermatology, London, UK.

Fig. 4.14
(A, B) EB with pyloric atresia: pyloric canal is obliterated by fibrous connective tissue.

Fig. 4.13
EB with pyloric atresia: in addition to blistering there is also deep ulceration.
By courtesy of M.J. Tidman, MD, Institute of Dermatology, London, UK.
α6β4 integrin subunits (junctional EB) have been described.48 Since both α6β4
integrin and plectin are expressed in villous trophoblast from the first trimes-
ter of pregnancy this feature has been used successfully for the prenatal diag-
nosis of this group of conditions.49
EBS, autosomal recessive
Autosomal recessive EBS is generalized with onset at birth. Blistering is prom-
inent with mild atrophic scarring. Ichthyotic plaques and focal palmoplantar
keratoderma are sometimes encountered. Nails may be dystrophic or absent.
Anemia, growth retardation, dental caries, and constipation can be complica-
tions.9 Mutations in keratin 14 underlie this disease; keratin 5 mutations have
not been described.50,51
EBS, Ogna
This form is autosomal dominant and presents at birth. It primarily involves
acral sites, but can become widespread. Blistering is prominent and ony-
chogryphosis is common. A tendency to bruise has been described.9,52 Lack of
muscular involvement distinguishes this form of disease from EBS with mus-
cular dystrophy described above; the mutation genotype may be predictive of
disease expression.42,53
Mutations in plectin underlie this syndrome.39,52
EBS, migratory circinate
This generalized form of EBS presents at birth with an autosomal dominant
inheritance pattern. Blistering is very prominent and associated with a migra-
tory circinate erythema and postinflammatory hyperpigmentation.9 Mutations
in keratin 5 have been described, but none is currently reported in keratin
14.39,54,55
Hemidesmosomal EB
This group previously included three variants:
• patients with generalized atrophic benign EB (GABEB) (others were
included in the junctional group; see below),
• EB with late-onset muscular dystrophy (formerly included in the simplex
group),
• EB with pyloric atresia (formerly included in the junctional category).
This subtype is of historical interest only as it no longer exists in the most
current classification scheme.

Junctional epidermolysis bullosa
Two major subtypes of this variant are recognized: junctional EB-Herlitz and
junctional EB-non-Herlitz (Other). This later group encompasses both local-
ized and generalized forms, cases with pyloric atresia, and three additional very
rare variants under the newly revised classification scheme.9 Junctional EB with
pyloric atresia was classified in the hemidesmosomal group in the prior classi-
fication scheme. All have an autosomal recessive mode of inheritance.
Junctional EB, Herlitz (Herlitz, gravis variant of junctional
EB, EB hereditaria letalis, EB atrophicans generalisata
gravis)
Within this generalized variant, no additional subtypes are recognized. Blisters
and erosions are present at birth accompanied by scarring and atrophy
(Fig. 4.15).56–58 Milia may be a feature.7 Healing with the formation of
­exuberant, vegetative or tumorous granulation tissue is a pathognomonic
­feature (Fig. 4.16).5 This is found particularly around the mouth, sides of the
neck, trunk, and about the nails.4 The nails may be dystrophic or absent and
scarring alopecia is sometimes evident.5 Severe oral involvement (including
­scarring and microstomia) is usually present and pitted dystrophic enamel is
characteristic (Fig. 4.17). Dental caries are frequently severe. Other ­features
may include musculoskeletal deformities, gastrointestinal lesions, laryngotra-
cheal stenosis, and genitourinary and ocular involvement. Esophageal involve-
ment may result in stenosis. Perforation with resultant infection is an
important cause of death. Severe growth retardation and anemia are usually
evident. Infantile mortality is high (42.2%).7 Mutations in one of the three
subunits of ­laminin-332 underlie this syndrome.59–61
Junctional EB, Other
The category contains six subtypes, two common and four rare.
JEB, non-Herlitz, generalized (generalized non-Herlitz junctional EB,
EB atrophicans generalisata mitis, generalized atrophic benign EB
(GABEB), hemidesmosomal EB, junctional EB mitis)
This somewhat milder form, in which the cutaneous features are similar to
the gravis form, includes some patients with laminin-332 gene mutations and
others with mutations in type XVII collagen previously classified in the hemi-
desmosomal group.9,62 Systemic involvement is typically mild or absent.63–66
Patients present at birth with extensive blistering and erosions accompanied
by mild scarring and widespread cigarette paper-like atrophy. Variable
Fig. 4.15
Junctional EB (Herlitz):
newly born infant with
blistering and nail
involvement. By courtesy
of J. McGrath, MD,
Institute of Dermatology,
London, UK.
Epidermolysis bullosa 107
Fig. 4.16
Junctional EB (Herlitz): infant showing granulation tissue at the edge of a healing
blister. By courtesy of the Institute of Dermatology, London, UK.
­ yperpigmentation and hypopigmentation are characteristic.63 Skin lesions
h
may be exacerbated during summer. Milia are variably present. Exuberant
­granulation tissue is less common than in the Herlitz variant. Other features
include dystrophic or absent nails (Fig. 4.18), oral erosions with mild scar-
ring, pitted dystrophic enamel, and severe dental caries. Ocular lesions include
recurrent corneal erosion, blistering, and corneal scarring.64 Follicular atro-
phy with resultant alopecia involving the scalp, axillary, and pubic hair in
addition to sparse eyelashes and eyebrows is common (Fig. 4.19).63 Large or
multiple melanocytic nevi have also been described as part of the phenotype58
but this is not currently believed to be a specific feature.5 Contractures do not
develop. Systemic involvement is usually limited to mild laryngeal and/or
esophageal lesions.4 Growth may be retarded and anemia is present in some
patients. Infantile mortality is high (up to 44.7%).7,32
JEB, non-Herlitz, localized
This milder and localized form of JEB is associated with mutations in type
XVII collagen rather than laminin-332.67,68 Genotypic correlations and immu-
nofluorescence antigen mapping may allow distinction of this form from the
more several generalized form.68
JEB with pyloric atresia
All EB with pyloric atresia was previously placed in the now defunct hemides-
mosomal category. These cases are now divided into two categories within
EBS and JEB. While both plectin and α6β4 integrin subunit mutations have
been noted in EBS with pyloric atresia, only the latter is believed associated
with JEB with pyloric stenosis.69–71 The clinical features are similar, with gen-
eralized blisters present from birth associated with atrophic scarring, dystro-
phic or absent nails, and milia on occasion. Large areas of aplasia cutis have
been described.67 This disease is usually fatal at an early age.
JEB inversa
Lesions, which are present at birth or develop in early infancy, are initially gen-
eralized, but later are predominantly localized to inverse (flexural) sites includ-
ing the axillae and groin.5 Blisters and erosions are accompanied by atrophic
scarring and nails may be dystrophic or absent. Other features that are some-
times evident include mouth erosions, maldeveloped teeth with enamel hyp-
oplasia, and occasional gastrointestinal lesions, particularly affecting the
esophagus and anus. Mutations in the subunits of laminin-332 are noted.9,58
JEB-late onset (progressiva)
In this variant, lesions do not present until late childhood, and consist of
blisters and erosions affecting the hands, elbows, knees, and feet.5 Nails
may be dystrophic or absent and enamel hypoplasia is characteristic. Mouth
erosions may be evident. Mild finger contractures are sometimes a compli-
cation.3,5 The mutation underlying this form of the disease is unclear.9
108 Inherited and autoimmune subepidermal blistering diseases

Fig. 4.17 Fig. 4.19

Junctional EB (Herlitz): note the scarring with microstomia and severe dental involvement. Generalized atrophic benign EB: note the sparsely distributed eyebrows and eye
By courtesy of J. McGrath, MD, St John's Dermatology Centre, London, UK. lashes. By courtesy of the Institute of Dermatology, London, UK.

Dominant dystrophic EB
Five subtypes are recognized; four of these are rare.
Dominant dystrophic EB, generalized
Autosomal dominant EB, generalized includes both the Cockayne-Touraine
and Pasini variants. This is because the two conditions are characterized by
identical type VII gene mutations and the albopapuloid lesions (white perifol-
licular papules and plaques) have been found to be an inconsistent finding
(Fig. 4.20).6,7 Generalized blisters are seen at birth (Fig. 4.21a).4,8 Alopecia
may be present and milia, atrophic scarring, and dystrophic or absent nails
are typical features (Fig. 4.21b). Oral involvement may be mild or absent.
Enamel hypoplasia is sometimes evident. Gastrointestinal and genitourinary
tract involvement is seen in a minority of patients. There is a slightly increased
risk of basal cell carcinoma and melanoma.75

Dominant dystrophic EB, acral

In this mild autosomal dominant localized variant, lesions present at birth or
in early childhood, particularly in an acral distribution. Blisters and erosions
in the absence of other significant lesions except for atrophic scarring, milia,
Fig. 4.18
Generalized atrophic benign EB: there is scarring and complete absence of nails.
By courtesy of the Institute of Dermatology, London, UK.

Laryngo-onycho-cutaneous (LOC) syndrome

A mutation in the gene encoding the laminin-332 α3 chain resulting in an
unusual N-terminal deletion underlies this syndrome.72 It was first described
by Shabbir and colleagues in 22 patients of Punjabi extraction and about 10
additional cases have been described.73,74 So far, this autosomal recessive con-
dition has not been described outside of this population. It can occur in a
nonconsanguineous context. It consists of epithelial defects resulting in cuta-
neous erosions, nail dystrophy, and chronic conjunctival and laryngeal granu-
lation tissue. Symblepharon and blindness are serious complications. Airway
obstruction and infection can also be problematic. The degree of skin fragility
is less than that seen in other variants of JEB. Under the new classification
system, based on molecular and clinical similarities to JEB, this syndrome has
been added as a rare variant.9,59

Dystrophic EB
Two major subtypes – dominant dystrophic EB and recessive dystrophic EB
(Hallopeau-Siemens) – are recognized and these are categorized into three
major subtypes (one dominant and two recessive) and nine rare dominant or
recessive groups. All subtypes are associated with mutations in the gene
encoding type VII collagen. 9
Fig. 4.20
Dystrophic EB: albopapuloid lesions on the lumbosacral area. These are an
inconstant finding in dystrophic EB. The lesions are not preceded by blistering and
probably represent connective tissue nevi. By courtesy of M.J. Tidman, MD, Guy's
Hospital, London, UK.

A B
and nail dystrophy may cease altogether after childhood.1 Extracutaneous
manifestations have not been recorded.
Dominant dystrophic EB, pretibial
This is a mild, localized, and typically symmetrical autosomal dominant form.
An autosomal recessive variant has recently been described (see below).76 The
onset is often delayed, patients usually presenting in early ­childhood.77 Blisters
and erosions accompanied by atrophic scarring and milia are ­particularly
seen on the pretibial region and dorsal aspects of the feet (Figs 4.22, 4.23).
The scarring may have a violaceous appearance reminiscent of hypertrophic
lichen planus.76 Lesions are also sometimes seen on the forearms and trunk.76
Pruritus and nail dystrophy are common. There are no teeth or hair
changes.77
Dominant dystrophic EB, pruriginosa
This variant, which presents in childhood, includes dominant and ­recessive
variants (see below).78 Patients present with highly pruritic, violaceous
Fig. 4.22
Dystrophic EB–pretibial: extensive erosions with scarring are localized to the front
of both shins. By courtesy of the Institute of Dermatology, London, UK.
Epidermolysis bullosa 109
Fig. 4.21
Dominant dystrophic EB
(Cockayne-Touraine): (A)
truncal involvement is present
in addition to the more typical
limb lesions; (B) hemorrhagic
blisters, scarring, milia and
nail dystrophy. By courtesy of
the Institute of Dermatology,
London, UK.
Fig. 4.23
Dystrophic EB–pretibial: close-up view. By courtesy of the Institute of Dermatology,
London, UK.
­ odular prurigo-like nodules developing against a background of blisters,
n
milia, nail dystrophy, and albopapuloid lesions.
Dominant dystrophic EB, bullous epidermolysis of the newborn
This exceptionally rare, self-limiting condition presents in the newborn with
blisters that usually resolve within the first 2 years and heal with mild atro-
phy, milia, and scarring.79,80 Most cases have been inherited as an autosomal
dominant, although recessive variants have also been documented.6
Recessive Dystrophic EB
This category is composed of seven subtypes, of which five are rare.
Recessive dystrophic EB, severe generalized (Hallopeau-Siemens;
polydysplastic EB; EB gravis)
This autosomal recessive variant is a much more serious form than its auto-
somal dominant counterpart.4,8 Blisters and erosions are present at birth and,
atrophy, scarring, anemia, and growth retardation are consistently present
(Figs 4.24, 4.25). Nikolsky's sign is positive. Destructive involvement of the
distal peripheries results in contractures and severe deformities including the
characteristic ‘mitten lesions’ (pseudosyndactyly) of the hands and feet (Figs
4.26–4.28).81 If the latter is left untreated, there may eventually be resorption
of the underlying bones (autoamputation). Nail dystrophy and milia are
marked, and scarring alopecia is common (Fig 4.29). Oral involvement is
severe, with blisters, erosions, and scarring. Excessive caries are usual.
110 Inherited and autoimmune subepidermal blistering diseases

Fig. 4.24
Recessive dystrophic EB (Hallopeau-Siemens): extensive blistering present at birth.
The disease process has involved the nails and those of the first two toes are
absent. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Fig. 4.27
(A, B) Recessive dystrophic EB (Hallopeau-Siemens): in addition to the gross mitten
deformity, there is very severe scarring and scaling. (A) By courtesy of R.A.J.
Eady, MD, and B. Mayou, MD, St Thomas' Hospital, London; (B) by courtesy of the
Institute of Dermatology, London, UK.
Fig. 4.25
Recessive dystrophic EB (Hallopeau-Siemens): note the scarring and extensive
erosions. By courtesy of the Institute of Dermatology, London, UK.

Fig. 4.26
Recessive dystrophic EB (Hallopeau-Siemens): weblike folds enveloping the toes Fig. 4.28
have resulted in a clublike appearance. By courtesy of R.A. Marsden, MD, St George's Recessive dystrophic EB (Hallopeau-Siemens): there is gross deformity of the knees.
Hospital, London, UK. By courtesy of J. McGrath, MD, Institute of Dermatology, London, UK.
 Epidermolysis bullosa 111

Fig. 4.30
Recessive dystrophic EB:
extensive esophageal
involvement with
complete separation of
Fig. 4.29 the mucosa has resulted
Recessive dystrophic EB in this dramatic, but
(Hallopeau-Siemens): note fortunately very rare,
the conspicuous milia. manifestation. By courtesy
By courtesy of the of R.A. Marsden, MD,
Institute of Dermatology, St George's Hospital,
London, UK. London, UK.

Gastrointestinal and renal complications are common.82,83 There is often con-

junctival involvement with keratitis and scarring, and lesions of the mucous
membranes result in difficulty in opening the mouth, dysphagia, and esopha-
geal stricture formation, with some infants eventually succumbing to terminal
respiratory infections (Fig. 4.30).84 Anal and genitourinary involvement may
also be present. Squamous cell carcinoma is a common complication of the
cutaneous scarring (occurring in 39.6% of cases) and is a significant cause of
mortality (Figs 4.31–4.33).85,86 Tumors are frequently multiple, have an aggres-
sive behavior, and may be associated with extensive metastatic spread.
Melanoma much less commonly develops. This variant of EB has a high mor-
tality: 38.7%.7

Recessive dystrophic EB, generalized other

This type is often referred to as non-Hallopeau-Siemens type. In contrast to
the severe generalized form, anemia and mental retardation are less common
and dental caries are not increased. In this variant the features are similar to
the Hallopeau-Siemens variant except that the extracutaneous lesions and
complications (e.g., anemia, mental retardation, and dental caries) are less
severe and the risk of developing cutaneous squamous cell carcinoma is
diminished (14.3%).4,8 The mortality for this variant of EB is 10.0%.87
Genotypic differences in mutational types and sites in the gene encoding type Fig. 4.31
VII collagen likely underlie differences in the phenotypic expression of this Recessive dystrophic EB (Hallopeau-Siemens): in this patient numerous large
disease.88 keratoses are evident. Many of these progress to squamous cell carcinoma. Courtesy
of R.A.J. Eady, MD, and B. Mayou, MD, St Thomas' Hospital, London, UK.
Recessive dystrophic EB, inversa
In this autosomal recessive form, lesions are present at birth and consist of
blisters, erosions, milia, and atrophic scarring, found particularly about the
flexural sites, including the inguinal regions, axillae, neck, and the lower Recessive dystrophic EB, centripetalis
back.89,90 Nail dystrophy is usually evident and sometimes scarring alopecia is This autosomal recessive localized form has been described in a single
seen. Severe oral and esophageal involvement (erosions and scarring) is patient. Presentation was at birth with widespread blisters. In adulthood,
characteristic.91 however, the distribution became acral. The blisters, milia, and severe scar-
ring with atrophy then showed a characteristic centripetal spread. Nail dys-
Recessive dystrophic EB, pretibial trophy and/or absence were also present. Despite the severe scarring,
The pattern of involvement is similar to the dominant form (see above), but contractures and deformities were not features.92 There were no extracuta-
can be more severe. neous manifestations.

Recessive dystrophic EB, pruriginosa Recessive dystrophic EB, bullous dermolysis of the newborn
The pattern of involvement is similar to the dominant form (see above), but The pattern of involvement is similar to the dominant form (see above), but
can be more severe. can be more severe.
112 Inherited and autoimmune subepidermal blistering diseases
Fig. 4.32
Recessive dystrophic EB (Hallopeau-Siemens): in addition to severe scarring
accompanied by autoamputation of the fingertips, there is a large ulcerated squamous
cell carcinoma. Courtesy of R.A.J. Eady, MD, and B. Mayou, MD, St Thomas' Hospital,
London, UK.
Fig. 4.33
Recessive dystrophic EB (Hallopeau-Siemens): in this patient there is a massive
squamous carcinoma, which has destroyed much of the knee. Courtesy of R.A.J.
Eady, MD, and B. Mayou, MD, St Thomas' Hospital, London, UK.
Kindler syndrome
Kindler syndrome has been added to the EB classification scheme due to simi-
larities to EB, and the hope that patients with this disease may benefit from the
greater molecular and pathogenetic understanding of EB as a whole. It does
not readily fit into any of the EB types as the level of blistering separation can
be intraepidermal, junctional or below the lamina densa. This disease is caused
by a mutation in the KIND1 gene that encodes the protein kindlin-1, a component
of contact foci in basal keratinocytes.93,94 First described in 1954, more than
50 cases are now published in the literature.95,96 Significant heterogeneity is
noted, but this rare autosomal recessive disease is associated with skin fragility
similar to other forms of EB associated with the symptoms of poikiloderma
and photosensitivity not seen in other forms of EB. Trauma-induced blistering
and photosensitivity often improve with age. Squamous cell carcinoma and
transitional cell carcinoma of the bladder have been described.97
All types of hereditary epidermolysis bullosa (simplex, junctional, and
­dystrophic) may rarely present with large nevi that often simulate melanoma on
clinical grounds. Histology, however, shows no evidence of mali­gnancy.98,99
Pathogenesis and histological features
The investigation of a patient with suspected EB should ideally include immu-
nofluorescence antigen mapping, ultrastructural, and molecular genetic
­studies. In general, routine histopathology often contributes little, other than
to confirm the presence of a subepidermal blister.
Immunofluorescent antigen mapping of basement membrane determinants
is a method of identification of the plane of cleavage in the various types of
EB that can sometimes avoid the need for ultrastructural studies.100,101
Essentially, the location of three antigens – type IV collagen, laminin-332,
and bullous pemphigoid antigen-1 – is determined by standard indirect immu-
nofluorescence of lesional (either naturally occurring or mechanically induced)
skin:7
• In simplex variants, all three antigens are found along the floor of the blister.
• In junctional lesions, bullous pemphigoid antigen-1 is identified mainly in
the roof of the blister, whereas laminin-332 and type IV collagen are
present along the floor.
• In dystrophic EB, the plane of cleavage is below the lamina densa and
therefore all three basement membrane antigens are present in the roof of
the blister.
The immunofluorescent investigation of skin samples for a wide range of
recognized basement membrane constituents known to be absent or
­diminished in the various subtypes of epidermolysis bullosa has proved to be
particularly valuable, and has also been shown to be of use in antenatal
(16–18 weeks' gestation) diagnosis.102–104
The monoclonal antibody KF-1, which localizes to the lamina densa, shows
an absence of labeling in nonlesional skin from patients with the severe
recessive dystrophic form of EB, whereas in the dominant variant it is
reduced.105,106
The monoclonal antibodies AF1 and AF2, which recognize antigens in and
immediately below the lamina densa (probably constituents of anchoring fibrils),
show an absence of immunolabeling in both normal and lesional skin from the
recessive dystrophic form, but appear normal in dominant dystrophic EB.107
LH7:2 is a monoclonal antibody directed against the NC-1 globular
domain of type VII collagen, which binds to the lamina densa and attached
anchoring fibrils.108,109 Labeling is absent or markedly reduced in the severe
recessive dystrophic form, patchily reduced in mild or localized recessive dys-
trophic variants, and normal in the dominant dystrophic variant.110,111
Immunolabeling with the monoclonal antibody GB3, which recognizes
laminin-332 (nicein/kalinin/epligrin), is reduced or absent in the junctional
(Herlitz) form of EB. It may be normal, reduced or absent in the non-Herlitz
junctional variants.112,113 Laminin-332 is a major constituent of the anchoring
filaments, which stretch from the hemidesmosomes to the lamina densa.
Two further antibodies, 19-DEJ-1 and AA3, characteristically fail to label
the basement membrane zone in all patients with junctional epidermolysis
bullosa and are therefore of additional diagnostic value.114 19-DEJ-1, which
recognizes uncein, has been recommended as the most reliable antibody for
evaluation and diagnosis of the major junctional variants.115,116
Bullous pemphigoid 180-kD antigen is demonstrably diminished or absent
as determined by immunofluorescence in many patients with generalized
atrophic benign EB.117
EB simplex
In EB simplex variants, blisters develop as a consequence of basal cell ­cytolysis
(Fig. 4.34). The plane of cleavage lies deep to the nuclei of the keratinocytes
such that wispy remnants of basal cell cytoplasm may be identified along the
floor of the blister cavity, which is therefore intraepidermal in location
(Figs 4.35, 4.36).118 In older lesions the blister often appears to be subepidermal
due to continued lytic changes of the residual keratinocyte cytoplasm
(Fig. 4.37). By direct immunoperoxidase antigen mapping on paraffin-embedded
sections, keratin, laminin, and type IV collagen staining may be identified along
the floor of the blister, confirming its intraepidermal location (Fig. 4.38).
Ultrastructural studies have shown that the earliest change is loss of keratin
filaments (tonofilaments).118,119 As a consequence, there is structural instabil-
ity and fragility of the keratinocytes. Keratin clumps similar to those described
in the Dowling-Meara variant (see below) have been a rare finding in EB simplex
Koebner.120 Loss of keratin filaments is subsequently followed by dissolution
 Epidermolysis bullosa 113

Fig. 4.34
EB simplex: the earliest histological feature in the development of a blister is Fig. 4.37
marked vacuolation of the basal keratinocytes, so-called cytolysis. EB simplex: old lesion; the features are those of a cell-free subepidermal blister and
are not specific.

Fig. 4.35
EB simplex: established lesion showing ‘subepidermal’ vesiculation.
Fig. 4.38
EB simplex: paraffin
immunoperoxidase
displays type IV collagen
along the floor of the
blister cavity (same case
as Fig. 4.37).

of the other keratinocyte cytoplasmic constituents. Suprabasal desmosomes

appear unaffected. The lamina densa and anchoring fibrils are normal. While
the hemidesmosomes generally appear normal, reduplication and increased
electron density have been described in a recent case report.121
The Dowling-Meara variant (including the subset with mottled pigmenta-
tion) is characterized by 1–5-μm homogenous intracytoplasmic clumps of
keratin filaments in addition to cytolysis (Fig. 4.39).122 These are present in
the basal keratinocytes and extend into the overlying prickle cell layer. They
may also be identified in the follicular outer root sheaths, dermal eccrine
sweat ducts, and sebaceous glands. The clumps are composed of keratins
5 (type II) and 14 (type I).122 In addition to intraepidermal vesiculation,
Fig. 4.36 ­intrakeratinocyte cleavage may also be found in the follicular infundibula.
EB simplex: basal keratinocyte cytoplasmic remnants are visible along the floor of The other skin appendage structures are not affected. The dermis may contain
the blister cavity. an infiltrate of lymphocytes and eosinophils.
114 Inherited and autoimmune subepidermal blistering diseases
A B
The keratoderma shows hyperkeratosis and acanthosis. Clumps of keratin
may also be evident.
Ultrastructurally, the level of cleavage is low within the basal keratinocytes, just
above the level of the hemidesmosomes (Figs 4.40, 4.41). In ­addition to cytolysis,
however, acantholysis may also sometimes be evident. The keratin filament
abnormalities include irregular whorled bundles in addition to homogeneous
clumps. They are present in normal skin in addition to lesional material
(Fig. 4.42).122,123 Desmosomes may appear diminished in number in the keratinocytes
showing tonofilament clumps. Basement membrane zone constituents are normal.
In EB simplex superficialis the plane of cleavage is in the upper epidermis
just beneath the stratum corneum.22 Additional clefts may also be evident in
the lower third of the epidermis.
It is now apparent that the majority of EB simplex develop as a direct
­consequence of keratin gene mutation, but mutations in desmoplakin,
­plakophilin, plectin, and α6β4 integrin subunits are seen in some of the rare
subtypes (see Table 4.2).124,125 Following the initial discovery of keratin
­filament clumps in Dowling-Meara EB and their subsequent identification as
keratins 5 and 14, it was shown that keratinocyte cultures from patients with
this disease exhibited an identical morphological abnormality.120 Genetic
linkage studies showed that EB simplex was associated with keratin gene
Fig. 4.40
EB simplex (Koebner): the
M blister cavity forms within
the basal keratinocyte.
Note the cytoplasmic
remnants along the
floor of the blister.
(M, melanosome.)
Fig. 4.39
EB simplex (Dowling-Meara): (A) electron micrograph
showing intrakeratinocyte splitting; (B) close-up view of
tonofilament clumps. By courtesy of J.A. McGrath, MD, and
R.A.J. Eady, MD, Institute of Dermatology, London, UK.
clusters on chromosomes 12 and 17.126–130 The gene for keratin 5 is carried on
chromosome 12q and that for keratin 14 is located on 17q. Truncated mutant
human keratin 14 gene induces the EB phenotype when introduced into trans-
genic mice and similarly causes an identical keratin abnormality when
expressed in ­transfected human keratinocytes.131,132 Specific missense muta-
tions or ­deletions have now been identified in patients with Dowling-Meara
(K5 and K14), localized (K5 and14), other generalized (K5 and14) subtypes,
and the the rare EB simplex subtypes with mottled pigmentation (K5), autosomal
recessive (K14), and migratory circinate (K5).133–138 The highly conserved end
domains of the keratin rod are particularly susceptible to significant mutation
with resultant instability of the filament assembly and consequent fragility of
basal keratinocytes following mild trauma.124
Plectin, which localizes to the inner plaque of the hemidesmosome, is a
member of the plakin family and in concert with BP230 is believed to be of
importance in keratin filament anchorage.10,14 Recently, mutation of the gene
PLEC1 encoding this protein has been described in patients with the muscular
dystrophy-associated, pyloric atresia, and Ogna subtypes.39 Plectin is associ-
ated with the Z-lines in the desmin cytoskeleton and this explains its
importance in myocyte adhesion and their role in the pathogenesis of EBS
with muscular dystrophy.139 Mutations in the genes encoding desmoplakin
and plakophilin-1, respectively, are associated with lethal acantholyic EB and
­plakophilin deficiency.19,20
EB (both the simplex and junctional forms) associated with pyloric atresia
results from α6β4 integrin missense mutations resulting in premature termina-
tion codons with synthesis of defective or nonfunctional α6 or β4 subunits.140–142
As a result, hemidesmosomes are hypoplastic or reduced in number.10 Mutations
in the gene encoding plectin are also noted in the simplex form.48,143
Exceptionally, amlyoid has been described in the Weber-Cockayne type of
EB.144 Dyskeratosis has been reported as a histologic feature in Dowling-Meara
EB but not in other variants, including Koebner EB or Weber Cockayne EB.145
The sample in this study, however, was small and further investigation is
required to confirm the specificity of this finding.
Junctional EB
Junctional EB variants are also characterized by subepidermal ­blistering, usually
unaccompanied by any substantial inflammatory cell infiltrate (Fig. 4.43).146
Ultrastructurally, the site of cleavage is through the lamina lucida (Fig. 4.44). The
hemidesmosomes may appear malformed, be ­diminished in number or

Fig. 4.41
EB simplex (Koebner): this high-power view shows the floor of the blister cavity.
Note the lamina densa (arrowed), hemidesmosomes (arrowheads) and basal
keratinocyte cytoplasm. (A, blister; B, cytoplasm; C, dermis.)
Fig. 4.42
Epidermolysis bullosa simplex (Dowling-Meara): numerous tonofilament clumps are
present in the adjacent clinically normal skin (arrowed). By courtesy of J.A. McGrath,
MD, Institute of Dermatology, London, UK.
absent.147–150 Hemidesmosome alterations as detected by electron microscopy,
however, are heterogeneous. In a morphometric study of numbers of hemidesmo-
somes per unit length of basement membrane, one of five patients with the Herlitz
variant and two of three patients with non-Herlitz variants had normal results.151
The same authors recorded an association between junctional EB and a reduction
in the numbers of hemidesmosomes with associated sub-basal plates.
Junctional EB is characterized by mutations in the genes that encode the
α3, β3 or γ2 chains of laminin-332 (laminin-5).152–158 Mutations resulting in
premature termination codons in the laminin-332 genes are present, for
example, in all cases of the Herlitz lethal variant.7,10 Nonsense mutations,
out-of-frame deletions or insertions and splicing errors affect both alleles,
resulting in reduced synthesis and defective assembly of trimeric laminin-5
molecules.10 The majority of mutations have affected the LAMB3 gene
although LAMA3 and LAMC2 gene abnormalities have also been docu-
mented. Non-Herlitz junctional EB variants, including some cases of general-
ized atrophic benign EB, are associated with milder missense mutations or
deletions in the laminin-332 genes.152,159,160 Laminin-332 is located within
anchoring filaments and in the lamina densa. The abnormal laminin-332
results in defective anchoring filaments with resultant instability at the base-
ment membrane region.
Epidermolysis bullosa 115
Fig. 4.43
Junctional EB: subepidermal cell-free blister.
Fig. 4.44
Junctional EB: lesional skin showing separation within the lamina lucida of the
dermoepidermal junction. By courtesy of R.A.J. Eady, MD, Institute of Dermatology,
and M.J. Tidman, MD, Guy's Hospital, London, UK.
Junctional EB, non-Herlitz (generalized and localized) is most commonly
a result of BP180 mutations (BPAG2/type XVII collagen).161–163 Nonsense
mutations or insertions/deletions with resultant premature termination
codons result in absence of type XVII collagen. This is a transmembrane col-
lagen that is thought to contribute to the anchoring filaments via its carboxy-terminal
segment.10 The amino-terminal globular domain resides within the cytoplasm
of the basal keratinocyte localizing to the outer plaque of the hemidesmo-
some. Less often, laminin-332 mutations are responsible for this clinical
phenotype.
Dystrophic EB
In the dystrophic variants the histological features are those of subepidermal
vesiculation or blister formation in the absence of any significant inflamma-
tory content (Fig. 4.45). The clinical subtypes show no particular distinguishing
features. The adjacent dermis is often markedly scarred due to previous epi-
sodes of blistering.
The squamous carcinoma that develops in association with recessive dys-
trophic EB is very often well differentiated (Fig. 4.46) and occasionally its
appearance suggests a verrucous variant. Whether this latter form has the
good prognosis usually evident with verrucous carcinoma is uncertain.
116 Inherited and autoimmune subepidermal blistering diseases

Fig. 4.45 Fig. 4.47

Dystrophic EB (Hallopeau-Siemens): in addition to obvious subepidermal blistering Dystrophic EB (Hallopeau-Siemens): lesional skin demonstrates cleavage
there is dermal scarring and chronic inflammation. immediately beneath the lamina densa of the dermoepidermal junction (arrowed).
By courtesy of R.A.J. Eady, MD, Institute of Dermatology, and M.J. Tidman, MD,
Guy's Hospital, London, UK.

Ultrastructurally, the site of cleavage is immediately below the lamina

densa (Fig. 4.47).164,165 In the autosomal dominant and some localized
recessive groups, anchoring fibrils are decreased in number, but may
appear ­morphologically normal, whereas in the generalized recessive
­variants (and occasionally in severe dominant cases), the fibrils are very
sparse or more often absent.166–168 Frequently, thin wispy filaments imme-
diately adjacent to the lamina densa are all that are visible. In a recent
morphometric study of basement membrane in various dystrophic forms,
using nonblistered skin, anchoring fibrils were completely absent in gen-
eralized recessive dystrophic EB. Reduced numbers of morphologically
normal anchoring fibrils were found in localized recessive and dominant
dystrophic variants.169 Type VII collagen expression in dystrophic EB,
however, as determined by LH7:2 immunolabeling, is not an all-or-none
phenomenon. Even in the recessive variant, some positive staining of thin,
­ill-formed filamentous structures may be seen immediately below the lam-
ina densa. Collagenolysis in the superficial dermis may also be seen in the
A more severe variants.
In transient bullous dermolysis of the newborn, in addition to reduced
numbers of anchoring fibrils, intracytoplasmic inclusions are seen in the basal
keratinocytes. These have a stellate appearance and represent retained type
VII and type IV collagen.170–172
Dystrophic EB variants are all caused by mutations in the type VII collagen
gene COL7A1.173–175 Over 100 distinct mutations have been identified.10 The
Hallopeau-Siemens severe recessive variant is characterized by nonsense
mutations, insertions, deletions or splicing errors, which cause premature ter-
mination codons affecting both alleles, resulting in very low levels of mRNA
and virtual absence of type VII collagen synthesis.10,172,173 Premature termina-
tion codon, missense, deletion, and substitution mutations have been identi-
fied in a number of the less severe dystrophic variants.7 Dominant dystrophic
EB is caused by a glycine substitution mutation resulting in a less severe vari-
ant in which type VII collagen, although defective, is still produced and
anchoring filaments are present albeit in reduced numbers.176,177 Transient
bullous dermolysis of the newborn also results from a mutation in
COL7A1.79,80
B Milia, which are most commonly seen in dystrophic EB, are small cysts within
the upper dermis, consisting of a mass of keratinized squames surrounded by a
Fig. 4.46 wall of squamous epithelium, thereby representing miniepidermoid cysts. They
(A, B) Dystrophic EB (Hallopeau-Siemens): biopsy from the forearm of a 30-year-old are not specific to epidermolysis bullosa, being found in a variety of conditions
patient showing a cell-free subepidermal blister. In addition, a well-differentiated associated with damage to the cutaneous adnexal structures (e.g., severe burns
squamous cell carcinoma extends into the subcutaneous fat. and porphyria cutanea tarda) and other blistering disorders.
 Bullous pemphigoid 117

Differential diagnosis (Fig. 4.51). Often they contain clear or bloodstained fluid. Any area of the
body may be affected, but the blisters are most commonly located about the
With the appropriate clinical information the histological diagnosis of EB
lower abdomen, the inner aspect of the thighs and on the flexural surfaces of
should not pose any problems. With the exception, however, of the
the forearms, the axillae, and groin (Fig. 4.52).14 Grouping of lesions as seen
Dowling-Meara variant, it is not usually possible to predict which subtype
the patient suffers from although, in specimens from early lesions, it is in dermatitis herpetiformis is not usually a feature and symmetry is character-
sometimes possible to identify the simplex variants of the basis of cytolysis. istically absent. A ‘cluster of jewels’ appearance of new blisters arising at the
Cell-free subepidermal blisters, however, may be seen in a variety of conditions edge of resolving lesions as seen in linear IgA disease may, however, ­occasionally
be a feature of bullous pemphigoid (Fig. 4.53).15 The lesions are often pruritic
including autolysis, EB acquisita, cell-free pemphigoid, suction blisters,
and a burning sensation is sometimes a feature. Nikolsky's sign is usually
bullous cutaneous amyloidosis, bullous lichen sclerosus, porphyria cutanea
negative. In contrast to mucous membrane pemphigoid, generalized bullous
tarda, and pseudoporphyria.
pemphigoid is not associated with scarring.
Because the genetic defects for so many of the EB subtypes are now known,
Reported mucosal involvement (frequently as ulcers) is highly variable,
prenanatal testing is possible.178 It is hoped that understanding of the molecu-
lar pathobiology of this disease may eventually lead to successful gene ther- ranging from 8% to 58%.16–18 In a series of 115 patients, 24% had oral
involvement and 7% had genital lesions.18 Lesions are found most often on
apy as was recently described for a patient with junctional EB using
the palate, the cheeks, lips, and tongue (Fig. 4.54). Other sites less commonly
transplanted epidermal stem cells genetically modified to express wildtype
involved include mucosae of the nose, pharynx, conjunctiva and, rarely, the
LAMB3.179,180
urethra and vulva (see below) (Fig. 4.55).17 In contrast to mucous membrane
pemphigoid, mucosal involvement in generalized bullous pemphigoid is not
associated with scarring.
Bullous pemphigoid
Clinical features
Bullous pemphigoid is not a single disease entity. Rather, there are many sub-
types, which have been classified into primary cutaneous and mucosal vari-
ants and into generalized and localized forms (Fig. 4.48).1–4 Bullous
pemphigoid (BP) is the most frequently encountered autoimmune bullous
dermatosis with an annual incidence of 6.6 new cases per one million of the
population.5,6

Generalized cutaneous pemphigoid

Any age group may be affected, but the generalized variant demonstrates
a predilection for the later years of life, showing a maximum incidence in
the seventh decade and over. Rarely, however, children and even infants
may be affected.7,8 The disease is associated with a worldwide distribu-
tion and shows no racial propensity. There are no significant human leu-
kocyte antigen (HLA) associations and the sex incidence is approximately
equal.
Prodromal events are numerous and include erythematous, urticarial and,
rarely, eczematous phases.9,10 Erythroderma, either preceding the bullous Fig. 4.49
phase or occurring simultaneously, is a very rare manifestation (erythroder- Erythrodermic BP: blistering has developed against a background of generalized
mic pemphigoid).11,12 Similarly, patients may present with a history of gener- erythroderma. By courtesy of the Institute of Dermatology, London, UK.
alized pruritus in the absence of visible skin lesions (pruritic pemphigoid). In
such circumstances, immunofluorescence investigations are essential to estab-
lish the correct diagnosis.13
The characteristic lesions of established disease are tense and often intact
blisters arising on normal or erythematous skin (Figs 4.49, 4.50). They may
measure up to several centimeters in diameter and are typically dome-shaped

Generalized
Vesicular
Polymorphic
Widespread Vegetans
Nodularis
Erythrodermic
Cutaneous
Seborrheic

Pretibial
Localized
Brunsting-Perry

Widespread Mucous Membrane

Mucosal
Desquamative Gingivitis
Localized
Oral
Fig. 4.50
Fig. 4.48 BP: early tense blister arising on an erythematous base. By courtesy of the Institute
Bullous pemphigoid: classification. of Dermatology, London, UK.
118 Inherited and autoimmune subepidermal blistering diseases

Fig. 4.51 Fig. 4.53

BP: tense, dome-shaped blisters. The flexures are typically affected. By courtesy of BP: new blisters arising at the edge of a healing lesion (‘cluster of jewels’ sign). Although
the Institute of Dermatology, London, UK. typically seen in childhood linear IgA disease, this is sometimes a feature of bullous
pemphigoid. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Fig. 4.54
Fig. 4.52 BP: oral erosions are an occasional finding. Intact blisters are rare. By courtesy of
BP: widespread, fluid- R.A. Marsden, MD, St George's Hospital, London, UK.
filled, hemorrhagic blisters
on the arms and legs
of an elderly female. By
courtesy of the late M.
Beare, MD, Royal Victoria
Hospital, Belfast, N.
Ireland.

Although bullous pemphigoid has been reported in association with a

variety of internal malignancies, this may just be coincidental, merely reflect-
ing the age incidence of these two diseases.19 In a series of almost 500 patients
from Sweden, no increased incidence of cancer was observed.20 Other stud-
ies, however, have shown that there may be a positive correlation between
internal malignancy and seronegative bullous pemphigoid patients.21
Generalized bullous pemphigoid is a serious condition with a significant
mortality ranging from 10% to 20%.1 Since the advent of steroid therapy and
immunosuppressive agents, patients are more at risk of developing severe iat-
rogenic disorders than of dying from their disease.22 Morbidity from this dis-
ease may be related more to the age and general state of health of the patient
than to the severity of blistering.23 Although mortality from the disease is low, Fig. 4.55
there has been a reported increase in mortality in the last 20 years of the BP: conjunctival injection is present. By courtesy of R.A. Marsden, MD, St George's
twentieth century.24 Hospital, London, UK.

Fig. 4.56
Bullous pemphigoid: occasionally erythematous urticarial lesions may be the
presenting feature. Blisters may not evolve until several weeks later. By courtesy of
R.A. Marsden, MD, St George's Hospital, London, UK.
Clinical variants of generalized pemphigoid
Urticarial bullous pemphigoid presents with large persistent erythematous
plaques, which sometimes display an annular or gyrate peripheral component
(Fig. 4 56, 4.57).1 Rarely, small vesicles are also to be found.
Vesicular pemphigoid is a rare clinical variant in which the cutaneous
manifestations show a striking overlap with dermatitis herpetiformis.25–28
Patients present with numerous small tense vesicles that may be symmetrical,
intensely pruritic, and therefore associated with conspicuous excoriation.
Polymorphic pemphigoid is a somewhat confusing entity, which is similar
to vesicular pemphigoid, but probably shows overlap with linear IgA
disease.29–31
Patients present with burning and itching lesions predominantly affecting
the extensor aspects of the limbs, back, and buttocks. Symmetry, grouping,
and a polymorphic clinical appearance of papules, vesicles, and variably sized
bullae emphasize a similarity to dermatitis herpetiformis. It has been sug-
gested that polymorphic pemphigoid is not an entity sui generis, but repre-
sents a potpouri of conditions including vesicular pemphigoid, linear IgA
disease, and mixed subepidermal bullous disease in which patients show both
linear IgG and linear IgA or dermal papillary granular IgA on direct
immunofluorescence.30
Pemphigoid vegetans is an exceedingly rare vegetative intertriginous vari-
ant that may be associated with chronic inflammatory bowel disease.32–39
Fewer than 10 cases have been documented. Patients present with vegetative,
crusted, purulent, and sometimes eroded lesions in the groin, axillae, neck,
hands, eyelids, inframammary, and perioral regions (Fig. 4.58). Vesicles and
bullae may also be evident. Scarring has been described.39 The etiology of the
vegetative lesions is unknown.
Seborrheic pemphigoid is a variant in which the clinical features are sug-
gestive of pemphigus erythematosus.31
Pemphigoid nodularis represents the extremely rare association of lesions
of bullous pemphigoid with intensely pruritic papules and nodules of nodular
prurigo predominantly affecting the trunk and extremities (Fig. 4.59).40–42
The association of pemphigoid nodularis with immune dysregulation, poly-
endocrinopathy, enteropathy, and X-linked (IPEX) syndrome is the subject of
a single case report.43
Exceptionally, patients may show immunofluorescent evidence of bullous
pemphigoid in the absence of clinical blistering.42 The cause of this unusual
phenomenon is unknown although in some patients at least, chronic scratch-
ing probably damages the basement membrane region with exposure of
bullous pemphigoid antigens. There is a female predilection (2:1).42 The age
range of this variant extends from 24 to 80 years but, as with classical bullous
pemphigoid, the majority of patients are elderly.
Bullous pemphigoid 119
Fig. 4.57
Bullous pemphigoid: close up view. By courtesy of R.A. Marsden, MD, St George's
Hospital, London, UK.
Dyshidrosiform pemphigoid is a rare variant of pemphigoid in which
patients develop 1–2-mm, tense ‘sago-grain-like’ vesicles on the palms and
soles resembling dyshidrosiform dermatitis (pompholyx).44–50 Lesions may be
localized, or precede or occur simultaneously with generalized disease.
Overlap with pemphigoid nodularis has been described.51
Childhood pemphigoid exhibits lesions that are similar to their adult coun-
terparts, but there is some tendency for lesions to be localized around the
face, lower trunk, thighs, and genitalia, reminiscent of linear IgA disease in
childhood (Fig. 4.60).7,8,52–61 Similarly, a ‘cluster of jewels’ ­appearance is
sometimes evident.7 Palmar, plantar, and oral lesions are often present and
may be the sole site of involvement in infants (Fig. 4.61). The mucous mem-
branes may be affected but scarring is absent. A number of children with pri-
mary localized penile and vulval lesions have also been described (Fig.
4.62).47,48,59,62,63 This is of particular clinical importance since it may be mis-
taken for evidence of sexual abuse. Childhood pemphigoid has a good prog-
nosis and, as in adults, is usually self-limiting. Although the etiology is
generally unknown, in some infant cases there appears to be a relationship to
prior vaccination or immunization.59,64 Differences between childhood and
infant cases have been described, but the importance of further subdividing
this group is unclear.64
Localized cutaneous pemphigoid
Although classical bullous pemphigoid not uncommonly presents initially as
localized lesions that after a few months become generalized, occasional
patients present with localized blisters that do not subsequently disseminate
(localized bullous pemphigoid).65 Traditionally, this group has been ­subdivided
into two variants:
• Brunsting-Perry pemphigoid predominantly affects the head and neck
and is associated with scarring.66
• Localized cutaneous nonscarring bullous pemphigoid (Eberhartinger and
Niebauer variant)67 predominantly affects the lower legs (in particular the
pretibial region) of females.
The former variant is considered in the section on mucous membrane
pemphigoid. Although the latter nonscarring cutaneous form particularly
affects the lower legs (Fig. 4.63), it may also present at a variety of other sites
including forearms and hands, breasts, chest, buttocks, and umbilicus. Lesions
in localized bullous pemphigoid may be related to trauma.67 This variant
shows a peak incidence in the sixth decade. As with generalized bullous pem-
phigoid, patients present with tense, sometimes hemorrhagic, bullae that arise
on normal or erythematous-appearing skin. Localized cutaneous nonscarring
bullous pemphigoid is generally associated with a good prognosis.67
120 Inherited and autoimmune subepidermal blistering diseases

Fig. 4.58
(A, B) Pemphigoid vegetans:
presentation as verrucous
lesions in the flexures
may result in considerable
diagnostic difficulties. By
courtesy of R.K. Winkelmann,
A B MD, The Mayo Clinic,
Scottsdale, Arizona, USA.

Fig. 4.60
Childhood BP: very rarely
this disease affects young
Fig. 4.59 children and infants.
Pemphigoid nodularis: in There is a widespread
addition to bullous lesions, distribution of bullae,
this patient also developed which characteristically
these pruritic nodules. arise on an erythematous
By courtesy of H. Shimizu, base. By courtesy of
MD, Keio University R.A. Marsden, MD,
School of Medicine, Tokyo, St George's Hospital,
Japan. London, UK.

Rare patients present with localized bullous pemphigoid at the site of
trauma without much evidence of disease elsewhere.68
Mucosal pemphigoid/desquamative gingivitis
Localized oral pemphigoid is a recently described variant of desquamative gin-
givitis.69–71 The latter, of multifactorial etiology by definition, affects the mar-
ginal and attached gingivae. It shows a female predominance (9:1) and presents
most frequently in the middle aged. Desquamative gingivitis may also be a
manifestation of lichen planus, mucosal pemphigoid, and pemphigus.41 The
diagnosis of localized oral pemphigoid depends upon the presence of a linear
band of immunoreactants at the epithelial basement membrane region on
direct immunofluorescence.69 Clinical features include erythema, edema, erosions,
and ulcers.72 The oral lesions are nonscarring. Bullous pemphigoid-associated
desquamative gingivitis may remain confined to the gingiva (the localized oral
pemphigoid type), but approximately an equal proportion of patients goes on
to develop full-blown cutaneous pemphigoid (Fig. 4.64).69
 Bullous pemphigoid 121

Fig. 4.63
Localized pemphigoid,
nonscarring variant:
lesions are found
particularly on the lower
Fig. 4.61 legs of females. The
Childhood BP: plantar involvement is sometimes the only site of disease. By courtesy prognosis is usually good,
of M. Liang, MD, The Children's Hospital, Boston, USA. but occasionally the
condition can become
generalized. By courtesy
of R.A. Marsden, MD,
St George's Hospital,
London, UK.

Fig. 4.62
Childhood BP: note the perineal scarring and isolated blister. By courtesy of M. Liang,
MD, The Children's Hospital, Boston, USA.

Pathogenesis and histological features Fig. 4.64

The histological features of bullous pemphigoid depend to some extent upon
the age of the lesion biopsied. Early erythematous and urticarial lesions most
often show upper dermal edema associated with a perivascular lymphohistio-
cytic infiltrate accompanied by usually conspicuous eosinophils (Figs 4.65
and 4.66). Eosinophilic spongiosis is sometimes evident and occasionally, if
eosinophils are present in sufficient numbers, flame figures may be a feature.
Mild interface changes characterized by basal cell hydropic degeneration can
be seen in early or prodromal lesions.
If the biopsy is taken from an established blister, the changes are most
often those of an inflammatory (cell-rich) variant.73 The blister, which is sub-
epidermal, is typically unilocular and covered by attenuated epithelium (Fig.
4.67). In early lesions the roof epidermis may appear unaffected or show
occasional to even confluent necrotic basal keratinocytes. The blister contents
include coagulated serum, fibrin strands, and large numbers of inflammatory
cells including conspicuous eosinophils (Fig. 4.68). Variable numbers of neu-
trophils may be present.
A typical finding in bullous pemphigoid is retention of the dermal papil-
lary outline (festooning) which project like sentries into the vesicle cavity
(Fig. 4.69). The underlying dermis is inflamed and usually shows widespread
Desquamative gingivitis: note the intense gingival erythema and retraction. Such
features may also be seen in mucous membrane pemphigoid and pemphigus. By
courtesy of P. Morgan, FRCPath, London, UK.
severe edema. An infiltrate of eosinophils and mononuclears surrounds the
blood vessels and extends between the adjacent collagen bundles.
Leukocytoclasis is not seen and features of vasculitis are absent. The adjacent
papillary dermis is often edematous and, very occasionally, eosinophil
microabscesses are a feature (Fig. 4.70). Exceptionally rarely, neutrophil
microabscesses may be seen (see vesicular pemphigoid), raising diagnostic
confusion with dermatitis herpetiformis. Eosinophilic spongiosis is also some-
times evident in the adjacent epidermis (Fig. 4.71).74
Cell-poor (noninflammatory) features are occasionally seen if biopsies are
taken from lesions arising on noninflamed skin (Fig. 4.72). Because inflam-
matory cells are sparse or, exceptionally, even absent in such cases, there may
be considerable problems with the differential diagnosis, particularly if ade-
quate clinical information and immunofluorescence findings are not
available.
122 Inherited and autoimmune subepidermal blistering diseases

Fig. 4.65 Fig. 4.68

Prebullous pemphigoid: there is upper dermal edema and a perivascular lymphohis­ BP: the blister cavity contains large numbers of eosinophils.
tiocytic infiltrate with conspicuous eosinophils.

Fig. 4.69
BP: preservation of the dermal papillary outline (festooning) is a characteristic
Fig. 4.66 feature.
Prebullous pemphigoid: there are numerous eosinophils.

Fig. 4.67 Fig. 4.70

BP: an established lesion showing a subepidermal tense, dome-shaped blister BP: the presence of eosinophil microabscesses in the dermal papillae is a useful
containing edema fluid, fibrin, and inflammatory cells. although rare diagnostic marker.

Fig. 4.71
BP: eosinophilic
spongiosis is sometimes
seen in the epidermis
adjacent to the blister.
Fig. 4.72
Cell-poor pemphigoid: this is a very uncommon variant and is most often seen if a
very early lesion is sampled. The blister contains only a little edema fluid and there
is a light chronic inflammatory cell infiltrate in the superficial dermis.
Vesicular/polymorphic pemphigoid is characterized by subepidermal vesi-
cles with features suggesting either bullous pemphigoid or dermatitis herpeti-
formis or both (Fig. 4.73). Neutrophil dermal papillary microabscesses,
which are often regarded as pathognomonic of dermatitis herpetiformis, may
be seen in this variant (Fig. 4.74).
Pemphigoid vegetans is characterized by acanthosis, often with pseudoepi-
theliomatous hyperplasia, papillary dermal edema with subepidermal clefting
or frank vesicle formation and an inflammatory cell infiltrate of eosinophils,
mononuclears, and occasional neutrophils.
Pemphigoid nodularis exhibits pruriginous lesions which are characterized
by hyperkeratosis and acanthosis, and which may amount to pseudoepithe-
liomatous hyperplasia and dermal fibrosis (Fig. 4.75). In the dermis, a
perivascular infiltrate of lymphocytes and eosinophils is present. The blisters
show typical features of bullous pemphigoid (Fig. 4.76).
Bullous pemphigoid 123
Fig. 4.73
Vesicular pemphigoid: (A) low-power view showing a multilocular blister; (B) the
blister contains a neutrophil-rich infiltrate.
Localized nonscarring (pretibial) bullous pemphigoid usually shows the his-
tology of cell-rich bullous pemphigoid. Localized oral pemphigoid is typified by
a subepithelial vesicle (when present) and cannot be distinguished histologically
from oral involvement in mucous membrane pemphigoid (see below).
Ultrastructurally, in early lesions of bullous pemphigoid, the dermoepider-
mal cleavage is seen to have developed between the plasma membrane of the
basal keratinocyte and the lamina densa, through the lamina lucida.75 The
lamina densa is therefore located along the floor of the blister
(Figs 4.77, 4.78). Degenerative changes in the basal cells, including villous
­process formation, mitochondrial swelling, and cytoplasmic vacuolization,
are frequently found. Hemidesmosomes may appear reduced in number or
may even be absent.76 Intercellular edema between adjacent basal cells is a
common finding.77 If specimens from established inflammatory lesions are
examined, the lamina densa is sometimes fragmented or entirely absent.48
Bullous pemphigoid is characterized by a linear antibasement membrane
zone antibody using the indirect immunofluorescent technique.78 Although
IgG is invariably present (and most commonly of the IgG4 subclass), other
immunoglobulins, including IgE, may be represented.79 Such antibodies are
present in around 75–80% of patients.80–83 Sensitivity can, however, be
increased to 90% if split skin is used as substrate.18 Although the antibody
titer does not correlate with disease activity or severity, more recently it has
been shown that serum antibodies to the NC16A domain of BP180 (a subunit
of the bullous pemphigoid antigen) do correlate with disease activity (see
below).84,85
Split skin indirect studies are essential in the investigation of a patient in
whom a linear IgG antibasement membrane antibody has been detected.86–88
124 Inherited and autoimmune subepidermal blistering diseases

A B

Fig. 4.74
Vesicular pemphigoid: (A) neutrophil microabscesses in the adjacent dermal papillae heighten the resemblance to dermatitis herpetiformis. It would be impossible to establish
the diagnosis of bullous pemphigoid without appropriate immuno-fluorescent findings; (B) preservation of the dermal papillae may be a clue to the correct diagnosis of
pemphigoid.

Fig. 4.75
Pemphigoid nodularis: this is a biopsy of a pruritic nodule showing hyperkeratosis,
irregular acanthosis, dermal chronic inflammation, and scarring.
Fig. 4.77
BP: electron micrograph showing the lamina densa lying along the floor of the
blister cavity.

Fig. 4.76
Pemphigoid nodularis: this subepidermal blister comes from the same patient as
shown in Figure 4.75. Pemphigoid nodularis is of particular importance because Fig. 4.78
the nodular lesions may precede clinical evidence of blistering. BP: high-power view of the lamina densa.

Such antibodies are also characteristic of mucous membrane pemphigoid, her-
pes (pemphigoid) gestationis, inflammatory epidermolysis bullosa, and bullous
systemic lupus erythematosus. The antibodies in pemphigoid variants (with the
exception of the anti-p105 and anti-p200 variants discussed below) bind to the
epidermal side of 1 M NaCl-split skin whereas those of inflammatory epider-
molysis bullosa and bullous systemic lupus erythematosus bind to the floor.
In those patients in whom indirect fluorescent studies are not available,
similar information may sometimes be obtained through the localization of
lamina densa constituents such as type IV collagen or laminin-1 using
­paraffin-embedded direct immunoperoxidase techniques. In pemphigoid, the
staining is found along the floor of the blister, whereas in inflammatory
­epidermolysis bullosa and bullous systemic lupus erythematosus it is located
along the roof (see Figs 4.7 and 4.8).
Bullous pemphigoid antibodies are capable of complement fixation in as
many as 75% of patients.89,90 Most of complement fixation in bullous pem-
phigoid antibody resides in the IgG4 subclass.91
Linear in vivo-bound immunoglobulin at the epidermodermal interface on
direct immunofluorescence is present in 90% or more of patients (Fig.
4.79).18,92 Complement (C3) is also usually present and is sometimes the sole
immunoreactant (Fig. 4.80).93 Other immunoglobulin subclasses including
IgM, IgA, and IgE may be detected occasionally.83,89,94 In addition to C3, the
other components of the classical complement pathway, in particular C5b-9
(the membrane attack complex) and members of the alternative complement
pathway, including properdin, factor B and B-1H-globulin, may also be iden-
tified.83,95 There is therefore evidence that both the classical and alternate
complement pathways are involved in the pathogenesis of bullous pemphig-
oid.96 The classical complement pathway, however, predominates. A recent
mouse model underscores the necessity of an intact innate immune system, as
depletion of complement or neutrophils or blockage of mast cell activation
prevents blister formation.97
The immunofluorescence findings in erythematous, pruritic, urticarial,
and eczematous prodromal lesions and childhood, dyshidrosiform, vesicular,
nodular, and vegetans variants are similar to those seen in the conventional
generalized disease.25–28,32–49,98,99 In polymorphic pemphigoid either linear IgG
or IgA deposits may be identified along the basement membrane region.29–31
The serum may contain either IgG or IgA antibodies.30
Immunofluorescence findings in localized cutaneous disease are variable.
In some reports, patients show positive direct immunofluorescence for IgG
and C3 at the epidermodermal junction and a positive indirect immunofluo-
Fig. 4.79
BP: direct
immunofluorescence of
perilesional skin showing
intense linear basement
membrane zone staining
(IgG).
Bullous pemphigoid 125
Fig. 4.80
BP: direct immunofluorescence showing C3 deposition (left), no staining is
seen in the negative control (right). By courtesy of B. Boghal, FIMLS, Institute of
Dermatology, London, UK.
rescent test for bullous pemphigoid antibody, while others may be positive for
in vivo-bound complement, but negative on indirect examination.66,67,99 One
series has shown that almost 70% of patients with localized pemphigoid have
circulating IgG antibodies in their sera and the presence of these can be rele-
vant for serum-based testing, as discussed below.67,100 A caveat is that in one
study, antibodies were also detected in more than half of normal subjects who
did not subsequently develop the disease.101,102 This finding is further dis-
cussed below.
By direct immunoelectron microscopy, the immunoreactants (IgG and C3)
are seen to be located within the hemidesmosomal plaque and upper lamina
lucida (Fig. 4.81).103–107 Indirect immunoelectron microscopic ­studies show
that the bullous pemphigoid antigen is most often detected ­intracellularly in
the region of the cytoplasmic face of the hemidesmosome (Fig. 4.82).104,108–110
The immunoelectron microscopic observations in childhood bullous pem-
phigoid, vesicular pemphigoid, polymorphic pemphigoid, pemphigoid nodu-
laris, pemphigoid vegetans, and localized pemphigoid are identical to those of
classic bullous pemphigoid.111,112
Two principal bullous pemphigoid antigens are recognized by Western
blot and immunoprecipitation studies: one is 230 kD (BPAG1) and the other
is approximately 180 kD (BPAG2) (Fig. 4.83).113–119 These represent products
of distinct genes.120–123
BP230 maps to the short arm of chromosome 6, locus 6p11-12.121 It
belongs to the plakin family and shows homology with plectin and the
­desmogleins.122 It is wholly intracellular and localizes to the hemidesmosome.
BP230 is not involved in the early stages of the pathogenesis of blistering but
is of importance as a secondary event; antibodies against this antigen are not
required for blister formation in most cases.124–126
BP180 (collagen type XVII) is the major pathogenic antigen in bullous
pemphigoid. The BPAG2 (COLI7A1) maps to the long arm of chromosome
10, locus 10q24.3.121 It is a transmembrane adhesion molecule comprising an
­intracytoplasmic N-terminal fragment, a transmembrane region, and a col-
lagenous ­extracellular C-terminal ectodomain.127 The latter constitutes part
of the anchoring ­filament and distally merges with the lamina densa. The
antibodies directed against BP180 in bullous pemphigoid most commonly
react with a short extracellular noncollagenous locus – NC16A (regions
MCW0-MCW3) – located within the upper lamina lucida proximal to the
collagenous segment (Fig. 4.84).127–130 It now appears that antibodies specific
to this area are ­generally required for blister formation and, while antibodies
may also target BP180 non-NC16A domains, these latter antibodies do not
appear to be pathogenic in most cases.124–26 This finding reconciles the fact
that antibodies to both BP180 and BP230 can be seen in a significant portion
of the population without blister formation as these are not against the criti-
cal NC16A region of BP180.84
126 Inherited and autoimmune subepidermal blistering diseases

Fig. 4.81 Fig. 4.83

BP: direct immunoperoxidase reaction using frozen tissue substrate showing BP: Western blot
electron-dense deposits in the lamina lucida. demonstrating the two
quite separate bullous
pemphigoid antigens.
By courtesy of M.M.
Black, MD, Institute of
Dermatology, London, UK.

More recently, two patients with a nonscarring, bullous pemphigoid-like

illness characterized by neutrophil-rich subepidermal blisters resembling
­dermatitis herpetiformis and antibodies to a unique 105-kD protein – ­so-called
anti-p105 pemphigoid – have been documented.141–143 This antigen localizes
to the dermal side of split skin on indirect immunofluorescence. Its precise
nature has not yet been determined.
Anti-p200 pemphigoid is characterized by antibodies to a lower lamina
lucida basement membrane antigen.144–146 Patients generally present with a

Basal keratinocyte

HD plaque

NH2 Globular cytoplasmic domain

Fig. 4.82
BP: immunogold electron microscopic preparation. Note that the immunoreactant
NC16a
to BP180 and BP230 is particularly located on the hemidesmosomes (open arrows). Transmembranous domain Cell membrane
However, deposits are also present within the lamina lucida, black arrows. (BC,
basal cell; DER, dermis.) By courtesy of H. Shimizu, MD, Keio University School of
Medicine, Tokyo, Japan.

Lamina lucida Rod-like interrupted

Between 50% and 90% of patients with generalized bullous pemphigoid collagenous domain
have antibodies that react with BP230 and 35–50% have antibodies that
react with BP180 that are readily detected by immunoblotting.131 However,
the sera in 100% of patients react with BP180 NC16A domain recombinant
protein.131 This latter finding underscores the usefulness of recent testing for
anti-NC16A domain antibodies from peripheral blood to distinguish bullous
pemphigoid from other disorders.100,132–134 COL1
Flexible ‘tail’
Circulating antibodies against BP180 or BP230 have also been defined in
Lamina densa COOH
many of the other less common variants of bullous pemphigoid, including
localized and vesicular forms, pemphigoid vegetans, erythrodermic pemphig-
oid, and pemphigoid nodularis.131,135–139
In childhood pemphigoid, the antibodies also react against the same anti- Fig. 4.84
A schematic representation of the BP180 molecule showing the globular
gens.140 In addition, rarely there may also be antibodies that react with the
intracellular NH2 domain, the membrane proximal NC16A domain and the flexible
linear IgA 120-kD antigen.140 The BP180 antigen is most often ­targeted, and rod-like interrupted collagenous structure of the extracellular domain. (HD,
immunoblot analyses have shown that the antibodies react ­specifically with hemidesmosome). Collagen XVII/BP180: a collagenous transmembrane protein
the NC16A domain as in adult patients. In some children at least, the IgG and component of the dermoepidermal anchoring complex. (Powell AM, ­
subclasses differ from adult disease, consisting of all IgG subclasses or IgG2 Sakuma-Oyama Y, Oyama N, Black MM. Department of Immunodermatology,
in isolation.18 IgE antibodies are not a feature of c­ hildhood disease. St John's Institute of Dermatology, St Thomas' Hospital, London, UK.)

nonscarring bullous pemphigoid-like illness although linear IgA disease-like
and dermatitis herpetiformis-like variants have also been reported.144 The dis-
ease has also been described in association with psoriasis.145 With split skin
indirect IMF, the antibodies bind to the floor of the blister cavity.144 With
indirect immunoelectron microscopy, the antibodies bind to the lower lamina
lucida.147,148 The identity of the 200-kD antigen has yet to be determined but
it is neither laminin nor type VII collagen.148
Anti-p450 pemphigoid has been documented in a single patient. The anti-
gen, which has been localized to the basal keratinocyte, belongs to the plectin
family.149 Its precise nature has yet to be determined.
Exceptionally, bullous pemphigoid may be associated with antiplectin
antibody.150
Bullous pemphigoid has been described following PUVA therapy for myco-
sis fungoides. More recently, a case arising in the setting of radiation therapy
has also been noted, perhaps suggesting a role for tissue damage in the patho-
genesis of this disease.151
A mechanism for blister development in bullous pemphigoid has been pro-
posed by Jordon et al.80,152 and is outlined as follows. Following antibody–
antigen interaction and complement fixation, various chemotactic agents
including C3a and C4a are produced.153 Mast cells degranulate under the
influence of the latter or IgE, and release ECF-A, NMW-NCF, ESM, hista-
mine, and enzymes.154 Eosinophils and neutrophils, so recruited, bind (possi-
bly via C3b receptors) to the basement membrane region. By direct cytotoxic
action (eosinophils are capable of antibody-dependent cellular cytotoxicity)
or via released proteases, particularly elastase, damage at the basement mem-
brane region results in the development of a vesicle. Lymphocytes elaborate
histamine-releasing factor (HRF), which increases mast cell degranulation
and perpetuates the process. A broad range of cytokines are involved in this
inflammatory reaction including interleukin (IL)-1, IL-4-IL-8, IL-10-IL-13,
IL-15 and interferon gamma (IFN-γ).155 As yet, their relative importance and
time sequences are unknown.
Bullous pemphigoid is therefore a true autoimmune disease in which
­antigen–antibody reaction and complement fixation results in a character-
istic and reproducible train of events, which is inevitably accompanied by
the development of subepidermal blister formation. The etiology or
­initiator (other than those associated with drugs or PUVA therapy, which
are the ­minority) is unknown. The question as to why self-tolerance breaks
down with the ­formation of symptomatic autoantibodies in patients with
this d
­ isease is an important question for further investigation.
Differential diagnosis
The inflammatory cell-rich variant of bullous pemphigoid must be distin-
guished from other subepidermal blistering dermatoses in which a heavy
inflammatory cell component is a typical finding. These include dermatitis
herpetiformis, linear IgA disease, inflammatory epidermolysis bullosa
acquisita, and bullous systemic lupus erythematosus (see Table 4.5).
Table 4.5
Differential diagnosis of cell-rich pemphigoid
Parameter BP EBA
DIMF Linear IgG, C3 Linear IgG, C3
IIMF IgG antibodies 75–80% IgG antibodies 25–50%
Split skin IMF Roof Floor
Type IV collagen Floor Roof
EM: site of split LL Sub-LD
Western blot BP180 kD 290 kD
BP230 kD (type VII collagen)
BP, bullous pemphigoid; BSLE, bullous systemic lupus erythematosus; DH, dermatitis herpetiformis; DIMF, direct immunofluorescence; EBA, epidermolysis bullosa acquisita; EM,
electron microscopy; IIMF, indirect immunofluorescence; IMF, immunofluorescence; LAD, linear IgA disease; LL, lamina lucida; sub-LD, sub-lamina densa.
Pemphigoid gestationis 127
Successful differentiation depends upon careful clinicopathologic correlation
and immunofluorescent studies or, more recently, serum-based immunologic
(ELISA) testing. Split skin indirect immunofluorescence or lamina densa anti-
gen mapping by type IV collagen or laminin-1 direct immunoperoxidase is
essential to determine the level of the split. Although electron microscopy,
immunoelectron microscopy, and immunoprecipitation or Western blotting
provide definitive information, such techniques are not necessary in the
majority of cases.
The cell-poor variant of bullous pemphigoid has a very wide range of ­differential
diagnoses including epidermolysis bullosa (congenital and acquired), porphyria
cutanea tarda, bullous amyloidosis, bullosa diabeticorum, and autolysis.
Pemphigoid gestationis
Pruritus is a very common symptom in pregnancy, occurring in up to 18% of
gravid females.1–4 When it occurs in the absence of significant cutaneous stig-
mata it is known as pruritus gravidarum. This may occasionally be associated
with a cholestatic pathogenesis. The specific pregnancy eruptions have long
been a source of considerable confusion and controversy in the literature,
largely due to a diverse range of terminologies and classifications. Recently,
Holmes has attempted to clarify the situation with the introduction of a new
and much simplified classification and others have proposed similar schemes.2,5
Therefore the specific dermatoses of pregnancy may be divided into:
• polymorphic eruption of pregnancy, where the predominant lesions are
urticarial; in the United States, the term pruritic urticarial papules and
plaques of pregnancy (PUPPP) has achieved greater popularity;
• pregnancy prurigo in which the lesions consist of itchy papules;
• pemphigoid (herpes) gestationis, an autoimmune dermatosis belonging to
the bullous pemphigoid group of diseases.
Pemphigoid gestationis is a bullous dermatosis of pregnancy and the puer-
perium. It may be exacerbated by the use of oral contraceptives and rarely
complicates hydatidiform mole and gestational (but not nongestational) cho-
riocarcinoma. The current evidence implicates an autoimmune-mediated
pathogenesis in which hormonal influences play a significant role.6,7
Clinical features
The term herpes (gestationis) is neither appropriate nor satisfactory. It is not
of viral etiology, nor has it anything to do with creeping (Gr. herpes, to creep).
It was originally so named because of the tendency of the disease to show
‘progressive involvement by peripheral extension’.3 Because of its intimate
relationship to bullous pemphigoid, the designation pemphigoid gestationis is
preferred. As the major larger series have consisted of patients derived from a
variety of sources, estimates of incidence have been very variable, ­ranging
from 1:3000 to 1:50 000 pregnancies.4,8–10 The more recent figures where
cases have had immunofluorescent confirmation would suggest that the latter
figure is the most accurate.3
BSLE LAD DH
Linear IgG, C3 Linear IgA Granular IgA
IgG antibodies 60% IgA antibodies 30% Antitransglutaminase antibodies
Floor Roof or floor or both N/A
Roof Roof or floor N/A
Sub-LD LL, sub-LD or both Papillary dermis
290 kD BP180 kD Antigen uncertain
(type VII collagen) BP230 kD
200/280 kD
285 kD
250 kD
290 kD
128 Inherited and autoimmune subepidermal blistering diseases

Pemphigoid gestationis may present in the first or any subsequent preg-

nancy.3 It may first also rarely present in the postpartum period. In one series,
30% of patients were primigravidae.9 In addition to developing in pregnant
or postpartum patients, pemphigoid gestationis has rarely been described fol-
lowing a hydatidiform mole and gestational choriocarcinoma.11,12 It has not,
however, been reported in nongestational variants such as those occurring in
Fig. 4.86
the ovary, mediastinum, and testis, or complicating malignant teratoma. Pemphigoid gestationis:
Pemphigoid gestationis is predominantly a disease of white females, being the blisters are tense and
exceedingly rare in blacks.13,14 Presentation is usually in the second or third dome-shaped.
trimester, most often developing in the sixth or seventh month, but the range By courtesy of R.C.
is variable from 2 months to 4 days postpartum.10,15 Although the disease Holmes, MD, Warneford
may rarely completely remit before delivery, most patients (up to 75%) Hospital, Oxford, UK.
develop an exacerbation, which is frequently severe, in the immediate puerpe-
rium when progesterone levels have fallen.15,16 Exceptionally, the infant may
contain clear fluid, but at times the fluid may become hemorrhagic (Fig.
show transient urticated erythema and blistering.4
4.86). They typically heal without scarring.
Pemphigoid gestationis usually complicates subsequent pregnancies, fre-
The umbilicus is frequently the site of initial involvement; spread to the
quently presenting earlier on and with more severe symptomatology.10
trunk and extremities then follows (Figs 4.87, 4.88).3 Surprisingly, lesions on
Sometimes, however, it may skip intervening pregnancies.3 This may be
the face and mucous membranes are distinctly uncommon. Eventually palmar
related to a change in paternity, or else due to compatibility at the HLA-D
and plantar manifestations may appear. Other than pruritus, symptoms are
locus.
usually mild, with stinging, burning, and pain being relatively infrequent.10
Pemphigoid gestationis may develop into a very protracted ‘postpartum’
illness associated with considerable morbidity and lasting up to 12 years.17,18
In the majority of patients, however, the disease resolves by about 6 months
postpartum.4 The disease may first present following a change in sexual part-
ner.3,19 Alternatively, recurrent disease may persist even when there has been
a change of sexual partner.7 This obviously calls into question the role of spe-
cific paternal antigens.
Exacerbation following the use of the oral contraceptive is a common
complication,10,20–23 affecting 20–50% of patients.3 Estrogens in particular
have been implicated.22 The condition may also relapse during menstruation
for some weeks or months postpartum and the return of symptoms (pruritus)
has also been noted to coincide with ovulation (again suggesting an estrogen
influence), although this is rare.3,10,22
Evidence has been published relating the duration of symptoms postpar-
tum to the practice of breast-feeding. Bullous lesions lasted only 5 weeks in
those who breast-fed compared to 24 weeks in those who bottle-fed. Although
hormonal factors must be implicated, the precise pathogenetic implications
underlying this observation are not fully understood.22
Pemphigoid gestationis is associated with intense pruritus, which may be
present for days or weeks before the onset of typical cutaneous manifesta-
tions.1 The dermatosis is characteristically polymorphous, consisting of ery-
thematous or urticarial papules and plaques, some with a polycyclic ­pattern,
and later vesicles and bullae develop at the periphery of spreading erythema-
tous plaques (Fig. 4.85).3,10,24 When fully evolved, the blisters are tense and

Fig. 4.87
Fig. 4.85 Pemphigoid gestationis: slightly raised erythematous lesions with a propensity to
Pemphigoid gestationis: prebullous phase showing erythema and small papules. cluster on the abdomen. By courtesy of R.C. Holmes, MD, Warneford Hospital,
By courtesy of the Institute of Dermatology, London, UK. Oxford, UK.
 Pemphigoid gestationis 129

Fig. 4.88
Pemphigoid gestationis: umbilical involvement is a common mode of presentation.
By courtesy of the Institute of Dermatology, London, UK.
Fig. 4.89
Pemphigoid gestationis: early erythematous lesion showing marked edema of the
papillary dermis and conspicuous eosinophils.

Occasionally, the presence of target or iris lesions may mimic erythema mul-
tiforme.25 Less commonly, features may initially suggest classical bullous
pemphigoid.25 Very occasionally, there is clinical overlap with dermatitis
herpetiformis.
Pemphigoid gestationis is not associated with pre-eclamptic toxemia and
there is no related maternal mortality.
Pemphigoid gestationis is accompanied by a significant increased risk of
developing Graves' disease and an increased risk of autoantibodies.26
The literature concerning the incidence and nature of fetal morbidity and
mortality is a source of some confusion. Kolodney therefore considered that
there was no evidence of an increased incidence of stillbirths or abortions;
however, his report predates the immunofluorescence era.5 An investigation
by Lawley et al.20 of a large series of cases where immunofluorescent confir-
mation was available, suggested that there was an increased risk of fetal mor-
bidity and mortality. More recently, evidence has been presented that patients
with pemphigoid gestationis are liable to deliver low weight and small-for-
dates infants, prematurely.27 In contrast, however, Shornick et al. failed to
show any evidence of significant fetal complications.7 It has been shown that Fig. 4.90
the onset of the disease in the first and second trimester and the presence of Pemphigoid gestationis: early erythematous lesion showing eosinophilic
blisters is associated with higher morbidity including premature birth and spongiosis.
low birth weight children.28 Morbidity, however, still remains low. The anti-
body can cross the placenta and, in approximately 5% of cases, this may be
associated with a mild and transient vesiculobullous eruption.29–32

Pathogenesis and histological features

The histopathologic features seen in biopsies from patients with pemphigoid
gestationis are variable, depending upon whether early erythematous lesions,
urticarial papular lesions, or fully established vesicles and bullae are
studied.33
In early lesions, the major pathological features are seen in the superficial
dermis where there is a perivascular inflammatory cell infiltrate consisting of
lymphocytes, histiocytes, and typically very large numbers of eosinophils.
This is associated with edema of the papillary dermis, which when marked
may result in a ‘teardrop’ appearance (Fig. 4.89).33 Sometimes there is accom-
panying spongiosis and this may be associated with large numbers of eosino-
phils (eosinophilic spongiosis, Fig. 4.90). Occasionally the infiltrate of
lymphocytes, histiocytes, and eosinophils is present in a linear distribution
along the dermoepidermal junction.3
Vacuolar degeneration of the basal keratinocytes, sometimes accompa-
nied by individual cell necrosis, may be a feature of the early lesions, but is
often more evident in the fully established vesicular or bullous stage.33 In the
latter, the blister is subepidermal in location and frequently contains large Fig. 4.91
numbers of eosinophils (Figs 4.91, 4.92).33 The underlying and adjacent Pemphigoid gestationis: established subepidermal blister.
130 Inherited and autoimmune subepidermal blistering diseases
Fig. 4.92
Pemphigoid gestationis: the blister cavity contains a heavy eosinophil infiltrate.
dermis is edematous and contains a predominantly perivascular lympho/his-
tiocytic infiltrate with large numbers of eosinophils. Leukocytoclasis and
eosinophil dermal papillary microabscesses are only rarely identified.33,34
Ultrastructural studies show that the cleavage plane lies within the lamina
lucida.33,35
Direct immunofluorescence of perilesional skin in pemphigoid gestationis
shows a linear basement membrane zone deposition of C3 in all patients.3,36–41
About 30–50% of cases also have an IgG band (less frequently IgM or IgA).36
They are present in nonlesional (perilesional) as well as in lesional skin.36
Recently, it has been suggested that demonstration of linear C3d deposition
at the dermoepidermal junction may be a useful tool in the diagnosis of the
disease.42 The authors of this study used immunohistochemistry in paraffin-
embedded, formalin-fixed material with good results. Complement pathway
components including properdin and properdin factor-B may also be identi-
fied.1 IgG and complement can often be detected along the amniotic basement
membrane region using direct immunofluorescence.38,43,44 Pemphigoid gesta-
tionis antigen has been detected in the placenta from early in the second
­trimester onwards.45 The antibody may also be found in the skin of infants of
affected mothers.29 Interestingly, serologic evidence of pemphigoid gestationis
without manifestation of the disease may be seen, An exceptional case of neo-
natal pemphigus in a child whose mother had clinical and serologic evidence
of pemphigus vulgaris but only serologic evidence of pemphigoid gestationis
has been described.46
Circulating complement-fixing (via the classical pathway) IgG antibodies
(pemphigoid (herpes) gestationis (HG) factor) can be detected in 50–75% of
cases by indirect complement immunofluorescence (Fig. 4.93).20,36,47–51 The so-
called HG factor is nothing more than a low titer IgG complement-fixing
antibasement membrane antibody.36 The antibody can be of any IgG subclass;
IgG1 and IgG4 have been reported as predominent.38,51 If monoclonal antibod-
ies directed against IgG are used, 100% of patients can be shown to possess
circulating HG factor.38 Approximately 25% of patients have ­antibasement
membrane zone antibodies detectable by conventional ­techniques.51 These bind
to the roof of 1 M NaCl-split skin.36 The antibody also reacts with amnion and
chorion basement membrane.42,44 The autoantibodies in the disease are directed
against collagen XVII which is the BP ­180-kD protein (BPAG2). The latter
plays a major role in cell adhesion and signaling. It has been demonstrated that
collagen XVII is present in the epithelial cells of the amniotic membrane and in
syncitial and cytotrophoblastic cells.52 Although the exact pathogenetic mecha-
nism of the disease is still unknown (see below), the presence of collagen XVII
in these tissues seems to play a major role in the mechanism of the disease.
With immunoelectron microscopy the immunoreactants are deposited
within the upper lamina lucida where they are most probably associated with
the sub-basal dense plate.53,54 In pemphigoid gestationis the antibody recog-
nizes BPAG2 (collagen type XVII) on Western ­immunoblot and localizes to the
Fig. 4.93
Pemphigoid gestationis: indirect complement immunofluorescence showing linear
deposition of IgG.
same NC16A domain as described in bullous pemphigoid.55–62
This can be detected in serum using the same test employed for bullous
­pemphigoid.60–62 Antibodies that recognize the 230-kD bullous ­pemphigoid
antigen are present in 10–26% of cases.56,57 Experimental models indicate that
antibodies against the NC16A domain of BP180 are the ­pathogenic antibodies
in pemphigus gestationis just as they are for bullous pemphigoid 7,62
Patients with pemphigoid gestationis have an increased incidence of HLA-
B8 (43–79%), HLA-DR3 (61–80%) and HLA-DR4 (52–53%). The paired
haplotypes HLA-DR3 and -DR4 are present in 54% of patients compared
with 3% in the general population.1,3,22,63,64 The phenotype, however, does not
appear to correlate with the clinical features of pemphigoid gestationis.3,65
Patients with pemphigoid gestationis also have a high incidence (100%) of
anti-HLA cytotoxic antibodies, particularly directed against the paternal
­antigens.36,63–66 These are, however, found in 25% of normal multiparous
women and therefore their possible role in the pathogenesis of pemphigoid
gestationis is uncertain.26
The pathogenesis of pemphigoid gestationis relates to antibody-associated
complement fixation with the production of leukocyte chemotactic factors,
mast cell degranulation, and associated dermoepidermal separation.36
The presence of pemphigoid gestationis antigen in both skin and amnion
raises the possibility that an initial antiplacental antibody cross-reacts with
skin, giving rise to the clinical features of pemphigoid gestationis.29 Support
for this theory has been the discovery that the HLA antigens -DP and -DR are
consistently expressed in the placentas of patients with this condition.64,67 The
main antigen present in both the skin and placenta seems to be collagen type
XVII and this, associated with genetic predisposition and specific HLA
­genotype, appears to trigger the disease.68
Differential diagnosis
The differential diagnosis includes epidermolysis bullosa acquisita, dermatitis
herpetiformis, linear IgA disease, and bullous systemic lupus erythematosus (see
Table 4.4). Pemphigoid gestationis must also be distinguished from pruritic urti-
carial papules and plaques of pregnancy (PUPPP) and pregnancy prurigo.
PUPPP is predominantly a disorder of first pregnancies. Lesions particu-
larly develop around abdominal striae, and periumbilical sparing is a charac-
teristic feature (Fig. 4.94). Eosinophilic spongiosis and subepidermal
blistering may be seen in established lesions and therefore, in the absence of
clinical details and immunofluorescence findings, distinction from pemphig-
oid gestationis may be impossible.
Pregnancy prurigo, which typically develops in the third trimester, ­presents
with pruritic papules and nodules (Fig. 4.95). Blisters are not a feature.
Histologically, the changes are those of a low-grade, non-specific spongiotic
dermatitis.

Fig. 4.94
Pruritic papules and plaques of pregnancy: note the erythematous papules
particularly related to the abdominal striae, and characteristic umbilical sparing.
By courtesy of R.C. Holmes, MD, Warneford Hospital, Oxford, UK.
Fig. 4.95
Pregnancy prurigo: there are erythematous papules and excoriations. Blisters are
not a feature of this condition. By courtesy of R.A. Marsden, MD, St George's
Hospital, London, UK.
Lichen planus pemphigoides
Clinical features
Lichen planus (lichen ruber) pemphigoides (Kaposi) must be distinguished
from the vesicles occasionally seen in lichen planus as a consequence of severe
hydropic degeneration (lichen planus vesiculosis).1,2 Rarely, lichen planus is
associated with a generally benign, bullous pemphigoid-like disease: lichen
planus pemphigoides. This represents a heterogeneous condition characterized
by basement membrane antibodies directed towards a number of antigens.
Clinically, the pemphigoid-like lesions are usually preceded by typical
lichen planus although rarely the blisters may develop first (Fig. 4.96). The
bullae, which are most numerous on the extremities, may arise on normal
skin, in areas of erythema or on lichenoid papules (Figs 4.97 and 4.98).
In some patients the blisters are generalized. Exceptionally, the blisters are
localized with typical lichen planus-like lesions elsewhere. A case with single
blisters on the soles has been described.3 They are tense, dome-shaped and
hemorrhagic or contain clear fluid. Evolution to pemphigoid nodularis-like
lesions has been described.4 Lichen planus pemphigoides more commonly
affects males and presents most often in the fourth and fifth decades.5,6
Exceptionally, however, cases have been documented in childhood.7–9 All
races may be affected.
Lichen planus pemphigoides 131
Fig. 4.96
Lichen planus pemphigoides: typical lichenoid papules are present on the anterior
aspect of the wrist. By courtesy of M.M. Black, MD, Institute of Dermatology,
London, UK.
Fig. 4.97
Lichen planus pemphigoides: note the blisters and erosions arising on an erythematous
base. Atypical target lesions are present. By courtesy of M.M. Black, MD, Institute of
Dermatology, London, UK.
Pathogenesis and histological features
The lichenoid lesions show the typical histopathological and immunofluores-
cent changes of lichen planus, but the bullae have features more suggestive of
bullous pemphigoid (Fig. 4.99). A variety of findings have been described.
Early erythematous lesions show intense dermal edema with a dense
­perivascular and interstitial eosinophil infiltrate; eosinophilic spongiosis may
also sometimes be evident. Established blisters are subepidermal and both
inflammatory (cell-rich) and cell-poor variants have been documented (Figs
4.100, 4.101).5 Eosinophils are variably present but often may be numerous.
Immunofluorescent examination of biopsies from peribullous skin reveals
linear deposition of IgG and complement.10–13 The serum contains an IgG
antibasement membrane antibody in up to 50–60% of patients. With NaCl-split
skin, the antibody generally labels the roof of the blister cavity. Ultrastructural
investigations have shown that the level of separation is ­usually through the
lamina lucida. By immunoelectron microscopy, the immunoreactants ­typically
localize to the hemidesmosome and lamina lucida.5,13,14 Mucous membrane
pemphigoid and epidermolysis bullosa acquisita ­(EBA)-like variants have,
however, also been documented.15
132 Inherited and autoimmune subepidermal blistering diseases

Fig. 4.98
Lichen planus pemphigoides: note the intact dome-shaped tense blister. By courtesy
of M.M. Black, MD, Institute of Dermatology, London, UK.

Fig. 4.100
Lichen planus
pemphigoides: there is a
subepidermal blister.

Fig. 4.99
Lichen planus
pemphigoides: the
lichenoid papules show
typical features of lichen
planus.

A number of antigens have been recognized in lichen planus pemphigoides
including BP180, BP230, and an as yet uncharacterized 200-kD protein of
keratinocyte derivation.1,15–23 The segment of the NC16A domain recognized
in lichen planus pemphigoides differs from BP, localizing to MCW-4 (the
more C-terminal end of the domain) as opposed to MCW-0 to MCW-3.24,25
Type VII collagen has also been implicated in the EBA-like variant although
the immunoblot was negative.15
Although the pathogenesis of lichen planus pemphigoides has not been
fully unraveled, it is likely that the basement membrane zone damage associ-
ated with lichen planus results in antigen exposure with subsequent autoanti-
body production and resultant bullous disease. So far, it is uncertain why only
a small percentage of patients with lichen planus are affected. The pathogen-
esis in those patients in whom the blisters develop first is unknown although a
different antigen may be involved. Exceptionally, cases have been documented
as an adverse drug reaction (e.g., to angiotensin-converting enzyme inhibitors,
complicating PUVA therapy, or in a patient taking paracetamol, ibuprofen,
and having narrowband UVB).26–35 There has been a suggestion that lichen
Fig. 4.101
Lichen planus
pemphigoides: the blister
contains eosinophils.
planus pemphigoides might be associated with internal malignancy but the
diagnosis lacked substantiation by immunofluorescence studies.36 Two addi-
tional cases involving a patient with multiple keratoacanthomas and colonic
adenocarcinoma indicating a Torre-Muir-like syndrome and association with
retroperitoneal Castleman disease have been noted more recently.37,38
Differential diagnosis
Lichen planus pemphigoides differs from typical bullous pemphigoid clini-
cally by its earlier age of presentation and predilection for the lower limbs. In
those cases associated with antibodies to BP180, epitope mapping may make
the distinction.
 Mucous membrane pemphigoid (cicatricial pemphigoid) 133

Mucous membrane pemphigoid (cicatricial

pemphigoid)
Mucous membrane pemphigoid represents a spectrum of diseases (e.g., ocular
pemphigoid, oral pemphigoid, benign mucous membrane pemphigoid) which
affect the mucosa and skin.1–4 With the advent of molecular studies identifying
the antigens involved, it is becoming clear that there are a number of ­relatively
well-defined clinicopathological variants that arise as a consequence of auto-
immune diseases directed against a number of different basement ­membrane
antigens. Although multiple systems are often affected, there is increasing
­evidence that pure ocular and oral variants may also be encountered.1,2

Clinical features
Mucous membrane pemphigoid is a rare blistering disorder in which mucosal
lesions predominate and in which scarring is a characteristic feature (although
not generally in the oral lesions).1,2,5 It is often associated with severe morbid-
ity, largely due to the effects of the scarring. As ocular and oral lesions pre-
dominate, many patients come to the attention primarily of the dental and
oral surgeons or ophthalmologists rather than dermatologists.
The incidence is estimated as being between 1:12 000 and 1:20 000 of the
population per year.2 It is associated with a female preponderance (2:1) and it
not uncommonly presents in the seventh decade. Very rare instances of child-
hood involvement have been reported.3,6–10 Mucous membrane pemphigoid is
a chronic disease and is rarely self-limiting. It shows no racial or geographic
predilection.
Oral lesions occur in 85–95% of patients and commonly follow mild
trauma.11 Bullae, erosions, and erythema most commonly affect the gingival
or buccal mucosa, but the hard and soft palate, tongue, and lips are also fre-
quently involved (Figs 4.102, 4.103). Desquamative gingivitis is the most
common manifestation.12,13 Patients with this condition present with painful,
swollen, erythematous lesions of the gums, which may be associated with
bleeding, blistering, erosions, and ulceration.14 Most cases of desquamative
gingivitis have lichen planus and only in a low percentage, around 9%, is the
process a manifestation of mucous membrane pemphigoid.15 Lesions limited
to the oral cavity is a distinctive subset, usually associated with a good
­prognosis although characterized by chronicity.1 Pharyngeal (19% of patients)
and esophageal (4% of patients) lesions may be complicated by scarring,
resulting in stenoses. Aspiration pneumonia is sometimes a fatal complica-
tion. Nasal lesions, which may occur in up to 15% of patients, lead to obstruc-
tion and occasionally cicatricial stenoses and septal ­perforation.16 Laryngeal
involvement, which occurs in 8% of patients, is sometimes ­complicated by
such severe stricture formation and edema that tracheotomy may be a life-
saving necessity.14
Fig. 4.103
Mucous membrane pemphigoid: in addition to erosions, intact blisters are evident.
By courtesy of P. Morgan, FRCPath, London, UK.
Ocular lesions, which occur in approximately 64% of patients, are a
source of considerable morbidity.17–19 The eye (in particular the conjunctiva)
may be a sole site of involvement.14 Early symptoms are those of a non-spe-
cific ­conjunctivitis. In more advanced lesions, subconjunctival fibrosis
­develops.20,21 Patients may therefore present with fibrous bands (sym-
blephara) stretching between the fornices and the globe (Fig. 4.104).
Eventually, ­contractures may obliterate the conjunctival sac. An essential
feature of ocular cicatricial ­pemphigoid is the production of an abnormal
tear film. This develops because of diminished lacrimal gland secretion (due
to ductal stenosis), impaired ­goblet cell mucus secretion and ocular exposure
due to impaired eye ­closure.20 The end result is ocular drying and eventual
keratinization of the ocular surface epithelium. Other important sequelae
include entropion, trichiasis (maldirected eyelashes, which can result in cor-
neal abrasion), ­erosions and perforation, corneal neovascularization and
scarring with opacification (Figs 4.105, 4.106). Primary corneal bullae have
been described but are very rare, and erosions are more typical.11 Corneal
lesions manifest as ­foreign body ­sensation, photophobia, and eventual
­blindness, which may be bilateral, occurring in up to 16% of patients.9
Ocular involvement may be classified into a number of stages of ­progression
(modified Foster staging system).22

Fig. 4.104
Fig. 4.102 Mucous membrane pemphigoid: there is a dense fibrous adhesion (symblepharon)
Mucous membrane pemphigoid: there is erosion of the buccal mucosa. By courtesy between the conjunctiva lining the eyelid and that covering the globe. By courtesy
of P. Morgan, FRCPath, London, UK. of the Institute of Dermatology, St Thomas' Hospital, London, UK.
134 Inherited and autoimmune subepidermal blistering diseases

Fig. 4.105 Fig. 4.107

Mucous membrane pemphigoid: in this advanced case there is entropion and Mucous membrane
trichiasis (inwardly directed eyelashes). By courtesy of D. Kerr-Muir, MD, pemphigoid: in addition to
St Thomas' Hospital, London, UK. erosions, marked scarring
of the vulva is present. By
courtesy of R.A. Marsden,
MD, St George's Hospital,
London, UK.

Fig. 4.106
Mucous membrane pemphigoid: here there is dense corneal scarring with complete
opacification. By courtesy of D. Kerr-Muir, MD, St Thomas' Hospital, London, UK.
Ocular involvement should not be confused with drug-induced pemphig-
oid (pseudo-ocular mucous membrane pemphigoid).2 This is a self-limiting
unilateral scarring disease of the eye, which most commonly develops as a
consequence of long-term use of eyedrops containing pilocarpine, echothio-
phate iodide, idoxuridine, timolol, and adrenaline (epinephrine) in the treat-
ment of glaucoma.23,24
Lesions of the female genitalia, which occur in 20% of patients, predomi-
nantly affect the labia majora and minora.14 Scarring is common and may
occasionally be associated with labial fusion (Fig. 4.107). In males, genital
lesions most often affect the prepuce and the glans penis and are occasionally
complicated by urethral stricture formation. Anal lesions affect up to 4% of
patients and sometimes cause stenosis.14
Cutaneous lesions are found in approximately 25–33% of patients with
mucous membrane pemphigoid and most often affect the scalp, face, and
neck.2,14,15 In some patients, presentation is similar to that of bullous pemphi-
goid, and fibrosis is not a feature.2 Lesions are generally few in number and
present as itchy, sometimes burning, tense bullae situated on an erythematous
or urticated base (Fig. 4.108). They tend to recur on previously affected sites.
Rarely, patients may suffer from a transient generalized bullous eruption.14
Nikolsky's sign is negative.21
Fig. 4.108
Mucous membrane
pemphigoid: note the
localized blistering and
erosion with scarring on
the lower leg of an elderly
female. By courtesy
of R.A. Marsden, MD,
St George's Hospital,
London, UK.
In the Brunsting-Perry variant of localized mucous membrane pemphig-
oid, scarring lesions are found predominantly on the head and neck
(Fig. 4.109).25,26 This condition shows a male predominance (2:1) and pres-
ents most often in the sixth decade. The lesions are slowly enlarging, ­atrophic
or scarred plaques measuring several centimeters or more in diameter and
­showing vesiculation and/or bullae formation, both centrally and at the
enlarging margin.27 The anterior portion of the scalp, the face ­(forehead,
­temporal regions, and cheeks), and the anterolateral aspects of the neck are
most often affected.27 In some patients, lesions are few in ­number and,
because of crusting, they may be clinically treated as actinic keratosis,
thereby ­delaying the diagnosis. Transient mucous membrane lesions may be
a feature, but ­scarring is not seen.25
 Mucous membrane pemphigoid (cicatricial pemphigoid) 135

Fig. 4.109
Brunsting–Perry localized pemphigoid: there is extensive alopecia in addition to
multiple erosions with scarring. By courtesy of R.A. Marsden, MD, St George's
Hospital, London, UK.
Fig. 4.110
Mucous membrane pemphigoid: in this example of a recurrent lesion, the
subepidermal blister is cell free and there is dermal scarring.

An exceptional case of anti-BP180 mucous membrane pemphigoid

­ resenting with concomitant pemphigus vulgaris limited to mucosal surfaces
p
has been described.28
Autoimmune blistering diseases are very rarely associated with HIV infec-
tion and only a single exceptional case of mucous membrane pemphigoid has
been reported in association with HIV.29

Pathogenesis and histological features

Mucous membrane pemphigoid has been described as a complication of
D-penicillamine therapy for rheumatoid arthritis, practolol and clonidine.14,30
Immunologically, characteristic cicatricial pemphigoid has also been described
following acute, severe, ocular inflammation in patients with Stevens-Johnson
syndrome.31 Although the results of HLA associations have been variable, an
increased frequency of HLA-DR4 and -DQw3 (DQB1*0301) correlates with
a heightened risk of developing ocular disease.32
The cutaneous lesions of mucous membrane pemphigoid are often indis-
tinguishable from those of cell-rich (inflammatory) bullous pemphigoid, com-
prising a subepidermal vesicle containing fibrin, edema fluid, and variable
numbers of inflammatory cells. Although eosinophils are usually evident, Fig. 4.111
they tend to be much less numerous than in generalized bullous pemphigoid. Mucous membrane
The dermis contains a perivascular lymphohistiocytic infiltrate, sometimes pemphigoid: high-power
with conspicuous plasma cells and accompanied by neutrophils and eosino- view of a similar lesion
phils. In older or recurrent lesions, scarring may be a feature (Fig. 4.110).
Less commonly, a cell-poor subepidermal blister is seen (Fig. 4.111). In late
lesions all that may be observed is a band of scarring in the superficial dermis
with or without a subepidermal split. If the latter is present, this is a good clue
to the diagnosis, especially in localized variants where the diagnosis is not
suspected on clinical grounds.
The histopathology of lesions in antilaminin 332 mucous membrane pemphi-
goid has been studied in a small number of cases.33 The features are nondiagnos-
tic and do not allow distinction from other autoimmune blistering diseases. There
is subepidermal blistering and a mild to moderate, superficial mixed inflamma-
tory cell infiltrate composed of lymphocytes, histiocytes, and neutrophils and/or
eosinophils. Scarring is not often seen as biopsies are taken from early lesions.
Oral lesions may rarely be characterized by vesiculation developing
between the stratified squamous epithelium (mucosa) and lamina propria
(Figs 4.112, 4.113). The latter is usually edematous and contains a mixed
inflammatory cell infiltrate consisting of lymphocytes, histiocytes, plasma
cells, and varying numbers of eosinophils and neutrophils (Fig. 4.114). More
commonly, however, the features seen are those of erosions or ulcers lined by
granulation tissue or fibrous tissue and showing non-specific acute or chronic
inflammation. The histology is frequently modified by intense acute inflam- Fig. 4.112
matory changes due to secondary infection. Mucous membrane pemphigoid: oral lesion showing an intact subepithelial blister.
136 Inherited and autoimmune subepidermal blistering diseases

Fig. 4.113 Fig. 4.115

Mucous membrane pemphigoid: note the preservation of the papillae. Mucous membrane pemphigoid: this specimen of conjunctiva shows complete
squamous metaplasia. Neovascularization of the lamina propria is evident. By
courtesy of A. Garner, MD, Institute of Ophthalmology, London, UK.

Fig. 4.114
Mucous membrane pemphigoid: in this example the infiltrate consists of Fig. 4.116
lymphocytes and histiocytes. Eosinophils are not a feature. Mucous membrane pemphigoid: section of cornea. The overlying pannus shows squamous
metaplasia, chronic inflammation, and neovascularization. Blood vessels are also present in
the cornea. By courtesy of A. Garner, MD, Institute of Ophthalmology, London, UK.
Conjunctival vesicles or bullae are very rarely seen in ocular cicatricial
pemphigoid. Although erosions may be a feature, more commonly one may
anticipate conjunctival squamous metaplasia with foci of hyperkeratosis and
parakeratosis accompanied by goblet cell depletion (Fig. 4.115).14 The lam-
ina propria is infiltrated by a mixed inflammatory cell population consisting
of lymphocytes, plasma cells, mast cells, and occasional eosinophils and neu-
trophils.21 Granulation tissue may be seen in early lesions, but dense scarring
is a feature of the later stage. In more severely affected patients, a variety of
intraocular manifestations, including iridocyclitis, rubiosis iridis, and the
development of synechiae, may be seen (Figs 4.116–4.118).
Laryngeal, pharyngeal and esophageal lesions occasionally show subepithe-
lial bullae, erosions, ulcers, inflammatory changes, and fibrosis are more likely
to be seen (Fig. 4.119). Chronic involvement may result in serious stenosis.
The histological features of the localized cutaneous scarring (Brunsting-
Perry) variant are indistinguishable from those of mucous membrane
pemphigoid.27
Electron microscopic observations are variable. In some patients, the split is in
the lamina lucida with the lamina densa lining the floor of the blister cavity
whereas in others, lamina densa is found along the roof of the blister, and occa-
sionally the lamina densa may be split, lining the roof and the floor.2,34 Fig. 4.117
Direct immunofluorescent findings in cicatricial pemphigoid are similar to Mucous membrane pemphigoid: this section shows iris impaction with anterior
those found in generalized bullous pemphigoid. Therefore a linear deposit of synechiae. Iritis and posterior synechiae are also present. By courtesy of A. Garner,
IgG (and sometimes IgA) and C3 is found at the basement membrane region MD, Institute of Ophthalmology, London, UK.

Fig. 4.118
Mucous membrane pemphigoid: this field shows anterior uveitis. There is
inflammation of the iris and ciliary body. By courtesy of A. Garner, MD, Institute of
Ophthalmology, London, UK.
Fig. 4.119
Mucous membrane
pemphigoid: postmortem
specimen showing
laryngeal erosion,
ulceration, and scarring.
of perilesional mucosa (the site of choice) or perilesional skin in approxi-
mately 80–97% of patients.35–39 The presence of IgA at the basement mem-
brane region accompanied by IgG and C3 is a diagnostic pointer towards
cicatricial pemphigoid.2 Examination of the oral mucosa is also of value in
the diagnosis of ocular disease.2 Direct immunoperoxidase of paraffin-embed-
ded tissue can be a satisfactory alternative if a specimen has not been taken
for direct immunofluorescence studies.40
Circulating antibasement membrane zone autoantibodies (IgG and/or IgA)
are sometimes present (26–36%) and are usually of low titer.36,41,42 Substitution
of normal buccal mucosa as substrate does not increase the yield of circulat-
ing antibodies.41 The antibody consists predominantly of IgG4 and IgG1
­subclasses, the presence of the latter conferring complement-­fixing ­ability.43
The presence of IgA may be linked to the mucosal membrane ­distribution of
this disease.44
Investigations of cicatricial pemphigoid antibodies using 1 M NaCl-split
skin have yielded variable results.45–47 Circulating antibodies may be detected
Epidermolysis bullosa acquisita (dermolytic pemphigoid) 137
in from 50% to 100% of cases with active disease.48,49 Although the majority
of sera have reacted with the epidermal side of the split, some have labeled the
floor (dermal side, subsequently shown to be due to antilaminin 332 antibod-
ies: see below), and exceptionally both the roof and the floor have been
labeled.45–49 There is also variation in indirect immunofluorescence findings
depending upon the predominant site of involvement. Thus, for example,
split skin indirect immunofluorescence may be positive in up to 81% of
patients with combined skin and mucosal disease whereas much lower figures
have been found in patients with mucosal disease only (18%) or isolated ocu-
lar disease (7%).2,50
The immunofluorescent findings in the Brunsting-Perry variant are the
same as those described for mucous membrane pemphigoid.51–54
Immunoelectron microscopic observations in mucous membrane pemphi-
goid have revealed two patterns of immune reactant deposition. IgG and C3
may be localized to the lower lamina lucida and lamina densa or else ­identified
overlying the hemidesmosome.55–61 There is no involvement of the sublamina
densa region. The variation can be explained by the different ­target antigens
involved, i.e., BP180, laminin 332 or β4 integrin.
In the Brunsting-Perry variant of localized chronic pemphigoid the immu-
noreactants are localized within the lamina lucida and on the undersurface of
basal keratinocytes.62 In a single case it was demonstrated that the ­antibodies
in the serum reacted with the C-terminal domain of the BP180 (BPAG2) pro-
tein.63 Additionally, however, the complement components C3 and C4 may
also be detected within the lamina densa and the upper papillary dermis. It is
­suggested that this latter finding might account for the scarring characteristic
of this disease process.62
A number of subsets of cicatricial pemphigoid have been delineated by
antigen analysis including variants characterized by antibodies to BP180,
laminin-332, and β4 integrin.43,47,57,64–74 Traditionally, this group of diseases
has been classified together, but the increasing demonstration of autoimmune
reactions to different cell adhesion molecules will likely ultimately lead to
subtyping of this disease similar to the cutaneous forms. For now, since the
clinical features are more uniform than those seen in the skin, these mucosal
cases are considered together. BP180 (collagen XVII) antibodies react with at
least two different sites on the extracellular domain of BP180. One is located
on the noncollagenous domain NC16A; the other is located within the
carboxy-terminal region.68,75–78 Antilaminin-332 (also called epiligrin) antibodies
to the γ3 subunit (sometimes accompanied by antilaminin type-6 antibodies)
are present in a minority of cases and, although the antibodies are usually
IgG, IgA, and IgE, antibodies against laminin-332 may also be found in a sub-
set of patients.79 Patients with antilaminin-332 antibodies have been classified
as having antiepiligrin mucous membrane pemphigoid (AEMMP). Some of
such cases are associated with internal malignancies (including lung, colon,
endometrium, stomach, ovary, pancreas, prostate, non-Hodgkin's lymphoma,
cutaneous T-cell lymphoma, and acute myeloblastic leukemia).80–84 Integrin
has been implicated in patients with ocular disease and an as yet unidentified
45-kD antigen, which binds to the epidermal side on split skin immunofluo-
rescence, has been identified in some patients with IgA antibodies.70,72,73
Autoantibodies to type VII collagen is of importance in some cases of
Brunsting-Perry cicatricial pemphigoid (these patients might be better classi-
fied within the epidermolysis bullosa acquisita spectrum, see below).85
Differential diagnosis
Apart from the presence of scarring in older lesions, mucous membrane pem-
phigoid is indistinguishable from bullous pemphigoid.
Epidermolysis bullosa acquisita (dermolytic
pemphigoid)
Epidermolysis bullosa acquisita (dermolytic pemphigoid) is a rare, chronic
blistering disease, which is characterized by variable clinical presentations
and which may therefore be mistaken for a number of other blistering disor-
ders including congenital epidermolysis bullosa and the other acquired auto-
immune bullous dermatoses.1,2 Annual incidence figures from France and
Central Germany are 0.17–0.26 per million of the population.3,4 In contrast
to its congenital counterpart, epidermolysis bullosa acquisita (EBA) usually
138 Inherited and autoimmune subepidermal blistering diseases

develops in adult life although cases in childhood have been documented.5,6 e­ pidermolysis bullosa. Scarring may then be extreme with resultant contrac-
Initially it was characterized as a porphyria cutanea tarda-like mecha- tures and syndactilism. Rarely, esophageal involvement has been documented
nobullous dermatosis. More recently, however, patients have been described with resultant stricture formation.10,13,14
in whom the disease has presented as a generalized inflammatory bullous der-
matosis.1 For many decades the diagnosis of EBA was one of exclusion. As a Bullous pemphigoid-like EBA
result of immunofluorescence and immunoultrastructural techniques This is the most commonly encountered inflammatory variant.15 On the basis
­combined with immunoblotting and immunoprecipitation, EBA is now of split skin indirect immunofluorescence (see below) it has been suggested
­recognized as an autoimmune dermatosis, type VII collagen (290 kD) repre- that a BP presentation may account for up to 50% of cases of EBA and that
senting the target antigen.1,8 A 145-kD antigen is also sometimes identified. 10–15% of patients diagnosed as BP, in fact, have EBA.15 Other authors,
This represents a cleavage product of the 290-kD antigen. however, have found that EBA is very rare compared to BP, the relative inci-
dence being approximately 25–50 cases of BP for every one case of EBA
Clinical features diagnosed.16,17
EBA was defined in 1971 by Roenigk and colleagues5 as follows: Patients present with a generalized eruption of large tense blisters, which
are often associated with erythema and show a predilection for the flexural
• clinical lesions resembling dystrophic epidermolysis bullosa (blisters
developing on the hands, feet, elbows, and knees following mild trauma and intertrigenous areas.18,19 Pruritus is common.15 Skin fragility is typically
and complicated by atrophic scarring, milia formation and nail dystrophy), absent and scarring and/or milia are not usually features unless the patient
concomitantly shows or evolves towards a mechanobullous phase.1,15
• an adult onset,
Infrequently, the clinical manifestations may resemble dermatitis herpetiformis
• a negative family history of epidermolysis bullosa,
(Fig. 4.122). Exceptionally, prurigo nodularis-like lesions may be seen.20
• exclusion of all other recognized bullous dermatoses including porphyria
cutanea tarda, bullous pemphigoid, dermatitis herpetiformis, pemphigus,
erythema multiforme, and bullous drug reactions.9
It has a wide age incidence ranging from 11 to 77 years, with a mean age
of 47 years. It is associated with a slight female predominance.
In addition to the mechanobullous classical form of EBA, inflammatory
variants, including bullous pemphigoid-like, mucous membrane pemphigoid-
like, and linear IgA disease-like variants, may also be encountered.1,10,11
A case of familial EBA has been described.12

Classical variant
The classical variant is the most commonly encountered variant of EBA.
Patients present with a porphyria cutanea tarda-like illness showing extreme
skin fragility, developing erosions, blistering and crusting in response to mild
trauma including shearing forces.5 Lesions are located on the backs of the fin-
gers and hands in particular and at other sites that are susceptible to trauma,
including the knees, elbows, and buttocks, but virtually any site may be
affected (Fig. 4.120).1,5 The blisters are characteristically noninflammatory,
painless, and tense, and may contain clear or bloodstained fluid.
Healing is usually associated with postinflammatory hyperpigmentation,
considerable scarring, and atrophy. Milia are frequently conspicuous, and
nail changes, including distal onycholysis, dystrophy, and anonychia with Fig. 4.121
nail bed scarring, are common complications (Fig. 4.121). More widespread Epidermolysis bullosa acquisita: conspicuous milia are present on the back of the
involvement may resemble dominant or more often recessive dystrophic hand. By courtesy of the Institute of Dermatology, London, UK.

Fig. 4.122
Fig. 4.120 Epidermolysis bullosa acquisita: in this patient with the dermatitis herpetiformis-like
Epidermolysis bullosa acquisita: there is a tense fluid-filled blister on the ankle. An inflammatory variant, blisters, erosions, and erythematous plaques are evident on
old lesion is also evident. By courtesy of the Institute of Dermatology, London, UK. the elbow. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
 Epidermolysis bullosa acquisita (dermolytic pemphigoid) 139

Mucous membrane pemphigoid-like variant

Some patients present with a mucous membrane pemphigoid-like variant,
characterized by mucous membrane involvement. The oral cavity is commonly
affected. Erosions, ulcers, and blisters may be seen on the tongue, gums, ­palate,
and buccal mucosa.11 Rarely, the larynx and esophagus are affected with
­resultant stricture formation.10 The anus, vulva, vagina, and bladder can very
occasionally be involved.21 Conjunctival lesions are an important, but infre-
quent, cause of morbidity.10,11,22 Symblepharon, epiphora, and even blindness
may occur. Alopecia is sometimes an additional feature.7,13

Brunsting-Perry variant
Some patients with the Brunsting-Perry variant of mucous membrane pem-
phigoid (characterized by blistering and scarring confined to the head and
neck) have antibodies against type VII collagen and therefore might better be
classified within the epidermolysis bullosa acquisita spectrum.7,23,24 Facial
involvement predominates.24,25 A very unusual localized case with periorbital Fig. 4.123
papulovesicular blisters has been reported.26 Epidermolysis bullosa acquisita (classical variant): there is a cell-free subepidermal
vesicle. Note the dermal scarring.
Linear IgA disease-like variant (IgA-EBA)
Epidermolysis bullosa acquisita may also present as a linear IgA disease-like
variant in which both adult and childhood patients have IgA autoantibodies
directed against type VII collagen (see below).27–29 In adults, ocular involve-
ment is often severe and blindness is not uncommon.28

Childhood EBA
Childhood EBA is extremely rare. Mucosal disease is often severe, and clini-
cal manifestations have included classical bullous pemphigoid and linear IgA-
like variants.6,8,30–33

Systemic disease
Epidermolysis bullosa acquisita has long been known to be associated with a
number of systemic illnesses, many with an immunologically mediated patho-
genesis. Most important are inflammatory bowel disease and diabetes melli-
tus.2,10,15,34–45 Approximately 30% of patients with EBA manifest inflammatory
bowel disease, predominantly Crohn's disease.42,46 Control of this improves
the skin condition in some patients. Interestingly, although up to 68% of
patients with inflammatory bowel disease have antibodies against collagen
type VII, only very few develop EBA.47 Presentation as a paraneoplastic phe-
Fig. 4.124
nomenon in association with internal malignancy has also on occasion been
Epidermolysis bullosa acquisita (classical variant): high-power view. There is fibrin
described.48,49 along the floor of the blister cavity. Note the absence of inflammatory cells.

Pathogenesis and histological features

The histological features are somewhat variable depending upon whether a
mechanobullous or an inflammatory lesion is biopsied.
The mechanobullous lesion is characterized by a bland, ‘cell-free’
­subepidermal vesicle containing only a few erythrocytes and a little fibrin
(Figs 4.123, 4.124). Usually, no significant inflammatory cell infiltrate is
present either within the blister cavity or in the adjacent or underlying dermis.
Sometimes, however, a small number of neutrophils, histiocytes, and eosino-
phils may be present. The basement membrane lines the roof of the blister.
Marked scarring of the adjacent dermis is often a feature and milia are
­frequently identified.
The inflammatory variant is characterized by a subepidermal vesicle
accompanied by a mixed inflammatory cell infiltrate comprising lympho-
cytes, histiocytes with prominent neutrophils, and eosinophils. Neutrophils
are usually the predominant cell type and in incipient lesions they may be
identified in a linear distribution adjacent to the epidermodermal junction.15
Occasionally, however, eosinophils predominate.24 Such inflammatory lesions
may resemble bullous pemphigoid or dermatitis herpetiformis (Figs 4.125,
4.126).2,50 Oral lesions show similar features of submucosal vesiculation with
an erythrocyte and inflammatory cell content.
By direct immunoperoxidase using paraffin-embedded material, type IV
collagen is found in the roof of the blister cavity (see Fig. 4.8).
Ultrastructurally, the level of the split in EBA is situated within the super-
ficial dermis immediately below the lamina densa (Fig. 4.127).51–53 The basal
keratinocytes appear normal. Anchoring fibrils have been variably reported
as reduced in number or absent.47–53
An occasional finding is the presence of electron-dense, amorphous granu-
lar material within the superficial papillary dermis close to, but separated
from, the lamina densa (Fig. 4.128).9,35 When present, the split is usually
below the electron-dense amorphous material, which is therefore located
within the roof of the blister.
By direct IMF, IgG and C3 are present in a linear distribution along the
basement membrane region (identical to BP) in a very high proportion of
cases of EBA (Fig. 4.129).9,10,36 Less commonly, IgM, IgA, properdin, and fac-
tor B may also be identified.1,52,53 In linear IgA disease-like patients, IgA may
be present in the absence of IgG.27–29 Positive direct immunofluorescence has
also been reported at a variety of other sites including the oral mucosa, con-
junctiva, cornea, esophagus, duodenum, and bladder.9,28,34
IgG antibasement membrane antibodies may be identified in 25–50% of
patients, thereby increasing the similarity to BP.2,47,51,54 In many patients the
antibasement membrane antibodies are associated with complement-fixing
properties.55 With split skin indirect IMF, which is more sensitive than con-
ventional indirect IMF, the immunoreactants line the floor of the induced
blister cavity.56–59
Direct and indirect immunoelectron microscopic studies have determined
that the immunoreactants lie on or below the lamina densa, corresponding to
the site of the electron-dense amorphous material mentioned above
140 Inherited and autoimmune subepidermal blistering diseases

A
A

B
B

Fig. 4.125
Fig. 4.127
(A, B) Inflammatory epidermolysis bullosa acquisita: in this bullous pemphigoid-like
(A, B) Epidermolysis bullosa acquisita: electron micrograph showing the lamina
variant, subepidermal blistering is associated with an eosinophil-rich infiltrate.
densa in the roof of the blister. (BC, blister cavity.)

Fig. 4.126
Inflammatory
epidermolysis bullosa
acquisita: dermatitis Fig. 4.128
herpetiformis-like variant, Epidermolysis bullosa acquisita: occasional deposits of finely granular electron-
with a neutrophil-rich dense material (immunoreactant) as seen in this field may be a useful diagnostic
infiltrate. pointer.

Fig. 4.129
Epidermolysis bullosa acquisita: (left) direct immunofluorescence shows linear
IgG deposition along the basement membrane region; (right) with split skin the
immunoreactant lines the floor of the induced lesion. By courtesy of Department of
Immunofluorescence, Institute of Dermatology, London, UK.
Fig. 4.130
Epidermolysis bullosa acquisita: direct immunoelectron microscopy showing
reactant deposition below the lamina densa.
(Fig. 4.130).1,51,52,60,61 Immunogold labeling confirms that the immunoglobu-
lin deposits are related to the anchoring fibrils (Fig. 4.131).62 As a conse-
quence of these additional observations, a modified set of criteria for the
diagnosis of EBA has been recommended:1,63
• clinical lesions of trauma-induced bullae occurring over the joints of the
hands, feet, elbows and knees, atrophic scars, milia and nail dystrophy,
or else presentation as a clinically inflammatory bullous or mucous
membrane pemphigoid-like process,
• postinfancy onset of the disease,
• no family history of EBA,
• exclusion of other bullous diseases,
• IgG at the basement membrane zone on direct immunofluorescence,
• demonstration of blister formation beneath the lamina densa,
• demonstration of IgG associated with anchoring fibrils beneath the basal
lamina by immunoelectron microscopy,
• localization of the immunoreactants to the floor of 1 M NaCl-split skin
by direct and or indirect immunofluorescence.
The EBA antigen (290 kD) is the globular (noncollagenous) carboxyl ter-
minus of type VII procollagen (Fig. 4.132).64–68 Type VII collagen is the major
constituent of anchoring fibrils which anchor the basement membrane
Epidermolysis bullosa acquisita (dermolytic pemphigoid) 141
Fig. 4.131
Epidermolysis bullosa acquisita: immunogold preparation showing localization of
the immunoglobulin to the anchoring fibrils. By courtesy of H. Shimizu, MD, Keio
University School of Medicine, Tokyo, Japan.
Fig. 4.132
Epidermolysis bullosa
acquisita: there are two
distinct antigens: one the
290-kD major antigen; the
other the 145-kD minor
antigen. By courtesy of I.
Leigh, MD, Royal London
Hospital Trust, London, UK.
through the lamina densa to the connective tissue constituents of the adjacent
dermis and is composed of three identical alpha-chains (each 290 kD). It is
synthesized by both human keratinocytes and fibroblasts in culture, and is
found in other mammalian skin including dog, cat, guinea pig, rat, mouse,
and hamster, but not in avian, reptilian, amphibian, or fish skin.69–72 Type VII
collagen has also been identified within the esophagus, mouth, anus, and
vagina. It has a high affinity for fibronectin, which is thought to be respon-
sible (at least in part) for adhesion between cells and matrix within the der-
mis.73 The interaction between the EBA antibody and type VII collagen is
thought to somehow upset this delicate relationship with consequent der-
moepidermal separation.74 Passive transfer of human EBA autoantibodies to
mice and immunization of mice with type VII collagen both lead to EBA dis-
ease models, confirming the importance of this autoantibody.75–78 An animal
model and human antibody characterization indicate that the pathogenic
antibodies of epidermolysis bullosa acquisita are often against the cartilage
142 Inherited and autoimmune subepidermal blistering diseases

matrix protein subdomain of the N-terminal noncollagenous domain of type

VII collagen.79 In some cases of inflammatory EBA the antibodies react against
epitopes in the triple-helical collagenous domain.80
The parallel between EBA and BP is obvious and it is tempting to extrapo-
late a similar downstream pathogenesis after autoantibody binds to its pro-
tein target.81 Although the current concept for EBA points to such a similarity,
additional confirmatory evidence is required. Recent studies have shown that
the pathogenesis is related, at least in part, to neutrophil recruitment medi-
ated by complement activation, and the generation of complement-derived
chemotactic activity (C5A) at the epidermal basement membrane region.74
Experimental models in which immune complexes are produced by treating
normal skin in organ culture with EBA complement-fixing antibodies has
been shown to result in complement-dependent neutrophil migration to the
basement membrane region and eventual dermoepidermal separation.55,82
Lack of complement-fixing function in the autoantibodies does not result in
tissue injury in one model.83 The precise mechanism whereby such blisters
evolve is unknown, but it has been suggested that leukocyte-derived proteases
and reactive oxygen intermediates may be important.54
The pathogenesis of the ‘cell-free’ mechanobullous variant is poorly under-
stood. It is also associated with antibasement membrane antibody, but there is Fig. 4.133
Bullous systemic lupus erythematosus: West Indian female with perioral blistering.
little if any evidence for neutrophil chemotactic activity. It has been proposed
By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
that separation at the dermoepidermal junction may result from an abrogation
of affinities between the type VII collagen and laminin-332 in addition to matrix
proteins such as fibronectin due to a direct effect of autoantibody deposition at
that site.1,84–86 An additional potential mechanism proposed is a direct effect of both sexes may develop the disease (Fig. 4.133).4,6–11 Presentation in children
the autoantibody on type collagen VII antiparallel dimer assembly leading to is exceptional.12,13
diminished anchoring fibril formation.1,87 The finding of domain specificity in Patients present with a widespread, sometimes pruritic, tense, vesicu-
EBA autoantibodies will direct focus toward the function of this cartilage matrix lobullous eruption that may affect both sun-exposed and nonsun-exposed
protein subdomain.81 It is intriguing that the pathogenetic autoantibodies in skin (Figs 4.134–4.136). The eruption can precede the onset of SLE or
EBA are against type VII collagen, the same protein genetically interrupted in develop subsequently.8,14 Lesions develop on flexural and extensor surfaces,
dystrophic epidermolysis bullosa, leading to nonfunctional anchoring fibrils. and mucosal (mouth and pharynx) lesions have been documented.4,8,15
Nonetheless, the clinical presentation of EBA is broad and includes features not A predilection for involvement of the upper trunk and supraclavicular
seen in dystrophic EB, such as bullous pemphigoid-like lesions. regions has been reported.4 Lesions may arise against a background of
­erythema or less commonly urticaria. Unlike EBA with which this disease
shares much in common, mechanobullous lesions are not seen, nor is there
Differential diagnosis ­evidence of scarring.4 Milia formation, although rare, has been recorded on
‘Cell-free’ EBA must be distinguished from congenital EB, porphyria cutanea two occasions and in both instances affected children.9,10 Postinflammatory
tarda, pseudoporphyria, and cutaneous bullous amyloidosis. Diagnosis can ­hyperpigmentation is a not uncommon complication. Surprisingly, patients
be achieved easily with the use of immunofluorescence. with bullous SLE do not usually develop other cutaneous manifestations of
Inflammatory EBA can be distinguished from bullous pemphigoid, mucous lupus. Bullous SLE has been recorded in a patient whose primary ­disease
membrane pemphigoid, and linear IgA disease by split skin IMF and, when developed as a consequence of hydralazine therapy and identical features
necessary, by Western blot (see Table 4.4). (including immunological) have been recorded in a patient with mixed
It is also important that dermoepidermal separation due to autolysis is not ­connective tissue disease.16
confused with in vivo blister formation. In autolysis the epithelium typically
shows marked eosinophilia and the nuclei are often lost.

Bullous systemic lupus erythematosus

Blisters may rarely develop as a manifestation of systemic lupus erythemato-
sus (SLE). They can therefore arise in a background of vasculitis or compli-
cate sunburn and photosensitivity.1,2 Occasionally vesicles form after extreme
basal cell hydropic change and consequent dermoepidermal separation.3
Patients with SLE manifest a wide range of antibodies resulting in numer-
ous complications, which include the development of autoimmune bullous
dermatoses such as bullous pemphigoid, dermatitis herpetiformis, pemphigus
vulgaris, pemphigus foliaceus, linear IgA disease, and ­epidermolysis bullosa
acquisita.4,5 More recently, an apparently unique dermatosis ­comprising a
widespread vesiculobullous eruption characterized by a ­dermatitis herpeti-
formis-like histology, linear basement ­membrane zone ­antibody deposition
(reacting with type VII collagen), and a striking response to dapsone has been
described in patients with SLE.6 This c­ onstitutes bullous SLE.

Clinical features Fig. 4.134

Bullous SLE – also termed bullous eruption of SLE, vesiculobullous SLE, SLE Bullous systemic lupus erythematosus: in this example there is a conspicuous
with herpetiform blisters – tends to present in the second and third decades inflammatory background. By courtesy of the Institute of Dermatology,
and although young black women are most often affected, all ages, races, and London, UK.

Fig. 4.135
Bullous systemic lupus erythematosus: numerous erosions are present over the
chest, shoulders, and upper arms. By courtesy of R.A. Marsden, MD, St George's
Hospital, London, UK.
Fig. 4.136
Bullous systemic lupus
erythematosus: tense
bullous pemphigoid-like
lesions. By courtesy of the
Institute of Dermatology,
London, UK.
Pathogenesis and histological features
Patients with bullous SLE (and EBA) have a significantly higher incidence of
HLA-DR2 compared to the normal population.4 This is thought to be associ-
ated with an increased risk of developing autoimmune diseases.17
The histological features of bullous SLE (BSLE) are those of a subepidermal
vesicle, often indistinguishable from dermatitis herpetiformis. The roof is usu-
ally intact and the blister cavity contains fibrin with large numbers of neutro-
phils and karyorrhectic debris (Fig. 4.137). Occasionally ­lymphocytes,
histiocytes, and eosinophils are also evident.4 The adjacent, nonbullous skin
characteristically shows subepidermal neutrophil microabscesses (Fig. 4.138).
The upper dermis contains a perivascular mixed inflammatory cell infiltrate
consisting of neutrophils, occasional eosinophils, lymphocytes, and histio-
cytes. Sometimes the features of a leukocytoclastic vasculitis are also present
(Figs 4.139–4.141).
Electron microscopy shows that the site of the split is below the lamina densa.4
Bullous systemic lupus erythematosus 143
Fig. 4.137
Bullous systemic lupus erythematosus: this shows the typical features of a
subepidermal, neutrophil-rich vesicle.
Fig. 4.138
Bullous systemic lupus
erythematosus: the
presence of a neutrophil
abscess in the papillary
dermis increases the
histological similarity of
this condition to dermatitis
herpetiformis.
Using direct immunofluorescence, the disease is characterized by the pres-
ence of immunoglobulin and complement at the epidermal basement mem-
brane region of both lesional and perilesional skin. Immunoglobulins are
frequently multiple: IgG is present in 100% of patients, IgA in 67%, and IgM
in 50%.4,7,8,17,18 Two patterns are recognized: granular in 40% of cases and
linear in 60%.8 Sometimes immunoreactants are also present within the walls
of the upper dermal vasculature, particularly venules.4 Indirect immunofluo-
rescence using 1 M NaCl-split skin as substrate shows the presence of a low
titer antibasement membrane antibody in those patients who demonstrate
linear positive direct IMF (type 1 BSLE).1,4,8,15,16,19–22 The antibodies generally
label the floor of the blister cavity although a roof (epidermal) variant has
rarely been described.8 Those that are negative on indirect IMF have been
classified as type 2 BSLE.4 Type 3 BSLE refers to those cases in which the
­target antigen is an epidermal rather than dermal epitope.6
Direct immunoelectron microscopy shows that the immunoreactants are
present on and immediately below the lamina densa, obscuring the anchoring
144 Inherited and autoimmune subepidermal blistering diseases

Fig. 4.139
Bullous systemic lupus erythematosus: this scanning view shows a central focus
of subepidermal vesiculation. Striking inflammatory changes outline the dermal
vasculature.
fibrils, and also occasionally somewhat deeper in the papillary dermis similar
to those seen in nonbullous SLE.4, 23–25 The antibody binds to the lamina
densa and sublamina densa in a manner identical to that seen in epidermoly-
sis bullosa acquisita.4,24
Western immunoblot has shown that these antibodies bind to antigens of
290 kD and 145 kD as described for EBA (i.e., type VII collagen).19 Recently,
rare patients with SLE have been shown to have circulating antibodies to type
VII collagen in the absence of blisters, and occasional patients with bullous
SLE have been shown to have antibodies which bind to both the roof and the
floor of NaCl-split skin, suggesting that a number of different basement mem-
brane antigens may be involved.1,4 The target antigen in the epidermal variant
of bullous SLE has not yet been identified although bullous pemphigoid anti-
gen 1 was identified in addition to type VII collagen and laminins-332 and -311
in one patient with combined epidermal and dermal staining on NaCl-split
skin indirect IMF, most likely representing a manifestation of postinflamma-
tory epitope spreading.25
The bullous SLE antibodies are associated with complement activation
activity, which results in neutrophil migration and adherence to the basement
membrane region.4 Neutrophil enzyme release is associated with basement
membrane damage and subsequent dermoepidermal separation.
Differential diagnosis
Bullous SLE shows obvious overlap with EBA. There are, however, a number
of discriminatory features. Bullous SLE is not associated with a mecha-
nobullous pathogenesis and scarring is not a feature. It develops most often
in a younger age group than EBA. The dermatitis herpetiformis-like histologi-
cal features are rarely seen in EBA and probably of greatest importance;
bullous SLE responds dramatically to dapsone therapy, but EBA does not.3

Dermatitis herpetiformis
Clinical features
Dermatitis herpetiformis and celiac disease are highly interrelated conditions
and best regarded as variable expressions of a common inherited tendency to
autoimmune disease.
Dermatitis herpetiformis (Duhring-Brocq disease) is a widespread, intensely
pruritic, papulovesicular eruption affecting all ages, but particularly people in
their second to fourth decades.1–4 The male to female ratio is 2:1.
The incidence of dermatitis herpetiformis is highest in Northern Europe,
Fig. 4.140 Scotland, and Ireland.2,5,6 It is less frequently seen in the United States.
Bullous systemic lupus erythematosus: this view shows florid leukocytoclastic Caucasians are mainly affected, the disease being rare in Asians and blacks.
vasculitis.
Case clustering is common and familial involvement (either dermatitis
­herpetiformis or celiac disease), possibly autosomal dominantly inherited, has
been documented in up to 10.5% of cases.2,7 Relatives of patients with
­dermatitis herpetiformis have an increased risk of developing celiac disease.2
The lesions, which may be symmetrical, are grouped mainly on the
­posterior scalp, shoulders, back, buttocks, and extensor aspects of the limbs
(Figs 4.142, 4.143). Scratching is often severe and therefore excoriation and/
or lichenification typically predominate with intact vesicles rarely being seen.
However, occasionally, larger blisters similar to those found in bullous
­pemphigoid may be evident. Patients sometimes present with urticarial
plaques and crusted erosions.2 Oral involvement is rare.3 Rarely, the initial
presentation may be with localized lesions in areas such as the scalp.8 The lat-
ter is not infrequently involved in more generalized disease. In one patient,
the presenting symptom was petechiae on the fingertips.9
The clinical response to dapsone (50–200 mg/day) is dramatic; therefore,
the drug is commonly administered for diagnostic as well as ­therapeutic
­purposes. Relief from pruritus occurs within a few hours of commencing
treatment and is soon followed by clearing of the rash. The eruption returns
2–3 days after dapsone is discontinued. The disease persists for many years
and is usually lifelong. A gluten-free diet may result in prolonged remission in
Fig. 4.141 some patients or lowering of the daily dapsone requirement in others.
Bullous systemic lupus erythematosus: this is a close-up view of the subepidermal At least 65–75% of patients with dermatitis herpetiformis show histological
vesicle shown in Figure 4.139. evidence of celiac disease (gluten-sensitive enteropathy, GSE). However, only
 Dermatitis herpetiformis 145

Pathogenesis and histological features

Fig. 4.142
Dermatitis herpetiformis:
excoriations are present
on the elbow and back of
the arm. Intact blisters are
uncommon in dermatitis
herpetiformis because of
the intense pruritus. By
courtesy of the Institute of
Dermatology, London, UK.
Patients with dermatitis herpetiformis (and celiac disease) have a high
incidence of HLA-B8 (80–90%), HLA-DR3 (90–95%) and HLA-DQ2
­(95–100%) compared to a normal control population (21%, 23%, and
40%, respectively).3,24–27 More recent studies, however, have demon-
strated that the increased incidence of HLA-B8 and -DR3 are due to
positive linkage disequilibrium. 28 The most current data suggest that the
significant positive HLA association in dermatitis herpetiformis lies with
the class II antigen DQ2.2,29 These HLA associations can be helpful
diagnostically.30
All patients with dermatitis herpetiformis have granular deposits of IgA
in the dermal papillae of perilesional skin, and many also show in vivo-
bound fibrin (Fig. 4.144).31,32 IgA has also been identified in the oral
mucosa.33 A  granular linear pattern may be seen and it seems to be more
common than previously reported.34 In patients with a linear pattern, careful
attention should be paid to the presence of granularity to avoid a misdiagno-
sis of ­linear IgA disease. Recently, a fibrillar pattern has also been docu-
mented.35 Two of the three patients reported with this pattern had clinical
features of dermatitis herpetiformis but lacked antitransglutaminase and
antiendomysial antibodies. Other immunoglobulins are not usually found,
but C3 is often present.36 This is associated with formation of the membrane
attack complex (C5–C9), which is thought to result in neutrophil chemo­
taxis and the evolution of subepidermal vesiculation.3,37 Cutaneous IgA

Fig. 4.143
Dermatitis herpetiformis: the buttocks are frequently affected. By courtesy of the
Institute of Dermatology, London, UK.

about 20% have clinical manifestations of malabsorption, these being usually

mild.10–15 The actual incidence of celiac disease is likely to be higher because the
mucosal abnormality in dermatitis herpetiformis is patchy and may be missed
unless multiple jejunal biopsies are taken.16–18 Interestingly, patients who appar-
ently do not have enteropathy may develop the ­condition when challenged with
large doses of gluten (latent GSE).13 It is therefore believed that all patients with
dermatitis herpetiformis have GSE to a greater or lesser extent.1–3 Relatives of
patients with dermatitis herpetiformis may show no evidence of the skin dis-
ease, but can have subclinical or overt s­ ymptoms of the enteropathy.
Patients with dermatitis herpetiformis may have antigastric parietal cell
antibody (10–25%), gastric hypochlorhydria (50–90%), and gastric ­atrophy
(50–70%).3 They may also have antithyroid antibodies and show an increased B
incidence of thyroid disease, insulin-dependent diabetes mellitus, and connec-
tive tissue diseases including systemic lupus erythematosus and Sjögren's syn- Fig. 4.144
drome.19,20 As with isolated celiac disease, there is an increased risk of Dermatitis herpetiformis: direct immunofluorescence showing (A) deposits of granular
intestinal lymphoma.21 IgA in the dermal papillae; (B) fibrin deposition in the dermal papillae. (A) By courtesy
Exposure to iodine may trigger or flare the disease.22,23 of the Department of Immunofluorescence, Institute of Dermatology, London, UK.
146 Inherited and autoimmune subepidermal blistering diseases

deposits may still be detected after dapsone therapy. They do, however, many levels of the biopsy will have to be examined before a microabscess is
sometimes disappear after a prolonged gluten-free diet.2 Cutaneous IgA found.
deposition is not seen in patients with celiac disease.2 Abscess evolution depends upon the initial presence of fibrin and
Electron microscopy reveals electron-dense, amorphous granular deposits ­polymorphs within the tips of the dermal papillae (Fig. 4.146), both of
in the superficial dermis showing no particular relationship with the base- which are associated with degenerative changes of the collagen and the
ment membrane region or any other specific structure.38,39 development of edema. Development of small subepidermal microvesicles
Immunoelectron microscopic observations initially suggested that the IgA follows, leading on to the formation of multilocular subepidermal
deposits were associated with elastic-containing microfibrillar bundles, but blisters.
more recently published work using antifibrillin antibodies has discounted Typically, the blister cavity contains edema fluid, a reticular network of
this theory.38,40 fibrin, and numerous polymorphs (Figs 4.147, 4.148). In contrast to bullous
Antigliadin antibodies, which are often used to assess celiac disease status, pemphigoid, the floor of the blister cavity usually shows effacement of the
are of limited value in the diagnosis of dermatitis herpetiformis.13 They have dermal papillary outline.
high specificity, but low sensitivity.13 Anti-smooth muscle endomysial anti- Within the dermis is a mixed inflammatory cell infiltrate consisting of lym-
body correlates with the gluten-sensitive state and appears before the devel- phocytes, histiocytes, and abundant neutrophils. Leukocytoclasis (nuclear
opment of any small intestinal histological abnormality in patients with dust, Fig. 4.149) is characteristic. Although blood vessels frequently show
dermatitis herpetiformis.13,41,42 Such endomysial antibodies are present in up endothelial swelling, there is no evidence of vasculitis. Occasionally, eosino-
to 70% of patients and are highly specific; they react with tissue transglu- phils are quite numerous in the infiltrate, but usually they are late arrivals,
taminase (tTG) (antitransglutaminase antibodies).43 Antibodies against epi- appearing 24–48 hours after the neutrophils. On occasions, biopsies from
dermal transglutaminase are found more frequently than the latter. typical dermatitis herpetiformis may show acantholysis, a cause of consider-
Antitransglutaminase antibodies, particularly those to epidermal tranglutam- able confusion (Fig. 4.150).
inase, seem to be the most sensitive serological marker of dermatitis herpeti-
formis.33,44 Patients with high levels of IgA and IgG transglutaminase
antibodies usually have more prominent mucosal villous atrophy and more
severe clinical disease.45 Gliadin is an important substrate for tissue transglu-
taminase forming gliadin–gliadin or gliadin–tTG complexes.46 Circulating
IgA antibodies to tTG are pathognomonic of dermatitis herpetiformis and
celiac disease.47 The gut subtype of transglutaminase is TG2 while that in the
skin is TG3. Cross-reactivity between these homologous proteins or antigenic
drift may underlie some of the mucosal and cutaneous features of this condi-
tion.48,49 Whatever the underlying mechanism, the IgA in some way ‘fixes’ in
the skin, resulting in complement activation via the alternative pathway.50–52
Neutrophil chemotaxins are then released and the ensuing inflammatory
reaction leads to dermal papillary edema, fibrin deposition, and eventual
vesiculation. There may be a role for cell-mediated ­immunity in this disease
as well, perhaps involving γ/δ T cells.53
The histological hallmark of dermatitis herpetiformis is the dermal papil-
lary neutrophilic microabscess, best seen in early erythematous lesions or well
away from the blister in an established eruption (Fig. 4.145).54–56 Occasionally,

Fig. 4.146
Dermatitis herpetiformis: in this early lesion, there are thin strands of fibrin visible
above the neutrophilic infiltrate.

Fig. 4.145
Dermatitis herpetiformis:
biopsy from an early
lesion showing Fig. 4.147
conspicuous neutrophil Dermatitis herpetiformis: an established subepidermal blister. Although early lesions
microabscesses. are usually multilocular, by 24–48 hours the lesion becomes unilocular.
 Linear IgA disease 147

Fig. 4.148
Dermatitis herpetiformis:
floor of the blister in
Figure 4.147 showing
an intense neutrophil
infiltrate.

Fig. 4.150
(A, B) Dermatitis herpetiformis: in this example acantholysis may result in
diagnostic confusion with pemphigus. Note that the blister is subepidermal.

Linear IgA disease

Fig. 4.149
Dermatitis herpetiformis: nuclear debris (karyorrhexis) within the dermis is a
characteristic feature.
Jejunal biopsy may reveal villous blunting, intestinal crypt elongation,
flattening of surface epithelial cells with loss of microvilli, and intraepithe-
lial γ/δ lymphocytic infiltration to a degree ranging from partial to subtotal
villous atrophy.57 If gluten is withheld from the diet, these changes revert to
normal.
Differential diagnosis
A neutrophil-predominant subepidermal vesicle accompanied by neutrophil
dermal papillary microabscesses in addition to dermatitis herpetiformis may
also be seen in the following conditions: vesicular pemphigoid, bullous sys-
temic lupus erythematosus, inflammatory epidermolysis bullosa, and linear
IgA disease. Distinction depends upon clinical information and the results of
immunofluorescent studies (see Table 4.4).
Linear IgA disease of adults by definition presents after puberty. It is
­characterized by the development of a sometimes self-remitting dapsone or
­sulfonamide-responsive dermatosis typified by subepidermal vesicles and
blisters in association with in vivo deposition of linear (homogeneous) IgA at
the basement membrane region on direct immunofluorescence of normal or
­perilesional skin.1–3 Childhood linear IgA disease (chronic bullous dermatosis
of childhood) is almost identical to the adult counterpart; however, there are
differences in clinical presentation and therefore these particular aspects are
described separately.
Linear IgA disease of adults is a rare disease, which was originally thought
to represent a variant of dermatitis herpetiformis4–6 or bullous pemphigoid.7,8
Some cases were reported under the rubric polymorphic pemphigoid (see
above) or intermediate (mixed) forms of bullous disease.9,10 More recently,
particularly following the application of immunoelectron microscopic and
immunoblotting techniques, it has been confirmed as a disease (or at least a
disease spectrum) sui generis.11–15
Its approximate incidence in the south of England is 1:250 000.16 In France
and central Germany, the incidence is 0.5 per million of the population.17,18 In
Singapore, the incidence has been estimated at 0.26 per million population.19
Although data for the United States are limited, the incidence in Utah has
been reported as 0.6 per 100 000.20 Some consider that this disease is
underdiagnosed.
148 Inherited and autoimmune subepidermal blistering diseases

Clinical features
Linear IgA disease of adults affects the sexes equally and, while the age distribu-
tion is wide, there are peaks in teenagers and young adults and in patients in
their sixties.1 It may present as a somewhat atypical bullous eruption showing
features suggestive of dermatitis herpetiformis or more commonly bullous pem-
phigoid (Fig. 4.151). Occasionally, it may initially resemble and be ­mistaken
clinically for erythema multiforme.21 Pruritus and/or a burning sensation are
common manifestations and early lesions may include urticarial, ­annular,
­polycyclic, and targetoid eruptions.15,22 The established dermatosis may be
vesicular or more often frankly bullous; blisters arising at the edge of erythema-
tous annular lesions (‘string of beads’ sign) are said to be characteristic.15
Sites affected in decreasing order of frequency include the trunk, limbs,
hands, scalp, face, and perioral region. The perineum and vagina may also be
affected with erosions and blisters.1 Mucous membrane involvement, which
is common, is of particular importance because it can be associated with scar-
ring. Important sites that may be affected include the eyes (conjunctivitis,
symblepharon, trichiasis, corneal opacification, and rarely blindness; Fig.
4.152), the mouth (erosions, blisters, and chronic ulceration), nasal cavity
(crusting and bleeding) and the pharynx (hoarseness).1,23–25 When these Fig. 4.152
mucosal symptoms are severe there is clinical overlap and diagnostic confu- Adult linear IgA disease: there is marked conjunctival injection and blepharitis.
sion with mucous membrane pemphigoid. By courtesy of the Institute of Dermatology, London, UK.
Childhood linear IgA disease (chronic bullous disease of childhood) not
uncommonly develops after an upper respiratory tract illness, often following
treatment with penicillin.26–29 Females are affected more often than males
(1.6:1) (Fig. 4.153). The average age of onset is 6 years, but very rare cases
in neonates have been described.30
Lesions, which can be pruritic or burning in the early stages, may be
urticated, annular or polycyclic in appearance and usually arise on normal
skin. Vesicles and large bullae (sometimes hemorrhagic) then predominate,
and although the perioral regions and genitalia are particularly affected, the
face, ears, trunk, limbs, hands, and feet are also often involved (Fig. 4.154).
Usually, the new lesions appear around those that are resolving (the ‘cluster
of jewels’ sign, Fig. 4.155). In older and black African children the clinical
appearances can suggest bullous pemphigoid. Healing is sometimes associ-
ated with postinflammatory hyper- or hypopigmentation. Mucous membrane
lesions are common (64%). Ocular symptoms of pain, grittiness, discharge
and redness are found in 40% of children; conjunctival scarring is present in
approximately 21%; oral lesions are found in up to 57%.
Fig. 4.153
Childhood linear IgA
disease: in this case
widespread erosions
on an erythematous
background are present
on the buttocks and legs.
Occasional intact vesicles
are also evident. By
courtesy of R.A. Marsden,
MD, St George's Hospital,
London, UK.

Although linear IgA disease in children was originally thought to be self-

Fig. 4.151
Adult linear IgA disease:
in this example the clinical
appearances of excoriated
lesions are suggestive of
dermatitis herpetiformis.
By courtesy of the
Institute of Dermatology,
London, UK.
limiting, it is now appreciated that symptoms may last over 5 years (25%)
and occasionally extend beyond puberty into adult life. Exceptionally, an
association with IgA nephropathy may be seen.31
Linear IgA disease is associated with increased expression of HLA-Cw7,
-B8, -DR2, -DR3 and -DQ2.32 The incidence of HLA-B8 association is vari-
able, with reported figures varying from 28% to 56% (normal range
20–25%).15,22 There is no evidence of an increase in HLA-B12.15 Linear IgA
disease is also associated with HLA-Cw7 and -DR3.1
Although in the earlier literature as many as 24% of patients with linear
IgA disease were thought to have associated gluten-sensitive enteropathy, the
incidence is almost certainly considerably lower.1 There are, however,
­occasional recent references documenting occasional patients with linear IgA
disease with clinical and histological evidence of gluten-sensitive enteropathy
in the presence of antiendomysial and antitransglutaminase antibodies.33,34

Fig. 4.154
Childhood linear IgA disease: groups of blisters are present on the vulva and inner
thighs. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
Fig. 4.155
Childhood linear IgA
disease: the arrangement
of blisters called the
‘cluster of jewels’. By
courtesy of R.A. Marsden,
MD, St George's Hospital,
London, UK.
It is possible that these cases represent dermatitis herpetiformis with linear
granular deposits of IgA in which the granularity has not been detected.
There are a number of reports documenting an association between linear
IgA disease and internal malignancy, including lymphoma and leukemia,
although whether this has significance is uncertain.35–38
Pathogenesis and histological features
Histologically, linear IgA disease is characterized most frequently by dermati-
tis herpetiformis-like features (Fig. 4.156).26,39,40 Occasionally, however, the
histological changes suggest bullous pemphigoid or sometimes a mixture of
both diseases (Fig. 4.157). Eosinophilic spongiosis may rarely be a feature.26
Ultrastructurally, the site of cleavage may be through the lamina lucida or
below the lamina densa.21
Linear IgA disease 149
Fig. 4.156
(A, B) Linear IgA disease: in this example the features are those of a neutrophil-rich
subepidermal vesicle reminiscent of dermatitis herpetiformis.
A homogeneous linear deposition of IgA along the basement membrane
region is found by direct immunofluorescence in 100% of patients (Fig.
4.158).26,41–43 Uninvolved skin (particularly of the back) is suitable.1 Oral
mucosa and conjunctiva may also show IgA deposition.1 The linear IgA anti-
gen is present in all stratified squamous epithelia and amnion but, in contrast
to the bullous pemphigoid antigen, is not found in bladder mucosa.42 IgG
may also be demonstrable in up to 25% of cases.12,15 IgM and C3 are occa-
sionally present.43
A low titer circulating IgA antibasement membrane zone antibody is pres-
ent in approximately 30% of patients.1 Use of conjunctiva as substrate may,
however, substantially increase this figure (up to 50%).23 Circulating IgG or
C3-binding antibasement membrane antibodies are seen only in those patients
with overlap syndrome.44 The IgA antibody is of pathogenetic significance
since it causes dermoepidermal separation after incubation with whole skin
cultures.45 Passive transfer of antibodies into a mouse model with human skin
graft also produces characteristic lesions.46 Blister fluid is also satisfactory for
indirect IMF.1
With split skin immunofluorescence, the titer may be higher and sensitiv-
ity is increased. The IgA antibasement membrane zone antibody variably
labels the epidermal side, the dermal side or both sides of the artificial ­blister
­cavity.47–49 Immunoelectron microscopy has shown similar results, with IgA
being present within the lamina lucida or below the lamina densa in associa-
tion with anchoring fibrils, and sometimes in both locations
(Fig. 4.159).50–55
Studies by Western immunoblotting indicate that linear IgA disease is a
heterogeneous condition. Thus, in those cases associated with dermal binding
on indirect NaCl-split skin IMF, the dermal antigens include 285-kD and
150 Inherited and autoimmune subepidermal blistering diseases

A B

Fig. 4.157
(A, B) Linear IgA disease: in this field the presence of eosinophils is more suggestive of bullous pemphigoid.

Fig. 4.158
Linear IgA disease: direct
immunofluorescence
showing linear IgA
deposition. By courtesy
of the Department of
Immunofluorescence,
Institute of Dermatology,
London, UK.
250-kD proteins and type VII collagen.14,49,56,57 Epidermal binding ­antibodies
react with BP230 (BPAG1), BP180 (BPAG2), and 200/280-kD antigens dis-
tinct from either of the BP antigens.58–60 The antigens 120 kD (LAD1) and
97 kD described in earlier reports represent proteolytic cleavage products of
BP180.61–64 Linear IgA disease 180-kD antibodies recognize the NC16A
domain of collagen XVII (BPAG2) also critical for bullous pemphigoid, pem-
phigoid gestationis, mucous membrane pemphigoid, and lichen planus pem-
phigoides described above.65–68 This fact is remarkable considering the variable
Fig. 4.159
Linear IgA disease: direct immunoperoxidase reaction using frozen tissue substrate.
There is an abundance of granular IgA beneath the basal lamina.
clinical features of these various ­autoimmune bullous disorders. LAD1 has
been identified as ladinin localizing to the extracellular domain of BP180 kD.69
Those patients with mixed IgA and IgG antibody-mediated disease also target
BP180.44 Recent reports suggest that antibodies against the NC16A domain
may be more important than those against the LAD1 cleavage product of
BP180, but not all cases contain the anti-NC16A antibodies.70–72
Drug-induced linear IgA disease is considered in chapter 14.
Differential diagnosis
The diseases from which linear IgA disease must be differentiated are derma-
titis herpetiformis, bullous pemphigoid, and inflammatory epidermolysis
bullosa. Points of distinction are considered in Table 4.4.
 Chapter

See
www.expertconsult.com
for references and
additional material
Acantholytic disorders
5
Introduction 151 Paraneoplastic pemphigus 163 Linear Darier's disease 173
IgA pemphigus 165 Transient acantholytic dermatosis 174
Pemphigus 151 Acantholytic dermatosis of the genitocrural area 176
Drug-induced pemphigus 167
Pemphigus vulgaris 152
Contact pemphigus 167 Warty dyskeratoma 176
Pemphigus vegetans 156
Familial dyskeratotic comedones 177
Pemphigus foliaceus 157 Acantholytic dermatoses with dyskeratosis 167 Acantholytic acanthoma 178
Endemic pemphigus foliaceus (fogo selvagem) 160 Hailey-Hailey disease 167
Acantholytic dyskeratotic acanthoma 179
Pemphigus herpetiformis 162 Relapsing linear acantholytic dermatosis 169
Focal acantholytic dyskeratosis 179
Pemphigus erythematosus 162 Darier's disease 169

Table 5.1
Introduction Antigens targeted in the pemphigus variants

The term acantholysis derives from the Greek akantha, a thorn or prickle, and Pemphigus variant Autoantigen
lysis, a loosening. In its simplest definition, the term is used to reflect a primary Pemphigus vulgaris Dsg3 (mucosal), Dsg1 (cutaneous),
disorder of the skin (and sometimes the mucous membranes) ­characterized desmocollins, pemphaxin, α9-acetylcholine
by separation of the keratinocytes at their desmosomal junctions (Fig. 5.1). receptor
A wide range of conditions are characterized by this feature, from inherited Pemphigus vegetans Dsg3, Dsc1, and Dsc2 in some patients
disorders such as Darier's disease and Hailey-Hailey disease in which a cal-
Pemphigus foliaceus Dsg1
cium pump gene mutation results in desmosomal instability through to the
autoimmune pemphigus group of diseases whereby autoantibodies directly Pemphigus erythematosus Dsg1
damage desmosomes with resultant keratinocyte separation and blister for- Fogo selvagem Dsg1, rarely also Dsg3
mation (Table 5.1). Desmosomes may also be damaged by secondary phe-
IgA pemphigus Dsc1, Dsg1 or Dsg3
nomena, for example following severe edema, either ­intercellular (spongiosis)
or intracellular (e.g., ballooning degeneration as is seen in ­various viral infec- Herpetiform pemphigus Dsg1, rarely also Dsg3
tions). Such processes, however, are not included in the acantholytic ­category Paraneoplastic pemphigus Desmoplakins I and II, envoplakin,
periplakin, BP230, plectin, Dsg1, and Dsg3
Drug-induced pemphigus Dsg1 or Dsg3
Dsc, desmocollin; Dsg, desmoglein. Modified from Martel, P., Joly, P. (2001)
Pemphigus: autoimmune diseases of keratinocyte's adhesion molecules. Clinical
Dermatology, 19, 667.

and are discussed elsewhere. The histological features of the conditions

described in this chapter show considerable overlap. The diagnosis is there-
fore dependent upon adequate clinical information and the results of immu-
nofluorescence investigations.

Fig. 5.1
Acantholysis: the keratinocytes are rounded and separated from each other to form
an intraepidermal blister. Villi formed from the underlying dermal papillae typically
project into suprabasal cavities.
Pemphigus
Pemphigus (Gr. pemphix, blister) refers to a group of chronic blistering dis-
eases which develop as a consequence of autoantibodies directed against a
variety of desmosomal proteins.1–5 The condition as a whole is rare, with an
annual incidence ranging from 0.1–0.7 per 100 000 of the general ­population.2
It is commoner in the Jewish population in which the annual incidence rises
to 1.6–3.2 per 100 000.6 Ashkenazi Jews are the most frequently affected.6
The incidence in India also appears to be higher than in other countries.7
There is no sex predilection.
152 Acantholytic disorders
The clinical features and, therefore, classification of these disorders
depends upon the level of separation within the epidermis:
• In pemphigus vulgaris (p. vulgaris) and pemphigus vegetans (p. vegetans)
the blisters are suprabasal.
• In pemphigus foliaceus (p. foliaceus), pemphigus erythematosus (p. erythe­
matosus) and fogo selvagem, the blisters are situated more superficially.
Pemphigus vulgaris is by far the most common variant, accounting for
80% of cases.8,9
In addition to affecting humans, pemphigus has been described in a variety
of animals including dogs, cats, goats, and horses.10
Pemphigus vulgaris
Clinical features
Pemphigus vulgaris (p. vulgaris) particularly affects the middle aged (onset
typically at 40–60 years of age) although occasionally (up to 2.6%) children
are affected.1–7 Self-limiting neonatal disease through transplacental transfer
of maternal autoantibodies has also rarely been documented (see pathogene-
sis).8–11 The disease begins in the mouth (Figs 5.2, 5.3) in 50–70% of patients
with painful erosions or bullae and, after a period of weeks or months, the
Fig. 5.2
Pemphigus vulgaris: painful erosions are present on the buccal mucosa. By courtesy
of R.A. Marsden, MD, St George's Hospital, London, UK.
Fig. 5.3
Pemphigus vulgaris: in this patient there is an intact blister on the floor of the
mouth. Pemphigus commonly presents in the mouth. By courtesy of the Institute
of Dermatology, London, UK.
blisters spread to involve the skin.12–15 Oral lesions most commonly affect the
buccal, palatine, and gingival mucosae.1,15–17 Pemphigus vulgaris is only rarely
confined to the skin.18,19
The typical skin lesion is a fragile, flaccid blister, which develops on nor-
mal or erythematous skin, and readily ruptures, leaving a painful, crusted,
raw, bloody erosion (Figs 5.4, 5.5). Lesions are most often seen on the
scalp, face, axillae, and groin, although in some patients they are generalized
(Figs 5.6–5.8).1–3,20 Blisters can be induced by rubbing the adjacent, appar-
ently normal skin with a finger – the Nikolsky sign. Direct pressure applied
to the center of the blister is also followed by lateral extension – the Asboe-
Hansen sign.2 Healing is often accompanied by postinflammatory hyperpig-
mentation but scarring is not a feature.2
Before the introduction of corticosteroid therapy, the lesions usually became
more extensive and in the past often led eventually to death. Treatment with
high doses of corticosteroids, immunosuppressants, such as azathioprine and
more recently biologicals has significantly reduced the mortality to 5–15%
and prolonged remissions without treatment are now being reported.2 A con-
siderable proportion of the deaths that do occur, however, are due to the
side effects of therapy and include staphylococcal infections and, to a lesser
extent, pulmonary embolism.2 Severe opportunistic infections due to a wide
range of organisms including listeria, nocardia, enterococci, herpes virus,
cryptococcus and candida may further complicate the disease.21–27
Fig. 5.4
Pemphigus vulgaris: since the blisters are superficial, erosions are more commonly
encountered. By courtesy of the Institute of Dermatology, London, UK.
Fig. 5.5
Pemphigus vulgaris: extensive erosions and blisters are present on the shin. By
courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.

Fig. 5.6
Pemphigus vulgaris: umbilical lesions showing intact blisters as well as raw
erosions. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
Fig. 5.7
Pemphigus vulgaris:
extensive trauma-induced
blisters. By courtesy
of the Institute of
Dermatology, London, UK.
Nail involvement seems to be more common than previously reported.
Patients may present with hemorrhagic paronychia, chronic paronychia,
trachyonychia, onycholysis or onychomadesis.17,28 Paronychia and onycho-
madesis are the most common nail changes encountered. Nail involvement is
more common in the nails of digits affected by periungual blisters and also in
patients with large number of skin blisters.29
Occasional modes of presentation include linear lesions and pemphi-
gus arising after surgery, burns, vaccination, and radiation therapy.30–39
Development after exposure to pesticides and a possible association with
cocaine snorting has also been reported.40,41 A very exceptional case has been
described in which blisters were initially confined to melanocytic nevi.42
P. vulgaris may also be rarely induced by a variety of drugs.
In addition to oral and cutaneous involvement, lesions have been described
at a wide variety of sites including the nasopharynx, larynx, ear, esophagus,
eye, external genitalia, urethra, and anal and colonic mucosa.1,43–45 Esophageal
lesions, although originally thought to be rare, have more recently been
Pemphigus 153
Fig. 5.8
Pemphigus vulgaris:
extensive disease can
be very disfiguring. By
courtesy of the Institute of
Dermatology, London, UK.
documented in as many as 63–87% of patients.46,47 Erosions and ulcers are
t­ ypically found and intact blisters are rare. Exceptionally, the whole mucosa
may be affected with subsequent sloughing – esophagitis dissecans superfi-
cialis.48 Ocular lesions are usually restricted to the conjunctiva, presenting as
conjunctivitis or small vesicles that rapidly rupture.2,49,50 Very rarely, scarring
may develop and corneal ulceration with perforation has been described.51
Vulval, vaginal, and cervical lesions are well recognized.52–56 Exceptionally,
the vagina may be the sole site of involvement.57 Penile lesions most com-
monly affect the glans.58 They are not usually followed by any significant
sequelae.
The development of pemphigus may be associated with a variety of dis-
orders including other autoimmune bullous dermatoses, particularly bullous
pemphigoid, lupus erythematosus, thymoma, and myasthenia gravis as
well as Hashimoto's thyroiditis, vitiligo, minimal change nephropathy, and
ulcerative colitis.59–66 It has also been described in a patient with the 1p36
deletion syndrome.67 As in the many other diseases with an immunological
pathogenesis, pemphigus is accompanied by an increased incidence of inter-
nal malignancy including thymoma, lymphoma, and multiple myeloma (see
paraneoplastic pemphigus).68,69 It has also been reported in association with
Kaposi's sarcoma.70
Pathogenesis and histological features
Pemphigus is an immunologically mediated disease.71,72 Examination of per-
ilesional skin by direct immunofluorescent techniques reveals in vivo-bound
immunoglobulin (usually IgG) and often complement (C3) in the intercel-
lular region of the epidermis (Fig. 5.9).73 Abundant antigen in the follicular
outer root sheath and germinal matrix may account for the marked scalp
involvement typical of pemphigus, and plucked hair follicles may serve as an
adequate substrate for direct immunofluorescence analysis.74,75 The in vivo-
bound IgG is mainly of the IgG1 and IgG4 subclasses.76
Indirect immunofluorescent techniques show that the serum of patients
with pemphigus contains an IgG antibody that reacts with the intercellular
region of normal squamous epithelium – the intercellular substance (pemphi-
gus) antibody.77 This antibody is, however, not entirely specific as it may be
found in a variety of other conditions, such as severe burns, penicillin drug
reactions, and following radiation therapy.78–80 Presumably, pemphigus anti-
gens are released into the circulation following such trauma with resultant
antibody production. Circulating antibodies are predominantly of the IgG1
and IgG4 subclasses; IgG3 is i­dentified much less often.81
154 Acantholytic disorders
Fig. 5.9
Pemphigus vulgaris: direct immunofluorescence. By courtesy of the Institute of
Dermatology, London, UK.
Circulating IgG is pathogenic.71,72 The level of the antibody titer closely
parallels the clinical state of the disease.82–85 IgG4 titers diminish during
remission whereas circulating IgG1 may continue to be present.72,83 Relapse is
commonly preceded by rising IgG4 antibody titers.83
P. vulgaris very occasionally may be evident in a neonate born of a mother
with active pemphigus vulgaris.8,86 Such autoantibodies cross the placenta,
inducing disease in the infant. The condition is, however, short lived, with
lesions disappearing, as the maternal antibodies are catabolized. Passive
transfer of IgG4 into neonatal mice results in the development of blisters.87
Purified IgG from pemphigus induces acantholysis in human skin explants
and keratinocyte cultures.88,89
The pemphigus antibody binds to the full thickness of the epidermis.
Compared with p. vulgaris, immunofluorescence studies on the sera of
p. foliaceus patients tend to show more staining in the superficial epidermis,
correlating with the level of the split.90,91 Conversely, the sera from patients
with p. vulgaris show more affinity for the lower epidermis. Despite these
trends, we generally do not base diagnoses on these (often subtle) differences
in immunofluorescence staining distribution.
The p. vulgaris antibody is directed at the extracytoplasmic domain of
the 130-kD epithelial desmosomal cadherin, desmoglein 3 (Dsg3), which
forms a complex with plakoglobin (85 kD).92–98 The p. vulgaris antibody,
however, does not recognize the latter. Many patients also have antibod-
ies that bind to the p. foliaceus antigen, desmoglein 1 (Dsg1), a 160-kD
polypeptide.99,100 Dsg3 is expressed primarily in the oral mucosa and, there-
fore, antibodies directed against this antigen result in mucosal pemphigus.
In contrast, Dsg1 is a cutaneous antigen and, therefore, antibodies directed
against it result in lesions affecting the skin but not the mucosa (cutaneous
pemphigus).90 Anti-Dsg1 antibodies also show cross-reactivity against Dsg4,
a recently identified member of the desmoglein family.101,102 While patient
sera contain antibodies against nonconformational epitopes of Dsg3, active
disease correlates with the presence of antibodies directed against the NH2-
terminal aspect of Dsg3, in particular ectodomains 2–4.103–105 Oral disease is
particularly associated with reactivity to ectodomains 1-4, which is reduced
in cutaneous pemphigus.103
Antibodies reactive to a number of other proteins including desmoplakin,
desmocollins, pemphaxin, and acetylcholine receptor have also been demon-
strated in the sera of p. vulgaris patients.106–110
Sera from patients with pemphigus vulgaris not infrequently contain
additional IgA antibodies, in particular against Dsg1 and Dsg3.111–113
Although the combination of both IgG and IgA antibodies has in some
instances been referred to as IgG/IgA pemphigus in the literature, this
appears to be an ­ill-defined and heterogeneous disease group.111,114 In addi-
tion to ­pemphigus vulgaris, the additional presence of anti-Dsg IgA anti-
bodies has also been demonstrated in pemphigus foliaceus, pemphigus
vegetans, pemphigus ­herpetiformis, and paraneoplastic pemphigus.111,115,116
Furthermore, so-called IgG/IgA pemphigus may show an atypical clinical
presentation, histological features more reminiscent of IgA pemphigus,
and the presence of IgA antibodies against desmocollins in a subset of
patients.114,117–123
The pathogenesis of the acantholysis is uncertain. Direct binding of
antibody to the desmosomal cadherins is of major importance and results
in internalization of Dsg3 and degradation by the endolysosomal path-
way.71,114,124 Plakoglobin has been implicated in mediating intracellular
events following IgG binding to Dsg3.125,126 In particular, the role of pla-
koglobin is signal transduction to the nucleus.125,127 There is also some evi-
dence to suggest that the process may involve, at least secondarily, the
action of local proteolytic enzymes.70 Pemphigus antibody induces expres-
sion of plasminogen activator receptor on the surface of keratinocytes.128
Binding of plasminogen activator to its keratinocyte cell membrane recep-
tor results in plasminogen activation with resultant production of plas-
min.129,130 This latter has non-specific proteolytic activity, which may
be responsible at least in part for the dissolution of the desmosomes.71
P. ­vulgaris antibodies stimulate production of keratinocyte phospholipase
C, inositol 1,4,5-triphosphate, and increase intracellular calcium. Protein
kinase C activation results in release of keratinocyte plasminogen activa-
tor and increased expression of plasminogen activator receptor.131–133 Other
factors, however, must be of greater importance since p. vulgaris IgG can
induce acantholysis in plasminogen activator knockout mice.134 An addi-
tional phenomenon is rapid phosphorylation of heat shock protein 27 and
p38MAPK resulting in reorganization and collapse of the cytoskeleton as
a result of IgG binding to Dsg3.135,136 This process is mediated by upstream
events involving EGF receptor kinase and src.137 Complement appears not
to be essential for acantholysis and it is thought that any involvement is
secondary, perhaps accelerating or extending the process.71 Although it has
been suggested that apoptosis may be induced by p. vulgaris IgG, and that
this mechanism may be important in the pathogenesis of the disease, a
recent study has shown that apoptosis is not a prerequisite for blistering
and may be a secondary phenomenon.138
T cells are also critical to the development of the antibody-mediated
acantholysis.70 CD4+ memory T cells are predominantly involved and both
T-helper 1 (Th1) and Th2 Dsg3-specific subtypes are represented.139,140 Th1
T-cell-derived interferon-γ stimulates production of IgG1, and Th2 cells
produce interleukin (IL)-4 and IL-13 which are responsible for secretion
of B-cell-derived IgG4.141 Both populations are therefore of importance in
stimulating production of p. vulgaris antibody.72 In addition, there is evi-
dence that tumor necrosis factor 1 (TNF-1), Fas-ligand and IL-1 are also of
importance in the development of acantholysis.142 Knockout mice for both
these cytokines show diminished acantholysis in passive antibody transfer
experiments.143
There is considerable evidence of a genetic background influencing suscep-
tibility to pemphigus as shown by strong associations with human leukocyte
antigen (HLA)-DRβ1*0402, HLA-DRβ1*1401 and HLA-DQβ1*0503.144–147
Perhaps surprisingly, however, there are only occasional documented reports
of familial occurrence.148–151
Pemphigus blisters rupture easily. It is therefore essential to biopsy an
early lesion to establish the correct diagnosis. The characteristic acantho-
lysis develops because of damage to the intercellular bridges. Acantholytic
cells are rounded and have intensely eosinophilic cytoplasm, pyknotic
nuclei, and perinuclear halos. An early lesion of p. vulgaris shows a slit-
like ­suprabasal cleft or vesicle containing occasional acantholytic cells. The
established blister contains acantholytic cells in clumps and in isolation
(Figs 5.10 and 5.11). Characteristically, the floor of the cavity is lined by
a single layer of intact basal cells, the so-called ‘tombstone’ pattern (Fig.
5.12).152
The acantholytic process frequently involves the epithelium of the adn-
exae, which can be a useful diagnostic clue in those lesions which lack the
roof of the blister (Fig. 5.13).153 The dermal papillary outline is usually main-
tained and, frequently, the papillae protrude into the blister cavity. Sometimes
the features of eosinophilic spongiosis are seen on biopsy, particularly in
early lesions.154 The blister cavity often contains a few inflammatory cells
(notably eosinophils) and, in the dermis, there is a moderate perivascular

Fig. 5.10
Pemphigus vulgaris: established blister showing marked acantholysis and scattered
neutrophils. The dermal papillae project into the cavity as villi.
Fig. 5.11
Pemphigus vulgaris:
(A) perianal mucosa
showing acantholysis and
B conspicuous villi; (B) high-
power view.
Pemphigus 155
Fig. 5.12
Pemphigus vulgaris: cell-free example showing a linear palisade of intact basal
keratinocytes – the so-called ‘tombstone’ appearance.
Fig. 5.13
Pemphigus vulgaris:
follicular involvement
distinguishes pemphigus
from Hailey-Hailey disease
in which it is not a feature.
chronic inflammatory cell infiltrate with conspicuous eosinophils, although
­sometimes these are scanty or even absent. Mucous membrane lesions show
similar histology.
Ultrastructurally, there is dilatation of the intercellular space with conse-
quent stretching of the desmosomal attachment points (Figs 5.14, 5.15).155
With progression, these separate and eventually disappear, residual cell
membranes often showing a pseudovillous morphology. Hemidesmosomes
are morphologically normal. Immunoelectron microscopy confirms that the
immunoreactants are located within the intercellular space.
Endemic pemphigus vulgaris
Patients with clinical and histological presentation of pemphigus vulgaris
but epidemiological features of fogo selvagem were identified in the Goiania
and Brasilia regions of Brazil, known endemic areas of pemphigus foliaceus.
These patients demonstrate classical mucocutaneous disease and antibodies
to both Dsg1 and Dsg3, but are remarkable for early onset of disease, fre-
quently before the age of 20.156
156 Acantholytic disorders

or without immunofluorescence studies, it may be impossible to establish a

definitive diagnosis. Darier's and Hailey-Hailey diseases are not associated
with immunoreactants.
Dyskeratosis in the form of corps ronds and grains is typical of Darier's dis-
ease, but is rarely seen in Hailey-Hailey disease, and is not a feature of pemphigus.
In Hailey-Hailey disease, the perivesicular epithelium is likened to a dilapidated
brick wall, an effect sometimes seen in p. vulgaris. More frequently, however, the
epithelium overlying and adjacent to the blister is essentially intact.
Acantholysis involving the follicular epithelium is often seen in pemphi-
gus, but usually not in Hailey-Hailey disease. The pemphigus-like variant
of Grover's disease is histologically indistinguishable from pemphigus, but
the clinical history, minute size of the lesions as viewed by the microscope,
and negative immunofluorescence findings make distinction relatively easy.
Extreme degrees of acantholysis in acantholytic solar keratosis may on rare
occasions be confused with the previously mentioned acantholytic disorders.
Similarly, it is important not to misinterpret the trivial finding of incidental
focal acantholytic dyskeratosis in a skin specimen removed or biopsied for an
unrelated finding.

Fig. 5.14
Pemphigus vulgaris: electron photomicrograph of an early lesion showing suprabasal,
intraepidermal vesiculation. Residual cytoplasm of basal keratinocytes lines the floor
of the blister. The lamina densa is clearly visible.
Fig. 5.15
Pemphigus vulgaris: electron photomicrograph of an early lesion showing marked
dilatation of the intercellular space. Cytoplasmic ‘villus’ formation is conspicuous
and only occasional desmosomes are apparent.
Differential diagnosis
The differential diagnosis of p. vulgaris includes a variety of conditions such
as Darier's disease, Hailey-Hailey disease, and transient acantholytic derma-
tosis (Grover's disease) (Table 5.2). In the absence of clinical information
Pemphigus vegetans
Clinical features
Pemphigus vegetans (p. vegetans), a chronic variant of p. vulgaris, has a
somewhat better prognosis than p. vulgaris with occasional cases associated
with spontaneous remission documented.1–3 It accounts for 1–2% of all cases
of pemphigus.1 As with the vulgaris variant, p. vegetans typically presents in
adults. There has, however, been a small number of cases described in child-
hood including a dapsone-responsive IgA-mediated variant.4–7 The lesions,
which present as blisters and erosions, are particularly prolific in the flexures,
especially the axillae, the groin, the inframammary region, the umbilicus and
at the margins of the lips. The scalp is also said to be a site of predilection.8,9
Soon thereafter, patients characteristically develop hypertrophic vegetations
and pustules at the blistered edges (Fig. 5.16).1
The oral cavity is commonly affected and a cerebriform or ‘scrotal’ tongue
is said to be a diagnostic clue in cases of early involvement.10–13 An exceptional
case of the disease restricted to the tongue has been reported.14 Esophageal
involvement presenting as erosions and white plaques has been described in
a number of patients and the nasal mucosa, larynx, vulva, vagina, penis, and
anus may also be affected.7,15–19 Nail involvement including onycholysis and
pustules is sometimes seen.20 Acral involvement can clinically be mistaken for
acrodermatitis continua suppurativa.21 A case has been described developing
after and restricted to a split-thickness skin graft.22 A further exceptional case
developed in association with intranasal heroin abuse and was restricted to the
nasal mucosa.23 Peripheral blood eosinophilia is commonly present.
Two clinical subtypes are recognized:24,25
• In the Neumann variant (the more serious form), lesions usually begin
as described in p. vulgaris, but the ensuing erosions develop vegetations.
The course of this variant is similar to that of p. vulgaris.
• In the Hallopeau variant (‘pyodermite vegetante’), the eruption begins as
pustular lesions that rapidly evolve into verrucous vegetating plaques.2
Bullae are usually not seen. This is a milder variant in which spontaneous
remission is not uncommon.

Table 5.2
Differential diagnosis of suprabasal pemphigus

Pemphigus vulgaris* Darier's disease* Hailey-Hailey disease*

Types of lesion Intraepithelial bullae Suprabasal clefts Intraepithelial bullae
Adjacent epithelium Intact Intact Disintegrating
Involvement of adnexae Yes Yes No
Corps ronds and grains No Yes Rarely
Dermal inflammation Mononuclears, eosinophils Mononuclears Mononuclears
IMF Positive Negative Negative
*The lesions of Grover's disease may histologically mimic any of these and can only be distinguished by immunofluorescence.
 Pemphigus 157

Fig. 5.17
Fig. 5.16 Pemphigus vegetans: the epidermis is hyperplasic and there are scattered abscesses.
Pemphigus vegetans:
axillary ulceration and
vegetative lesions. From
the slide collection of the
late N.P. Smith, MD, The
Institute of Dermatology,
London, UK.

Pathogenesis and histological features

Support for the thesis that p. vegetans is a variant of p. vulgaris is based on
the finding that both subtypes are associated with IgG and C3 deposition in
the epidermal intercellular space on direct immunofluorescence, and circu-
lating ‘pemphigus’ antibody.25 P. vegetans is characterized by an antibody
directed at the desmosomal cadherin, desmoglein 3.26–28 Antibodies against
desmocollins 1 and 2 as well as periplakin have also been documented.29,30
Rarely, additional IgA antibodies to Dsg3 may also be detected.31
Precipitating factors for this variant of pemphigus are largely unknown.
Exceptionally, however, p. vegetans has been linked with the angiotensin-
­converting enzyme (ACE) inhibitors, captopril and enalapril.32,33 Lesions
localized to the nasal mucosa in a patient with longstanding nasal heroin
abuse have been reported and an association with human immunodeficiency
virus (HIV) infection documented.19,34,35 There are few reports relating p. veg-
etans with an underlying malignancy and in one patient a p.vegetans-like
Fig. 5.18
lesion was a manifestation of paraneoplastic pemphigus.33,36–40
Pemphigus vegetans:
Although a variant of p. vulgaris, p. vegetans shows strikingly different follicular involvement is
histological features. Suprabasal acantholysis is present but is often subtle, seen on the right.
being masked by an exuberant proliferation of squamous epithelium which
may sometimes show pseudoepitheliomatous hyperplasia (Fig. 5.17). The
epithelial proliferation involves both the epidermis and the infundibular folli-
­hyperplasia and microabscesses may be confused with p. vegetans. In par-
cular epithelium. Characteristically, there is an intense inflammatory cell infil-
ticular, pyostomatitis vegetans must be excluded in patients presenting with
trate containing numerous eosinophils, and intraepidermal microabscesses
oral involvement. The latter is usually associated with inflammatory bowel
are often seen (Figs 5.18, 5.19). Eosinophilic spongiosis is a feature.41,42 The
disease and although it may mimic p. vegetans clinically and histologically,
inflammatory changes and epithelial proliferation are sometimes so marked
direct immunofluorescence is invariably negative. Halogenoderma may also
that the true nature of the lesions is obscured. Very occasionally, 10–40-μm
show similar histological features.
eosinophilic hexagonal Charcot-Leyden crystals have been described within
the eosinophil-rich microabscesses.32,43 The diagnosis of p. vegetans is eas-
ily overlooked and is made only by the pathologist with a high index of Pemphigus foliaceus
suspicion.
Clinical features
Differential diagnosis Pemphigus foliaceus (p. foliaceus) is considerably more uncommon than
Since early lesions may be similar, or identical, to p. vulgaris, the same differ- p. vulgaris and although it most often affects the middle aged and elderly,
ential diagnosis as discussed for that variant should be considered. In estab- it has a very variable age of onset, sometimes affecting younger adults and
lished lesions associated with squamous epithelial hyperplasia, the suprabasal even, occasionally, children.1–8 Very exceptionally, maternal antibodies have
cleft formation is often focal and easily overlooked. Infections, ­particularly been known to cross the placenta, resulting in neonatal disease.9–11 In general,
fungal and bacterial, that are associated with ­pseudoepitheliomatous ­nonendemic p. foliaceus in children is relatively benign and of short duration.6
158 Acantholytic disorders

Fig. 5.21
Pemphigus foliaceus:
crusted lesions are evident
Fig. 5.19 on the back of this young
Pemphigus vegetans: male. From the collection
there are numerous of the late N.P. Smith,
eosinophils. Note the MD, The Institute of
acantholysis. Dermatology, London, UK.

The superficial blisters of p. foliaceus are exceedingly fragile and there-

fore much less obvious; erosions and large leafy scales or crusts are often
predominant (Figs 5.20–5.22). The lesions may remain localized to the
scalp, nose, face, and trunk for many months or years, leading to a ­mistaken
diagnosis of seborrheic dermatitis, seborrheic keratosis, or even lupus
­erythematosus. Sometimes the eruption involves the entire surface of the body
or produces a clinical resemblance to exfoliative dermatitis (erythroderma)
(Fig. 5.23).12,13 Mucous membrane involvement is rare.1 Exceptionally,
patients may present with localized disease, typically restricted to the face.14,15
The development of pustular lesions is exceptional.16 P. foliaceus often has
a much more benign course than p. vulgaris, although patients with severe

Fig. 5.20
Pemphigus foliaceus:
multiple erosions
are present with B
background erythema
and postinflammatory Fig. 5.22
hyperpigmentation. Pemphigus foliaceus: (A) there are numerous crusted lesions on the lower
Courtesy of The Institute of abdomen and in the groin, (B) high-power view. From the slide collection of the late
Dermatology, London, UK. N.P. Smith, MD, The Institute of Dermatology, London, UK.

Fig. 5.23
Pemphigus foliaceus: in this patient, there is generalized erosion with scaling
and erythroderma. By courtesy of R.A. Marsden, MD, St George's Hospital,
London, UK.
­ isease, requiring ­corticosteroid and immunosuppressant therapy, still have
d result of an antibody-mediated cellular response rather than purely the result
an appreciable ­mortality. The ­disease may be complicated by Kaposi's vari-
celliform eruption.17
Very occasionally, patients may develop p. foliaceus during or after a pre-
vious episode of p. vulgaris and vice versa.18–20 The development of bullous
pemphigoid following an episode of p. foliaceus has also been described.21,22
This is accompanied by an antigen shift, possibly as a result of intermo-
lecular epitope spreading.19,23–25 A case of a blistering disorder displaying
­features of bullous pemphigoid and pemphigus foliaceus has been described
in ­association with consumption of Spirulina algae.26 The coexistence of both
p. ­vulgaris and p. foliaceus in one patient has also been reported.27 A fur-
ther case of paraneoplastic pemphigus with concomitant clinical features of
­pemphigus foliaceus and the presence of antibodies against desmoglein 1 was
recently reported.28
In addition to idiopathic p. foliaceus, drug-induced variants, notably due
to penicillamine, may also be encountered (Fig. 5.24). A localized form
may also be associated with topical drugs such as imiquimod and has been
reported following radiation therapy.29–32 Pemphigus foliaceus is rarely asso-
ciated with an underlying malignancy including ­non-Hodgkin's lymphoma
and esophageal cancer.33,34
A B
Fig. 5.24
Pemphigus foliaceus: (A) in this patient, the eruption was induced by penicillamine therapy; (B) close-up view of intact blisters, erosions and crusting. By courtesy of R.A.
Marsden, MD, St George's Hospital, London, UK.
Pemphigus 159
Pathogenesis and histological features
Similar to other variants of pemphigus, p. foliaceus is an immunologically medi-
ated disease. Examination of perilesional skin by direct ­immunofluorescent
techniques reveals in vivo-bound immunoglobulin (usually IgG) and often
complement (C3) in the intercellular region of the epidermis.1 Abundant anti-
gen in the follicular outer root sheath and germinal matrix may account for
the marked scalp involvement typical of pemphigus.35
Indirect immunofluorescent techniques show that the sera of patients with
p. foliaceus contain an IgG antibody that reacts with the intercellular region
of normal squamous epithelium.36 IgG4 predominates followed by IgG1.37,38
IgG3 is also sometimes present. This may be of importance since IgG3 is
the most efficient activator of complement.37 Some 60–70% of patients have
­positive indirect immunofluorescence.39
The p. foliaceus antibody binds to a 160-kD desmosomal cadherin, des-
ignated desmoglein 1 (Dsg1).40,41 The sera of p. foliaceus patients bind to
the extracellular amino terminal domain of bovine Dsg1 whereas sera from
both p. vulgaris and p. vegetans patients react with the intracellular domain
of Dsg1.42,43 Compared with p. vulgaris, immunofluorescence studies on the
sera of p. foliaceus tend to show more staining in the superficial epidermis,
correlating with the level of the split.44,45 Conversely, the sera from patients
with p. vulgaris show more affinity for the lower epidermis. Anti-Dsg1 anti-
body is pathogenic.46 Injection of purified anti-Dsg1 antibodies from sera of
patients with p. foliaceus into neonatal mice induces subcorneal acantho-
lysis in a pattern typical of p. foliaceus.47 Acantholysis is thought to be the
of steric hindrance.48 Internalization of nonclustered Dsg1 has been put for-
ward as a possible mechanism resulting in lack of newly formed desmosomes
rather than a disruption of pre-existing structures.49 Increasing evidence sug-
gests that the blistering is the result of the activation of p38 mitogen-acti-
vated protein kinase-dependent signaling by the p. foliaceus IgG antibodies.50
Rarely, patient sera contain additional IgG antibodies directed against des-
moglein 3 (Dsg3) and the presence of additional IgA antibodies against Dsg1
as well as Dsg3 has also been detected.3,51,52 Furthermore, three patients have
been reported with clinical and histological features of p. foliaceus but direct
immunofluorescence findings reminiscent of p. erythematosus. Antibodies
recognizing bullous pemphigoid antigen1 (BP230) as well as a 190-kD
­protein co-migrating with periplakin were detected in these patients in addi-
tion to anti-Dsg1 antibodies.53 The use of D-penicillamine may be associated
with the acquisition of a pemphigus-like antibody and the development of
p. foliaceus.54
Since the blisters of p. foliaceus are superficial, they are therefore fragile
and it is often very difficult to obtain an intact lesion for diagnosis. Patients
commonly have erosions without blisters, and frequently the clinician does
not suspect a bullous disorder. Usually, the cleft or blister lies within the
160 Acantholytic disorders
A B
Fig. 5.25
Pemphigus foliaceus: (A) in this example, there is a cell-free, subcorneal blister; (B) occasional acantholytic cells are present adjacent to the roof.
g­ ranular layer or beneath the stratum corneum (Fig. 5.25). The roof of the
fragile blister is often not present, having sloughed either before or after
biopsy. Acantholysis is frequently difficult to detect, but usually a few acan-
tholytic cells can be found attached to the roof or floor of the blister. In those
cases where the blister is missing, a careful inspection of the hair follicles
may reveal focal acantholysis. Sometimes the blister contains numerous acute
inflammatory cells (Fig. 5.26), particularly neutrophils, which can make dis-
tinction from subcorneal pustular disorders, including bullous impetigo, a
dermatophyte infection, candidiasis, pustular psoriasis, and subcorneal pus-
tular dermatosis especially difficult.55,56 Eosinophilic spongiosis may also be
seen.57
Differential diagnosis
The histological features in the superficial forms of pemphigus may be eas-
ily overlooked and, since bullae are often not appreciated by the clinician,
the unwary pathologist may not consider a bullous disorder when evaluat-
ing the biopsy. A high index of suspicion is therefore critical. The differential
diagnosis of superficial pemphigus includes bullous impetigo, staphylococcal
scalded skin syndrome, IgA pemphigus, and subcorneal pustular dermatosis
(Table 5.3). Distinction depends upon a careful consideration of the clinical
information, the results of bacterial culture, and immunofluorescent studies.
Fig. 5.26
Pemphigus foliaceus: in this example, the blister cavity contains numerous neutrophils.
Acantholytic cells are conspicuous.
Table 5.3
Differential diagnosis of superficial pemphigus: conditions characterized by
subcorneal pustules
Superficial pemphigus
IgA pemphigus
Subcorneal pustular dermatosis
Pustular psoriasis
Reiter's syndrome
Pustular drug reaction
Bullous impetigo
Staphylococcal scalded skin syndrome
Pustular fungal infection
Endemic pemphigus foliaceus (fogo
selvagem)
Clinical features
Fogo selvagem (Brazilian pemphigus foliaceus, ‘wild fire’, endemic pemphigus
foliaceus) is endemic in regions of Brazil and has also been documented in other
areas of Central and South America including Colombia, El Salvador, Paraguay,
Venezuela, and Peru.1–11 An endemic area has also been described in Tunisia.12,13
The condition is associated with poverty and malnutrition and particularly
affects children and young adults. Results from a more recent epidemiological
study demonstrated disease manifestation also in patients of higher socioeco-
nomic class and urban areas.14 There is a striking familial incidence.4 Most cases
are found along major rivers, and people especially at risk include farmers and
workers involved in land clearing and road construction.2 It appears that the
majority of patients live at an altitude of between 500 and 800 meters, and that
their homes are generally within 10–15 kilometers of running fresh water and in
the path of prevailing winds, thus suggesting a likely insect vector.4,15 In support
of this, a case-controlled epidemiological study has provided evidence that bites
by the black fly (family Simuliidae) are a significant risk factor for development
of the disease and it has been proposed that a component of the saliva may trig-
ger an antibody response in susceptible individuals.16–18 Simulium nigrimanum,
which is found in the same areas in which Brazilian fogo selvagem occurs, has
been identified as being the likely species involved.17
The clinical presentation of fogo selvagem has been divided into a number
of categories including localized and generalized forms:2,4
• Localized disease presents in a variety of ways including small blisters
and erosions or violaceous papules and plaques distributed mainly in the
seborrheic areas. Such lesions may be clinically misdiagnosed as discoid
lupus erythematosus.
 Pemphigus 161

Fig. 5.27
Brazilian pemphigus foliaceus: this woman with chronic disease shows very severe
scaling. Blisters are not apparent. By courtesy of S.A. Pecher, MD, Amazonas, Brazil.
were detected.32,33 Patients have circulating CD4+ memory T cells with a Th2
cytokine profile that proliferate in response to the extracellular domain of
Dsg1 and are thought to be of importance in the initiation and progression of
the disease by stimulating B-cell production of autoantibodies.34–36 The sys-
temic kinin system appears to be activated in patients with fogo selvagem but
the significance of this finding and its mechanism of action in blister forma-
tion are unclear.37
Patients often share the HLA phenotype DRB1*0102 and lack DQB1*0201
which is thought to represent a dominant protective gene found in unaffected
persons living in endemic regions.38,39 HLA-DRB1*0404, *1402 and *1406
may also confer susceptibility.4,28,34
The histological changes of fogo selvagem are identical to the other forms
of superficial pemphigus (p. foliaceus and p. erythematosus).40 Since the blis-
ters are superficial, often only nonbullous erosions are present for histologi-
cal examination. It is very difficult to obtain an intact lesion for diagnosis.
Typically, the cleft or blister lies within the granular layer or beneath the stra-
tum corneum. Acantholysis is frequently subtle but usually a few acantho-
lytic cells can be found attached to the floor of the blister. The blister roof is
often missing. Blisters may contain numerous inflammatory cells, particularly
neutrophils. This feature may cause confusion with infection or other sub-
corneal pustular disorders. Eosinophilic spongiosis is also sometimes present,
­particularly if biopsies of early lesions are examined (Figs 5.28, 5.29).

• Generalized presentation includes bullous exfoliative, exfoliative

erythrodermic, and disseminated plaque and nodular (resembling nodular
prurigo) variants (Fig. 5.27).4
With resolution, patients may sometimes develop hyperpigmentation.19
The antibody does not cross the placenta and therefore neonatal disease is
not a feature.20 Patients with fogo selvagem appear to have no increased risk
for other concomitant autoimmune disorders.21
In contrast to Brazilian fogo selvagem, endemic disease in the area of El
Bagre, Colombia, shows several unusual and distinguishing features.22 The dis-
ease affects an older population with a strong male predilection and clinical fea-
tures reminiscent of pemphigus erythematosus. In addition to the more ­classical
presentation, patients develop hyperkeratotic plaques on the face, chest, and
back reminiscent of discoid lupus erythematosus as well as an erythematous
macular lesion in a butterfly-like distribution in the central face.22 Active dis-
ease is also accompanied by conjunctivitis. The disease also shows characteris-
tic immunological and histological changes, which are discussed below.

Pathogenesis and histological features

The immunological features of fogo selvagem are similar to p. foliaceus.
Indirect immunofluorescent techniques show that the sera of patients with Fig. 5.28
Brazilian pemphigus foliaceus: in this example of an early lesion, the features of
fogo selvagem contain an IgG4 antibody that reacts with desmoglein 1.15,23
eosinophilic spongiosis are evident.
Passive transfer of this antibody to BALB/c neonatal mice results in acan-
tholysis and subcorneal blistering clinically indistinguishable from that of
human disease.24–26 Low-titer IgG1 and IgG2 antibodies may also be pres-
ent and nonpathogenic IgG1 antibodies are present in unaffected individuals
and in the preclinical stages of patients from endemic areas.15,24 IgG antibod-
ies may be accompanied by IgM antibodies, a finding seen more frequently
in individuals from rural rather than urban areas. Furthermore, additional
IgM antibodies are detected more frequently associated with fogo selvagem
than pemphigus foliaceus.27 Fogo selvagem is otherwise histologically and by
immunofluorescence indistinguishable from nonendemic foliaceus and, like
the latter, the antibody recognizes epitopes in the ectodomain of Dsg1.28,29
Epitope recognition is conformation specific and calcium dependent, and
recently intramolecular epitope spreading has been implicated in the patho-
genesis of the disease. Epitope spreading appears to be related to onset of dis-
ease as well as disease modulation with remission and relapse.30 Specifically,
it has been shown that sera from patients in the preclinical stage or in remis-
sion recognize epitopes in the COOH-terminal region of the ectodomain of
Dsg1 while antibodies against epitopes in the NH2-terminal region of the
ectodomain are detected at disease onset.15,30 Interestingly, a study has sug-
gested that the presence of serum IgG4 antidesmoglein-1 in asymptomatic
individuals may suggest preclinical disease.31 A subset of patients may also Fig. 5.29
have antibodies to Dsg3, and in up to 36% of sera from individuals from Brazilian pemphigus foliaceus: there is superficial dermal edema and a perivascular
the Terena reservation of Liao Verde, Brazil, additional anti-Dsg3 ­antibodies inflammatory cell infiltrate with conspicuous eosinophils.
162 Acantholytic disorders
The verrucous plaques and nodules seen occasionally in localized or
chronic fogo selvagem show acanthosis, hyperkeratosis, parakeratosis, and
papillomatosis.41 Acantholysis is invariably present.
The hyperpigmentation characteristic of remission is a direct result of
­pigmentary incontinence.
The histological findings in the endemic form described in the El Bagre
area in Colombia are identical to those of fogo selvagem in active disease.
In addition, liquefactive degeneration of the epidermal basal cell layer is
observed in a quarter of biopsies.22 By direct immunofluorescence, a posi-
tive lupus-band test is detected in 40% of patients in addition to IgG depo-
sition on the surface of keratinocytes. Reactive antibodies are of the IgG4
subtype with Dsg1 being the major antigen. Sera from patients also contained
additional antibodies against antibasement membrane zone as well as further
IgG1 anticell-surface antibodies, which may represent desmoplakin1, envo-
plakin, and periplakin.42
Recently, criteria have been proposed to establish a diagnosis of fogo
­selvagem as distinct from nonendemic p. foliaceus:4
• clinical evaluation,
• presence of subcorneal acantholysis,
• positive direct and indirect immunofluorescence and/or
immunoprecipitation or ELISA assays,
• confirmatory epidemiological data.
Differential diagnosis
As with p. foliaceus, the histological features in fogo selvagem may be easily
overlooked and a high index of suspicion is critical to making the diagno-
sis. The differential diagnosis includes p. foliaceus, p. erythematosus, bullous
impetigo, staphylococcal scalded skin syndrome, and subcorneal pustular
dermatosis. Careful clinical correlation, immunofluorescence studies, and
sometimes bacterial culture are necessary to establish a definitive diagnosis.
Pemphigus herpetiformis
Clinical features
Pemphigus herpetiformis (p. herpetiformis, herpetiform pemphigus, acantho-
lytic dermatitis herpetiformis) is a variant of pemphigus which shows clinical
features resembling dermatitis herpetiformis with the histology and immu-
nofluorescent findings of pemphigus.1–6 It is rare, accounting for only up to
7.3% of cases of pemphigus.2 The sexes are affected equally and there is a
wide age range varying from 31 to 83 years.3
Patients typically present with intensely pruritic, grouped, erythematous
papules and plaques, vesicles and blisters, sometimes associated with mucous
membrane involvement.2 Urticaria may also be a presenting feature.7 The
Nikolksy sign is variably present. Although lesions are often generalized,
there is a tendency for the extensor surfaces of the extremities to be par-
ticularly involved. Exceptionally, herpetiform pemphigus may be associated
with psoriasis, systemic lupus erythematous or with an underlying malig-
nancy including prostate and lung cancer (see paraneoplastic pemphigus).8–12
Although in some patients the clinical manifestations remain herpetiform
throughout, in others, the features evolve into more typical p. foliaceus,
fogo selvagem and, less commonly, p. vulgaris.2,4–6 Contrariwise, patients
with typical p. foliaceus and p. vulgaris may go on to develop a herpetiform
eruption.13 IgA pemphigus may also present with herpetiform lesions.14,15 In
­general, p. herpetiformis has a benign course, most patients responding well
to sulfones or steroids.2,3,16
Pathogenesis and histological features
Immunofluorescence testing shows IgG in an intercellular pattern char-
acteristic of the pemphigus group of disorders on both direct and indirect
techniques.1,2,4,16 In most patients, Dsg1 (p. foliaceus antigen) is the tar-
get autoantigen.4,6,17,18 However, in some patients, antibodies against Dsg3
(p. vulgaris antigen) have also been documented.18,19 A single patient has been
reported with both IgG as well as IgA antibodies against Dsg1 in addition to
anti-Dsc (desmocollin) 3 IgG.15 Why antibodies to Dsg1 in patients with
p. herpetiformis often fail to induce appreciable acantholysis compared with
p. foliaceus is uncertain. It is postulated that the p. herpetiformis antibody
t­ argets a different epitope although this has yet to be confirmed. Recently, two
patients with neutrophil-rich histology were shown to co-localize ­pemphigus
antibody and the neutrophil chemoattractant IL-8. In addition, circulating
IgG antibody up-regulated cultured keratinocyte IL-8 expression, thereby
offering an explanation for the neutrophil recruitment.20,21
The biopsy findings are variable and often non-specific. Although eosino-
philic spongiosis is most typical, spongiosis associated with either a mixed
eosinophilic and neutrophilic, or a neutrophil-predominant infiltrate may
also be encountered.4,22 Intraepidermal vesicles and pustules, also of variable
composition, are often present and dermal papillary neutrophil microab-
scesses have been described.2,6,16 Acantholytic cells are usually (but not invari-
ably) identified. A requirement for multiple biopsies before a diagnosis can be
established is a common theme in the literature.
Differential diagnosis
There is both clinical and histological overlap with IgA pemphigus and
­dermatitis herpetiformis. Immunofluorescence allows for distinction between
these entities. It should also be noted that, exceptionally, dermatitis herpeti-
formis may histologically show occasional acantholytic cells in the absence of
any evidence of pemphigus herpetiformis.
In those cases where eosinophilic spongiosis is the predominant histologi-
cal feature, the differential diagnosis also includes hypersensitivity reactions
and infection (bacterial and fungal). Immunofluorescence studies and special
stains for microorganisms will eliminate these possibilities.
Pemphigus erythematosus
Clinical features
Pemphigus erythematosus (p. erythematosus, Senear-Usher syndrome) is
a mild localized form of superficial pemphigus with the histological and
immunofluorescent findings of p. foliaceus combined with features of lupus
­erythematosus.1–6 In general, the latter is subclinical, being suggested only
by laboratory findings, but there are also rare reports of full-blown systemic
disease being present.4 The condition shows a worldwide distribution and a
slight female predominance.5 Exceptionally, it has been described in children
although immunological confirmation of the diagnosis is available in only
one case.7–10
Clinically, it is commonly confined to the head, neck, and upper trunk, and
typically resembles p. foliaceus. Lesions are erythematous, scaly, and crusted,
with or without superficial vesicles, blisters or erosions. Facial ­involvement
often shows a butterfly distribution reminiscent of lupus erythematosus
or seborrheic dermatitis (Fig. 5.30).1 Mucous membrane involvement is
­exceedingly rare.2
Fig. 5.30
Pemphigus erythematosus: there is scaliness and erythema affecting both cheeks.
By courtesy of the Institute of Dermatology, London, UK.
 Pemphigus 163

There are reports of p. erythematosus developing after treatment with a
number of drugs, notably D-penicillamine, and there are also instances attrib-
uted to therapy with propranolol, captopril, pyritinol, thiopronine, ceftaz-
idime, and cefuroxime.11–15 P. erythematosus has also been described as a
complication of heroin abuse.16
P. erythematosus may rarely be associated with thymoma.3,17–19 Typically,
the thymoma precedes the onset of cutaneous lesions, which often present
following thymectomy.18 Most tumors have been benign but one malignant
variant has been documented.19 P. erythematosus may also be a manifestation
of paraneoplastic pemphigus.3
Pathogenesis and histological features
Pemphigus erythematosus, in addition to intercellular staining, also shows
granular deposition of IgG and complement along the basement mem-
brane region (positive lupus band test) (Figs 5.31 and 5.32).2,20,21 Typically
the ­latter deposits are found within sun-exposed skin but in some patients
normal, nonsun-exposed skin may also be positive.2 Pemphigus antibody is
­generally present on indirect immunofluorescence, and antinuclear factor
may also be identified.20,21 Anti-DNA antibodies and antibodies to extract-
able nuclear antigens are negative except in those patients with features of
systemic lupus erythematosus.4 In common with p. foliaceus, the antibody
reacts with Dsg1.22
P. erythematosus has histological changes that are identical to those seen in
p. foliaceus and fogo selvagem. As the blisters are superficial, it is often very
difficult to obtain an intact lesion for diagnosis. Usually, the cleft or blister
lies within the granular layer or beneath the stratum corneum. As with the
other forms of superficial pemphigus, acantholysis is frequently difficult to
detect, but usually a few acantholytic cells can be found attached to the roof
or floor of the blister. The blister may contain numerous acute inflammatory
cells, particularly neutrophils, which can make distinction from subcorneal
pustular disorders especially difficult.

Differential diagnosis
The differential diagnosis includes the other forms of superficial pemphi-
gus (p. foliaceus and fogo selvagem), bullous impetigo, and staphylococ-
cal scalded skin syndrome, in addition to subcorneal pustular dermatosis.
Distinction depends upon a careful consideration of the clinical information,
the results of bacterial culture, and immunofluorescence studies.

Paraneoplastic pemphigus
Clinical features
Paraneoplastic pemphigus is a variant of pemphigus, quite distinct from
p. vulgaris and p. foliaceus.1 Paraneoplastic pemphigus may be associated
with a variety of tumors, such as B-cell lymphoproliferative disorders and
hematopoietic malignancies, Castleman's disease, Waldenström's macro-
globulinemia, thymoma (occasionally with myasthenia gravis), Hodgkin's
Fig. 5.31 lymphoma, carcinomas (e.g., carcinoma of bronchus, pancreas, liver, uterus,
Pemphigus breast, and liver), and sarcomas (including dendritic follicular cell sarcoma,
erythematosus:
round cell liposarcoma, leiomyosarcoma, and inflammatory myofibroblas-
typical intercellular
immunofluorescence with
tic tumor).2–47 We have seen an exceptional association with systemic mas-
granular staining (IgG) at tocytosis. Lymphoma is most often the coexistent neoplasm.1 In a case of
the basement membrane a patient with non-Hodgkin's lymphoma, the disease developed only after
region. By courtesy six cycles of fludarabine, raising the possibility of an association with the
of B. Bhogal, FIMLS, medication.48 In a further exceptional case, a patient presented with a dis-
Institute of Dermatology, ease fulfilling the diagnosis of paraneoplastic pemphigus by histology, immu-
London, UK. noblotting, and immunoprecipitation. However, no neoplasm was found in
8 years of follow-up.49
Paraneoplastic pemphigus has been defined by Sapadin and Anhalt as
follows:50
• painful mucosal erosions and a polymorphous skin eruption in the
context of an occult or confirmed neoplasm (Fig 5.33),
• histopathological changes of keratinocyte necrosis, intraepidermal
acantholysis, and vacuolar-interface dermatitis,
• direct immunofluorescence showing intercellular IgG and complement
accompanied by linear or granular complement at the dermal–epidermal
junction (Fig 5.34),
• indirect immunofluorescence showing circulating antibodies to simple,
columnar, and transitional epithelia in addition to a more typical
pemphigus pattern of binding to skin and mucosa,
• circulating autoantibodies that immunoprecipitate a high molecular
weight complex of polypeptides from keratinocyte extracts weighing
250, 230, 210, 190, and 170 kD.
Although the disease may develop in a wide age range (7–83 years), the
majority of patients have been in the fifth to eighth decades and there is a
male predominance.5 Exceptionally, children may be affected.4,51–54 Lesions
are seen in both the mucosa and the skin. Patients present with refractory,
Fig. 5.32 painful, persistent erosions of the oral mucosa and vermilion border of the
Pemphigus erythematosus: immunoelectron micrograph showing immunoreactant lips. In addition, the tongue, gingiva, floor of mouth, palate, oropharynx,
beneath the lamina densa in addition to occupying the intercellular space. By and nasopharynx can be affected.5 Manifestation confined to the skin or oral
courtesy of B. Bhogal, FIMLS, Institute of Dermatology, London, UK. mucosa is exceptional.22,55,56 Esophageal disease has been described and the
164 Acantholytic disorders
Fig. 5.33
Paraneoplastic pemphigus: there are numerous erosions and crusted lesions.
Courtesy of The Institute of Dermatology, London, UK.
Fig. 5.34
Paraneoplastic pemphigus: IgG is evident in an intercellular distribution.
trachea and bronchi may be affected.57–59 The latter is sometimes accompa-
nied by an invariably fatal bronchiolitis obliterans-like disorder.46,58,59 Colonic
involvement is unusual.60 Frequently, patients also have severe pseudomem-
branous conjunctivitis with symblephara, and eventual blindness may occur.5
The vulva, vagina, and penis are sometimes affected.4 Rarely, the disease is
accompanied by other autoimmune disorders including myasthenia gravis
and alopecia areata.46,56
Cutaneous lesions are typically polymorphic and often present as a pruritic
papulosquamous dermatosis with subsequent blistering. The trunk, proximal
extremities, palms, and soles are characteristically affected.61 Nail involve-
ment may occur. Although the eruption typically resembles p. vulgaris, it may
also mimic p. foliaceus, IgA pemphigus, bullous pemphigoid, linear IgA dis-
ease, lichen planus pemphigoides, erythema multiforme, and toxic epidermal
necrolysis.39,62–67 P. vegetans-like lesions have been described.49 Paraneoplastic
pemphigus is associated with a very high mortality.5
Pathogenesis and histological features
In paraneoplastic pemphigus, circulating antibodies bind to desmosomal and
hemidesmosomal plakin family members including 250-kD (desmoplakin I),
230-kD (bullous pemphigoid antigen), 210-kD (a doublet originally thought
to be desmoplakin II but later determined to represent envoplakin) and a
190-kD antigen (periplakin).68–71 The presence of antibodies to envoplakin
and periplakin (both cornified envelope constituents) is believed to be highly
specific for paraneoplastic pemphigus and the linker domain of plakins may
be of particular significance.72,73 There are also antibodies to an as yet unde-
termined 170-kD antigen.66 Antibodies to Dsg1 and 3 are also usually pres-
ent and plectin (another plakin family member) antibodies may be found.74,75
Anti-Dsg antibodies are thought to be of particular importance in the ini-
tiation of lesions, disrupting the cell membrane and thereby exposing des-
mosomal and hemidesmosomal plakin proteins with resultant autoantibody
formation.68,76
Direct immunofluorescence shows IgG deposition affecting the whole
thickness of the epidermis whereas C3 is found only on the lower layers.68,77–79
Characteristically, the intercellular staining is often focal and faint.77,78
In addition, complement is present along the basement membrane region.
Immunoglobulin deposition in the respiratory epithelium has also been docu-
mented.57–59 Indirect studies confirm the presence of a circulating antibody
although the membrane deposition is often masked by strong cytoplasmic
labeling.68 This latter can be reduced or abolished by serum dilution.68
In paraneoplastic pemphigus, in addition to binding to stratified squamous
epithelium, the antibody labels transitional epithelium, pseudostratified
respiratory epithelium, small and large intestinal mucosa, and thyroid epi-
thelium.78 It also reacts with myocardium and skeletal muscle. Rat bladder
epithelium is said to be highly specific for paraneoplastic pemphigus.79 Up to
25% of cases, however, are negative.80
Recently, there has been accumulating evidence demonstrating consider-
able heterogeneity within disorders designated as paraneoplastic pemphi-
gus in addition to overlap with other immunobullous diseases. Patient sera
frequently contain additional IgA antibodies against Dsg3 and a patient
with IgA antibodies to desmocollins analogous to IgA pemphigus has
recently been reported.66,81 Immunophenotypic variability among paraneo-
plastic pemphigus patients has thus been established. The documentation
of patients displaying p. vulgaris-like or p. foliaceus-like features has led
some authors to suggest that immunobullous disorders arising in association
with malignancy would be best viewed as representing a spectrum rather
than a distinct entity.62 Included within this spectrum are other nonpem-
phigus immunobullous disorders resembling erythema multiforme, graft-
­versus-host disease, and lichen planus. The description of antibodies reactive
with desmoplakin I and II in some patients with erythema multiforme raises
the possibility that these autoantibodies play a pathogenic role in a ­subset
of patients.82 However, further study will be necessary to determine the
­significance of this finding.
Analogous to other forms of pemphigus, recent studies have suggested a
genetic predisposition. HLA typing has identified HLA-Cw*14 as the pre-
disposing allele in a Chinese population while DRB1*03 was identified in a
French study.83,84
The histological findings in paraneoplastic pemphigus are highly variable
but are characterized by an admixture of suprabasal acantholysis, often resem-
bling p. vulgaris, with cleft or vesicle formation (sometimes involving adnexal
epithelium), and interface changes with basal cell liquefactive degeneration,
dyskeratotic keratinocytes, and lymphocytic exocytosis (Figs 5.35–5.37).69,85
Spongiosis is often present.3 A perivascular and lichenoid chronic inflamma-
tory cell infiltrate is typically seen in the superficial dermis.77 In some cases,
the histological features may closely simulate lichen planus. Eosinophils,
however, are rare. Pigmentary incontinence is frequently evident.85
Acantholysis-like change has also been described affecting the bronchial
lining epithelium and brochiolitis obliterans-like features may be seen.57,59
Differential diagnosis
The biopsy findings of admixed acantholysis and interface change appear to
be relatively non-specific. This contention is demonstrated by skin lesions
in patients with typical autoimmune pemphigus without evidence of neo-
plasia that have histological features considered typical of paraneoplastic
pemphigus.79
The differential diagnosis includes mainly interface dermatitides (e.g.,
drug eruption, lichen planus, erythema multiforme, graft-versus-host disease)
rather than other variants of pemphigus. A very high index of suspicion on
the part of the pathologist and clinician alike and confirmatory immunofluo-
rescence studies are prerequisites to achieving a correct diagnosis.
 Pemphigus 165

Fig. 5.35 Fig. 5.37

Paraneoplastic pemphigus: this medium-power view shows suprabasal acantholysis Paraneoplastic pemphigus: note the basal cell hydropic degeneration and cytoid
and interface change. Note the hyperkeratosis and hypergranulosis. Courtesy of bodies. There is an intense lymphohistiocytic infiltrate. A single eosinophil is
N. Brinster, MD, Virginia Commonwealth University Medical Center, Richmond, evident. Courtesy of N. Brinster, MD, Virginia Commonwealth University Medical
Virginia, USA. Center, Richmond, Virginia, USA.

• Patients with SPD-like IgA pemphigus present with superficial flaccid

pustular lesions, often arising on an erythematous base and typically
affecting the trunk and proximal limbs, although the intertriginous sites
are predilected.11 Very uncommonly, there is exclusive involvement of
the oral mucosa and perianal skin.23 Occasionally, there is generalized
skin involvement. Lesions are crusted and progress with peripheral
extension to form ringlike and rosette patterns.15 The features may be
indistinguishable from classical non-IgA-associated SPD.
• Patients with the IEN IgA dermatosis variant present with generalized
pustules and crusts and erythematous macules with peripheral vesicles
forming the so-called sunflower-like configuration (Figs 5.38, 5.39).7
A dermatitis herpetiformis-like presentation with grouped edematous
papules may also be encountered.11,12,15
Pruritus is common and is sometimes severe.8

Fig. 5.36
Paraneoplastic pemphigus: higher-power view of acantholysis with suprabasal
cleft formation. Courtesy of N. Brinster, MD, Virginia Commonwealth University
Medical Center, Richmond, Virginia, USA.

IgA pemphigus
Clinical features
IgA pemphigus is a rare dapsone-responsive variant of pemphigus that, as its
name suggests, is characterized by intercellular IgA deposition and presents
clinically with pustular rather than bullous or vesicular lesions.1–6 This disease
has been described under a number of different names, such as intraepidermal
neutrophilic IgA dermatosis, IgA pemphigus foliaceus, IgA herpetiform pem-
phigus, intraepidermal IgA pustulosis, intercellular IgA dermatosis, and inter-
cellular IgA vesiculopustular dermatosis.7–16 Most patients are middle aged Fig. 5.38
IgA pemphigus:
or elderly but children may also be affected.8,17–21 The sex incidence is equal.
erythematous lesions
There is no racial or geographic predilection.8,11 Drug-induced variants have
and an intact vesicle are
occasionally been documented.22 present. From the slide
IgA pemphigus is divided into two major subtypes: subcorneal pustular collection of the late
dermatosis (SPD) variant (IgA pemphigus foliaceus) and intraepidermal neu- N.P. Smith, MD, The
trophilic IgA dermatosis (IEN) variant (IgA pemphigus vulgaris).7 Other less Institute of Dermatology,
readily classifiable variants may also be encountered. London, UK.
166 Acantholytic disorders

Fig. 5.39 Fig. 5.40

IgA pemphigus: high-power view showing pus-filled intact blisters and an erosion. IgA pemphigus: this biopsy is from the edge of an established blister. Note the
From the slide collection of the late N.P. Smith, MD, The Institute of Dermatology, heavy inflammatory cell infiltrate and focal acantholysis.
London, UK.

The lesions in occasional patients resemble classic p. vulgaris or p.

f­ oliaceus. In one childhood case, a p. vegetans-like presentation associated with
­α1-antitrypsin deficiency was documented.18 Mucous membrane involvement
in either variant is exceptional.17 Nikolsky's sign has been reportedly nega-
tive at least in a subset of patients.2,12,13 IgA pemphigus tends to be a chronic
relapsing but relatively benign disorder.11,12,15
A significant number of patients (approximately 20%) may have an
associated monoclonal gammopathy, usually of the IgA class.11,24–26 Two
documented cases have been benign and the others have represented B-cell
lymphoma or multiple myeloma.11

Pathogenesis and histological features

SPD IgA pemphigus is characterized by intercellular IgA deposition in the
upper epidermis, and circulating IgA antibodies which preferentially bind to
the upper epidermis are typically present.4 In contrast, in the IEN variant, IgA
is deposited preferentially in the lower epidermis, and circulating antibodies
also generally bind to the lower epidermis. In some patients, however, the IgA
antibody binds to the entire thickness of the epithelium. A linear subcorneal
distribution has also been documented.9 Complement is not usually present
and IgG and IgM are absent.7 The antibodies are of the IgA1 subclass and
are usually of low titer.4,17 They have been identified in approximately 50%
of patients.12
By immunoelectron microscopy performed on a limited number of cases,
the immunoglobulin has been identified within the intercellular space, on
the keratinocyte cell membrane, in some cases showing desmosomal accen-
tuation.27–29 In the SPD type, labeling has been predominantly detected
in extracellular spaces between keratinocytes at desmosomes while label-
ing is mainly in intercellular spaces in nondesmosomal areas in the IEN
variant.30
The two subtypes result from autoantibody production to different
­desmosomal proteins.31 Patients with the SPD variant show reactivity with
desmocollin 1.32–35 In contrast, anti-Dsg1 or anti-Dsg3 IgA antibodies are
present in the IEN variant.19,36–38 One patient with the SPD variant showed
both anti-Dsc1 as well as anti-Dsg1 IgA.39 In some patients, however, nei-
ther desmocollins nor desmogleins appear to be involved, suggesting that IgA
pemphigus is a heterogeneous group of conditions.13,18,35,38
Histologically, in the SPD variant, vesicles are typically found in a sub-
corneal location associated with a neutrophil infiltrate. It is thought that the
presence of IgA is responsible for the striking neutrophil response of this dis-
order since IgA is associated with neutrophil chemotaxis and neutrophils bear
IgA receptors.40,41
In the IEN variant, the pustules can be distributed throughout all ­layers of
the epidermis and may also involve the hair follicles (Figs 5.40, Figs 5.41).18
Fig. 5.41
IgA pemphigus: the blister cavity contains neutrophils and eosinophils.
Acantholytic cells are usually (but not always) present. Typically, they are
sparse and, as such, this diagnostic clue may be very easily overlooked.11–13
Prominent dyskeratotic cells have been described in a single case of IgG/IgA
pemphigus.42 Significant numbers of eosinophils may also be seen in occa-
sional IEN cases.20,43 Neutrophil dermal papillary microabscesses have also
been described, sometimes accompanied by neutrophil spongiosis.12,20 A
perivascular infiltrate of neutrophils, lymphocytes, and histiocytes surrounds
the superficial vascular plexus and eosinophils may also sometimes be pres-
ent. In addition to the major variants characterized by pustules, some patients
with IgA pemphigus show histological features typical of classic p. vulgaris,
p. foliaceus or even, exceptionally, p. vegetans.4,18
Differential diagnosis
The differential diagnosis includes subcorneal pustular dermatosis, typical
p. foliaceus, and infections such as bullous impetigo. Although clinically sub-
corneal pustular dermatosis tends to be more restricted to the flexural sites,
absolute distinction from the subcorneal variant of IgA pemphigus depends
upon immunofluorescent studies. Gram stain and a periodic acid-Schiff (PAS)
should always be included in the histological workup to exclude an infective
process.
 Acantholytic dermatoses with dyskeratosis 167

Drug-induced pemphigus
There are at least 25 drugs that have been shown to be associated with the
development of pemphigus.1 Penicillamine and captopril are the most com-
mon offenders; however, enalapril, propranolol, bisoprolol, glibenclamide,
cilazapril, penicillins, cephalosporins, rifampicin, pyrazolon derivatives, and
lisinopril, among others, have also been implicated.1–8 Some drugs such as
penicillamine may elicit either p. foliaceus or p. vulgaris, but the former is
much more common.
Symptoms disappear in most patients following withdrawal of causative
drugs that contain a sulfhydryl group (thiol drugs). Non-thiol drugs are much
less likely to be associated with remission following withdrawal.2
Histologically, drug-induced pemphigus resembles sporadic counterparts
with positive direct immunofluorescence in most, but not all, patients.9 As
expected, given the different variants of pemphigus that drugs may induce,
antibodies against both Dsg1 and Dsg3 have been documented.10 It has been
suggested that a monoclonal antibody against desmogleins 1 and 3 may be
useful in the diagnosis and prognosis of drug-induced pemphigus.11 Staining
with this antibody is usually patchy in idiopathic pemphigus and diffuse in
drug-induced pemphigus. Furthermore, cases of drug-induced pemphigus Fig. 5.42
with diffuse pattern tend to have a poorer prognosis. Hailey-Hailey disease: erythematous and scaly lesions are present in the groin
and on the labia majora. From the slide collection of the late N.P. Smith, MD, The
Institute of Dermatology, London, UK.
Contact pemphigus
as the genitalia, umbilicus, inframammary regions and scalp, may also be
Clinical features affected. Rarely the disease may be generalized.4,5 Nikolsky's sign is some-
There is a growing body of literature documenting contact with topical sub- times positive.3 Vesicles and bullae, arising on normal or erythematous skin,
stances preceding the onset of pemphigus. The pathogenesis is not under- are soon replaced by erosions, crusting and scaly plaques sometimes resem-
stood, but in some cases the exposure is thought somehow to trigger or bling impetigo (Figs 5.43, 5.44).2,6 Healing is accompanied by hyperpig-
induce pemphigus. The term ‘contact pemphigus’ has been proposed as a mentation, but scarring is not a feature.3 Lesions are frequently itchy and
designation for this phenomenon, which has been described in the vulgaris, malodorous. Sometimes pain is a considerable problem, particularly if fissur-
vegetans, foliaceus and erythematosus variants.1,2 Substances that have been ing is present.3 Symptoms often improve with advancing age.1 Superinfection
implicated include nickel, pesticides, chromium sulfate, tincture of benzoin, by Candida albicans, herpes virus, and Staphylococcus aureus are frequent
phenol, diclofenac, dihydrodiphenyltrichlorethane, ketoprofen, feprazone, complications.7,8 Segmental involvement has rarely been reported as a result
and imiquimod.1–14 Clearly, further study is necessary to elucidate the rela- of type 1 or type 2 mosaicism according to the classification by Happle, and it
tionship between exposure to topical agents and contact pemphigus. has now become clear that at least some of the cases of relapsing linear acan-
tholytic dermatosis represent type 2 segmental Hailey-Hailey disease.9–13
Pathogenesis and histological features The development of the lesions is related to mechanical trauma, stress,
Whether this phenomenon relates to systemic absorption, contact allergy or and ultraviolet radiation and exacerbation of the disease has been reported
a direct ‘toxic’ effect on epidermal antigens is as yet unknown. It is interest- due to scabies, contact irritation, and patch testing.14–18 An exceptional case
ing to note that in the majority of documented cases, the patient has been of a patient developing the disease while on efalizumab for psoriasis has been
exposed to the offending agent for a considerable period of time before the reported.19 Symptoms often improve or even disappear during winter, but
onset of the blistering eruption.6 tend to worsen in summer.1,20 Mucosal involvement is unusual. Anogenital
Biopsy of contact pemphigus shows histological features similar to those disease, however, occasionally presents as multiple 3–5-mm diameter warty
of p. vulgaris, although one patient developed features more reminiscent of
pemphigus vegetans. Immunofluorescent studies show intercellular IgG and
sometimes C3.

Differential diagnosis
The main differential diagnosis is with classic pemphigus. Only clinical infor-
mation will allow distinction of contact pemphigus from other members of
the pemphigus family of disorders.

Acantholytic dermatoses with dyskeratosis

Hailey-Hailey disease
Clinical features
Hailey-Hailey disease (benign familial pemphigus) is a rare, episodic, acan-
tholytic disorder with an autosomal dominant mode of inheritance.1,2 In only
about two-thirds of patients, however, is a family history obtained. There is
an equal sex incidence.2,3
Lesions usually present in the second to fourth decades and appear par- Fig. 5.43
ticularly at sites of minor trauma or friction, especially flexural, around the Hailey-Hailey disease: lesions are most often seen in the flexures as a consequence
neck, and in the axillae and groin (Fig. 5.42). However, other sites, such of friction. By courtesy of the Institute of Dermatology, London, UK.
168 Acantholytic disorders

differentiation demonstrate premature expression and reduced levels of invo-

lucrin due to increased mRNA degradation, and it has been proposed that
intact ATP2C1 is necessary for basal cell layer keratinocytes to maintain their
undifferentiated state.56,57 A number of interesting observations have been
made recently in both Hailey-Hailey and Darier's disease that provide further
insight into how the alteration in the calcium gradient affects ATP receptors
and keratin expression.58 In both diseases there is a lower level of calcium in
the basal cell layer of the epidermis compared to normal skin, the ATP recep-
tor P2Y2 is not identified at the cellular membrane in affected cells whereas
P2X27 which is usually not present on the cellular membrane is expressed in
these cells probably mediating apoptosis. Furthermore, both keratins 14 and
10 are expressed in diseased cells whereas these keratins are mutually exclu-
sive in normal keratinocytes.
While early lesions show suprabasilar lacunae, established Hailey-Hailey
disease is characterized by massive acantholysis associated with suprabasal
vesicle or bulla formation.3 Typically, however, the acantholysis is incom-
plete, the cell retaining some connections and giving an appearance often
­likened to a ‘dilapidated brick wall’ (Figs 5.45–5.47). The adnexal epithelium
is usually spared. Occasionally, dyskeratotic cells resembling the corps ronds
Fig. 5.44 and grains of Darier's disease are seen.
Hailey-Hailey disease: close-up view of keratotic warty lesions. By courtesy of the
Institute of Dermatology, London, UK.

papules.21 This occurs most often in females, particularly blacks, and some-
times may be a presenting feature. In such instances there is overlap with
papular acantholytic dyskeratosis of the vulva.22
Asymptomatic white longitudinal bands may be present on the fingernails
in up to 70% of affected patients.1,23 The other nail changes of Darier's dis-
ease are absent.
Significant associated conditions have not been documented with the pos-
sible exception of a bipolar disorder and a patient with affective disorder (see
Darier's disease).24,25 An association with supernumerary nipples has been
documented in one Tunisian family.26
Exceptionally, squamous carcinoma has been documented as a compli-
cation in patients with Hailey-Hailey disease.27 It is likely, however, that
those arising on the vulva have a human papillomavirus-associated basis.28,29
Condylomatous change and evidence of HPV infection has recently been
detected in genital lesions of the disease.30,31
While it has rarely been reported that Darier's disease may coexist with
Hailey-Hailey disease, the available evidence supports the contention that
these two conditions represent completely different entities.32
Fig. 5.45
Pathogenesis and histological features Hailey-Hailey disease: early lesion showing the characteristic ‘dilapidated brick wall’
appearance.
Hailey-Hailey disease is primarily an abnormality of cell adhesion.
Development of this disease has recently been shown to be caused by mul-
tiple mutations in ATP2C1 on chromosome 3q21–24, a gene that encodes the
calcium pump SPCA1.33,34 SPCA1 is a Ca2+/Mn2+ ATPase present within the
membrane of the Golgi apparatus and responsible for the transport of Mn2+
as well as Ca2+ ions into the Golgi.35,36 Over 100 mutations have been identi-
fied spanning the entire ATP2C1 gene including missense, frameshift, splice
site as well as nonsense mutations.37–46 However, no clear genotype–pheno-
type correlation has emerged as yet. Studies have shown that calcium regula-
tion in cultured keratinocytes is impaired.33 In addition, there is evidence that
integrity of intercellular junctions may be dependent on intracellular calcium
stores.47–50 The precise mechanism by which the abnormality in the calcium
pump causes acantholysis is not known. However, the addition of calcium to
monolayers of squamous cells in culture elicits stratification.48 In contrast,
cells grown in low calcium medium fail to stratify.50 It should be noted that
Darier's disease, another disorder showing acantholysis, is also associated
with a mutation in another calcium pump – ATP2A2. That both of these dis-
orders of acantholysis are associated with mutations in a calcium pump is
strong evidence for an important role in maintaining cell–cell cohesion.
Immunohistochemical studies have confirmed that the major desmosomal
proteins and glycoproteins are synthesized in Hailey-Hailey disease and dis-
tributed along the plasma membranes in uninvolved epidermis.51 In lesional Fig. 5.46
skin there is marked cytoplasmic labeling for the desmoplakins (DpI, DpII), Hailey-Hailey disease: in this example, there is marked hyperkeratosis, parakeratosis,
desmogleins (Dsg2, Dsg3) and the desmocollins.51–55 Studies on keratinocyte and acanthosis. Villi project into the blister cavity.

Fig. 5.47
Hailey-Hailey disease:
in contrast to Darier's
disease, dyskeratosis is
usually minimal or even
absent.
Ultrastructural studies have primarily disclosed abnormalities of the des-
mosome-tonofilament units, characterized by diminished numbers of desmo-
somes and clumped tonofilaments.59–62 The latter have a linear distribution in
the basal keratinocytes, but develop a whorled configuration in the suprabasal
layers.60,62 The cell membranes show microvillus formation.59 An electron
microscopic study of artificially induced early lesions suggests the desmo-
somal splitting precedes the tonofilament clumping.61 Dyskeratotic cells are
characterized by condensed tonofilaments surrounding pyknotic nuclei.
Differential diagnosis
The histological features of Hailey-Hailey disease must be distinguished from
those of Darier's disease, p. vulgaris, and Grover's disease. Pemphigus is dis-
tinguished from Hailey-Hailey disease by the presence of relatively intact epi-
thelium in the adjacent epidermis (versus disintegrating ‘dilapidated brick
wall’) and involvement of adnexal structures. In difficult cases, positive
immunofluorescence staining supports a diagnosis of pemphigus. Darier's
disease tends to show prominent suprabasal cleft formation with involve-
ment of adnexae and is associated with numerous corps ronds and grains.
These points of distinction are summarized in Table 5.2.
Immunofluorescence studies for immunoglobulin and complement are
invariably negative, aiding in the distinction from immunobullous disorders.
Distinction from acantholytic dermatosis of the genital area can, however,
be extremely difficult. In fact, the relationship between these disorders is not
well understood. The combination of clinical features of a lesion or lesions
localized to the vulvogenital area and a negative family history favors acan-
tholytic dermatosis of the genital area.
Relapsing linear acantholytic dermatosis
Clinical features
Relapsing linear acantholytic dermatosis (Hailey-Hailey-like epidermal
nevus) is an exceptionally rare nevus-like condition characterized by ery-
thematous plaques with vesicles and erosions arranged in a linear distribu-
tion along Blaschko's lines.1–3 It typically undergoes spontaneous resolution
followed by recurrence and has a chronic course. Insufficient cases have been
documented to precisely determine its relationship to Hailey-Hailey disease.
Recent data, however, demonstrate that at least some of the patients harbor
mutations in the gene responsible for Hailey-Hailey disease, the ATP2C1.
Acantholytic dermatoses with dyskeratosis 169
The disease has been shown to be a type-2 mosaicism according to Happle,
resulting in homozygosity for the mutated gene and pronounced disease in a
segmental distribution superimposed on more classical disease in a heterozy-
gous individual.4–7
Histological features
The features are indistinguishable from Hailey-Hailey disease.
Darier's disease
Clinical features
Darier's disease (keratosis follicularis, morbus Darier), which is character-
ized by abnormal keratinocyte adhesion, is a rare hereditary disorder, usually
transmitted in an autosomal dominant pattern. In a large series, however,
47% of patients had no clear family history of Darier's disease.1 Presumably
these cases represent new mutations or evidence of incomplete penetrance.
Its documented incidence is variable. In Oxfordshire (UK), the incidence is
1:55 000, in the north of England it is 1:36 000, in the west of Scotland it is
1:30 000, whereas in Denmark it is 1:100 000.2–5 The sex incidence is equal,
although males appear to be more severely affected than females. The disease
usually presents in the first or second decade (with a peak around puberty)
and often follows exposure to ultraviolet light.1 Exceptionally, patients may
not present until their sixth or seventh decade.6 Darier's disease is a long-term
illness. Remissions do not occur, although some patients show improvement
with increasing age.6
The lesions are frequently itchy and, less commonly, painful.1,6 They
are characterized by greasy, crusted, keratotic yellow-brown papules and
plaques found particularly on the ‘seborrheic’ areas of the body – the scalp,
forehead, ears, nasolabial folds, upper chest, back, and supraclavicular fos-
sae (Figs 5.48–5.52).1,5 There is mild involvement of the flexures in the
majority of patients although sometimes this distribution predominates.1,6
Lesions may be induced or exacerbated by stress, heat, sweating, and mac-
eration.1,7 In some areas the lesions have a warty appearance, while in the
flexures they are often vegetative, malodorous (a particularly distressing
problem), and often secondarily infected (Figs 5.53, 5.54).6 Bullous lesions
generally following sun exposure can occur, albeit rarely.8–10 Leukodermic
macules in black patients have also been described.11–14 Additional features
including cutaneous horns and hemorrhagic palmar lesions have also been
documented.15–18
Patients with Darier's disease are susceptible to bacterial (particularly
Staphylococcus aureus), dermatophyte, and viral infections.1,19,20 There are
rare case reports of eczema vaccinatum and eczema herpeticum complicating
Fig. 5.48
Darier's disease: in this patient keratotic brown papules are present on the back of
the neck. From the slide collection of the late N.P. Smith, MD, The Institute
of Dermatology, London, UK.
170 Acantholytic disorders
Fig. 5.49
Darier's disease: close-up view of keratotic papules. From the slide collection of the
late N.P. Smith, MD, The Institute of Dermatology, London, UK.
Fig. 5.50
Darier's disease: this patient shows a striking symmetrical distribution. From the
slide collection of the late N.P. Smith, MD, The Institute of Dermatology, London, UK.
Darier's disease and a patient who developed localized anogenital cowpox
has also been reported.21–23 Life-threatening Kaposi's varicelliform eruption is
a rare but important complication.24–26 No consistent abnormality of immune
function has been found to explain this.27,28 Recently, however, persistence of
intracellular S. aureus small-colony variants in a patient with Darier's disease
has been shown to be of importance in chronic cutaneous infection and resis-
tance to antibiotic therapy.29 Whether this mechanism is involved in other
patients awaits confirmation.
Other cutaneous manifestations of Darier's disease include unilateral, lin-
ear or zosteriform variants, which some regard as acantholytic, dyskeratotic
epidermal nevi rather than true Darier's disease (see below).30,31 It is more
likely that these variants, at least in part, result from genetic mosaicism.32
The hands are affected in 96% of patients.1 Pits and punctate keratoses
with focal disruptions of the skin ridges of the palms and soles are charac-
teristic features (Fig. 5.55).1,6,33 Acrokeratosis verruciformis-like lesions are
common on the backs of the hands.1 Indeed, acrokeratosis verruciformis of
Hopf, a localized disorder of keratinization of distal extremities, is closely
related to Darier's disease and appears to be caused by mutations in the same
gene.34,35
Nail changes are a particularly important diagnostic feature.1,2,6,36,37
Longitudinal white or red streaks (often both), some of which ­terminate
Fig. 5.51
Darier's disease: lesions
may be induced by heat,
sweating, and maceration.
From the slide collection
of the late N.P. Smith,
MD, The Institute of
Dermatology, London, UK.
Fig. 5.52
Darier's disease: close-up view. From the slide collection of the late N.P. Smith, MD,
The Institute of Dermatology, London, UK.
in a small nick on the free margin, are typical findings (Figs 5.56,
5.57).1 Painful splitting and subungual hyperkeratoses are additional
­manifestations.1 The toenails are affected less often (and less severely) than
the ­fingernails.1 Subtle hand and nail manifestations may sometimes be a
­presenting feature.6
The mucous membranes of the mouth, pharynx, larynx, esophagus, and
female genitalia can also be affected.38–41 Oral lesions are present in up to
50% of patients and consist of small white papules on the hard palate.42,43
Large nodular and verrucous plaques are also sometimes present and occa-
sionally there are gingival, buccal mucosal, and tongue lesions.15 Involvement
of the salivary ducts is said to be uncommon and results in ­salivary gland
swelling with obstruction and sialadenitis.44,45 Recently, however, one
series reported an incidence of 30% involvement of the parotid gland.42
Anal ­involvement may present as pruritus ani or less often as ­vegetating
­malodorous plaques.46

Fig. 5.53
Darier's disease: skin
involvement as severe
as this is fortunately
extremely rare. By
courtesy of M. Greaves,
MD, the Institute of
Dermatology, London, UK.
Fig. 5.54
Darier's disease: severe involvement can be very disfiguring and a source of
considerable disability and embarrassment. By courtesy of M. Greaves, MD, the
Institute of Dermatology, London, UK.
Ocular lesions, particularly affecting the cornea, are seen in up to 76%
of patients.47 Peripheral corneal opacities and central epithelial irregularity
are the usual findings. Pannus formation may rarely be present. Lesions are
­typically asymptomatic.
Associated systemic abnormalities are unusual, but include epilepsy,
­pulmonary lesions, bone cysts, low intelligence, and small stature.1 Various
neuropsychiatric problems including depression and bipolar disorder have
been linked with Darier's disease.6,48 There is some evidence to suggest that
there is familial cosegregation of bipolar disorder with Darier's disease, at
least in a proportion of cases.48,49
Rare and likely incidental associations include visceral malignancy, horse-
shoe kidney, hemodialysis, gynecomastia, cutis verticis gyrate, and Fanconi
anemia.50–55
Spontaneous remissions in Darier's disease are rare, and in the majority of
patients the disease persists throughout life.
Acantholytic dermatoses with dyskeratosis 171
Fig. 5.55
Darier's disease: palmar pits are a helpful diagnostic clue. By courtesy of J. Wilkinson,
MD, Wycombe General Hospital, High Wycombe, UK.
Fig. 5.56
Darier's disease:
parallel white and red
longitudinal streaks are
pathognomonic features.
By courtesy of the
Institute of Dermatology,
London, UK.
Pathogenesis and histological features
Positional cloning studies of different families have all shown the gene of
Darier's disease to be located at 12q23-q24.56,57 Mutations in ATP2A2, a
gene that encodes for SERCA2 (type 2 sarcoendoplasmic reticulum CA2+-
ATPase), cause the disease and have been identified in the majority of patients
screened.57 So far, over 100 different mutations have been reported. They are
predominantly missense mutations, but frameshift and splice site mutations
as well as mutations resulting in a premature stop codon have also been iden-
tified.58–67 However, no clear genotype–phenotype correlation has emerged.
The disease is likely a result of haploinsufficiency since only one correct copy
of the ATP2A2 gene is expressed.68 The mutant copy may furthermore lead
to enhanced proteasome-mediated degradation and/or protein dimerization
resulting in complete loss of SERCA2 activity.68,69 The precise mechanism
of how mutations in the ATP2A2 gene lead to disease is unknown although
172 Acantholytic disorders

Fig. 5.58
Fig. 5.57 Darier's disease: very early lesion showing multiple characteristic corps ronds.
Darier's disease: notches
on the free margin of the pyknotic nucleus surrounded by a clear halo enclosed within a basophilic
nail are common findings. or eosinophilic ‘shell’ (Fig. 5.58). Variable amounts of highly irregular
By courtesy of the keratohyalin granules may also be evident.
Institute of Dermatology, • Grains are located within the horny layer and consist of somewhat
London, UK. flattened oval cells with elongated cigar-shaped nuclei and abundant
keratohyalin granules.
In the fully established lesion there is hyperkeratosis and often parakera-
there is emerging evidence to suggest that the integrity of intercellular junc-
tosis, sometimes arranged in a clearly defined tier (Figs 5.59–5.61). The epi-
tions is dependent on the intracellular calcium stores.70 SERCA is a ubiqui-
dermis may appear acanthotic or atrophic and typically shows acantholysis
tously expressed calcium-ATPase and its function is the transport of cytosolic
with suprabasal cleft formation in which the underlying dermal papillae, cov-
calcium ions into the endoplasmic reticulum.68 There are three different genes
ered by a single layer of epithelium, project into the cavity (villus formation).
encoding these proteins, resulting in a total of nine different isoforms. Of the
The roof contains variable numbers of grains and the adjacent epithelium has
different isoforms only SERCA2b appears to be expressed in keratinocytes.71
variable numbers of corps ronds. Occasionally, epithelial proliferation can be
Loss of SERCA2 function can therefore not be compensated for, explaining
marked, resulting in pseudoepitheliomatous hyperplasia. Bullous lesions are
the severe skin manifestations in the absence of further systemic involvement
illustrated in Figures 5.62 and 5.63.
in most patients with Darier's disease.68 Ultimately, intact intracellular cal-
There may be a perivascular chronic inflammatory cell infiltrate in the
cium ion homeostasis has been identified as a major factor in the complex
superficial dermis, although this is not a common finding.
process of desmosome assembly and is necessary for intracellular interactions
The histological features of the oral, pharyngeal, laryngeal, and esopha-
between desmosomal cadherins and intracellular plaque proteins such as pla-
geal lesions are similar to those described in the skin although dyskeratosis
koglobin.68,72 Apoptosis in Darier's disease resulting in dyskeratotic cells is
is said to be less conspicuous.42 Salivary gland lesions show ductal dilata-
likely directly related to the imbalance in calcium homeostasis, and immuno-
tion and squamous metaplasia of the lining epithelium with acantholysis and
histochemical studies have revealed reduced expression of antiapoptotic pro-
dyskeratosis.44,45
teins of the bcl-2 gene family in lesional epidermis.73–75
No single specific ultrastructural abnormality has been identified in
Darier's disease. Changes described have included complete loss of desmo-
somes in foci of acantholysis with formation of cell membrane microvilli,
cytoplasmic vacuolization, cell membrane defects, abnormal tonofilament
aggregation, clumping and distribution, premature and abnormal forma-
tion of keratohyalin granules and membrane coating (Odland) bodies, and
excessive lipid lamellae between the flattened keratinocytes of the stratum
corneum.76–80 Hemidesmosomes and the lamina densa usually appear morpho-
logically normal, although discontinuities of the latter have been described.
Ultrastructurally, corps ronds are characterized by large dense keratohyalin
masses, numerous membrane coating granules, and tonofilament clumps.76
They are distributed particularly around the nucleus, often surrounding a
perinuclear cytoplasmic halo containing distended vesicles. Grains of Darier
are composed of nuclear remnants with surrounding dyskeratotic debris.76
Acantholysis develops as a consequence of desmosomal breakdown and
dissociation of tonofilaments, although which comes first is uncertain.
The histological features of Darier's disease depend upon a variable
­interplay between acantholysis and abnormal keratinization (dyskeratosis),
the acantholysis resulting in suprabasal cleft formation (and rarely vesicles
or even blisters), and the dyskeratosis manifesting as corps ronds and grains
of Darier. Fig. 5.59
• Corps ronds are large structures, usually most conspicuous in the Darier's disease: scanning view through a typical lesion. Note the keratotic tier and
granular layer, and consist of an irregular eccentric and sometimes suprabasal cleft formation.

Fig. 5.60
Darier's disease: higher-power view showing the well-developed vesicle with
suprabasal acantholysis and well-developed corps ronds and grains.
Fig. 5.61
Darier's disease: in this example both corps ronds and grain of Darier are evident.
Fig. 5.62
Darier's disease: bullous variant showing suprabasal acantholysis, epidermal
regeneration and a subcorneal blister.
Acantholytic dermatoses with dyskeratosis 173
Fig. 5.63
Darier's disease: high-power view of Figure 5.62 showing multiple corps ronds.
Corneal lesions are characterized by corneal epithelial edema, subepithe-
lial granular deposits, and basement membrane thickening. Acantholysis and
dyskeratosis are not seen.47
Differential diagnosis
Although warty dyskeratoma, Hailey-Hailey disease, and pemphigus are
­considered in the differential diagnosis of Darier's disease, their distinction is
not challenging when clinical information is considered. Warty dyskeratoma
is a single umbilicated lesion that typically forms more pronounced papillary
structures. Hailey-Hailey disease is characterized by full-thickness epidermal
acantholysis and does not show extensive dyskeratosis. Grover's disease may
be indistinguishable from Darier's disease in a given biopsy, but the lesions are
usually small, spanning only a few rete ridges. The presence of some combina-
tion of spongiosis, and changes mimicking more than one of the ­acantholytic
dermatoses, is characteristic of Grover's disease. In cases that show only Darier-
like changes, clinical information should allow for ­definitive diagnosis.
Linear Darier's disease
Clinical features
Linear Darier's disease (acantholytic dyskeratotic epidermal nevus, unilat-
eral Darier's disease, zosteriform Darier's disease, segmental Darier's disease)
is a rare acquired condition characterized by the development of grouped,
keratotic, sometimes pruritic, yellow-brown papules which affect the trunk,
trunk and limbs, limbs, scalp, vulva, and face in decreasing order of frequency
(Fig 5.64).1–9 Their linear distribution corresponds to the lines of Blaschko.
Lesions may be aggravated by sunlight, heat, and sweating. Although a wide
age range may be affected, the majority of patients are in the third or fourth
decade. There is an equal sex incidence. There is no family history of Darier's
disease. Usually, patients are free from other stigmata of Darier's disease but
there are very occasionally reports of patients with linear lesions associated
with ipsilateral nail changes and palmar pits typical of Darier's disease.10,11
Pathogenesis and histological features
The precise nature of this lesion remains conjectural. Although many authors
prefer to regard it as a variant of epidermal nevus with superimposed acantho-
lytic dyskeratosis, there is an alternative school of thought which believes that
many, if not all, such lesions represent localized or unilateral Darier's disease,
arguing that the condition develops as a consequence of genetic mosaicism.
Certainly, the late age of onset is unlike a typical epidermal nevus, which usu-
ally presents in childhood. The distribution along the lines of Blaschko and
the occasional reports of additional Darier-like features on the ipsilateral side
of the body offers support to a concept of localized Darier's disease. Recently,
174 Acantholytic disorders

Fig. 5.64 Fig. 5.65

Linear Darier's disease: the trunk is a commonly affected site. Note the small papules. Grover's disease:
Courtesy of the Institute of Dermatology, London, UK. innumerable
erythematous papules
ATP2A2 mutations have been identified in lesional tissue but not unaffected are present on the chest
skin patients with linear acantholytic epidermal nevi, confirming the relation- wall. By courtesy of the
ship of these lesions to Darier's disease.12,13 Institute of Dermatology,
London, UK.
Histologically, these lesions are indistinguishable from Darier's disease.

Differential diagnosis
Very rarely, true epidermal nevus may show histological features of acan-
tholysis and dyskeratosis presenting against a background of a verrucous
plaque characterized by marked acanthosis and papillomatosis.14,15 Such
lesions, which are present at birth, would be best classified as epidermal
nevus ­showing acantholysis and dyskeratosis rather than being included in
the spectrum of acantholytic dyskeratotic epidermal nevus.

Transient acantholytic dermatosis

(Grover's disease)
Clinical features
Transient acantholytic dermatosis (persistent acantholytic dermatosis) is a
primary acquired, self-limiting, acantholytic disease of unknown etiology,
seen predominantly in the middle aged or elderly although there are rare
reports of the disorder in children.1–5 Males are affected more often than
females (3:1).2,3 The white races are predominantly affected.5 Cases involv-
ing blacks are exceptionally rare.6 The disease shows a predilection for the
winter months in nonhospitalized patients.7 Although the disease is usu-
ally transient, persistent and recurring variants have also been described
(persistent acantholytic dermatosis) in the literature.8–10 The development
of Kaposi's varicelliform eruption is a rare and unusual complication of
the disease and occult colonization by herpes simplex virus has also been
documented.11,12
The skin lesions are usually rather polymorphic, consisting of 1–3-mm
erythematous, red-brown or flesh-colored papules, vesicles, and eczema-
tous plaques with a predilection for the chest, back, and thighs (Figs 5.65
and 5.66).2 The palms and soles are unaffected. Superimposed excoria-
tions are associated with the intensely pruritic eruption. Pustular, bullous,
nummular, follicular herpetiform, and zosteriform variants have all been
­documented.2,13–16 The mucous membranes, palms, and soles are commonly
spared although there are rare reports of oral, nasal, and laryngeal involve-
ment.2,17,18 Postinflammatory pigmentary changes following resolution of
the acute phase are common. Transient acantholytic dermatosis has been
described in ­association with leukemia and lymphoma in addition to numer-
ous solid tumors including carcinoma of kidney, renal pelvis, bladder, and
prostate.2,19–24 In one study, 25% of patients had some form of malignancy.21
Other rare associations include scabies, renal failure, peritoneal dialysis,
Fig. 5.66
Grover's disease: close-up view. By courtesy of the Institute of Dermatology,
London, UK.
and renal as well as bone marrow transplantation.25–29 It is likely, however,
that the majority of these associations are coincidental. Transient acantho-
lytic ­dermatosis shows a positive correlation with asteatotic eczema, allergic
­contact dermatitis, and atopic dermatitis.3,30,31
Pathogenesis and histological features
The pathogenesis of Grover's disease is incompletely understood. There are,
however, a number of important known etiological factors including:
• sun exposure,
• excessive heat and sweating,
• ionizing radiation,
• adverse reaction to drugs.
Transient acantholytic dermatosis has long been known to be associated
with sun exposure.2,3,32–35 The lesions are photodistributed and the patients
commonly give a history of having recently spent time in the sun.36 There
is also a well-established relationship to excessive heat and sweating.35,37–39
 Acantholytic dermatoses with dyskeratosis 175

Bedridden, febrile patients are particularly at risk and as a result it has

been proposed that the pathogenesis might be analogous to that of miliaria.
Occlusion of sweat ducts and increased sweating resulting in acantholysis
mediated by high concentrations of sweat urea has been proposed, although
this has yet to be proven.40 More recent immunohistochemistry studies have
not generally offered support for this hypothesis although bedridden, febrile
patients may occasionally show prominent involvement of the eccrine duct;
this has been termed sudoriferous acrosyringeal acantholytic disease.21,41,42
Associations with sunlamps, sun parlors, PUVA therapy, steam bath, hot tub,
hot water bottle, and polyester jogging suits have also been documented.1,2,21
Despite these well-recognized associations, there must be other important
predisposing factors, since overexposure to sunlight and excessive sweating
are extremely common yet this disease is rare.
Very occasional reports have described transient acantholytic dermato-
sis developing after radiotherapy for cancer, exceptionally with lesions con-
fined to the area of the port.2,22,43,44 Only a small number of drugs have
been associated (rarely) with the development of transient acantholytic der-
matosis.2 There are reports of lesions following treatment with sulfadox-
ine-pyrimethamine, 2-chlorodeoxyadenosine, D-penicillamine, recombinant
interleukin-4, cetuximab, and induction chemotherapy for allogeneic bone Fig. 5.68
Grover's disease: high-power view showing acantholysis.
marrow transplantation.45–50 The presence of eosinophils in the dermal
inflammatory cell infiltrate has raised the possibility of a hypersensitivity
reaction.21 Occasional cases arising in patients with HIV infection have been
recorded.21
Despite the histological similarity to Darier's and Hailey-Hailey diseases,
there is no evidence of a mutation in the ATP2A2 gene.51
There have been a variety of both direct and indirect immunofluores-
cence observations including lupus erythematosus-like, bullous pemphigoid-
like, and pemphigus-like findings.21,52 These are reviewed in reference 2. They
are the exception rather than the rule and are unlikely to be of any great
significance.
Immunohistochemistry observations have included a reduction or absence
of desmosomal staining with cytoplasmic redistribution of the proteins,
­desmoplakins I and II, plakoglobin, and desmoglein.53–55 Redistribution and
dissolution of desmosomal attachment plaques have been demonstrated as
the first stage in the development of Grover's disease.55
Instead of featuring specific histopathological changes, transient acantholytic
dermatosis mimics three other diseases: Darier's disease, Hailey-Hailey disease,
and pemphigus (p. vulgaris and p. foliaceus) (Figs 5.67–5.70).21 The first is by
far the most commonly encountered. Thus, in the typical case, there is hyperker-
atosis, parakeratosis, acanthosis, and acantholysis ­accompanied by corps ronds
formation and grains of Darier. In the Hailey-Hailey pattern, the acantholy- Fig. 5.69
sis is much more pronounced such that the dilapidated brick wall appearance Grover's disease: this example is indistinguishable from pemphigus vulgaris.
is seen. Follicular involvement may be present. In the ­pemphigus-like ­variant,

Fig. 5.67 Fig. 5.70

Grover's disease: low-power view showing an intact intraepidermal vesicle. Grover's disease: early lesion showing intraepidermal vesiculation.
176 Acantholytic disorders

­ yskeratosis is typically absent. Multiple specimens from any one patient

d
may disclose differing histological variants, and superimposed spongiosis is
often present. Occasional bullae are encountered. A variable dermal mononu-
clear infiltrate is usual and significant numbers of eosinophils are seen in some
cases.21
Patients with sudoriferous acrosyringeal acantholytic disease show, in
addition to typical features of Grover's disease, acantholysis of the ­superficial
portion of the eccrine duct.

Differential diagnosis
Clinically, transient acantholytic dermatosis is easily differentiated from
Darier's disease, Hailey-Hailey disease, and pemphigus. However, the biopsy
findings often mimic these diseases. A histological clue to the diagnosis is the
small size of the lesion. Usually only one or two small discrete lesions that
span a few rete ridges are noted. This is in contrast to other acantholytic­
dermatoses, which tend to involve the entire biopsy. Biopsies from a patient
with Grover's disease often show varying features mimicking more than one
of the acantholytic dermatoses and occasionally a number of patterns are
seen in a single biopsy specimen. Sometimes, a biopsy will show non-spe-
Fig. 5.71
cific features of spongiotic dermatitis. The association of both spongiosis and Warty dyskeratoma: scaly nodule on the scalp, a commonly affected site. By courtesy
acantholysis may be a useful pointer to the diagnosis of Grover's disease (see of the Institute of Dermatology, London, UK.
also Table 5.2).
in the literature.2,3 Although the cutaneous lesions are believed to be of folli-
Acantholytic dermatosis of the cular derivation, histologically similar nodules have been described affecting
the oral and vulval mucosa.8–11 The former occur most often on ­keratinized
genitocrural area mucosa of the palate, alveolar ridge, and gingiva.9 Subungual warty dyskera-
toma-like lesions have also been documented.12
Clinical features
In acantholytic dermatosis of the genitocrural area (papular acantholytic Pathogenesis and histological features
dermatosis of the vulvocrural area) focal dyskeratosis and/or acantho- The etiology of warty dyskeratoma is unknown, although in the past authors
lysis may present as an isolated phenomenon on the vulvocrural region have suggested an effect of actinic radiation or possibly a viral infection.
of young or middle-aged females.1–10 Lesions sometimes extend on to the Neither of these has been substantiated. There is no relationship with Darier's
thigh and perineum.5 Patients present with variably pruritic, multiple, disease. Multiple lesions have been associated with chronic renal disease.5,6
0.1–0.4-mm isolated or groups of white papules, solitary keratotic nod- Warty dyskeratoma is most probably of follicular derivation. Thus, many
ules or, less often, with erythematous or white plaques measuring up to examples appear in continuity with a dilated hair follicle and, less frequently,
1.0 cm in diameter involving the labia majora or inguinal region. More a sebaceous gland may be evident.3,6 The recent observation of positive stain-
recently, cases with histologically similar findings have been described in ing with antibodies directed towards cortex and inner root sheath provides
males, presenting on the penis, scrotum, thigh, perianal region, and in the additional support. Mucosal and subungual variants must have a different
anal canal.11,12 derivation.
Family history is invariably negative for either Darier's or Hailey-Hailey Histologically, warty dyskeratoma is composed of a widely dilated cup-
disease and, by definition, there is no evidence of similar lesions elsewhere on shaped or cystic lesion containing keratinous debris and often associated
the body.4 Two cases have developed in the presence of syringomas.1 with a hair follicle (Fig. 5.72). Superficially, the keratinous debris contains
­conspicuous corps ronds and grains of Darier. The adjacent and deeper
Pathogenesis and histological features ­epithelium shows marked acantholysis and suprabasal villi are a prominent
The pathogenesis is unknown although it is likely that the moist environment feature (Figs 5.73 and 5.74). The underlying dermis is often infiltrated by
of the body folds is of importance. Candida albicans infection has accompa- lymphocytes and histiocytes, and sometimes plasma cells are evident.
nied a number of cases although this may have been coincidental.4,6 With the
exception of one case showing intracellular IgG and C3 staining, immuno-
fluorescence (when performed) has been negative.3–5,8
The lesions show features of hyperkeratosis, parakeratosis, acantho-
sis, and acantholysis, sometimes with dyskeratosis, resembling Darier's or
Hailey-Hailey disease. Warty dyskeratoma-like features associated with fol-
licular involvement may also be encountered.2,4 Typically, minimal or no
inflammation is present.

Warty dyskeratoma
Clinical features
Warty dyskeratoma is a peculiar hyperkeratotic, umbilicated, persistent nodule
that usually presents on the sun-exposed skin of the head and neck of middle-
aged adults, although lesions on the trunk and extremities have ­occasionally
been documented (Fig. 5.71).1–4 Most cases are solitary, but occasional patients
with multiple tumors have been reported, particularly in Japanese patients.3,5–7
Lesions are commonly asymptomatic but ­occasionally discharge and bleeding Fig. 5.72
may be encountered.2 There are conflicting data ­regarding gender distribution Warty dyskeratoma: typical scanning view of a cystic nodule with acantholysis.

Fig. 5.73
Warty dyskeratoma: note
the acantholysis and villi.
Fig. 5.74
Warty dyskeratoma: corps
ronds are conspicuous.
Oral lesions can be morphologically indistinguishable although a num-
ber of cases more likely represent focal acantholytic dyskeratosis arising
in a background of a benign trauma-related keratosis. A single case report
has documented verruciform xanthoma-like features within a typical oral
lesion.13
Differential diagnosis
Although there are histological similarities with familial dyskeratotic come-
dones, Darier's disease, Hailey-Hailey disease, and Grover's disease, deeply
penetrating crateriform lesions with villus formation are not associated with
these entities. In addition, the clinical findings of a solitary umbilicated
Acantholytic dermatoses with dyskeratosis 177
nodule should not be confused with any of the above disorders with the
­possible exception of familial dyskeratotic comedones; however, villi are not
­conspicuous in the latter. There is also considerable overlap with both focal
acantholytic dyskeratosis and acantholytic acanthoma; however, in neither of
these conditions is there a deeply penetrating crateriform lesion.
Familial dyskeratotic comedones
Clinical features
Although thought to be common, familial dyskeratotic comedones have been
extremely rarely documented in the literature. To date, fewer than 10 families
have been reported.1–8 The condition is characterized by an autosomal domi-
nant mode of inheritance. Lesions develop in childhood or adolescence and
are permanent.5 Patients present with 1–3-mm diameter papules containing
small hard keratotic plugs, which on removal leave crateriform lesions resem-
bling comedones (Fig. 5.75). Cutaneous horns may also sometimes be appar-
ent (Fig. 5.76).2 Lesions are often generalized but show a predilection for
the extremities, particularly the forearms and thighs. The face, scalp, palms,
soles, and mucous membranes are typically unaffected. Some patients com-
plain of pruritus or inflammation. There is no evidence of ectodermal dyspla-
sia and systemic lesions are absent.
Histological features
The lesions are characterized by a follicle-like crateriform cystic cavity con-
taining laminated hyperkeratotic and parakeratotic debris and lined by
squamous epithelium showing dyskeratosis and sometimes acantholysis at
the base (Figs 5.77, 5.78).4 Grains of Darier are typically present but corps
ronds are sparse and poorly developed. Villi, as seen in Darier's disease, are
not a feature. Hair shafts and sebaceous glands are absent.
Differential diagnosis
The consistent folliculocentric nature of the eruption and absence of nail and
oral mucosal changes help to distinguish familial dyskeratotic comedones
from Darier's disease. Corps ronds, a characteristic finding in Darier's dis-
ease, are usually not prominent in familial dyskeratotic comedones. Villus
formation and well-developed corps ronds within a solitary lesion distinguish
warty dyskeratoma.
Fig. 5.75
Familial dyskeratotic
comedones: numerous
comedones are present
on the penis and foreskin.
By courtesy of B.J.
Leppard, MD, Royal South
Hants Hospital, UK.
178 Acantholytic disorders
Fig. 5.76
Familial dyskeratotic
comedones: a small
cutaneous horn is seen
arising on the scrotum. By
courtesy of B.J. Leppard,
MD, Royal South Hants
Hospital, UK.
Fig. 5.77
Familial dyskeratotic
comedones: this section
comes from the edge of a
lesion. Note the dell with
associated hyperkeratosis
and parakeratosis. The
acanthosis is in part due
to the oblique angle of the
cut. By courtesy of B.J.
Leppard, MD, Royal South
Hants Hospital, UK.
Diffuse familial comedones differ by the absence of dyskeratosis.9,10
Familial dyskeratotic comedones may also be mistaken for Kyrle's and
Flegel's diseases:
• Kyrle's disease typically presents on the extensor aspect of the lower
extremities and presents in adulthood. There is no familial incidence.
Histolo­gically, it is characterized by transepidermal elimination of
parakeratotic and inflammatory debris. There is no dyskeratosis.
• Flegel's disease typically presents in older adults and is characterized by
epidermal atrophy, interface change, and dyskeratosis. A keratin-filled
crateriform lesion is absent.
Fig. 5.78
Familial dyskeratotic
comedones: note the
superficial dyskeratosis.
By courtesy of B.J.
Leppard, MD, Royal South
Hants Hospital, UK
Perforating folliculitis presents in adults and shows a predilection for the
extremities. It is characterized by a crateriform lesion containing a distorted
and often curled-up hair shaft.
Acantholytic acanthoma
Clinical features
Acantholytic acanthoma is a common entity consisting of a solitary, usually
asymptomatic, keratotic papule or plaque, 0.5–1.5 cm in diameter, often
with overlying scale/crust. It usually presents on the trunk, arm or neck
and is clinically thought to be a seborrheic keratosis or actinic keratosis.1–5
A  case with central umbilication reminiscent of molluscum contagiosum
has also been described.6 Very occasionally multiple lesions have been docu-
mented.7 Some patients report pruritus. Patients are usually elderly (median
age 60 years) and there is a predilection for males (2:1).2,4 Lesions are not
seen about the head, palms, and soles and the mucous membranes appear
to be spared.2
Pathogenesis and histological features
The pathogenesis of this lesion is unknown. Although one case has been doc-
umented in association with immunosuppression, it is likely that this was
coincidental.7
Diagnosis is one of exclusion and depends upon the solitary nature of the
lesion. The histological features are those of hyperkeratosis, acanthosis, and
papillomatosis accompanied by acantholysis affecting all or any layer of the
epidermis (Figs 5.79 and 5.80).1 Dyskeratosis may be evident. A perivascular
lymphohistiocytic chronic inflammatory cell infiltrate, sometimes with occa-
sional eosinophils, may be present in the superficial dermis.
Differential diagnosis
In acantholytic seborrheic keratosis the acantholysis is typically focal and
the lesion elsewhere shows the typical features of horn cysts and squamous
eddies.8 Darier's disease, acantholytic dermatosis of the genitocrural area,
warty dyskeratoma and pemphigus, Hailey-Hailey disease, and Grover's
disease may show similar histological features but are easily ­distinguished
clinically. Acantholytic actinic keratosis also shows dysplasia in addition to
acantholysis.

Fig. 5.79
Acantholytic acanthoma: low-power view showing hyperkeratosis, parakeratosis,
intraepidermal vesiculation, and multiple foci of acantholysis.
Fig. 5.80
Acantholytic acanthoma: high-power view showing acantholysis and dyskeratosis.
Acantholytic dyskeratotic acanthoma
Clinical features
Acantholytic dyskeratotic acanthoma is a recently described entity with
­clinical features similar to acantholytic acanthoma. There is a predilection for
the trunk of middle-aged to elderly adults with an equal gender distribution.1
They are solitary lesions characteristically measuring less than 1 cm with a
clinical impression of basal cell carcinoma, actinic keratosis or squamous cell
carcinoma in situ.1,2
Pathogenesis and histological features
The pathogenesis of acantholytic dyskeratotic acanthoma is unknown.
Acantholytic dermatoses with dyskeratosis 179
Histological characteristics include regular epidermal acanthosis ­showing
acantholytic dyskeratosis with grains and corps ronds.1,2 Acantholytic
acanthosis is typically confluent, affecting varying levels of the epidermis.
Occasionally, it may be confined to the granular and corneal layers or it
may be nonconfluent and multifocal.1 Cup-shaped endophytic growth and
­follicular involvement are not observed.
Differential diagnosis
Acantholytic dyskeratotic acanthoma differs from acantholytic acanthoma by
the presence of marked dyskeratosis. Focal acantholytic dyskeratosis shows
identical histological features but is an incidental finding rather than a clini-
cally distinct lesion. Warty dyskeratoma is characterized by its cup-shaped
and endophytic growth. Pemphigus, Darier's disease, and Grover's disease
differ in their clinical presentation.
Focal acantholytic dyskeratosis
Clinical features
By definition, this is an incidental histological feature without a clinical
correlate.
Pathogenesis and histological features
Focal acantholytic dyskeratosis is a descriptive histopathological term ­referring
to the finding of Darier-like features within the epidermis overlying or adja-
cent to an otherwise unrelated pathological lesion.1,2 The pathogenesis is not
known. The histological features comprise hyperkeratosis, parakeratosis with
suprabasal cleft formation, acantholysis, and dyskeratosis.3 These changes
may be seen in the overlying or adjacent epithelium in a variety of lesions,
such as basal cell carcinoma, melanocytic nevi, chondrodermatitis nodularis
helicis, malignant melanoma, dermatofibroma, and as part of an epidermal
nevus (Fig. 5.81). Focal acantholytic dyskeratosis has recently been described
in a patient with pityriasis rubra pilaris.4 It is important to ­recognize this as
an incidental finding to avoid misdiagnosis as Darier's disease.
Fig. 5.81
Focal acantholytic dyskeratosis: this example showing the changes of Darier's disease
was an incidental finding adjacent to a completely unrelated lesion. There was no
clinical evidence of Darier's disease.
Chapter
Spongiotic, psoriasiform and
6 pustular dermatoses
See
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for references and
additional material

ECZEMATOUS DERMATITIS 180 Actinic prurigo 194 Inflammatory linear verrucous epidermal
Eosinophilic spongiosis 194 nevus 214
Eczema – general considerations 180 Erythroderma 194
Sulzberger-Garbe syndrome 195
Bazex syndrome 215
Endogenous dermatitis 180
Atopic dermatitis 180 Vein graft site dermatitis 195
Papular acrodermatitis of childhood 195 PUSTULAR DERMATOSES 215
Seborrheic dermatitis 182
Discoid dermatitis (nummular eczema) 183 Pityriasis rosea 196 Pustular drug reactions 215
Hand eczema (dyshidrotic eczema, palmoplantar Juvenile plantar dermatosis 199
eczema, pompholyx) 183 Miliaria 199 Subcorneal pustular dermatosis 215
Autosensitization (Id) reaction 184 Fox-Fordyce disease 200 Toxic erythema of the neonate 217
Transient acantholytic dermatosis with prominent
Exogenous dermatitis 184 eccrine ductal involvement 200 Infantile acropustulosis 217
Contact dermatitis 184
Infective dermatitis 186 Transient neonatal pustular melanosis 218
PSORIASIFORM DERMATOSES 201
Asteatotic dermatitis 186 Eosinophilic pustular folliculitis of
Lichen simplex chronicus 188 Psoriasis 201 infancy 218
Nodular prurigo and prurigo nodule 190
Reiter's syndrome 211
Stasis dermatitis and acroangiodermatitis 192
Pityriasis alba 193 Pityriasis rubra pilaris 211

Eczematous dermatitis
This chapter discusses a number of disorders under the rubric eczematous der-
matitis, also called eczema and spongiotic dermatitis. The term eczema refers to
a group of disorders that share similar clinical and histological features but may
have different etiologies. Some object to a diagnosis of eczema since it does not
reflect a specific disease but is a non-specific term that simply can be used for any
clinical lesion that exhibits spongiosis, which clinically manifests as moist, often
‘bubbly’ papules or plaques superimposed on an erythematous base. The patho-
genesis of some forms is poorly understood. The histopathologist usually can-
not render a more specific diagnosis other than ‘spongiotic dermatitis ­consistent
with eczematous dermatitis’ and precise classification within the differential
diagnosis of spongiotic dermatitis is often not possible. For these reasons, this
class of disorders is discussed as a group. Distinguishing clinical, pathogenetic,
and histological features are presented in the appropriate sections.
Eczema – general considerations
Eczema encompasses a number of disorders with variable etiologies and
­clinical manifestations and is one of the most common complaints of patients
visiting dermatology clinics.
The earliest clinical lesions are erythema and aggregates of tiny pruritic ves-
icles, which rupture readily, exuding clear fluid, and later become encrusted
(Fig. 6.1). More chronic lesions become scaly and thickened (lichenification),
resulting in lichen simplex chronicus (Fig. 6.2). Lichenification occurs if the
skin is continually scratched or rubbed as, for example, in atopic dermatitis.
Therefore, the clinical features of dermatitis depend upon the duration of the
lesions, site(s) involved, and the amount of scratching.
For instance, in pompholyx (acute vesicular dermatitis of the hands and
feet), the fluid is trapped beneath the thickened horny layer as small tense
white blisters resembling rice grains. In other regions where the skin is loosely
attached, as on the eyelids, scrotum, and backs of hands, tissue edema is often
marked.
Eczematous dermatitis has two major etiological classifications:
• endogenous dermatitis, related to major constitutional or hereditary
factors,
• exogenous dermatitis, involving environmental factors.
Endogenous dermatitis
Atopic dermatitis
Clinical features
Although atopic (infantile or flexural) dermatitis may begin at any age, it usu-
ally commences from about the sixth week onwards. It is characterized by a
chronic, relapsing course.1 In the infantile phase lesions are present mainly
on the head, face, neck, napkin area, and extensor aspects of the limbs (Fig.
6.3). As the patient grows older and enters childhood, the eruption shifts to
the flexural aspects of the limbs. Chronic atopic cheilitis may also be evident.1
Pruritus is intense and constant scratching and rubbing leads to lichenifica-
tion and frequent bouts of secondary bacterial infection (Fig. 6.4).2,3 Atopic
eczema is commonly associated with dry skin (xerosis). Vesiculation is uncom-
mon. There is an increased risk of dermatophyte and viral infections.1

Fig. 6.1
Eczema: this is a plaque of discoid eczema. Small vesicles are present at the edge
of the lesion. By courtesy of the Institute of Dermatology, London, UK.
Fig. 6.2
Lichenification: pronounced pebbly lichenification on the dorsum of the hand of a
patient with atopic dermatitis. Bizarre forms, as seen here, are not uncommon in
black children. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
The disease improves during childhood and, in over 50% of cases, clears
completely by the early teens. Approximately 75% of patients with atopic
dermatitis have a family history of atopy and up to 50% have associated
asthma or hay fever.4,5 The condition typically worsens in the winter months.
It is associated with an increased incidence of contact dermatitis, ­particularly
affecting the hand.6 Other features that may be seen include ichthyosis
(50%), nipple eczema, conjunctivitis, keratoconus, bilateral anterior cata-
racts, sweat-associated itching, wool intolerance, perifollicular accentuation,
food intolerance and white dermatographism.5 Infraorbital folds (Dennie-
Morgan folds) are said to be characteristic of atopic dermatitis, particularly
when double.1
Pathogenesis
Atopy is defined as a genetically determined disorder encompassing dermati-
tis, asthma, and hay fever. It is associated with excess immunoglobulin E (IgE)
antibody formation in response to common environmental antigens. A subset
of patients with ‘intrinsic atopic dermatitis’ represents perhaps 10–30% of
Endogenous dermatitis 181
Fig. 6.3
Atopic dermatitis: lesions on the face and trunk are particularly seen in infants and
young children. This child has bilateral involvement of the cheeks. By courtesy of
J. Dayrit, MD, Manila, The Philippines.
Fig. 6.4
Atopic dermatitis: these crusted, exudative and infected lesions with lichenification are
characteristic. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
patients with atopy; this does not appear to be due to a response to an envi-
ronmental antigen.7 Atopic dermatitis is a multifactorial disease. Its pathogen-
esis is complex and, despite recent advances, only incompletely understood.
In addition to a genetic susceptibility, the main elements responsible for the
initiation and maintenance of the disease state include abnormal skin barrier
function, abnormal activity of the innate and adaptive immune systems, as
well as environmental factors and infectious agents.7–15
Since patients with atopic dermatitis often have a personal or family his-
tory of asthma or allergies, a genetic predisposition to the disease has long
been suspected. Recent studies have demonstrated that loss-of-function
­mutations in the FLG gene, encoding the cornified envelope protein pro-
filaggrin, are present in a significant subset of patients with atopic derma-
titis and represent the highest risk factor for development of the disease.16
Together with involucrin and loricrin, filaggrin is a major constituent of the
cornified envelope during terminal keratinocyte differentiation responsible
for intact epidermal barrier function. Disruption of the skin barrier function
appears to be of particular significance in the initiation and early stages of
the disease. Nevertheless, 40% of patients with FLG mutations never develop
atopic ­dermatitis and FLG mutations have been identified in only 14–56%
of patients, indicating that other factors may also play an important role in
the pathogenesis of the disease. In addition to the cornified envelope, epider-
mal barrier function is maintained also by other factors such as proteases
and protease inhibitors as well as direct keratinocyte–keratinocyte interac-
tion. Increased expression of kallikrein-related peptidases has been observed
in the stratum corneum in atopic dermatitis and in one study a 4-bp ­insertion
182 Spongiotic, psoriasiform and pustular dermatoses

into the 3′ untranslated region of KLF7 leading to increased levels of this with atopic dermatitis is colonized with Staphylococcus aureus. In contrast,
protease was identified in patients with atopic dermatitis.13,17,18 However, this S. aureus is found on the skin of only a minority of control subjects.33 Disease
finding has not been substantiated in further studies.13 Linkage has also been severity has been shown to correlate with the presence of toxigenic S. aureus.34
demonstrated to the gene SPINK5, encoding the serine protease inhibitor It is thought that staphylococcal superantigens SEA and SEB (staphylococcal
LEKTI. LEKTI, expressed at the granular cell layer, is an important inhibi- enterotoxins A and B, respectively) activate T cells.34–37 In a study of children
tor of the kallikrein-related peptidases KLK5 and KLK7 and is responsible with atopic dermatitis, there was a correlation of disease severity and pres-
for controlling desquamation. Linkage to SPINK5 is, however, significantly ence of SEA and SEB antibodies.35 Recently, application of SEB was shown to
weaker than to profilaggrin.13 A further mechanism involved in skin barrier be associated with T-cell activation in both normal and atopic patients.38 In
function is the presence of intercellular junctions, and recent data have dem- summary, there is mounting evidence that staphylococcal superantigens play
onstrated reduced expression of the tight junction protein claudin-1 in atopic a role in the symptomatology of atopic dermatitis. Whether superantigens
dermatitis.15 play a key role in the development of disease or simply exacerbate symptoms
Many lines of evidence also implicate an abnormal immune response as in atopic patients requires further study.
pivotal in the pathogenesis of atopy. It is interesting to note that atopy is cured
by bone marrow transplantation in patients with Wiskott-Aldrich syndrome,
an immunological disorder characterized by susceptibility to infection and
Seborrheic dermatitis
thrombocytopenia, in addition to eczematous dermatitis.19 Wiskott-Aldrich
syndrome shows an X-linked recessive pattern of inheritance and is charac- Clinical features
terized by depletion of nodal and circulating T lymphocytes. Contrariwise, Seborrheic dermatitis is a common dermatosis which affects up to 1–3% of
patients without a prior history of atopy may develop atopic disease follow- the population.39–41 There is a male predominance. It presents in infants, with
ing transplantation of bone marrow from an atopic individual.20 a second peak affecting adults.42 There is often a family history of the disease.
Patients with atopic dermatitis have an abnormal immune reaction to a It particularly affects those areas where sebaceous glands are most numerous,
variety of environmental antigens leading to production of IgE antibodies i.e., the scalp, forehead, eyebrows, eyelids, ears, cheeks, presternal and inter-
and a T-cell response.9,21–23 There is evidence that certain subpopulations of scapular areas (Figs 6.5, 6.6).43 Occasionally, the flexural regions are affected
T cells selectively circulate to and perform immune surveillance for the skin (intertrigo). Often the lesions of seborrheic dermatitis are sharply margin-
and lymph nodes that drain cutaneous sites.9,23 This subset of lymphocytes ated, dull red or yellowish, and covered by a greasy scale.43 They are therefore
is characterized by a unique immunophenotype and is defined by expression easily confused with psoriasis.
of cutaneous lymphocyte antigen (CLA). In patients with atopic dermatitis, Dandruff and cradle cap are also sometimes included within the spectrum
antigens such as dust mites and bacteria activate CLA T cells, resulting in the of seborrheic dermatitis.
production of cytokines, which stimulate eosinophils to produce IgE, which, Seborrheic dermatitis is one of the most common dermatoses seen in
in turn, promotes mast cells and basophils to release cytokines and chemot- patients with acquired immunodeficiency syndrome (AIDS). Seborrheic der-
actic factors in what has been termed the intermediate-phase response.8 The matitis has also been associated with stress and neurological disorders includ-
so-called late-phase reaction is characterized by migration of eosinophils, ing Parkinson's disease, syringomyelia, and trigeminal nerve injury.44
lymphocytes, histiocytes, and neutrophils from the circulation into the der-
mis and epidermis. Pathogenesis
Factors released by the various cells present in the dermis certainly play
The precise pathogenesis of this condition is unknown. Surprisingly, and in
a role in the generation of the clinical appearance and induction of pruritus,
spite of the distribution (and the name) of the disease, sebaceous gland activ-
leading to scratching and rubbing. In the early phase, mechanical trauma and
ity and sebum composition appear to be normal.44
skin barrier disruption lead to release of proinflammatory cytokines (IL-1α,
Seborrheic dermatitis is associated with heavy colonization of the skin by
IL-1β, TNF-α, GM-CSF) which activate cellular signaling and induce expres-
the lipophilic yeast Malassezia furfur (Pityrosporum ovale) while more recent
sion of vascular endothelial cell adhesion molecules after receptor binding
data have identified a predominance of Malassezia restricta and Malassezia
to endothelial cells.15,24,25 These steps subsequently initiate transvascular
globosa.41,45–50 Although many workers in the field believe this to be of etio-
migration of inflammatory cells.8,26 Chemokines released by inflammatory
logical importance, an almost equal number are unconvinced. The body of
cells attract a more directed cellular immune response. In particular, CCL27,
evidence favoring a significant relationship relates to the successful treatment
CCL22, and CCL17 are increased in patients with atopic dermatitis and levels
correlate with disease activity.14,25 Disease onset is related to TH2 cytokines
IL-4, IL-13, and IL-31 while disease maintenance (chronic phase) is associate
dwith TH1 cytokines. Other T cells, such as Treg and TH17, are also present
in cutaneous lesions but their precise role is uncertain.14 The demonstration
that squamous cells in patients with atopic dermatitis show increased produc-
tion of GM-CSF, a cytokine thought to play a role in Langerhans/dendritic
cell function, further suggests that a keratinocyte defect may be involved in
the pathogenesis of atopy.27
Another area of interest has been the role of superantigens in the patho-
genesis of atopy as well as other immunologically mediated cutaneous and
noncutaneous disorders.28–33 Although superantigens have been implicated in
the pathogenesis of psoriasis and Kawasaki's disease, in addition to atopic
dermatitis, their precise role in these and other diseases is not well understood
and is controversial.29,30 Further research is necessary to clarify the role of
superantigens in immunologically mediated diseases.
Superantigens are microbiological (viral, bacterial, fungal) toxins that
­stimulate CD4+ T cells. They bind to T-cell receptors and to the class II major
histocompatibility complex (MHC), thus stimulating lymphocyte prolifer-
ation, activation and release of cytokines, as well as T-cell-mediated tissue
damage. They may also stimulate B cell activation. Superantigens are power-
ful mediators of the immune system by virtue of their ability to stimulate a Fig. 6.5
large population of T cells in a non-specific manner. Staphylococcal superan- Seborrheic dermatitis: there is diffuse erythema and scaling of the scalp. By
tigens have, in particular, been an area of research.32 The skin of most patients courtesy of B. Al Mahmoud, MD, Doha, Qatar.
 Endogenous dermatitis 183

Fig. 6.6 Fig. 6.8

Seborrheic dermatitis: note the marked scaling. By courtesy of the Institute of Discoid eczema: the lesion is sharply defined and there is a pronounced scale.
Dermatology, London, UK. By courtesy of the Institute of Dermatology, London, UK.

of seborrheic dermatitis with antifungal therapy.39,40,51 Whether this implies a

causal relationship or merely an exacerbating factor is, however, uncertain.

Discoid dermatitis (nummular eczema)

Clinical features
The presence of single or multiple pruritic, coin-shaped, erythematous
plaques with vesiculation, particularly involving the lower legs, forearms,
and backs of hands (Figs 6.7–6.9) characterize this chronic form of derma-
titis.52 The absence of a raised border clinically distinguishes it from ring-
worm.52 There are two peak ages of onset: it affects young women (15–30
years of age) and middle-aged adults of both sexes. The disease tends to
chronicity.

Fig. 6.9
Discoid eczema: there is
extensive involvement
of the leg. A sharply
demarcated erythematous
and scaly circular lesion
is present just below the
knee. By courtesy of R.A.
Marsden, St George's
Hospital, London, UK.

Pathogenesis
The pathogenesis is poorly understood. A participatory role for organisms in
the pathogenesis has been suggested but not been widely accepted.53 Discoid
dermatitis may follow irritants such as soap, acids or alkalis (Fig. 6.10).52
Sometimes it may be a manifestation of atopy and, occasionally, it develops
as a consequence of nickel, chromate or cobalt allergy.54,55 Generalized dis-
ease has also been documented in the setting of interferon alpha-2b plus riba-
virin treatment for hepatitis C infection.56
Fig. 6.7
Discoid eczema:
circumscribed,
Hand eczema (dyshidrotic eczema,
erythematous lesions palmoplantar eczema, pompholyx)
on the forearm, a
characteristic site. By
courtesy of the Institute
Clinical features
of Dermatology, London, Hand eczema is characterized by a recurrent pruritic vesicular eruption of
UK. the palms, soles or digits. Because of the increased thickness of the keratin
184 Spongiotic, psoriasiform and pustular dermatoses
Fig. 6.10
Discoid eczema: lesions localized to the fingers most often represent a contact
irritant reaction. By courtesy of R.A. Marsden, St George's Hospital, London, UK.
Fig. 6.11
Hand eczema: tense yellow vesicles are present. By courtesy of B. Al Mahmoud, MD,
Doha, Qatar.
layer at these sites, the vesicles appear as small pale papules before rupturing
(Figs 6.11, 6.12). Occasionally, frank bullae can form. With the passage of
time, the affected parts may show scaling and cracking. The nails sometimes
become dystrophic, with discoloration and transverse ridging.57 In the major-
ity of cases the cause is unknown, although heat or psychological stress may
precipitate an attack.57 In some patients there is a personal or family history
of atopy or coexisting tinea pedis. Rubber, latex, chromium, cobalt or nickel
sensitivity may be the trigger.58–62 The condition can be exacerbated by heat
and, rarely, it is photoinduced.63
Pompholyx is often associated with hyperhidrosis.58 Females are affected
slightly more often than males and patients are predominantly in the second
to fifth decades.59 A familial autosomal dominant form has been reported
where the candidate gene has been mapped to chromosome 18q22.1-
18q22.3.64
Pathogenesis
The pathogenesis is obscure. It has been noted that serum IgE levels are often
raised.58
Fig. 6.12
Hand eczema: more chronic example showing marked scaling. From the collection
of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.
Autosensitization (Id) reaction
Clinical features
On occasion, patients will develop generalized spongiotic dermatitis in
response to a dermatosis or infection at a distant site. The eczematous derma-
titis resolves if the underlying infection or specific dermatosis is successfully
treated. This phenomenon has also been designated an autoeczematization
or Id reaction. The lesions that characterize the Id reaction may be a local-
ized pompholyx-like eczematous dermatitis of the hands and feet or scattered
papules on the trunk and limbs.65–69 Disorders that may be associated with
the Id reaction include fungal infection (e.g., dermatophyte infection), scabies
infestation, molluscum contagiosum, tick bite, pediculosis capitis, and bacte-
rial and mycobacterial infections.65–69 A generalized nummular dermatitis has
been reported in association with localized dental infection.70
Pathogenesis
The pathogenesis of the Id reaction is poorly understood but some data sug-
gest that an abnormal T-cell-mediated immune response directed against skin
antigens is responsible for this curious disorder.71
Exogenous dermatitis
Contact dermatitis
This form of dermatitis is due to external agents and is divided into two vari-
ants: allergic contact and irritant contact.
Allergic contact dermatitis
Allergic contact dermatitis is an idiosyncratic cell-mediated immunologi-
cal reaction to an environmental allergen, which may be present in very
low concentration. Common examples seen in clinical practice include
sensitivity to nickel (found in items such as jewelry, buttons, watches,
and suspenders), constituents of synthetic rubber (e.g., thiuram in rubber
gloves), primula, poison ivy, topical medicaments (e.g., neomycin, anti-
histamines, local anesthetics), and chromates found in cement and leather
(Figs 6.13–6.15).72–82
Dinitrochlorobenzene (DNCB) is a potent contact sensitizer and this is
used as a test of cell-mediated immunity.83,84
A growing understanding of allergic contact dermatitis has emerged over
the last decade with the preponderance of evidence pointing to a T-cell-
mediated hypersensitivity reaction.3,85–88 It is thought that antigens causing
allergic contact dermatitis are often unstable (haptens) and need to bind to

Fig. 6.13
Contact dermatitis: this early erythematous predominantly macular eruption
developed as a reaction to fabric softener. By courtesy of J. Dayrit, MD, Manila,
The Philippines.
Fig. 6.14
Contact dermatitis: bilateral involvement in a patient using a watch on the right
wrist and a leather bracelet on the left wrist. From the collection of the late N.P.
Smith, MD, the Institute of Dermatology, London, UK.
epidermal host proteins.3,85 These hapten–protein interactions are formed via
covalent binding of electrophilic residues of the chemical with amino acids,
especially cysteine.89–91 In contrast, metal ions, such as nickel, are thought
to form noncovalent protein–metal chelate complexes.89 In the sensitization/
initiation phase of the disease, hapten-specific T cells are generated in lymph
nodes after the initial contact of the skin with a potent hapten.91 Langerhans
cells in skin and dendritic cells in lymph nodes process antigen and stimulate
appropriate naive CLA T cells. CLA-positive T cells are a subset of T cells
that express a skin-selective homing receptor and perform immune surveil-
lance for the skin and lymph nodes that drain cutaneous sites.92 CLA-positive
T cells proliferate when stimulated by the appropriate antigen or antigen–
protein complex. The number of CLA-positive memory T cells increases with
repeated exposures to its antigen.3,85 When the patient is exposed to the anti-
gen, the elicitation phase, the CLA-positive T cells are activated and release
cytokines which lead to the immune reaction responsible for the clinical and
histological features associated with allergic contact dermatitis.87 CD8+ T cells
appear to be the main effector cell in the elicitation phase.89 Keratinocytes
are also thought to play a role through the release of cytokines after hapten
exposure and binding.88
Exogenous dermatitis 185
Fig. 6.15
Contact dermatitis: a
severe reaction to poison
ivy. From the collection
of the late N.P. Smith,
MD, the Institute of
Dermatology, London,
UK.
Occasionally, exposure to strong haptens may result in the development
of allergic contact dermatitis in previously unsensitized individuals (primary
allergic contact dermatitis).89
Ingested or inhaled allergens in a person who has been previously sen-
sitized by cutaneous absorption may result in a clinical picture similar to
allergic contact dermatitis (e.g., ingested nickel, chromium or cobalt may
result in the appearances of hand eczema).93 Much less commonly, systemic
allergic contact dermatitis may be histologically associated with an erythema
­multiforme-like eruption, vasculitis or urticarial morphology.93 This is thought
to result from systemic exposure of a hapten via hematogenous transport to
the skin.94 It may occur with or without prior sensitization, and a large num-
ber of drugs have been implicated in the pathogenesis.94
Irritant contact dermatitis
Irritant contact dermatitis, which is much more common than allergic con-
tact dermatitis, follows exposure to physical or chemical substances capable
of direct damage to the skin. Mechanisms of damage are variable and include
keratin denaturation, removal of surface lipids and water-holding substances,
damage to cell membranes, and/or direct cytotoxic effects.95 Acute irritant
dermatitis usually results from a relatively short single exposure to a potent
irritant, such as strong acid or alkali, whereas chronic cumulative insult or
‘wear and tear’ dermatitis is due to more prolonged contact with one or more
weaker irritants, for example, soap and water, detergents or industrial oil and
plants (Fig. 6.16).96–100
Most forms of occupational dermatitis of the hands, including ‘house-
wives’ and ‘wedding ring’ dermatitis are of the irritant contact type. A diag-
nosis of contact dermatitis is made from the history and distribution of
lesions and, in the case of allergic dermatitis, is confirmed by patch testing
to the suspected allergen. Although both forms of contact dermatitis tend to
be confined to exposed areas, the reaction may eventually spread to involve
nonexposed sites and can persist even when the causative agent is removed
from the environment.
Similar to atopic dermatitis, loss-of-function mutation in the FLG gene,
encoding filaggrin, may confer an increased susceptibility to chronic irritant
contact dermatitis evoking an underlying skin barrier defect in the pathogen-
esis of the disease.101
186 Spongiotic, psoriasiform and pustular dermatoses
Fig. 6.16
Contact dermatitis: there is a superimposed pustular element due to an infection
in this patient with a contact reaction to a domestic antiseptic. By courtesy of B. Al
Mahmoud, MD, Doha, Qatar.
Infective dermatitis
Infective dermatitis is a severe chronic and recurrent eczematous dermati-
tis showing pronounced exudation and crusting and presenting in children
with human T-cell lymphotropic virus type 1 (HTLV-1) infection.102–105 Adult
onset is exceptional.106,107 The disease has a predilection for the scalp, flex-
ures, the ears and feet, and sometimes around wounds and ulcers (Fig. 6.17),
and is frequently associated with Staphylococcus aureus and beta-hemolytic
Streptococcus infection of the skin and nasal vestibule. It occurs in regions
where HTLV-1 is endemic. It has frequently been reported in Jamaica, while
presentation in Japan appears relatively rare.108 Development of the disease
may be associated with a defective immune system and may be a risk factor
for the development of other HTLV-1-related diseases such as adult T-cell leu-
kemia and tropical spastic paraparesis.109,110
Asteatotic dermatitis
Commonly seen in the elderly, particularly in winter and in those with minor
degrees of ichthyosis, asteatotic dermatitis (eczema craquelé) may be precipi-
tated by excessive washing, exposure to detergents, cold winds or low humid-
Fig. 6.17
Infective dermatitis: lesions affecting the foot web spaces are often due to
staphylococci or streptococci and are associated with excess sweating. By
courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
Fig. 6.18
Asteatotic dermatitis: these typical appearances are the result of scaling and
fissuring. By courtesy of B. Al Mahmoud, MD, Doha, Qatar.
ity, all of which tend to dry the skin.111 The affected regions are inflamed and
criss-crossed by scaly lines and superficial fissures (Fig. 6.18). Asteatotic der-
matitis may be associated with internal malignancy, including lymphoprolif-
erative disorders and solid tumors.112–115
Pathogenesis and histological features
The histopathological features of spongiotic dermatitis include both dermal
and epidermal changes. Their relative proportions vary to some extent with
the subtype, but perhaps more importantly, with the stage of evolution of the
disease. It is essential not to consider the changes of spongiotic dermatitis as
static: different features are seen at different stages.116–118 Attempting to dis-
tinguish the various clinical subtypes based on histological features alone is
generally futile. Instead, once the disorder has been recognized as spongiotic
in nature, clinical examination is a much more satisfactory method of deter-
mining the particular variant.
The histological hallmark of spongiotic dermatitis is the presence of inter-
cellular edema or spongiosis (L., Gr. spongia, sponge). Slight degrees of intra-
cellular edema may also be evident but may easily be overlooked. In the early
stages of development, spongiosis results in widening of the intercellular
spaces, rendering the intercellular bridges conspicuous (Fig. 6.19). Further
accumulation of fluid leads to the eventual development of an intraepidermal
vesicle. A common finding in association with the intercellular edema is lym-
phocytic infiltration of the epidermis (exocytosis). In severe contact irritant
dermatitis, the epidermis may be infiltrated by large numbers of neutrophil
polymorphs in association with necrotic keratinocytes.119 In addition, such
reactions may be accompanied by dermoepidermal separation resulting in a
vesicle or blister. The lesions very often become traumatized and may show
marked crusting.
Spongiotic dermatitides not uncommonly become infected with bacterial
or fungal organisms. Superimposed infection may dramatically alter the his-
tological picture by causing marked acute inflammation with subepidermal,
intraepidermal, and subcorneal pustules. Such changes may dominate the his-
tological picture and obscure the underlying spongiotic dermatitis. Use of
stains for organisms – Gram, periodic acid-Schiff (PAS) – or cultures are nec-
essary to evaluate for infection.
Concomitant with these changes are varying degrees of epithelial prolif-
eration, ranging from mild acanthosis in early acute dermatitis to marked
psoriasiform epidermal hyperplasia in chronic variants. Parakeratosis is
frequently seen overlying spongiotic foci, while hyperkeratosis is a usual
accompaniment of chronic spongiotic dermatitis that has been scratched or
rubbed (lichenification).
The dermis is often congested and edema is usually marked in active
lesions. The vessels of the superficial vascular plexus are surrounded by a
 Exogenous dermatitis 187

Fig. 6.19
Dermatitis: the earliest visible manifestation of intercellular edema is widening of
the intercellular spaces with accentuation of the intercellular bridges.
Fig. 6.21
Acute dermatitis:
the vesicle contains
mixed inflammatory cell infiltrate composed of lymphocytes, histiocytes, and lymphocytes and
occasional eosinophils or neutrophils. The degree and composition of der- occasional eosinophils.
mal inflammation is highly variable. Eosinophils may be numerous in allergic
contact dermatitis.119
Traditionally, spongiotic dermatitis is subclassified histologically into
acute, subacute, and chronic variants:
• In acute lesions, vesiculation and blister formation may be seen (Figs
6.20–6.22).
• Acanthosis and spongiosis, often with vesiculation, also characterize
subacute spongiotic dermatitis (Fig. 6.23).
• In chronic spongiotic dermatitis, although spongiosis is evident, it may be
subtle, and vesicles are uncommon. Epithelial acanthosis is marked and
often shows a psoriasiform pattern (Fig. 6.24).
Systemic contact dermatitis may be associated with the features of vascu-
litis or erythema multiforme.120 As with other forms of spongiotic dermatitis
the histological appearances can be divided into acute, subacute, and chronic
forms. Spongiosis is more conspicuous in the acute phase although it is never
marked. In contrast, the epidermal hyperplasia becomes more conspicuous
and psoriasiform towards the chronic end of the spectrum.

Fig. 6.22
Acute dermatitis: in contact reactions, Langerhans cell-rich vesicles are often
present, as shown in this picture. These should not be mistaken for the Pautrier
microabscesses of mycosis fungoides.

The features of seborrheic dermatitis are often non-specific and subtle. It

is characterized by hyperkeratosis and parakeratosis, the latter particularly
related to hair follicles and typically associated with neutrophil exocytosis
(Figs 6.25, 6.26). Yeasts may sometimes be found in the stratum corneum
particularly if PAS stained sections are examined. Epidermal acanthosis with
thickened rete ridges is present and often marked in chronic lesions. It is,
however, somewhat irregular in contrast to the uniform hyperplasia charac-
teristic of psoriasis. Variable spongiosis with lymphocyte exocytosis is com-
mon. The dermis may be edematous and mild vascular dilatation is usually
seen. A mixed inflammatory cell infiltrate consisting of lymphocytes, histio-
Fig. 6.20 cytes, and small numbers of eosinophils surrounds the superficial vascular
Acute dermatitis: fluid-filled vesicle due to intense spongiosis. plexus.
188 Spongiotic, psoriasiform and pustular dermatoses

Fig. 6.23
Subacute dermatitis showing patchy parakeratosis, crusting, marked acanthosis Fig. 6.25
with considerable elongation (and fusion) of the epidermal ridges, and focal Seborrheic dermatitis:
spongiotic vesiculation. The dermis contains an intense lymphocytic infiltrate. in this field, there is
perifollicular psoriasiform
hyperplasia. Parakeratosis
is present on either side
of the follicular ostium.

Fig. 6.24
Chronic dermatitis (lichenification): there is hyperkeratosis with hypergranulosis
and psoriasiform hyperplasia. The papillary dermis is fibrosed and there is a patchy
chronic inflammatory cell infiltrate.

Differential diagnosis
Although spongiosis is a characteristic feature of spongiotic dermatitis, it
is also encountered in many other inflammatory dermatoses (Table 6.1),
particularly superficial dermatophytoses. A diagnosis of spongiotic der-
matitis should never be made until a stain for fungus (e.g., PAS reaction)
has been performed to exclude this possibility. This is especially impor-
tant since the common treatment of spongiotic dermatitides – topical
corticosteroids – would exacerbate a fungal infection (tinea incognito)
(Figs 6.27–6.29).
Lichen simplex chronicus
Clinical features
The term lichen simplex chronicus (circumscribed neurodermatitis) refers to
the development of localized areas of thickened scaly skin complicating pro-
longed and severe scratching in a patient with no underlying dermatological
Fig. 6.26
Seborrheic dermatitis:
there is parakeratosis, and
occasional neutrophils are
present.
condition (Fig. 6.30).1 Lichenification is an identical process in which an
underlying intensely pruritic dermatosis such as atopic eczema is present.2
Dermatophyte infections, stasis dermatitis, and chronic allergic contact
dermatitis may also predispose to lichenification. Picker's nodules and nodu-
lar prurigo are related conditions (see below).3
Patients present with profound pruritus and localized scaly plaques with
accentuated skin markings described as resembling tree bark. There is a pre-
dilection for females, and young to middle-aged adults are predominantly
 Exogenous dermatitis 189

Table 6.1
Conditions featuring spongiosis

• Pityriasis rosea
• Superficial fungal infections
• Herpes gestationis (early lesions)
• Polymorphic eruption of pregnancy
• Erythema multiforme
• Miliaria rubra
• Erythema annulare centrifugum
• Guttate parapsoriasis
• Acral papular eruption of childhood
• Eczema
• Lichen striatus
• Insect-bite reaction
• Prurigo nodularis

Fig. 6.29
Spongiotic superficial dermatophyte infection: numerous fungal hyphae are seen in
this PAS-stained section.

Fig. 6.27
Spongiotic superficial dermatophyte infection: there is marked subcorneal
vesiculation.

Fig. 6.30
Lichen simplex chronicus:
thick, scaly erythematous
plaques are present on
the shins, a commonly
affected site. By courtesy
of R.A. Marsden, MD,
St George's Hospital,
London, UK.

Histological features and pathogenesis

Fig. 6.28
Spongiotic superficial dermatophyte infection: higher-power view.
affected. Accessible skin is particularly affected and the nape and sides of the
neck, the thighs, the lower legs and ankles, vulva, and scrotum are sites gen-
erally involved.2
Pebbly lichenification refers to a distinct variant in which lichenoid
papules follow intense scratching in patients with inflammatory dermatoses
such as atopic eczema.2
Although the etiology and pathogenesis of lichen simplex chronicus remains
elusive, psychological factors may play an important role.4,5 Recent data fur-
ther suggest that an underlying neuropathy may be of importance in at least
a subset of patients.6
Histologically, lichen simplex chronicus is characterized by marked hyperk-
eratosis, sometimes with small foci of parakeratosis, and a usually prominent
granular cell layer (Fig. 6.31).7 The epidermal ridges are elongated and irregu-
larly thickened. Mild spongiosis is variably present depending upon the cause.
A perivascular and sometimes interstitial inflammatory cell infiltrate consisting
of lymphocytes, histiocytes, and small numbers of eosinophils is present in the
superficial dermis. Enlarged, angulated myofibroblasts are sometimes evident
and, as in many other chronic skin conditions, scattered small, multinucleated
cells, so-called Montgomery giant cells, are identified. Papillary dermal fibrosis is
190 Spongiotic, psoriasiform and pustular dermatoses

Fig. 6.33
Fig. 6.31 Nodular prurigo: typical
Lichen simplex chronicus: there is hyperkeratosis, patchy parakeratosis, and globular nodules; the
elongation of the rete ridges. intervening skin appears
normal. From the
collection of the late N.P.
Smith, MD, the Institute
of Dermatology, London,
UK.

Fig. 6.32
Lichen simplex chronicus:
there is hypergranulosis.
Note the vertically
orientated collagen fibers,
a characteristic feature. Fig. 6.34
Nodular prurigo: there are scattered, excoriated discrete nodules on the buttocks
and thighs. Note the postinflammatory hyperpigmentation. By courtesy of R.A.
a characteristic feature and in some cases nerve hyperplasia is seen (Fig. 6.32).3 Marsden, MD, St George's Hospital, London, UK.
In our experience, however, the latter feature is distinctively uncommon.

Nodular prurigo (prurigo nodularis) and
prurigo nodule (picker's nodule)
Clinical features
Nodular prurigo is characterized by the development of chronic, intensely
pruritic, lichenified, and excoriated nodules.1,2 It occurs over a wide age
range, from 5 to 75 years, with a mean of 40 years. Rarely, children are
affected.3 Disease duration ranges from 6 months to 33 years, with a mean
of 9 years. Nodular prurigo occurs equally in men and women. It shows
significant overlap with lichen simplex chronicus, although this is not uni-
formly accepted.1,2
Individual lesions are often described as globular with a warty and excori-
ated surface and may measure up to 2 cm in diameter (Fig. 6.33).2 They are
often grouped, symmetrical, and occur predominantly on extensor aspects
of the (distal) limbs (Figs 6.34, 6.35).1 The trunk may also be affected.2
Occasional disseminated cases have been described.2 The palms and soles are
typically uninvolved.2 The intervening skin usually appears normal. Similar-
looking lesions are sometimes seen in patients with eczema (see below).
The majority of patients with nodular prurigo are perfectly well and inves-
tigations are unhelpful; however, occasionally nodular prurigo is found in
patients with gluten enteropathy.4 Psychosocial disorders have been reported
in a high proportion of patients.5 In some cases the eruption occurs after an
insect bite, but subsequent lesions develop spontaneously.5
 Exogenous dermatitis 191

Fig. 6.35
Nodular prurigo: in this Fig. 6.36
patient there is very Nodular prurigo: there is hyperkeratosis, hypergranulosis, and
severe involvement of pseudoepitheliomatous hyperplasia. The dermis is scarred and there is a
the shins and dorsal perivascular and interstitial chronic inflammatory cell infiltrate.
surface of the feet. By
courtesy of the Institute
of Dermatology, London,
UK.

The pruritus is episodic and may be precipitated or aggravated by heat and

anxiety.5 Significant laboratory abnormalities may include anemia, eosino-
philia, and raised serum IgE levels.5
Nodular prurigo (eczema) is defined as lesions of nodular prurigo arising
on a background of overt eczema.5 While this distinction is of academic inter-
est it has no clinical or prognostic importance.
A prurigo nodule is a solitary variant that develops as a consequence of
localized scratching and picking.
On occasion, nodular prurigo is accompanied by the features of bullous
pemphigoid (pemphigoid nodularis).6

Pathogenesis and histological features

Classical nodular prurigo, which is focal and characterized by hyperplasia,
has recently been related particularly to follicular epithelium.2,7 In the epider-
mis this manifests as orthohyperkeratosis, hypergranulosis and acanthosis, Fig. 6.37
sometimes to the degree of pseudoepitheliomatous hyperplasia (Figs 6.36, Nodular prurigo: higher-power view.
6.37).8 Superficial mild spongiosis and focal parakeratosis is occasionally
present and the features may resemble chronic eczema.5 Subepidermal fibrin
deposition is sometimes a feature.9
In the dermis there is vascular hyperplasia, with dilated vessels in both the
papillary and reticular dermis. New vessel formation is apparent and there
is a surrounding perivascular mild inflammatory cell infiltrate, consisting
mainly of lymphocytes and some histiocytes, plasma cells, occasional eosino-
phils and scattered, superficial, small multinucleated cells (Montgomery giant
cells) (Fig. 6.38).8 Mast cells are present in normal numbers.1 The infiltrate
has been described as having an inverted triangular configuration extending
from the superficial dermis.2 This has not been the present author's experi-
ence. Occasionally, the dermal features include lymphoid follicles with germi-
nal center formation, thereby resembling a persistent insect bite reaction.5 An
additional finding is the presence of fibrosis of the papillary dermis.8
With light microscopy the nerves may appear normal, increased in number
or occasionally hyperplastic (Fig. 6.39).1,5 Special neural stains or S-100 pro-
tein immunocytochemistry may accentuate mild proliferative changes. Nerve
changes, however, do not appear to be essential for the diagnosis.1 Studies
have shown no evidence of true neuroma formation and it is thought by some
authors that the neural changes are secondary to chronic trauma and scratch-
ing of the intensely pruritic nodules.1,5,7 This intense pruritus may have been Fig. 6.38
partly responsible for the large amount of attention given to ­neural changes in Nodular prurigo: note the conspicuous eosinophils.
192 Spongiotic, psoriasiform and pustular dermatoses

Acroangiodermatitis (pseudo-Kaposi's sarcoma, congenital dysplastic

angiopathy, arteriovenous malformation with angiodermatitis) refers to the
clinical manifestation of purple macules, nodules, and sometimes verrucous
plaques typically developing on the dorsal aspects of the feet and toes in
patients with severe and longstanding venous insufficiency.7 Varicose veins
are often present. The condition is of particular importance in that it may
be clinically mistaken for Kaposi's sarcoma.8 Identical lesions have been
described complicating Klippel-Trénaunay, Stewart-Bluefarb, and Prader-
Willi syndromes, surgical arteriovenous fistulae as seen for example in hemo-
dialysis patients, complicating poorly fitting suction socket prostheses on
amputation stumps and on paralysed limbs.9–22

Pathogenesis and histological features

The pathogenesis of stasis dermatitis and acroangiodermatitis is unknown
although it may be related to the tissue anoxia that typically results from
increased venous pressure or circulatory disturbance.13
Stasis dermatitis shows, in addition to the epithelial changes of spongiotic
dermatitis, marked hemosiderin deposition in the dermis accompanied by fibro-
sis and a characteristic lobular pattern of superficial and/or deep dermal neo-
Fig. 6.39
Nodular prurigo: in our experience, nerve hyperplasia is an uncommon observation.
vascularization (Figs 6.41–6.45). Inflammatory cells – including lymphocytes,
histiocytes, and variable numbers of plasma cells – are often numerous, and
erythrocyte extravasation is usually prominent.
nodular prurigo in the past. Very rarely, however, hyperplastic nerve trunks are
associated with Schwann cell proliferation, giving rise to small neuromata.10
Electron microscopy has shown vacuolation of Schwann cell cytoplasm,
together with loss of definition of internal structure of the mitochondria.5,10,11

Stasis dermatitis and acroangiodermatitis

Clinical features
Stasis (varicose) dermatitis usually involves the medial aspect of the lower leg
or ankle, but may be more widespread, and develops as a complication of
impaired venous return from the lower limbs.1 Superficial varicose veins are a
frequent predisposing factor. The lesion appears as an itchy, scaly, often swol-
len and hyperpigmented area. Such changes are often seen around chronic
stasis ulcers (Fig. 6.40). Malignant tumors (both squamous and basal cell car-
cinomas) may occasionally develop at the edge of these ulcers.2–5 Furthermore,
in the early stages of the disease, the lesion may present singly and can be clini-
cally mistaken for a cutaneous malignancy, i.e., squamous cell carcinoma.6

Fig. 6.41
Stasis dermatitis: there is hyperkeratosis, focal parakeratosis and marked epidermal
hyperplasia. The dermis is chronically inflamed and scarred.

Fig. 6.40
Stasis dermatitis: there is
vesiculation, exudation,
and crusting on the lower
leg around a stasis ulcer,
which was precipitated
by allergy to the antibiotic
dressing. By courtesy
of R.A. Marsden, MD,
St George's Hospital, Fig. 6.42
London, UK. Stasis dermatitis: note the increased vascularity.
 Exogenous dermatitis 193

Fig. 6.43 Fig. 6.46

Stasis dermatitis: there is marked mural fibrin deposition. The features often overlap Acroangiodermatitis showing lobular capillary proliferation, red cell extravasation,
with atrophie blanche. and a chronic inflammatory cell infiltrate.

In acroangiodermatitis, the vascular proliferation is often so exuberant that

it may mimic a vascular neoplasm, most often Kaposi's sarcoma (Fig. 6.46).23

Differential diagnosis
Acroangiodermatitis differs from Kaposi's sarcoma by the absence of a spin-
dle cell population or irregular lymphatic-like vascular channels dissecting
the dermal collagen. In addition, the promontory sign (tumor vessels partially
surrounding normal vessels and the adnexae) is absent. In acroangiodermati-
tis, the hallmark is the presence of lobular capillary proliferation.
In cases where the diagnosis is in doubt, CD34 immunocytochemistry is of
value. The spindle cells in Kaposi's sarcoma express this antigen whereas those
in acroangiodermatitis do not.24 Smooth muscle actin emphasizes the pericytes in
acroangiodermatitis and a reticulin stain can be used to highlight the lobularity.

Pityriasis alba
Clinical features
Fig. 6.44
Pityriasis alba is a very common form of chronic dermatitis usually affecting
Stasis dermatitis: in this view, there is marked new blood vessel formation and
abundant hemosiderin is present. preadolescent children of either sex.1 In the United States, the prevalence is
1.9% in a healthy population.2 The lesions are seen on the face in particu-
lar, but the shoulders, upper extremities, and legs may also be involved (Figs
6.47–6.49).1,3 Early lesions present as slightly scaly, mildly pruritic, round to
oval pink plaques measuring from 0.5 to 5.0 cm or more in diameter, which
later appear as scaly hypopigmented lesions.1 The races are equally affected
although lesions are more prominent in dark-skinned persons.1,4 The condi-
tion usually resolves spontaneously after months or years.

Pathogenesis and histological features

The etiology is unknown although some authors believe it may be a form
of atopic dermatitis since many patients also have features of classic
atopic dermatitis or a family history of atopy.5 However, some patients
with pityriasis alba lack typical features of atopy. An association with
xerosis has also been postulated and the condition has also been linked to
copper deficiency.6,7
The histological features of the early stage include follicular dilatation and
plugging with infundibular spongiosis, parafollicular parakeratosis, and seba-
ceous gland atrophy accompanied by a superficial perivascular lymphocytic
infiltrate and edema.8 In the later stages, the changes are those of chronic
non-specific dermatitis including hyperkeratosis, parakeratosis sometimes
Fig. 6.45 accompanied by mild acanthosis, and slight spongiosis.8–10 There is variable
Stasis dermatitis: the hemosiderin can be highlighted with a Prussian blue reaction hypo- and hyperpigmentation of the basal keratinocytes with reduced or nor-
for iron. mal numbers of melanocytes and pigmentary incontinence.8,11
194 Spongiotic, psoriasiform and pustular dermatoses
Fig. 6.47
Pityriasis alba: there are
multiple hypopigmented,
scaly patches on the
arms. Lesions are more
obvious in the colored
races. By courtesy of C.
Furlonge, MD, Port of
Spain, Trinidad.
Fig. 6.48
Pityriasis alba: there is
striking leukoderma on
the cheek and chin, which
are commonly affected
sites. By courtesy of R.A.
Marsden, MD, St George's
Hospital, London, UK.
Actinic prurigo
Clinical features
Actinic prurigo is a rare familial photodermatitis with a female predilection
and disease onset in childhood (4–5 years of age) although disease manifesta-
tion has also been documented in adulthood.1–4 The disease is most commonly
observed in Native Americans as well as Latin Americans. Caucasians, Asians,
and Australians are less frequently affected.1,2,4,5 The clinical presentation is varied.
Patients typically present with intense pruritus and an erythematous papular
Fig. 6.49
Pityriasis alba: lesions in white-skinned patients are much more subtle. By courtesy
of the Institute of Dermatology, London, UK.
eruption. Lesions may form nodules and plaques and there may be evidence of
lichenification and excoriation due to repeated scratching and postinflamma-
tory scarring.1–3 Sun-exposed areas of the face, neck, upper chest, forearms, and
hands are predominantly involved. The lips and conjunctiva are also frequently
affected.1,3 Associated cheilitis particularly affecting the lower lip is characterized
by edema, fissuring, ulceration, and chronic dry scaling and may be the sole mani-
festation.6 Conjunctival involvement results in photophobia, hyperemia, and for-
mation of a pseudopterygium.1,3 The disease course of actinic prurigo is chronic
with significant adverse impact on the quality of life.7 Remission may be observed
in the winter months in patients living in geographic areas with significant varia-
tion of sunlight throughout the year.1,3 In a subset of patients with childhood onset,
symptoms will improve in adulthood with occasional spontaneous remission.3
Pathogenesis and histological features
Using phototesting, the majority of patients show increased sensitivity to a
broad spectrum of UVA as well as UVB radiation.1,2 The disease has strong
associations with HLA haplotypes, in particular DRB1*0407 (60–70% of
patients) and DRB1*0401 (20% of patients).3
The histological features are often nondiagnostic and areas of excoriation
are frequently biopsied. In late lesions changes include regular epidermal acan-
thosis with overlying hyperparakeratosis and some degree of hypergranulosis.
There is an associated marked superficial to mid-dermal perivascular chronic
inflammatory cell infiltrate composed predominantly of lymphocytes. In the pap-
illary dermis focal fibrosis may be seen and there is often pigment incontinence.
Lymphoid follicles can be present especially in areas of ulceration, particu-
larly in lesions on the lip. Eosinophils are frequently noted. Biopsies from the
lip show similar epidermal features in addition to spongiosis and basal cell
vacuolar change. Dermal edema and prominent telangiectatic vessels are fur-
ther characteristic features. An associated lymphoplasmacytic infiltrate may
be bandlike or show lymphoid follicles with germinal centers. The latter is
mainly seen in conjunctional biopsies.
Eosinophilic spongiosis
Eosinophilic spongiosis is the histopathological term used to describe spon-
giosis in which eosinophils are the predominant cell type.1–5 Eosinophilic
spongiosis is a non-specific finding with which a considerable number of der-
matoses may be associated. Table 6.2 lists dermatoses in which eosinophilic
spongiosis is commonly encountered. Detailed discussion of each of these dis-
orders is found in the appropriate chapters.
Erythroderma
Spongiotic dermatitis is one of the causes of erythroderma. Sometimes incor-
rectly called exfoliative dermatitis, erythroderma is applicable only when the

Table 6.2
Diseases featuring eosinophilic spongiosis
• Incontinentia pigmenti
• Pemphigus
• Bullous pemphigoid
• Linear IgA disease
• Pemphigoid (herpes) gestationis and polymorphic eruption of
pregnancy
• Insect-bite reactions
• Atopic eczema
• Contact dermatitis
• Grover's disease
• Drug reactions
Fig. 6.50
Erythroderma: the entire skin surface is erythematous and slightly scaly. The
appearances are relatively non-specific and give no indication of the cause. By
courtesy of the Institute of Dermatology, London, UK.
entire skin surface is inflamed, erythematous, and scaly (Fig. 6.50).1–5 The clini-
cal features are remarkably consistent irrespective of the underlying disease and
therefore often pose a diagnostic challenge. Pruritus is variable, being particu-
larly severe in the Sézary syndrome and in mycosis fungoides. Lymphadenopathy
is usually present (dermatopathic lymphadenopathy). Prolonged erythroderma,
particularly in the elderly, may be complicated by cardiac failure, peripheral
circulatory collapse, hypothermia, and infection. Patients with erythroderma
are frequently biopsied since the clinical examination findings are often non-
specific. Diagnosis without clinical information is often not possible.1 Table
6.3 lists the various causes of erythroderma. The specific diseases that cause
­erythroderma are discussed in detail in the appropriate chapters.
Sulzberger-Garbe syndrome
Clinical features
Sulzberger-Garbe syndrome (distinctive exudative discoid and lichenoid
chronic dermatosis) was originally described as a widespread pruritic eruption
associated with discoid lesions in middle-aged Jewish males.1–3 Involvement
of the penis was said to be characteristic. Transformation from eczematous
Exogenous dermatitis 195
Table 6.3
Causes of erythroderma
• Dermatitis
• Lymphoma (mycosis fungoides, T-cell leukemia, Hodgkin's lymphoma)
• Drugs (gold, penicillin, etc.)
• Psoriasis
• Pityriasis rubra pilaris
• Ichthyosiform erythroderma
• Scabies
• Lichen planus
to lichenoid lesions and vice versa is also thought to be a typical feature. The
lesions are chronic, lasting from months to years, but eventually resolving.
Pathogenesis and histological features
The existence of Sulzberger-Garbe syndrome as a distinctive entity is contro-
versial. Some authors consider patients classified under this designation as
having nummular dermatitis.3
Biopsy of exudative lesions shows a non-specific spongiotic dermatitis.
Biopsy of lichenoid lesions is characterized by a bandlike lymphocytic infil-
trate. Variable numbers of eosinophils may be present.
Vein graft site dermatitis
Occasionally, patients undergoing coronary artery bypass develop an eczema-
tous dermatitis in the region of the scar from the saphenous vein donor site.1,
2 The pathogenesis is unclear. Since patients often have objective evidence of
neuropathy, some authors believe that the neuralgia may play a pathogenic
role.1 It is also possible that stasis changes play a role in this disorder.
Biopsy shows non-specific spongiotic dermatitis.
Papular acrodermatitis of childhood
Clinical features
Papular acrodermatitis of childhood (Gianotti-Crosti syndrome, infantile
papular acrodermatitis) is a rare disease representing a cutaneous response to
a number of viral infections. It is characterized by the acute onset of mono-
morphic, symmetrical flat-topped papules or papulovesicles, 1–10 mm across,
which range in color from pink to red or brown and are located primarily
on the face (particularly the cheeks), buttocks, and extensor surfaces of the
forearms and legs, with the trunk typically being spared (Figs 6.51–6.53).1–4
Lesions are usually blanchable although petechial and hemorrhagic variants
can be rarely encountered.4 A positive Koebner phenomenon is sometimes
elicited.4 The lesions are occasionally pruritic and are self-limiting, lasting
up to 3 weeks. Mucous membranes are not affected. Infants and children are
predominantly affected although there are occasional reports of the condition
developing in adults.4–9
Systemic signs include hepatosplenomegaly and axillary and inguinal
lymphadenopathy. Sometimes a fever is evident. There may be an anicteric
acute hepatitis and occasionally patients progress to chronic liver disease.
Pathogenesis and histological features
In the original and early reports, Gianotti-Crosti syndrome was documented
following infection with hepatitis B virus.10–12 More recently cases have been
reported in association with hepatitis A virus, coxsackievirus, influenza virus,
Epstein-Barr virus, cytomegalovirus, parainfluenza virus, human herpesvi-
rus-6 (HHV-6), poxvirus, parvovirus, and rotavirus.13–25 In addition, the dis-
ease had been associated with HIV infection.26 Gianotti-Crosti syndrome has
also been reported following Mycoplasma infection, Lyme borreliosis, and
immunization.27–35 The pathogenesis is unknown although viral antigenemia
and immune complex-mediated mechanisms have been proposed.36
Biopsies of skin lesions show entirely non-specific histological features.
The epidermis often appears normal or it may be mildly acanthotic with
­parakeratosis. Lymphocytic exocytosis is usually present.3 The upper dermis
contains a lymphohistiocytic infiltrate in a perivascular distribution and there
196 Spongiotic, psoriasiform and pustular dermatoses

Fig. 6.53
Gianotti-Crosti syndrome: the papules are very uniform. A viral etiology is often
identified. By courtesy of C. Gelmetti, MD, Milan University, Italy.

In cases with hepatitis, the appearances are those of an acute viral hepa-
titis, which usually resolves over a period of up to 6 months. Rarely, chronic
disease ensues.

Fig. 6.51 Pityriasis rosea

Gianotti-Crosti syndrome: the eruption is present on the face and arms, there is
sparing of the trunk. By courtesy of C. Gelmetti, MD, Milan University, Italy.
Clinical features
Pityriasis rosea (‘rose-colored scale’) presents as an acute inflammatory der-
matosis characterized by self-limiting oval papulosquamous lesions on the
trunk and extremities.1–3 The disease appears to be more common in females,
and 75% of cases occur between the ages of 10 and 35 years.4 It is character-
ized by seasonal variation, being most common in the months of December to
February.5 Although pityriasis rosea typically presents as a solitary episode,
recurrent disease may occur in up to 2% of patients.6,7
In the majority of cases the disease first manifests itself with the appear-
ance of a ‘herald patch’, a single red scaly lesion that increases in size over
48 hours up to 2–10 cm in diameter (Fig. 6.54).8 A significant proportion of
patients report symptoms, including pyrexia, headache, malaise, arthralgia,
chills, vomiting, diarrhea, and lymphadenopathy, up to 2–3 weeks before the
onset of the eruption.9
After the appearance of the herald patch there is a ‘secondary incu-
bation period’ of 7–14 days before the generalized eruption of pink to
salmon-colored elliptical scaly lesions (Fig. 6.55).10 The latter are approxi-
mately 1 cm in length and their longest axes occur along the Blaschko skin
tension lines, producing the characteristic ‘fir’ or ‘Christmas tree’ effect.
There is usually an erythematous center, the periphery of the macule being
Fig. 6.52 slightly brown and scaly. In dark-skinned patients the macules tend to be
Gianotti-Crosti syndrome: darker than the surrounding skin (Fig. 6.56). The lesions spread from the
note the widespread chest to the abdomen, thighs, arms, and back, generally within 2 weeks,
erythematous papules persist for 2—4 weeks, and fade over a further 2 weeks. Pityriasis rosea
on the cheeks of this may be pruritic.
young girl. By courtesy of Oral lesions have been described in up to 16% of patients.4 They may take
C. Gelmetti, MD, Milan
the form of a single large erythematous plaque, bullae, multiple hemorrhagic
University, Italy.
puncta, round erythematous macules and plaques or erythematous annular
lesions.4,11–14
is also swelling of endothelial cells sometimes accompanied by marked papil- Several morphological variants may occur: a papular variant is seen in
lary dermal edema.31 Scattered eosinophils may be present.36 Occasionally, a young children, pregnant women and those of Afro-Caribbean descent; a
more lichenoid pattern of inflammation is encountered. There is no evidence vesicular or bullous variant may occur in infants and children; and an urti-
of vasculitis. carial form has also been noted.5,14,15 Occasionally, pityriasis rosea has a pur-
Direct immunofluorescence is negative.3 puric, hemorrhagic component.5,14,16 Localized and unilateral forms, and
By immunohistochemistry, the infiltrate consists of an admixture of CD4+ an ‘inverse’ form presenting on the face and extremities, have also been
helper T cells and CD8+ cytotoxic T cells.19,36,37 documented.17
 Exogenous dermatitis 197

A B

Fig. 6.54
Pityriasis rosea: (A) the ‘herald patch’ which marks the onset of this dermatosis, is marked by an arrow; (B) close-up view. By courtesy of R.A. Marsden, MD, St George's
Hospital, London, UK.

Pathogenesis and histological features
The exact etiology of pityriasis rosea is unknown; however, most of the evi-
dence points to an infectious, probably viral, cause. It sometimes complicates
an upper respiratory tract infection.18 The herald patch may develop at the
site of an insect bite, particularly fleas, but patches have also occurred in areas
of old trauma and scars, suggesting an isomorphic (Koebner's) response.17
Atypical pityriasis rosea has also been described in bone marrow transplant
recipients and following treatment with interferon-alpha (IFN-α) as well as
Hodgkin's disease, and a pityriasis rosea-like eruption has been documented
due to drugs such as imatinib mesylate, ACE inhibitors, and hydrochlorothi-

A B

Fig. 6.55
Pityriasis rosea: (A) the secondary rash presents as small pink slightly scaly macules; (B) close-up view. From the collection of the late N.P. Smith, MD, the Institute of
Dermatology, London, UK.
198 Spongiotic, psoriasiform and pustular dermatoses
Fig. 6.56
Pityriasis rosea: in pigmented skin, there is often postinflammatory
hyperpigmentation and the erythematous nature of the eruption is not apparent. By
courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
azide.19–23 Case clustering in establishments with communal living supports an
infectious etiology. Recently, HHV-7, as well as HHV-6 and HHV-8, has been
identified in peripheral blood mononuclear cells in addition to plasma and
skin of patients with pityriasis rosea, and herpes virus-like particles have been
identified in cutaneous lesions of pityriasis rosea by electron microscopy.24–33
Other workers, however, have failed to confirm this observation.28,34,35 Rarely,
a pityriasis rosea-like eruption may be a manifestation of HIV/AIDS.36
The histopathological features are those of a non-specific subacute or
chronic dermatitis and comprise focal hyperkeratosis and angulated paraker-
atosis with slight acanthosis (Figs 6.57–6.60).37 The granular cell layer may
be absent beneath the foci of parakeratosis. Intraepidermal cytoid bodies are
present in as many as 50% of cases.38,39 Focal acantholytic dyskeratosis has
occasionally been documented.40 A lymphohistiocytic infiltrate surrounds the
vessels of the superficial vascular plexus and there is slight spongiosis. Rarely,
spongiotic vesiculation may be evident.5 Occasionally, scattered eosinophils
are present. Red cell extravasation is a not infrequent feature and occasional
erythrocytes may be seen within the epidermis.
Immunocytochemical staining has demonstrated that the dermal infiltrate
consists mainly of T cells, including helper and suppressor cells, together with
Fig. 6.57
Pityriasis rosea: low-power view showing multiple foci of scale with psoriasiform
hyperplasia.
Fig. 6.58
Pityriasis rosea: small foci of parakeratotic scale are a characteristic finding. The
epidermis shows mild spongiosis.
large numbers of Langerhans cells.41 Human leukocyte antigen DR (HLA-DR,
Ia-like antigen) has been demonstrated on the surface of keratinocytes, and
this has been interpreted as showing that they are taking an active role in cel-
lular immunity.42–44 HLA-DR antigen may also be expressed on the surface of
the T-helper cells.43
Differential diagnosis
Guttate psoriasis shows considerable overlap with pityriasis rosea. The presence
of neutrophils within the parakeratotic mounds favors a diagnosis of psoriasis.
A wide range of drugs has been associated with a pityriasis rosea-like erup-
tion including barbiturates, ketotifen, clonidine, captopril, isotretinoin, gold,
bismuth, arsenic, organic mercurials, methoxypromazine, D-penicillamine,
tripelennamine hydrochloride, metronidazole, and salvarsan.15,17 In such cases,
the distinction depends upon clinicopathological correlation. The presence of
large numbers of eosinophils is a clue to a hypersensitivity reaction.
Acute and subacute eczematous dermatitis may also be confused with
pityriasis rosea. The presence of lens-shaped parakeratosis and limited spon-
giosis favors pityriasis rosea. Again, clinical findings should help make this
distinction.
Fig. 6.59
Pityriasis rosea: there
is spongiosis and a
perivascular lymphocytic
infiltrate. The angulated
tier of parakeratosis
(teapot lid sign) is
characteristic.
 Exogenous dermatitis 199

Fig. 6.60 Fig. 6.62

Pityriasis rosea: in this field, there is red cell extravasation. Juvenile plantar
dermatosis: close-up
view showing scaling
Pityriasis lichenoides chronica is characterized by interface change and and fissuring. By
vacuolar degeneration of the basal layer of the epidermis, features not seen courtesy of the Institute
in pityriasis rosea. of Dermatology, London,
A PAS stain is mandatory in all cases to exclude a dermatophyte infection. UK.

Juvenile plantar dermatosis
Clinical features
Scaly palms and soles with loss of a normal epidermal rete pattern charac-
terize juvenile plantar dermatosis. The affected area often has a shiny red
appearance with fissures (Figs 6.61, 6.62).1–4 As its name suggests, the dis-
ease is seen in prepubertal children with a mean age of 9.6 years.1 The most
common sites affected are the volar aspect of the great toe and the ball of
the foot.1 The hand is only rarely affected. Patients often have a personal or
family history of atopy.2,4 The disorder usually lasts for 6 months to several
years before resolving.1,3 However, many patients develop features of classic
eczema of the hands later in life.2
Pathogenesis and histological features
The pathogenesis of this disorder is not understood; however, it has been sug-
gested that synthetic footwear may play a role in its development.3
Biopsy shows epidermal acanthosis and subacute to chronic spongiosis.1
Variable parakeratosis and hypogranulosis may be seen. A lymphocytic infil-
trate centered on the eccrine duct is said to be characteristic.1
Differential diagnosis
The histological changes are probably non-specific but the presence of chronic
inflammation centered on the sweat duct should suggest juvenile plantar derma-
tosis in the appropriate clinical setting and allow distinction from other spongi-
otic dermatitides, which typically spare the acrosyringium. One group could not
identify PAS-positive material occluding sweat ducts in multiple histological sec-
tions of juvenile plantar dermatosis (compare with miliaria).1 A PAS stain with
diastase digestion should also be performed to evaluate for fungal infection.

Miliaria
Clinical features
This common disorder, although most often seen in children, may affect any
age group but congenital presentation is rare.1 It develops as a consequence
of obstruction to the outflow tract of the intraepidermal component of the
eccrine sweat duct and is associated with excessive sweating and exposure to
high humidity. Traditionally, the condition is subdivided into three subtypes:
miliaria crystallina, miliaria rubra, and miliaria profunda.2,3
• In miliaria crystallina the level of obstruction is within the stratum
corneum, and results in the formation of small, clear vesicles, located
Fig. 6.61 particularly on the trunk (Fig. 6.63). There are accompanying symptoms
Juvenile plantar
of a high fever and pronounced sweating.
dermatosis: multiple
erythematous lesions
• Miliaria rubra (prickly heat) is particularly common in hot, humid
are present on the climates and is due to obstruction within the prickle cell layer, resulting
soles of the feet. By in erythematous papules and vesicles, usually located about the
courtesy of the Institute trunk and intertriginous regions (Fig. 6.64). This form of miliaria is
of Dermatology, London, particularly common in infants. The term miliaria pustulosa has been
UK. applied to the above subtypes when pustules develop. Miliaria rubra
200 Spongiotic, psoriasiform and pustular dermatoses
Fig. 6.63
Miliaria crystallina: tiny vesicles resembling water droplets are scattered over the
abdomen of this young male. By courtesy of R.A. Marsden, MD, St George's
Hospital, London, UK.
Fig. 6.64
Miliaria rubra: the characteristic appearance is of large numbers of minute papules
and vesicles. By courtesy of M.M. Black, MD, Institute of Dermatology, London, UK.
and its pustular variant have also been found in association with
pseudohypoaldesteronism, type I.4,5,6
• In miliaria profunda, also typically seen in tropical climates, the
obstruction is at level of the sweat duct. Small papules are seen on the
trunk and occasionally the extremities.
Pathogenesis and histological features
The pathogenesis of miliaria is poorly understood. It has been suggested that
bacteria play a role in the development of the disease. There is evidence that
extracellular polysaccharide substance (EPS), a PAS-positive material pro-
duced by some strains of Staphylococcus epidermidis, obstructs the sweat duct
and causes the disease.7 Normal controls who had S. epidermidis swabbed on
to the volar aspect of their forearms followed by occlusion and heat devel-
oped miliaria. These results have not been replicated with other bacteria.7
Biopsy revealed EPS in lesions from several patients.
A subcorneal vesicle containing a few neutrophils characterizes miliaria
crystallina, while rubra involves an intraepidermal spongiotic vesicle. In
both variants the lesions can be seen to be centered upon an intraepider-
mal eccrine sweat duct. Miliaria pustulosa is characterized by features of
miliaria in addition to an intraepidermal or subcorneal pustule. Miliaria
profunda is characterized by spongiosis of the dermal portion of the eccrine
duct, often associated with dermal chronic inflammation adjacent to the
affected duct.
Fox-Fordyce disease
Clinical features
Fox-Fordyce disease (apocrine miliaria, chronic itching papular eruption of
the axillae and pubic region) presents as a chronic papular eruption, associ-
ated with pruritus, and located in areas containing apocrine sweat glands
(i.e., the axillae, the pubic area, the vulval labia, the perineum, and areola)
(Fig. 6.65).1–3 The papules are discrete, firm, and flesh-colored or pigmented.
Associated hair loss is often present.
The disease is uncommon and over 90% of reported cases have occurred
in women, usually aged 13–35 years. Rarely, prepubescent and postmeno-
pausal patients have been described.4,5
Pathogenesis and histological features
Patients with Fox-Fordyce disease have apocrine anhidrosis. Although eccrine
sweating is normal, apocrine sweating does not occur due to the keratotic
plugging of the apocrine duct orifice. The continued secretion of sweat, how-
ever, causes the duct to rupture and an apocrine sweat retention cyst forms
in the epithelium. The exact cause of the follicular plugging is unknown,
but a hormonal link has been postulated. Occasional instances of coexistent
hidradenitis suppurativa have been recorded.6
Follicular infundibular plugging is present in association with acanthosis,
parakeratosis, spongiosis, and an underlying non-specific chronic inflamma-
tory cell infiltrate. Dilation of the apocrine glands may be present and the
presence of perifollicular foamy histiocytes is a frequent and diagnostically
helpful feature.7–9 Further reported findings include vacuolar change, dysker-
atosis, and parakeratotic lamellae affecting the follicular infundibulum.10 The
keratinous obstruction prevents the outflow of apocrine secretion and leads
to the diagnostic feature of an intrafollicular sweat retention vesicle; serial
sections may be needed to demonstrate this lesion.11,12
Transient acantholytic dermatosis with
prominent eccrine ductal involvement
Grover's disease (transient acantholytic dermatoses) is discussed more com-
prehensively elsewhere; however, since it is commonly associated with spongi-
osis (often in the absence of acantholysis), it deserves mention in this chapter.
Recent studies of Grover's disease have shown a strong correlation with high
temperature and sweating and it has been suggested that its pathogenesis may
be analogous to that of miliaria.1–3 Supporting this concept is the development
of Grover's disease in bed-ridden and febrile patients. The lesions are usually
present on the back. These patients often have prominent involvement of
the eccrine duct and the lesions have been termed sudoriferous acrosyringeal
acantholytic disease (sudoriferous Grover's disease).4 Biopsies taken from
patients with sudoriferous acrosyringeal acantholytic disease often show, in
addition to typical features of Grover's disease, acantholysis of the superfi-
cial portion of the eccrine duct. When acantholysis is present and a clinical
history is provided, the diagnosis is usually straightforward. However, not
uncommonly, biopsies taken from patients with Grover's disease show spon-
giosis only (often eosinophilic spongiosis). In these patients, a diagnosis of
Grover's disease may still be made in the appropriate clinical setting.
It is important to note that myriad cutaneous disorders may show some
degree of spongiosis. For example, such disparate conditions as mycosis fun-
goides and psoriasis are not uncommonly associated with a degree of spon-
giosis. In this chapter, we have focused our discussion on entities for which
spongiosis is a dominant and fairly consistent histological finding. Other enti-
ties that may occasionally be associated with some degree of spongiosis are
discussed in the appropriate chapters.
 Psoriasis 201

Fig. 6.65
Fox-Fordyce disease: (A) there are numerous white
papules. The axilla is a characteristic site; (B) close-up
A B view. By courtesy of the Institute of Dermatology,
London, UK.

Psoriasiform dermatoses
The psoriasiform reaction pattern is defined by the presence of epidermal
hyperplasia with fairly uniform and marked enlargement of the rete ridges.
Although confluent parakeratosis with neutrophil exocytosis is characteris-
tic of psoriasis (the prototype of this group of conditions), this feature is not
included within the definition, which would otherwise become too restrictive.
Diseases in addition to psoriasis which may manifest a psoriasiform pattern
include Reiter's syndrome, pityriasis rubra pilaris, lichen simplex chronicus,
psoriasiform drug reactions, subacute and chronic spongiotic dermatitis,
parapsoriasis, and pityriasis rosea (herald patch). Other conditions in which
psoriasiform hyperplasia may sometimes be a feature include dermatophyte
infections and candidiasis, secondary syphilis, scabies infestation, inflamma-
tory linear verrucous epidermal nevus, necrolytic migratory erythema, acro-
dermatitis enteropathica, and pellagra. Neoplastic conditions such as Bowen's
disease and mycosis fungoides, which often show marked epidermal hyper-
plasia, are not included in this definition.
(Fig. 6.69). The scalp, the extensor surfaces (mainly the knees and elbows),
the lower back, and around the umbilicus are particularly affected. The clini-
cal features, however, show regional variation: scalp involvement often shows
very marked plaque formation, whereas on the penis scaling is commonly
minimal and the features may be mistaken for Bowen's disease (Figs 6.70–
6.72). Linear lesions (linear psoriasis) follow previous trauma (koebneriza-
tion) (Fig. 6.73).
Psoriasis may manifest in a variety of other ways.
• Guttate (eruptive) psoriasis presents as small (0.5–1.5 cm in diameter)
papules over the upper trunk and proximal extremities, typically in
younger patients (Figs 6.74–6.76).

Psoriasis
Clinical features
Psoriasis is a chronic relapsing and remitting disease of the skin that may
affect any site.1 It is one of the commonest of all skin diseases, with a reported
incidence of 1–2% in Caucasians.2,3 It is rare among blacks, Japanese, and
native North and South American populations.4 Males and females are
affected equally. Although psoriasis may occur at any age, it most frequently
presents in the teens and in early adult life (type I psoriasis).5 A second peak
in which the disease is often milder appears around the sixth decade (type II
psoriasis).5
The classic cutaneous lesion of psoriasis vulgaris (plaque psoriasis),
developing in about 85–90% of patients with psoriasis, is raised, sharply
demarcated, with a silvery scaly surface (Figs 6.66–6.68).6,7 The underly-
ing skin has a glossy, erythematous appearance. If the parakeratotic scales Fig. 6.66
are removed with the fingernail, small droplets of blood may appear on the Psoriasis: typical plaque disease showing bilateral and fairly symmetrical
surface (Auspitz's sign); this is diagnostic. Plaques, when multiple, are often distribution. In this example, the silvery scale is well demonstrated. From the
symmetrical and annular lesions due to central clearing are a common finding collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.
202 Spongiotic, psoriasiform and pustular dermatoses

Fig. 6.67 Fig. 6.69

Plaque psoriasis: note the symmetry of these lesions. By courtesy of R.A. Annular psoriasis: central clearing of plaques results in annular lesions. By courtesy
Marsden, MD, St George's Hospital, London, UK. of R.A. Marsden, MD, St George's Hospital, London, UK.

• Psoriasis inversa is characterized by the development of plaques in the

flexures (Fig. 6.77).
• Generalized pustular psoriasis (von Zumbusch) is an acute variant,
characterized by fever of several days' duration, together with the
sudden appearance of sterile pustules, 2–3 mm across, over the trunk
and extremities (Fig. 6.78).8 The surrounding skin is erythematous
and confluence may result in a generalized erythroderma (Fig. 6.79).
Usually, recurrent episodes of fever occur, followed by fresh outbreaks
of pustules (Fig. 6.80). Systemic signs include weight loss, weakness,
and hypocalcemia, with a raised white cell count and high erythrocyte
sedimentation rate (ESR). Although the precipitating factor is often
unknown, pustular psoriasis may follow a streptococcal or viral
infection. Withdrawal of systemic steroid therapy is also a known
predisposing cause.9 Treatment with systemic steroids or intensive
topical regimens has also been incriminated.10 Other risk factors for
developing a pustular episode include drugs, pregnancy, hypocalcemia,

Fig. 6.70
Plaque psoriasis: the scalp is a commonly affected site. By courtesy of the Institute
of Dermatology, London, UK.

Fig. 6.71
Plaque psoriasis: in this
extreme case, the initial
Fig. 6.68 diagnosis was Norwegian
Plaque psoriasis: close-up scabies. Surprisingly,
view showing the thick alopecia is an uncommon
scale. From the collection complication. By courtesy
of the late N.P. Smith, of R.A. Marsden, MD,
MD, the Institute of St George's Hospital,
Dermatology, London, UK. London, UK.
 Psoriasis 203

Fig. 6.74
Guttate psoriasis: this infant shows a characteristic distribution over the trunk.
By courtesy of M. Liang, MD, Children's Hospital, Boston, USA.

Fig. 6.72
Psoriasis: penile lesion showing a sharply demarcated, erythematous, eroded,
slightly scaly plaque. By courtesy of C. Furlonge, MD, Port of Spain, Trinidad.

Fig. 6.75
Guttate psoriasis: this close-up view shows the erythema and scaling.
By courtesy of the Institute of Dermatology, London, UK.

Fig. 6.73
Plaque psoriasis: linear involvement is a manifestation of koebnerization following
trauma. By courtesy of the Institute of Dermatology, London, UK.

and sunlight or phototherapy.11 Uncommon variants of pustular

psoriasis include an annular form, exanthematous pustular psoriasis,
juvenile and infantile pustular psoriasis.12,13 The annular variant is
a somewhat less serious variant in which, due to central clearing,
lesions develop an annular or gyrate morphology.11 Often, the systemic
manifestations are less florid. The exanthematous variant, which tends
to develop de novo, may sometimes follow an infection or represent
a pustular drug reaction.11 Impetigo herpetiformis most probably
represents pustular psoriasis of pregnancy although some authors
classify it as a separate entity.14
• In psoriatic erythroderma, there is an intense generalized erythema
affecting the entire skin surface, associated with desquamation (Fig.
6.81). Ectropion may be present and scalp involvement is sometimes
followed by hair loss. Erythroderma may be precipitated in patients
with psoriasis vulgaris by infection with Staphylococcus aureus, abrupt Fig. 6.76
curtailment of steroid or methotrexate therapy, and sunburn.11 Systemic Guttate psoriasis: as with plaque disease, guttate psoriasis is associated with a
symptoms including fever, chills, shortness of breath, fatigue, and Koebner phenomenon. By courtesy of the Institute of Dermatology, London, UK.
204 Spongiotic, psoriasiform and pustular dermatoses
Fig. 6.77
Flexural (inverse)
psoriasis: this is a rare
variant in which the
lesions develop on
flexural skin.
Fig. 6.78
Pustular psoriasis (von Zumbusch): note the extreme generalized erythema and
pustulation. This variant is rare and may sometimes prove fatal. By courtesy of R.A.
Marsden, St George's Hospital, London, UK.
myalgia are commonly present.11 Biochemical abnormalities include
hypoalbuminemia, anemia, and dehydration.15 High-output cardiac
failure is an important complication.
• Localized (mixed) pustular psoriasis represents the development of
pustules on pre-existent plaques.9 This variant most often develops in
acute flares of psoriasis or following treatment.11 It sometimes represents
a harbinger of a more generalized process.
• Palmoplantar pustular psoriasis of Barber (pustulosis palmaris et
plantaris) refers to a chronic recurrent pustular dermatosis localized to
the palms and soles (Figs 6.82, 6.83). It shows a strong predilection
for females (9:1) in the fourth to fifth decade of life and the disease is
associated with a history of smoking.6,16,17 In about 25% of patients there
is coexistent chronic plaque psoriasis.6
• Acrodermatitis continua (acropustulosis) of Hallopeau is a rare sterile
pustular eruption of the fingers or toes, involving the nails and slowly
extending proximally (Figs 6.84, 6.85).
Fig. 6.79
Pustular psoriasis: early
stage showing intense
erythema. By courtesy
of the Institute of
Dermatology, London, UK.
Fig. 6.80
Pustular psoriasis: close-up view showing typical pustules arising on a background
of intense erythema. By courtesy of the Institute of Dermatology, London, UK.
The nail is frequently affected in psoriasis; lesions may include pitting,
discoloration, onycholysis, subungual hyperkeratosis, nail grooving, splinter
hemorrhages and complete loss in pustular psoriasis.18
Patients with psoriasis have a higher incidence of certain comorbidities
including, depression, obesity, type 2 diabetes mellitus, hyperlipidemia,
hypertension, metabolic syndrome, cardiovascular disease, Crohn's disease,
and multiple sclerosis, as well as cutaneous and visceral malignancies.6,19
Psoriatic arthritis
Psoriatic arthritis has a prevalence of 0.02–7% but more recent data suggest
that it could be as high as 30%.20 It may take a number of different forms
(Fig. 6.86):21
• The most common is an asymmetrical involvement of a few joints of the
fingers or toes; this accounts for over 70% of cases.
• In 15% of cases a symmetrical polyarthritis, clinically indistinguishable
from rheumatoid arthritis, but seronegative, is seen.
 Psoriasis 205

Fig. 6.83
Palmoplantar pustular psoriasis: close-up view of palmar pustules.
By courtesy of the Institute of Dermatology, London, UK.

Fig. 6.81
Psoriatic erythroderma: there is generalized erythema. Patients are at risk of
dehydration, hypoalbuminemia, and anemia. By courtesy of R.A. Marsden,
St George's Hospital, London, UK.

Fig. 6.84
Acropustulosis continua: there is pustulation with erythema and scaling, the nail
has been shed, and there is damage to the nail plate. By courtesy of R.A. Marsden,
St George's Hospital, London, UK.

Fig. 6.82
Palmoplantar pustular
psoriasis: there is intense
erythema, scaling, and
numerous pustules. By Fig. 6.85
courtesy of the Institute of Acropustulosis continua: a particularly severe example. By courtesy of S. Dalziel,
Dermatology, London, UK. MD, University Hospital, Nottingham, UK.
206 Spongiotic, psoriasiform and pustular dermatoses
Fig. 6.86
Psoriatic arthropathy: joint involvement is a rare manifestation. Lesions of the
interphalangeal joints, while said to be characteristic, are an uncommon finding.
In this patient there is gross deformity. By courtesy of R.A. Marsden, St George's
Hospital, London, UK.
Fig. 6.87
Psoriatic arthropathy:
classic type. Note the
destruction of the distal
interphalangeal joint
of the first finger. By
courtesy of the Institute
of Dermatology, London,
UK.
• In approximately 5% of cases the distal interphalangeal joints are
involved, the classical picture of psoriatic arthropathy (Fig. 6.87).
• A further 5% have a destructive and severely deforming arthritis,
arthritis mutilans.
• The remaining cases have ankylosing spondylitis, with or without
peripheral joint involvement (Fig. 6.88).
Psoriatic arthritis is associated with a high incidence of mitral valve pro-
lapse with resultant incompetence.22 The peak age of onset is 36–45 years
of age, although the destructive form may occur earlier. A high incidence of
immunoglobulin gene polymorphism has been identified in patients with pso-
riatic arthritis, suggesting an inherited predisposition.23
Psoriatic arthritis in children, although uncommon, is of importance
because frequently the arthritis precedes the onset of the skin lesions. A care-
ful examination for nail changes and questioning about a family history may
be of value in establishing the diagnosis.
Pathogenesis and histological features
Although the etiology of psoriasis remains incompletely understood, consid-
erable advances have been made in the past two decades to unravel the com-
plex mechanisms involved in the pathogenesis of this common dermatosis.
For many years psoriasis was considered to represent a primary epidermal
hyperproliferative disorder. More recent studies, however, have shown that
a T-lymphocyte-driven immune process is central to the development of the
psoriatic plaque and, in fact, may represent the earliest stage in its evolution.
Other important factors include genetic influences, the environment, and the
contribution of keratinocyte-derived mediators of the inflammatory process.
Fig. 6.88
Psoriatic arthropathy: sacroiliitis. Note the virtual obliteration of the sacroiliac joints.
By courtesy of R.A. Marsden, St George's Hospital, London, UK.
The inherited predisposition to develop psoriasis has long been known.
A positive family history is common. Documented prevalence rates in first-
degree relatives have ranged from 7.8% to 17.6%.24,25 Monozygotic twins
have a concordance of 64–70% while that of dizygotic twins is in the order of
14–23%.26 Linkage analysis has identified at least nine separate loci (PSORS1–
9).6,7,27–30 PSORS1 shows the strongest genetic susceptibility, being implicated
in 35–50% of familial psoriasis. 6,7,31,32 The locus is present on chromosome
6p within the major histocompatibility complex and more recent data have
demonstrated HLA-Cw6 as the susceptibility allele on PSORS1.31,32
Genetically, psoriasis is a heterogeneous disease at the level of PSORS1
and two distinct types have been identified:5
• Type I disease which affects young adults and includes guttate psoriasis is
characterized by a familial segregation involving HLA-Cw6.5,33
• Type II disease includes psoriasis vulgaris presenting at an older age
(over 50 years) as well as palmoplantar pustulosis and shows no familial
segregation and no association with the PSORS1 locus.4,33,34 Patients with
pustular psoriasis have a higher incidence of HLA-B27, as do those with
psoriasis and peripheral arthritis, and this is most marked if spondylitis
is present.35 Further genes related to increased genetic susceptibility for
psoriasis include the interleukin-23 receptor gene on chromosome 1p,
the interleukin-12B gene on chromosome 5q, zinc finger protein 313 on
chromosome 20q, the CDKAL1 gene on chromosome 6p, the PTPN22
gene on chromosome 18p, the IL-4–IL-13 cytokine gene cluster on
chromosome 5q, the LCE3B/3C gene on 1q, and the PSORS2 locus on
chromosome 17q.7
The IL-23 receptor is of interest as it is also associated with ankolysing
spondylitis and psoriatic arthritis while the CDKAL1 gene has also been
­associated with Crohn's disease and type-2 diabetes mellitus.7
Certain factors are known to induce psoriasis in a person who is geneti-
cally predisposed. There is a tendency for lesions to develop at sites of previ-
ous skin trauma (e.g., mechanical friction, sunburn or childhood illnesses such
as varicella); this is termed the isomorphic or Koebner's phenomenon.36–38
Infections are well known as predisposing factors in the onset of psoriasis.
In children in particular, upper respiratory tract infections frequently trig-
ger psoriasis, while infections with Streptococcus pyogenes are implicated in
the development of acute guttate psoriasis, together with an exacerbation of
other forms of psoriasis.39–42 Specific streptococcal serotypes, however, do not
appear to be implicated.
Other factors known to exacerbate psoriasis include stress, bereavement,
HIV/AIDS, withdrawal of corticosteroids after prolonged use, and treatment

with a number of drugs including lithium, antimalarials, and beta-blocking
agents.6,43
The development of the psoriatic plaque results from a complex interplay
between keratinocyte hyperproliferation with loss of differentiation, changes
in the superficial dermal vasculature, and a T-lymphocyte-mediated inflam-
matory component.44 The relative roles of keratinocyte hyperplasia, vascular
changes, and immunological reactions have been the subject of much discus-
sion in the recent literature.45 Most recently, the focus has been particularly
directed towards the importance of the innate as well as adaptive immune
systems.7
In the skin there is an increased epidermal proliferation rate: the transit
time of keratinocytes through the epidermis in normal skin is 56 days; in pso-
riatic skin it is shortened to 7 days.46,47 The epidermal cell cycle is probably
shortened, and there is a large increase in the number of proliferating genera-
tive cells in the basal layers, where up to three layers of proliferating cells may
be seen compared with only one in normal resting epidermis.
Vascular proliferation predominantly affecting the postcapillary venules
of the dermal papillae appears to be one of the earliest manifestations of
psoriasis.48 This is mediated by upregulation of αVβ3 integrin and vascular
endothelial growth factor (VEGF).49–51
The current weight of evidence suggests that a T-cell-mediated immune
reaction is central to the pathogenesis of psoriasis.44,52 Clinical studies sup-
porting this hypothesis include the response to antilymphocyte therapies
such as ciclosporin.53 More recently, remission in patients with severe pso-
riasis has resulted from treatment with an activated T-lymphocyte selective
toxin DAB389 IL-2 that interacts with the receptor-binding domain of IL-2.54
Successful responses to therapy with monoclonal anti-CD3 and anti-CD4
antibodies adds further support.55,56 Additional evidence has come from bone
marrow transplantation studies. Unaffected patients develop psoriasis follow-
ing a transplant from an affected donor whereas patients are cured of their
disease following transplantation from an unaffected donor.57 In vitro stud-
ies in which intradermal injection of T-helper lymphocytes from an affected
patient into severe combined immunodeficient mice results in the development
of typical psoriasis further supports a T-lymphocyte-driven pathogenesis.58
The innate immune system appears to play an important part in the early
stages of the disease and increased numbers of activated plasmacytoid den-
dritic cells are present in early psoriatic lesions.59 Production of interferon
alpha by plasmacytoid dendritic cells and TNF-α and INF-γ by natural killer
cells leads to activation of myeloid dendritic cells and subsequent prolifera-
tion of T cells through IL-12 and IL-23 release.7,60
Although CD4 T-helper (Th) lymphocytes are probably of importance in
the earliest stages of plaque development, the major population is charac-
terized by CD8 expression. The immunophenotype of the T cells includes
CD45RO+, HLADR+, CD25+ and CLA+, indicating activated skin-specific
memory cells.61 The lymphocyte cytokine profile, which includes IL-2, IL-17,
interferon gamma (IFN-γ), and absence of IL-4, IL-10, and tumor necrosis
factor alpha (TNF-α), reflects a predominantly Th1-mediated inflammatory
reaction as well as IL-17-A producing type 17 helper T (Th17) cells.7,62–64
Th17 cells are of particular importance for epithelial immunosurveillance
and produce IL-22, a molecule involved in keratinocyte differentiation and
proliferation.65,66 IFN-γ is central to the development of the plaque. In vitro
studies have shown that the keratinocyte proliferation is IFN-γ dependent.67
Also, IFN-γ injection in normal human skin results in epidermal prolifera-
tion.68 In addition to the lymphocyte-derived cytokines discussed above, the
keratinocytes themselves are a rich source of inflammatory mediators, which
are likely to be of importance in initiating the inflammatory reaction and
the development and maintenance of the psoriasiform plaque.69 In particular,
keratinocytes secrete IL-1α, IL-1β, and TNF-α. These cytokines play a major
role in angiogenesis, in recruitment of circulating lymphocytes, and induc-
ing expression of a number of endothelial cell adhesion molecules includ-
ing E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell
adhesion molecule-1 (VCAM-1).69–71 These last are of particular importance
in facilitating the extravasation of lymphocytes through the endothelium.52
Keratinocytes are also a valuable source of chemokines including IL-8, mela-
noma growth stimulatory activity alpha (MGS/GRO-α), gamma inducible
protein 10 (IP-10), and molecule chemoattractant protein 1 (MCP-1).69 IL-8
is of importance in both neutrophil and T-lymphocyte chemotaxis.72 It also
Psoriasis 207
promotes keratinocyte proliferation and induces angiogenesis.73,74 IL-8 is pre-
dominantly derived from superficial keratinocytes and the associated neu-
trophils within the psoriatic plaque. MGS/GRO-α is an additional powerful
neutrophil chemoattractant.69
The pathogenesis of psoriasis therefore involves interaction between
injured keratinocytes and activated lymphocytes through the release of vari-
ous cytokines developing in a background of genetic predisposition.71 The
precise relationship between the T-cell-driven immune reaction and epider-
mal hyperplasia, however, remains unclear. Similarly, the initiator(s) of this
process are uncertain. Although autoantigens and bacterial superantigens are
currently favored, the possibility of a direct consequence of lymphocyte–kera-
tinocyte interaction has not yet been disproved.74
In biopsies of the early lesions, the histological features consist primarily
of dermal changes.75–79 The evolution of the psoriatic plaque consists initially
of the development of tortuous, dilated, and frequently congested capillaries
in the superficial papillary dermis accompanied by edema and a perivascu-
lar mononuclear cell infiltrate (Fig. 6.89).75 This vascular change is common
to all forms of psoriasis and may even be seen in biopsies from clinically
resolved lesions following treatment.78 Lymphocytes then migrate into the
lower epidermis, which becomes spongiotic. Subsequently, the upper epider-
mis shows focal vacuolation and eventual loss of the granular cell layer with
the resultant formation of parakeratotic mounds. Migration of neutrophils
from capillaries in the dermal papillae through gaps in the epidermal base-
ment membrane and hence to the stratum corneum completes the process.
Psoriasiform hyperplasia of the affected epidermis then follows.
Classical plaque psoriatic lesions show marked and characteristic acan-
thosis of the epidermal ridges, which are evenly elongated and club-shaped at
their bases, alternating with long edematous papillae, which are club-shaped
at their tips (Figs 6.90–6.93). Fusion of adjacent ridges is commonly pres-
ent in established lesions. The suprapapillary plate is typically thinned and
the epidermal surface is covered by confluent parakeratosis associated with
diminution or loss of the granular cell layer. The lower suprabasal layers of
the epidermis can frequently be seen to be actively dividing. Large tortuous
capillaries are present in the papillary dermis and there is a slight perivascular
lymphocytic infiltrate in the subpapillary dermis. Palmar and plantar lesions
may sometimes cause diagnostic difficulty as spongiosis can be marked, and
occasionally vesiculation is evident.78
The diagnostic features of active lesions include the ‘Munro microab-
scess’ and ‘spongiform pustule of Kogoj’. Munro microabscesses represent
an accumulation of polymorphs within the parakeratotic stratum corneum.
Spongiform pustules are seen beneath the keratin layer and consist of small
accumulations of neutrophils and occasional lymphocytes intermingled with
the epidermal cells in foci of spongiosis.
Fig. 6.89
Evolving psoriasis: in the early stages, there is capillary dilatation, with spongiosis,
as shown in this field. A small parakeratotic mound is also demonstrated.
208 Spongiotic, psoriasiform and pustular dermatoses
Fig. 6.90
Plaque psoriasis: scanning view showing extensive parakeratosis, regular
acanthosis, club-shaped epidermal ridges, and ridge fusion.
Fig. 6.91
Plaque psoriasis: closer view showing parakeratosis with neutrophil aggregates
(Munro microabscess). There is marked dilatation and tortuosity of the capillaries
within the dermal papillae. Spongiosis is also present.
Fig. 6.92
Plaque psoriasis: Munro microabscess, spongiform degeneration, and parakeratosis.
Fig. 6.93
Plaque psoriasis: tortuous and dilated capillaries.
In guttate psoriasis, the histological features overlap with those of evolv-
ing disease.78 Parakeratosis associated with loss or diminution of the granular
cell layer is limited to small foci contrasting with a background of orthokera-
tosis (Figs 6.94, 6.95). Neutrophils are seen surmounting the parakeratotic
tiers. Acanthosis is much less marked than in fully established plaque disease.
Neutrophils and lymphocytes are commonly present in the superficial papil-
lary dermis and mild spongiosis is often a feature, particularly if biopsies of
early lesions are examined.80
In generalized pustular psoriasis and its three variants the histological pic-
ture is slightly different in that the spongiform pustule occurs as a macropus-
tule and is the characteristic lesion (Figs 6.96, 6.97).79 As the spongiform
pustule increases in size, the epidermal cells die, with resulting central cavita-
tion. At the edges, a shell of thinned epidermal cells remains. Eventually there
is migration of neutrophils into the horny layer and the picture resembles that
of a large Munro abscess. Although the epidermal and dermal features may
be similar to those of psoriasis vulgaris, particularly if the pustule has devel-
oped against a background of plaque-type disease, more often the features
are much less well developed (Fig. 6.98). Frequently, therefore, there is no or
only minimal epidermal hyperplasia although tortuous and dilated capillaries
accompanied by a lymphocytic or mixed lymphocytic and neutrophil infiltrate
are usually seen.11
Fig. 6.94
Guttate psoriasis: the multiple discrete, parakeratotic mounds are characteristic.
Hyperplasia is not as well developed as in plaque disease.
 Psoriasis 209

Fig. 6.95 Fig. 6.98

Guttate psoriasis: close-up view. Pustular psoriasis: in this patient, the lesions developed dramatically in the absence of
significant plaque disease. There is only mild hyperplasia of the underlying epidermis.

In palmar/plantar pustular lesions, the initial changes are those of spon-

Fig. 6.96
Pustular psoriasis: a macropustule is present. Typical psoriasiform hyperplasia with
parakeratosis is seen in the adjacent epidermis.
giosis with lymphocytic exocytosis in the lower epidermis.80 As the lesion
­progresses, neutrophils infiltrate the epidermis and a macropustule develops.
In psoriatic erythroderma the histological features are variable but in the
majority of cases a positive diagnosis can be established.81 Most commonly,
the features are those of evolving psoriasis similar to guttate psoriasis, i.e.,
slight epidermal hyperplasia, focal diminution or loss of the granular cell
layer, and mild spongiosis (Fig. 6.99). Parakeratosis is often limited to slight
change overlying the hyperplastic epithelium and neutrophils are variably
present (Fig. 6.100). A lymphohistiocytic infiltrate is present in an edema-
tous papillary dermis and dilated, tortuous, spiraling vessels are regularly
evident. Extravasated red blood cells are a constant finding. Less commonly,
the features are those of psoriasis vulgaris and sometimes the changes overlap
regressing psoriasis.
In resolving lesions, foci of hyperkeratosis overlying hypergranulosis are
scattered through the parakeratotic scale and the epidermal hyperplasia is less
marked (Fig. 6.101).
Current treatment for severe widespread plaque psoriasis may include
the use of PUVA therapy. Over the recent years it has been shown that this
is associated with an increased risk (albeit low) of cutaneous squamous
cell carcinoma and dysplastic keratoses.82–85 Patients at most risk include

Fig. 6.99
Fig. 6.97 Psoriatic erythroderma: there is only very focal parakeratosis with scattered
Pustular psoriasis: close-up view. neutrophils. The epidermal hyperplasia is only slight.
210 Spongiotic, psoriasiform and pustular dermatoses

Fig. 6.100 Fig. 6.102

Psoriatic erythroderma: close-up view of parakeratosis and neutrophil karyorrhectic Bullous pemphigoid and pustular psoriasis: on the left is a subcorneal pustule while
debris. on the right is a subepidermal blister.

Fig. 6.101 Fig. 6.103

Resolving psoriasis: newly formed basket-weave orthokeratin is seen underlying Bullous pemphigoid and pustular psoriasis: higher-power view of the blister.
focal residual parakeratosis.

those who have had more than 200 PUVA treatments and/or a cumula-
tive dose in excess of 1000 J/cm2. There is some evidence to suggest that
these tumors behave in a low-grade fashion, with little risk of metastatic
spread.85
Psoriasis may rarely coexist with a number of autoimmune bullous
dermatoses including bullous pemphigoid, pemphigus vulgaris, linear IgA
disease, and epidermolysis bullosa acquisita.86–92 Although not in all cases,
there is often a relationship to treatment, particularly with PUVA ther-
apy. In some instances, the histology may show features of both conditions
(Figs 6.102–6.104).

Differential diagnosis
The differential diagnosis of psoriatic lesions includes a number of
conditions:
• Pityriasis rubra pilaris differs from psoriasis by the presence of
alternating parakeratosis and hyperkeratosis in both vertical and
horizontal directions (spotty parakeratosis). Neutrophil infiltration of the
stratum corneum is not a feature of pityriasis rubra pilaris unless there is Fig. 6.104
secondary infection. Bullous pemphigoid and pustular psoriasis: higher-power view of the pustule.
 Pityriasis rubra pilaris 211

• Lichen simplex chronicus typically shows scarring of the dermal papillae

due to persistent rubbing, and there is no thinning of the suprapapillary
plate. Hyperkeratosis and hypergranulosis are often marked and there is
minimal parakeratosis unless there is a background of spongiosis.
• Papulosquamous drug eruptions (e.g., due to lithium or propranolol)
may appear similar to psoriasis, but a moderate to high number of
eosinophils is usually present in the infiltrate.
• Seborrheic dermatitis typically shows psoriasiform hyperplasia and
corneal neutrophil infiltration may sometimes be a feature. It differs from
psoriasis by the presence of a more conspicuous spongiotic component,
which in psoriasis only occurs in early lesions and is usually not marked.
In those cases where the distinction is not possible, the term ‘sebo-
psoriasis’ is sometimes used.
• Pustular psoriasis and its variants are all similar; they must be
distinguished from other pustular eruptions, including conditions such
as pustular dermatophytoses, bacterial impetigo, and pustular drug
eruptions. Pustular psoriasis may be differentiated from subcorneal
pustular dermatosis by the absence of spongiform change or degeneration
in the latter condition. Gram and PAS stains and culture will exclude Fig. 6.105
infective conditions. Superficial pemphigus can be distinguished by Pityriasis rubra pilaris: there is characteristic hyperkeratosis and surrounding
the presence of acantholysis and the usual absence of psoriasiform erythema. At the edges individual follicular lesions are evident. By courtesy of M.M.
hyperplasia. In IgA pemphigus, acantholytic cells are usually, but not Black, MD, Institute of Dermatology, London, UK.
always, present and this diagnostic clue may be very easily overlooked,
but should allow distinction from psoriasis. In lesions of IgA pemphigus
that lack acantholytic cells, immunofluorescence studies may be
necessary to make the distinction from pustular psoriasis if the clinical
diagnosis is in doubt.

Reiter's syndrome
The skin lesions of Reiter's syndrome typically show psoriasiform hyperpla-
sia with parakeratosis. The epidermis is markedly acanthotic with elonga-
tion and hypertrophy of the epidermal ridges. The suprapapillary plates are
thinned and there is infiltration of the epidermis by neutrophils, associated
with the formation of spongiform pustules, microabscesses, and ultimately
macropustules indistinguishable from pustular psoriasis. A perivascular lym-
phohistiocytic infiltrate with neutrophils is seen in the upper dermis.

Pityriasis rubra pilaris

Clinical features
Pityriasis rubra pilaris is an erythematous papulosquamous disorder character-
ized by follicular plugging (often best seen on the dorsal aspects of the hands
and feet), perifollicular erythema that becomes confluent, palmoplantar hyper-
keratosis, and pityriasis capitis.1–3 It is an uncommon disease, accounting for
approximately one of every 5000 new dermatological referrals in the United
Kingdom.3 Males and females are affected equally and the age distribution
tends to peak in the first and fifth decades.3 Although the majority of cases doc-
umented have affected Caucasian patients, occasional reports describing pityri-
asis rubra pilaris in black African patients have recently been published.4
Pityriasis rubra pilaris has been classified clinically into five types:3
• Type I, classical adult pityriasis rubra pilaris, is seen in over 50% of
patients. Initially, a single erythematous patch appears on the upper
half of the body (typically the face and scalp) and gradually spreads as
large areas of sometimes pruritic or burning follicular hyperkeratosis
with erythematous perifollicular halos (Fig. 6.105).4 The erythematous
areas coalesce and many patients develop generalized erythroderma
(Fig. 6.106). Characteristically, occasional islands of unaffected skin
are present (Fig. 6.107). Follicular papules on the dorsal aspects of
the fingers and extensor surfaces of the wrists, arms, and thighs are
said to be characteristic.5 Fine and powdery scaling occurs on the face
and scalp, with coarser scaling on the lower body (Fig. 6.108). The
erythema has an orange–yellow tint, which is more noticeable on the
palms and soles, together with marked hyperkeratosis (Fig. 6.109).
Fig. 6.106
Pityriasis rubra pilaris:
confluence of lesions
leads to extensive
erythroderma.
By courtesy of the
Institute of Dermatology,
London, UK.
The nails are also affected, showing distal yellow–brown discoloration,
subungual hyperkeratosis, nail thickening, and splinter hemorrhages.6
Ectropion is often present,7 and there may be diffuse alopecia.8 Oral
lesions are uncommon and include diffuse hyperkeratosis and macular
erythema with white streaks reminiscent of lichen planus.5 Prognosis for
patients in this group is good, with up to 80% resolving within 3 years.
• Type II, atypical adult pityriasis rubra pilaris, occurs in approximately
5% of patients and is manifested by atypical morphological features
and a lengthy duration, often up to 20 years. The scaling is more
ichthyosiform and there are often areas of eczematous change. The
prognosis in this group is poor, with only 20% resolving within 3 years.
• Type III, classical juvenile pityriasis rubra pilaris, resembles the classical
adult form except for its age distribution; it affects children up to 2 years
of age, accounting for approximately 10% of patients (Fig. 6.110). More
often, however, the eruption commences on the lower half of the body.
212 Spongiotic, psoriasiform and pustular dermatoses
Fig. 6.107
Pityriasis rubra pilaris: characteristic, scattered islands of unaffected skin are evident.
By courtesy of the Institute of Dermatology, London, UK.
Fig. 6.108
Pityriasis rubra pilaris: in this patient, the scale is conspicuous.
By courtesy of the Institute of Dermatology, London, UK.
Fig. 6.109
Pityriasis rubra pilaris:
palmar and plantar
erythema with
hyperkeratosis are
frequent manifestations.
Sometimes, there is an
orange–yellow tint, as
seen in this patient. By
courtesy of the Institute
of Dermatology, London,
UK.
Fig. 6.110
Pityriasis rubra pilaris:
classical juvenile type.
Note the very extensive
distribution of the lesions.
By courtesy of M.M.
Black, MD, Institute of
Dermatology, London, UK.
The prognosis in this group is good, most patients clearing within 1 year
but a recurrence rate of up to 17% has been reported.9
• Type IV, circumscribed pityriasis rubra pilaris, affects 25% of patients
and presents in prepubertal children. Sharply defined areas of follicular
hyperkeratosis and erythema are seen on the knees and elbows, together
with occasional scaly erythematous patches on the rest of the body and
palmoplantar hyperkeratosis.10
• Type V, atypical juvenile pityriasis rubra pilaris, accounts for approximately
5% of patients; presentation occurs early in life and this type has a lengthy
duration. Characteristic follicular hyperkeratosis is present, together with a
mild erythema. Ichthyosiform features are sometimes seen.5 The skin of the
feet and hands may become thickened and scleroderma-like.
Familial variants, which account for 0–6.5% of cases, mostly present with atyp-
ical features as described in type V pityriasis rubra pilaris.5 In most families, inheri-
tance has been via an autosomal dominant mechanism with variable expression
and reduced penetrance although a recessive form has also been postulated.11
Pityriasis rubra pilaris has been reported in association with HIV
­infection.12,13 Nodulocystic acneiform or furuncle-like lesions and lichen
spinulosus may also be present. This is a particularly severe variant, which
responds poorly to therapy.13 Further associations include rheumatological
disease, in particular arthritis, dermatomyositis, and underlying malignancy
possibly representing a paraneoplastic phenomenon.14–25
Pathogenesis and histological features
The etiology of pityriasis rubra pilaris is largely unknown. It has been associ-
ated with abnormal vitamin A metabolism but there is little evidence in sup-
port for this other than a frequent response to vitamin A or retinoid therapy.5
Linkage to autoimmune disease, immune dysfunction, internal malignancy,
infections and, particularly in recent years, to human immunodeficiency
virus, have also been described.5,13,26,27 In the majority of cases, however, there
is no preceding or associated condition. Pityriasis rubra pilaris is associated
with an increased rate of epidermopoiesis.28–32
Fully developed follicular papules show characteristic features comprising
conical follicular plugging, with marked uniform acanthosis of the epidermis
and broad epidermal ridges and dermal papillae (Fig. 6.111).28,29,33 There is
hyperkeratosis, with foci of parafollicular parakeratosis. In the dermis there
is a mild to moderate inflammatory cell infiltrate and sebaceous atrophy.
Although the histological features may be non-specific, biopsies from
established, nonfollicular lesions comprise alternating orthokeratosis and
parakeratosis in both vertical and horizontal directions, focal or confluent
hypergranulosis, thick suprapapillary plates, broad epidermal ridges, narrow
 Pityriasis rubra pilaris 213

Fig. 6.113
Fig. 6.111 Pityriasis rubra pilaris: alternating hyperkeratosis and parakeratosis.
Pityriasis rubra pilaris:
follicular lesion showing
the conical keratin plug.
Parakeratosis is present
above the adjacent
epithelium.

dermal papillae, and a perivascular lymphocytic infiltrate in the superficial

dermis (Figs 6.112–6.114).34 Small numbers of plasma cells and eosinophils
are sometimes present.26 Superficial blood vessels may appear slightly dilated.
Occasionally there is also mild spongiosis with scattered intraepidermal lym-
phocytes.27 Neutrophil infiltration as seen in psoriasis is not usually a feature
of pityriasis rubra pilaris and its presence may indicate a bacterial or fungal
superinfection. Acantholysis with or without dyskeratosis involving follicular
and interfollicular epithelium has recently been emphasized, and exception-
ally a lichenoid infiltrate has been documented.26,35–38
In early lesions, the diagnosis is often problematical. Parakeratosis is usu-
ally poorly developed and lamellar orthohyperkeratosis predominates.34
Hypergranulosis is present and the rete ridges are broadened and slightly
elongated. The suprapapillary plates may be mildly thickened.
In erythrodermic lesions, the keratin layer may be thinned or lost and the
granular cell layer diminished.34
Palmar and plantar lesions show hyperkeratosis, focal parakeratosis, and
mild acanthosis (Fig. 6.115).

Fig. 6.114
Pityriasis rubra pilaris:
close-up view.

Fig. 6.115
Pityriasis rubra pilaris:
plantar lesion showing
hyperkeratosis, focal
Fig. 6.112 parakeratosis, and regular
Pityriasis rubra pilaris: there is hyperkeratosis with focal parakeratosis and acanthosis with a rounded
psoriasiform hyperplasia. lower border.
214 Spongiotic, psoriasiform and pustular dermatoses Inflammatory linear verrucous epidermal nevus

Differential diagnosis
Pityriasis rubra pilaris may be confused both clinically and histologically
with psoriasis. Features in favor of pityriasis rubra pilaris include follicular
plugging with parakeratosis of the adjacent epithelium, focal parakeratosis,
broad rete ridges, thickened suprapapillary plates, increased granular cell
layer, and an absence of tortuous dilated capillaries immediately adjacent to
the epidermis. In psoriasis the acanthosis is typically more marked and often
strikingly regular, the rete ridges are thin and often fused, the suprapapillary
plate is thinned, parakeratosis is usually confluent, and characteristic collec-
tions of neutrophils are seen in the overlying parakeratotic stratum corneum
in association with spongiform degeneration of the underlying superficial
epidermis.

Inflammatory linear verrucous

epidermal nevus
Clinical features
Fig. 6.117
Inflammatory linear verrucous epidermal nevus (ILVEN) is an uncommon
Inflammatory linear verrucous epidermal nevus (ILVEN): in this view there is marked
condition which usually presents in infants or young children as an intensely psoriasiform epidermal hyperplasia with massive hyperkeratosis. Mild chronic
pruritic, persistent, scaly, unilateral, linear erythematous lesion following inflammation is seen in the superficial dermis.
the lines of Blaschko.1 Individual lesions are discrete, scaly papules, which
coalesce to form plaques.2 Superimposed lichenification and excoriations are
commonly present. Although lesions may be widely distributed, the leg, thigh,
and buttock are sites of predilection (Fig. 6.116).1,3 Females are more often
affected than males (4:1).2 The left side of the body is most often involved.2,4,5
Much less commonly, the disorder is bilateral and, exceptionally, the condi-
tion is generalized.6–8 Familial cases have been documented and adults may
sometimes be affected.7–11 Occasionally inflammatory linear verrucous epi-
dermal nevus coexists with psoriasis and rarely it presents as part of the epi-
dermal nevus syndrome.12,13 Exceptionally, the condition is associated with
arthritis.14

Histological features
Histologically, the nevus is characterized by sharply demarcated, alternating
parakeratosis and orthohyperkeratosis (Figs 6.117–6.119).2,5,15 The epider-
mis shows papillomatosis with psoriasiform hyperplasia and absence of the

Fig. 6.118
Inflammatory linear verrucous epidermal nevus (ILVEN): alternating hyperkeratosis
and parakeratosis is characteristic.

Fig. 6.116
Inflammatory linear
verrucous epidermal
nevus (ILVEN): patients
present with scaly,
erythematous, itchy
papules and plaques
in a linear distribution,
showing a predilection
for the legs. From the
collection of the late N.P.
Smith, MD, the Institute
of Dermatology, London, Fig. 6.119
UK. Inflammatory linear verrucous epidermal nevus (ILVEN): close-up view.
 Subcorneal pustular dermatosis 215

granular layer below the foci of parakeratosis contrasting with a thickened

granular cell layer underneath the orthohyperkeratosis. Occasionally, Munro
microabscesses are a feature. The rete ridges are elongated and thickened.
Focal slight spongiosis is present, accompanied by lymphocytic exocytosis.
A mild perivascular lymphocytic infiltrate is seen in the superficial dermis.

Differential diagnosis
ILVEN must be distinguished from linear psoriasis.16 In ILVEN, parakera-
tosis alternates with orthohyperkeratosis in contrast with psoriasis where
the parakeratosis is confluent. Similarly, the thickened rete ridges of ILVEN
contrast with the thinned ones of psoriasis. By immunocytochemistry, in
ILVEN, involucrin expression is markedly diminished in the epithelium deep
to the parakeratosis, while it is increased in the epithelium underlying the
hyperkeratosis.17 In psoriasis, there is a general increase in involucrin expres-
sion throughout the entire lesion.
Rare cases of ILVEN showing histiocyte infiltration of the underlying
­dermis reminiscent of verruciform xanthoma have been documented.18–21

Bazex syndrome (acrokeratosis Fig. 6.120

paraneoplastica) Bazex syndrome: note the
violaceous discoloration
Clinical features of the ear. By courtesy of
J.L. Bolognia, MD, Yale
Bazex syndrome denotes an acral psoriasiform dermatosis in association Medical School, CT, USA.
with internal malignancy.1–3 Elderly patients, usually males, present with
a symmetric erythematous or violaceous, scaly eruption affecting the ears,
nose, fingers, and toes (Fig. 6.120).1 The knees and elbows may some-
times be involved. Vesicles and bullae are less common manifestations.4
In patients with black or dark-brown skin, the lesions can present with
hyperpigmentation.2 Palmoplantar lesions are keratodermatous and nail
involvement ranges from paronychia, horizontal or vertical ridging, yellow
discoloration and thickening to onycholysis and subungual keratotic debris
(Fig. 6.121).1
Patients with Bazex syndrome invariably have an associated systemic malig-
nancy, most often affecting the oropharynx, larynx, esophagus, and lung, in
descending order of frequency.1 Cervical lymph node metastases are com-
monly present. Persistence of the cutaneous lesions is rare and they commonly
regress following successful treatment of the underlying malignancy.2,5

Histological features
Histologically, there is considerable overlap with psoriasis and chronic spon-
giotic dermatitis, the epidermis showing hyperkeratosis, parakeratosis, and
acanthosis. In addition however, dyskeratosis and interface changes reminis-
cent of lichen planus are also commonly present.1 A perivascular or less com-
monly lichenoid chronic inflammatory cell infiltrate is present in the superficial Fig. 6.121
dermis. Bazex syndrome: keratoderma. By courtesy of J.L. Bolognia, MD, Yale Medical
Bullous lesions may be subepidermal or, less often, intraepidermal.1,6 School, CT, USA.

Pustular dermatoses

Pustular drug reactions
This topic is discussed in the chapter on adverse reactions to drugs.
Subcorneal pustular dermatosis
Clinical features
Subcorneal pustular dermatosis (Sneddon-Wilkinson disease) is a rare
chronic, relapsing, and apparently noninfective eruption of unknown eti-
ology.1,2 It predominantly affects females (4:1) and is usually diagnosed
during the middle years of life. Pediatric cases have, however, occasion-
ally been described.3,4 It may be associated with a benign or malignant IgA
paraproteinemia (up to 40% of cases) or multiple myeloma, and sometimes
pyoderma gangrenosum is also present.5–15 Other associations include rheu-
matoid arthritis, systemic lupus erythematosus, hyperthyroidism, Crohn's
disease, multiple sclerosis, IgG cryoglobulinemia, bullous pemphigoid, mor-
phea, diffuse scleroderma, Sjögren syndrome, marginal zone lymphoma,
chronic lymphocytic leukemia, squamous carcinoma of the bronchus, and
metastatic gastrinoma, although it is doubtful whether these are of any great
significance.15–26
Clinically, patients present with waves of superficial flaccid pustules in
circinate or serpiginous groups and sheets, particularly in the folds of the
body, such as the axillae (Figs 6.122, 6.123) and groins, beneath the breasts,
216 Spongiotic, psoriasiform and pustular dermatoses

Fig. 6.122
Subcorneal pustular
dermatosis: typical
example showing a
Fig. 6.123
succession of pustules
Subcorneal pustular dermatosis: close-up view of early lesions characterized by
spreading outwards from
numerous pustules arising on an erythematous background. By courtesy of R.A.
the axilla. At the periphery
Marsden, MD, St George's Hospital, London, UK.
the lesions are healing
with crust formation. By
courtesy of R.A. Marsden,
MD, St George's Hospital,
London, UK.

and on the abdomen. Fluid levels are sometimes evident. Typically, the
mucous membranes, face, scalp, and peripheries are spared. Healing is rapid,
usually within a few days or weeks, and the condition responds to dapsone,
although not as dramatically as dermatitis herpetiformis. Postinflammatory
hyperpigmentation is common.
Canine subcorneal pustular dermatosis, particularly affecting Miniature
Schnauzers, has been reported.27

Pathogenesis and histological features

The etiology of subcorneal pustular dermatosis is unknown. Intercellular
IgA deposits have been identified in a significant number of cases by direct
immunofluorescence and many patients have a circulating IgA pemphigus
antibody. These cases have been documented in the literature as IgA pemphi- Fig. 6.124
gus.28–33 Subcorneal pustular dermatosis should be restricted to the immuno- Subcorneal pustular dermatosis: situated immediately below the stratum corneum
fluorescence-negative group. is a blister cavity containing edema fluid and numerous neutrophils. The epidermis
The characteristic lesion is a subcorneal pustule, which appears to sit on shows neutrophils in transit. Within the papillary dermis is a neutrophil and
the skin surface (Fig. 6.124). The contents of the pustules are predominantly lymphocytic infiltrate.
neutrophils, although an occasional eosinophil may be identified. The epi-
dermis beneath the pustule shows surprisingly little change except for poly-
morphs in transit and perhaps slight intercellular edema (Fig. 6.125).
Older lesions may contain acantholytic cells (Fig. 6.126). In the dermis,
superficial blood vessels are surrounded by a non-specific mixed inflamma-
tory cell infiltrate consisting of neutrophil polymorphs and mononuclear
cells.

Differential diagnosis
The histological features of subcorneal pustular dermatosis cannot be reli-
ably distinguished from those of bullous impetigo, staphylococcal scalded
skin syndrome, pemphigus foliaceus, and IgA pemphigus. Impetigo is, how-
ever, a disease of young children and, although a Gram stain is often negative,
cultures should grow staphylococci or streptococci.
The staphylococcal scalded skin syndrome (Ritter's disease) is predomi-
nantly a disease of infants, but rarely it may present in adults. Clinically it
is different from subcorneal pustular dermatosis, being characterized by the
development of large flaccid blisters, which rupture, leaving extensive areas
of denuded skin.
Although acantholysis is typical of the pemphigus group of diseases, it Fig. 6.125
may occasionally be seen in impetigo, staphylococcal scalded skin syndrome, Subcorneal pustular dermatosis: close-up view.

Fig. 6.126
Subcorneal pustular
dermatosis: in addition
to neutrophils there are
scattered acantholytic
keratinocytes.
These features are
indistinguishable from
those of pemphigus
foliaceus.
subcorneal pustular dermatosis, and pustular psoriasis. In difficult cases the
demonstration of positive immunofluorescence will establish the diagnosis of
pemphigus (however, see IgA pemphigus).
There has been considerable controversy in earlier literature concerning
the relationship between subcorneal pustular dermatosis and pustular psoria-
sis, with some authors claiming them to be one and the same condition and
others equally determined that they are quite different. In our view, these are
two distinct diseases. Thus, in subcorneal pustular dermatosis, there is no
family history and there is no evidence of more typical psoriasiform lesions
elsewhere. Subcorneal pustular dermatosis responds to dapsone in the vast
majority of cases and histologically spongiform change deep to the pustule
(typical of psoriasis) is characteristically absent. Psoriasis is not associated
with monoclonal gammopathy or multiple myeloma.
Toxic erythema of the neonate
Clinical features
Toxic erythema of the neonate (erythema toxicum neonatorum, erythema neo-
natorum) is a very common self-limiting disorder affecting from 48% to 72%
of all newborn infants.1–7 There is no racial predilection but males appear
more commonly affected.2,8 It presents as an asymptomatic erythematous mac-
ular rash usually in the first 3 days of life.1,9 Occasionally, it may be evident
at birth and, exceptionally, the onset is delayed until the second week after
birth.5,6,10 Sometimes there are papules and vesicles and, in some patients, pus-
tule formation is evident. The condition most often affects the forehead, face,
chest, trunk, and extremities.1 The palms and soles are typically uninvolved.
The eruption is asymptomatic and very typically transient, with lesions often
lasting only a number of hours or days.1 Full resolution is usually achieved by
1–5 days although recurrences may occur in up to 11% of neonates.2 Toxic
erythema of the neonate is frequently associated with a peripheral blood
eosinophilia.
Pathogenesis and histological features
The etiology of this condition is completely unknown.2 While an acute graft-
versus-host type of reaction resulting from transfer of maternal lymphocytes
Infantile acropustulosis 217
during delivery was initially thought to be of pathogenetic importance, more
recent data favor an immunological response to the initial colonization of the
skin by commensal microorganisms.11–16
Early erythematous lesions show a somewhat nondescript perivascular
inflammatory cell infiltrate with conspicuous eosinophils, which may be seen
penetrating the epidermis in close proximity to hair follicles. In an established
lesion, the pustules are follicular, lie subcorneally, and contain large numbers
of eosinophils and occasional neutrophils.17 The external root sheath of the
infundibulum may also be affected.
Differential diagnosis
Toxic erythema of the neonate must be distinguished from incontinentia pig-
menti. The latter, however, is characterized by eosinophilic spongiosis, a fea-
ture not seen in toxic erythema. In miliaria rubra the vesicles are related to
sweat ducts rather than hair follicles and typically contain mononuclear cells
rather than eosinophils. Toxic erythema of the neonate must also be distin-
guished from infantile acropustulosis, transient neonatal pustular melanosis,
and infantile eosinophilic pustular folliculitis (see below).
Infantile acropustulosis
Clinical features
This uncommon condition usually presents in the first year of life and is
sometimes evident at birth.1–4 There is a marked male predilection. Although
it is most often seen in black children, it has occasionally been reported in
Asians and whites.5–8
The disorder presents as crops of intensely itchy, erythematous papules
1–5 mm in diameter, vesicles, and pustules, which are found most often on the
palms and soles, but the volar surfaces of the wrists, the ankles, the face, and
scalp may occasionally be affected (Fig. 6.127).6 The mucous membranes
are spared.1 Lesions are often present for 1–2 weeks and tend to recur every
2–4 weeks. With progression, the duration of the eruption diminishes and the
remission lasts for gradually increasing periods of time. Spontaneous resolu-
tion has usually occurred by 2–3 years of age.
Pathogenesis and histological features
The etiology and pathogenesis of this condition are unknown. However, infan-
tile acropustulosis may be associated with atopy and hypereosinophilia.6,9–11
Sometimes, a history of prior or concurrent scabies infection is present but
whether this is causal is uncertain.4
Fig. 6.127
Infantile acropustulosis: typical small pustules centered about the base of the
thumb. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
218 Spongiotic, psoriasiform and pustular dermatoses
Histology reveals a subcorneal pustule containing predominantly
­ eutrophils, although occasionally small numbers of mononuclears and
n Eosinophilic pustular folliculitis of infancy
eosinophils are evident. Eosinophil-rich pustules have also been described but
with hindsight most such cases probably represent eosinophilic pustular fol-
liculitis.11 Slight acantholysis of the adjacent epidermis has been described.12
The underlying dermis often contains a perivascular chronic inflammatory
cell infiltrate, sometimes with scattered neutrophils and eosinophils. Direct
and indirect immunofluorescence tests are negative.
Differential diagnosis
The diagnosis of infantile acropustulosis depends upon careful clinicopatho-
logical correlation. Conditions that may enter the differential diagnosis
include scabies, pompholyx, Candida and dermatophytosis, herpes simplex,
juvenile dermatitis herpetiformis, toxic erythema of the neonate, bullous
impetigo, eosinophilic pustular folliculitis occurring in infancy, and transient
neonatal pustular melanosis.
Transient neonatal pustular melanosis
Clinical features
Transient neonatal pustular melanosis is an uncommon condition which pres-
ents with vesicles and pustules on the forehead, under the chin, on the nape of
the neck, chest, back, and buttocks.1–4 In contrast to eosinophilic pustular follic-
ulitis of infancy, the scalp is rarely involved. It affects 4–5% of black infants and
0.1–0.3% of white infants.2 There is no sex predilection.3 Lesions, which present
at birth or during the first day of life, heal rapidly to leave small brown macules
with a peripheral scale, and have usually disappeared by 3 months of age.3
Histological features
Histologically, the features are identical to those of infantile acropustulosis:
i.e., a subcorneal neutrophil-rich pustule sometimes accompanied by small
numbers of eosinophils.1
Clinical features
Eosinophilic pustular folliculitis (Ofuji's disease), which is largely a con-
dition of adults and presents as recurrent episodes of itchy follicular pap-
ules and pustules on the face, trunk, and extremities, may rarely develop
in infants.1–6 There is a predilection for males.1 In the infantile form,
lesions, which may be present at birth or develop during the first 24
hours, are found particularly on the scalp, hands, and feet.1,7–10 The trunk
and limbs can also be affected.2 Patients present with 1–3-mm white
to yellow crusted pustules arising on an erythematous base.1,2 A blood
eosinophilia is often present.7,11 The condition persists from 3 months to
up to 5 years.2
Pathogenesis and histological features
The etiology is unknown, although in a small number of cases an associa-
tion with atopy has been documented.12 In contrast to the adult disease, HIV
infection is very rarely present.13
The histological features are those of an eosinophil-rich ‘spongiotic’ pus-
tule related to the outer root sheath of the hair follicle from the stratum
corneum to the level of insertion of the sebaceous duct.14–18 A heavy inflam-
matory cell infiltrate consisting of eosinophils, lymphocytes, and histiocytes
is present in the adjacent dermis. The reported histological features are, how-
ever, less distinctive and specific compared to classic, adult-type, eosinophilic
pustular folliculitis.10,19
Numerous other pustular dermatoses may be encountered including
superficial pemphigus, particularly IgA pemphigus, pustular drug reac-
tions, bullous impetigo and staphylococcal scalded skin syndrome, pustu-
lar dermatophyte infections, pustular lesions in pyoderma gangrenosum,
and necrolytic migratory erythema. These are discussed elsewhere in this
book.
 Lichenoid and interface Chapter

See
www.expertconsult.com
for references and
additional material
dermatitis
Wei-Lien Wang and Alexander Lazar
7
Lichenoid dermatoses 219 Interface dermatoses 237 Rothmund-Thomson syndrome 246
Lichen planus 219 Erythema multiforme 238 Blooms' syndrome 247
Lichen nitidus 229 Toxic epidermal necrolysis and Stevens-Johnson Cockayne's syndrome 248
Lichenoid keratosis 231 syndrome 241 Dyskeratosis congenita 248
Lichen striatus 232 Paraneoplastic pemphigus 245 Graft-versus-host disease 249
Adult Blaschkitis 233 Poikiloderma 245 Pityriasis lichenoides 255
Keratosis lichenoides chronica 234 Poikiloderma of Civatte 245
Erythema dyschromicum perstans 236 Mitochondrial DNA syndrome-associated
Lichenoid and granulomatous dermatitis 236 poikiloderma 246

The term ‘lichenoid’ refers to inflammatory dermatoses which are character-
ized by a bandlike lymphohistiocytic infiltrate in the upper dermis, hugging
and often obscuring the dermoepidermal interface. Lichen planus is the proto-
typic lichenoid dermatitis (Box 7.1). Interface dermatitis refers to the presence
of basal cell vacuolization (hydropic degeneration) and is often accompanied
by single-cell keratinocyte apoptosis (Box 7.2). These two terms are by no
means mutually exclusive as most lichenoid infiltrates are accompanied by
interface change. However, some dermatoses are characterized primarily by
interface change without a lichenoid infiltrate such as lupus erythematosus
and erythema multiforme.
Lichenoid dermatoses
Lichen planus
Clinical features
Lichen planus (Gr. leichen, tree moss) is a common, usually intensely pruritic,
symmetrical, papulosquamous dermatosis.1,2 Its prevalence in the general
population is approximately 1%, and it most often presents in the fourth to
sixth decades with a slight female predominance.3,4 It is uncommon in child-
hood.5,6 Occasional familial cases have been reported.7,8
The disease is characterized by small, smooth, shiny, flat-topped polygonal
papules measuring several millimeters to 1 cm in diameter and often having a
violaceous color (Fig. 7.1). Delicate white lines known as Wickham's striae
typically cross the slightly scaly surface (Fig. 7.2). The lesions are found
most commonly on the flexor aspect of the wrists, the forearms, the exten-
sor aspect of the hands and ankles, the lumbar area and the glans penis (Fig
7.3). Lichen planus is associated with a positive Koebner's phenomenon. It is
a usually self-limiting although sometimes protracted disorder, patients clear-
ing of lesions within weeks to 1 or 2 years.
Oral involvement, which is very common (affecting up to 60% of
patients with cutaneous disease), shows a marked female preponderance
and presents most often in the seventh decade. It may sometimes be the sole
manifestation (an estimated 15–35% of patients with oral lichen planus
never develop skin lesions).9–14 The buccal mucosa, vestibule, tongue, and
gingivae are most often affected, in decreasing order of frequency.12 Patients
frequently present with a white lacelike pattern, but papules, plaques and
erosions, ulcerated, atrophic, and bullous variants may also be found (Figs
7.4–7.6).1,15 Lesions are usually asymptomatic, although erosions and bul-
lae are sometimes tender and painful. Chronic ulcerated oral lichen planus
is of particular importance because it has been related to an increased risk,
albeit low, of developing squamous cell carcinoma (Fig 7.7). The risk of
developing malignancy is debated, with current literature suggesting that
0–12.5% of affected patients will develop an oral malignancy.12,16–22 Oral
involvement in lichen planus and its relationship to cutaneous squamous
cell carcinoma is discussed in greater depth elsewhere. Involvement of the
gums may present as desquamative gingivitis.1 Other mucous membranes
that may be involved include those of the pharynx, larynx, esophagus,
nose, anus, and genitalia.23 Familial cases of lichen planus limited to oral
involvement are noted.24
Ocular involvement is rare and may include eyelid lesions, blephari-
tis, conjunctivitis, keratitis, punctate corneal opacities, iridocyclitis, and
chorioretinitis.25,26
Esophageal involvement, although rare, is an important potential
cause of morbidity, and is the most frequently involved gastrointestinal
site.27 Concomitant oral lesions are invariably present. To date, middle-
aged or elderly females are typically affected.28–31 Complications include
chronic dysphagia and stricture formation affecting the mid or upper
esophagus.28,32–35 Patients with esophageal lichen planus may have a
risk of developing squamous cell carcinoma. The role of surveillance is
uncertain.27,28,30,31,36,37
Genital lesions in lichen planus are common (particularly in males),
being present in up to 25% of patients, and sometimes adopting an annu-
lar configuration (Fig. 7.8).1 Similar annular lichen planus may be found
elsewhere on the body, including intertriginous areas.38 Occasionally, penile
lesions are the sole expression of the disease.39 Vulval lesions may be found
in up to 51% of females with cutaneous involvement.40 Sometimes gingi-
val and female genital lesions may coexist as a variant of erosive lichen
planus, the so-called vulvovaginal-gingival syndrome.41–44 Patients present
with dyspareunia and intense burning vulval pain. The vulva appears con-
gested and there may be erosions, which are often surrounded by a white
reticulate border. Vaginal involvement similarly presents as dyspareunia
220 Lichenoid and interface dermatitis

Box 7.1
Causes of lichenoid dermatitis

• Lichen planus
• Lichenoid graft-versus-host disease
• Lichen nitidus
• Lichenoid keratosis
• Lichenoid drug reaction
• Fixed drug reaction
• Lichen planopilaris
• Lichen striatus
• Adult Blaschkitis
• Lichen aureus
• Lichenoid mycosis fungoides
• Ashy dermatoses
• Lichenoid and granulomatous dermatitis

Box 7.2 A
Causes of interface dermatitis

• Lichenoid dermatoses (see Box 1.)

• Erythema multiforme
• Stevens-Johnson syndrome/toxic epidermal necrolysis
• Connective tissue disorders: lupus erythematosus, dermatomyositis,
and mixed connective tissue disorders
• Graft-versus-host disease
• Poikiloderma including those related to rare inherited disorders
• Interface drug reactions
• Interface viral exanthem
• Pityriasis lichenoides

and often postcoital bleeding due to inflammatory, desquamative, and ero-

sive changes. More typical features of lichen planus may be encountered
elsewhere on the body. Squamous carcinoma is an important complication
of chronic vulval lichen planus.45 The development of penile cancer is rare.46
Genital involvement in lichen planus is discussed elsewhere. B
The nails are affected in about 10% of patients with lichen planus; mani-
festations include thinning of the nail plate, longitudinal ridging, striations, Fig. 7.2
pterygium formation, subungual hyperkeratosis and, very rarely, complete Lichen planus: (A) note the characteristic Wickham's striae at the edge of these
destruction of the nail (Figs 7.9).1 Although nail involvement in children is pigmented lesions; (B) Wickham's striae are evident on these lesions, which have
said to be rare, some authors regard twenty-nail dystrophy of childhood as a arisen on the back, an uncommonly affected site. (A) From the collection of the late N.P.
Smith, MD, the Institute of Dermatology, London, UK. (B) Courtesy of J. Dayrit, MD,
variant of localized lichen planus, although not all accept this hypothesis.47–51
Manila, The Philippines.

Fig. 7.1 Fig. 7.3

Lichen planus: there are typical flat-topped polygonal papules on dorsum of the Lichen planus: there is extensive bilateral involvement of the flexor aspect of
hand. From the collection of the late N.P. Smith, MD, the Institute of Dermatology, the forearms. From the collection of the late N.P. Smith, MD, the Institute of
London, UK. Dermatology, London, UK.

Fig. 7.4
Lichen planus: this lace-like pattern is characteristic. From the collection of the late
N.P. Smith, MD, the Institute of Dermatology, London, UK.
Fig. 7.5
Lichen planus: there
is extensive ulceration
of the buccal mucosa.
By courtesy of
R.A. Marsden, MD,
St George's Hospital,
London, UK.
Most lesions of lichen planus heal within 6–18 months of onset. However,
oral and hypertrophic variants and lichen planopilaris tend to have a chronic
course. Postinflammatory hyperpigmentation, which may be very disfiguring,
is not uncommon, particularly in colored races (Fig. 7.10).
A number of variants of lichen planus merit specific mention:
• Lichen planopilaris (follicular lichen planus), presents as single or
multiple plaques of scarring alopecia associated with a spectrum of
lesions including typical lichenoid papules involving the scalp to brown
or violaceous keratotic follicular papules affecting the trunk and
extremities (Figs 7.11–7.13).52–55 Nonscarring plaques with prominent
follicular papules may also be present. Linear lesions have rarely been
described.56–58 Some authors suggest that scalp lichen planus represents
pseudopélade of Brocq.59,60 Children can also be affected. 61
• Atrophic lichen planus, the clinical features of which merely reflect
resolution of the more typical active phase.
Lichenoid dermatoses 221
Fig 7.6
Lichen planus: the tongue
is commonly affected. By
courtesy of M. Blanes,
MD, Alicante, Spain
Fig. 7.7
Lichen planus: there is an ulcerated squamous carcinoma on the lower lip. By
courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
• Lichen planus actinicus (lichen planus subtropicus, summertime actinic
lichenoid eruption (SALE)), develops in patients with prolonged exposure
to sunlight and, therefore, usually manifests in spring or summer,62–66
with improvement or remission in the autumn or winter. It occurs
particularly in the Middle East (especially Egypt) and the Far East and
affects younger people, with a maximum incidence in the second and
third decades and a slight female predominance (Fig 7.14). Affected sites
include the lateral aspects of the forehead, the dorsum of the hands, the
forearms, face, and neck. The eruption can include a mixture of lichen
planus-like and lichen nitidus-like lesions, whereas in others, the lesions
appear as purely one or the other (see actinic lichen nitidus, below).
Typically, the lichen planus lesions have an annular configuration with a
bluish-brown, rather atrophic center and slightly raised border. They may
sometimes coalesce to form circinate plaques. Occasionally, a melasma-
like appearance has been documented.66 There is usually little pruritus
and Koebner's phenomenon is commonly absent. The nails are often
unaffected.
222 Lichenoid and interface dermatitis
B Fig. 7.10
Fig. 7.8
Lichen planus: (A) typical papules are present on the shaft of the penis; (B) note the
erythematous erosions around the vulval introitus and labia minora. (A) From the
collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK;
(B) By courtesy of S. Neill, MD, Institute of Dermatology, London, UK.
• Lichen planus pigmentosus, most commonly encountered in the tropics
in dark-skinned patients, is characterized by the development of variably
pruritic pigmented dark-brown macules predominantly affecting exposed
skin and the flexures (Figs 7.15, 7.16). The most common affected sites
include the face and neck.67–72 There is no sex predilection. The disorder
is characterized by periods of exacerbation and remission.4 Exceptionally,
involvement of the oral mucosa has been documented.5
• Hypertrophic lichen planus, which represents superimposed lichen
simplex chronicus, commonly affects the lower limbs, particularly the
shins, and manifests as highly pigmented warty plaques (Fig. 7.17).73
Familial lichen planus shows an increased incidence of this variant.74
The lesions are intensely itchy and very persistent. There may be an
attendant (albeit very slight) risk of neoplastic transformation although
the evidence is weak and based largely on case reports.75
Fig. 7.9
Lichen planus: there is longitudinal ridging and striation affecting the thumbnail,
with inflammatory changes in the nail folds. From the collection of the late N.P.
Smith, MD, the Institute of Dermatology, London, UK.
Lichen planus: postinflammatory hyperpigmentation is a common manifestation.
By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
• Ulcerative lichen planus, a chronic variant affecting the fingers, hands,
soles, and toes, is often associated with permanent loss of the nails (Figs
7.18, 7.19). Squamous cell carcinoma may complicate this variant of
lichen planus.76
Other variants include lichen planus linearis, which occurs predominantly
in children, and the rare vesicular or bullous variants, which must be distin-
guished from lichen planus pemphigoides. Bullous lichen planus implies the
development of vesicles or bullae on pre-existent lichenoid lesions as a con-
sequence of severe basal cell hydropic degeneration. It is more often a histo-
logical finding rather than a clinical observation. In contrast, lichen planus
pemphigoides is characterized by the development of large tense bullae aris-
ing on normal or erythematous skin in a patient with typical lichen planus
elsewhere. It represents the combined expression of lichen planus and bullous
pemphigoid.77
Childhood lichen planus shows a modest male predominance (2:1).5,6,61,78
Although mucosal involvement is said to be rare, recent series report a fre-
quency of 14–39%.6,61,78 Hypertrophic lesions may be seen in up to 26%
of cases.6
 Lichenoid dermatoses 223

Fig. 7.13
Lichen planopilaris: follicular lichenoid papules are clearly seen in this patient. By
courtesy of the Institute of Dermatology, London, UK.

Fig. 7.11
Lichen planopilaris: there are characteristic hyperpigmented follicular papules, which
are confluent in some areas. The limbs are commonly affected. By courtesy of R.A.
Marsden, MD, St George's Hospital, London, UK.

Fig. 7.14
Lichen planus actinicus: there is marked facial hyperpigmentation representing
postinflammatory changes. From the collection of the late N.P. Smith, MD, the
Institute of Dermatology, London, UK.

Fig. 7.12
Lichen planopilaris: marked inflammatory changes with scarring and secondary hair
loss. These changes are difficult to distinguish from those of pseudopélade and
chronic discoid lupus erythematosus. From the collection of the late N.P. Smith,
MD, the Institute of Dermatology, London, UK.

Pathogenesis and histological features

The etiology of lichen planus is unknown. Theories of infectious (bacterial
and viral), autoimmune, metabolic, psychosomatic, and genetic causes have
all had their proponents. Currently, however, it is thought that lichen planus
represents an abnormal delayed hypersensitivity reaction to an as yet undeter-
mined epidermal neoantigen, possibly to a combination of an external anti- Fig. 7.15
gen coupled with an internal self-antigen.79,80 The association of lichen planus Lichen planus pigmentosus: there are coalescent pigmented papules. From the
with a number of viral infections including hepatitis B and C and human collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.
224 Lichenoid and interface dermatitis
Fig 7.16
Lichen planus pigmentosus: the face is a commonly affected site. From the
collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.
Fig. 7.17
Hypertrophic lichen planus: raised, warty, violaceous plaques on the shin of an
elderly man. These lesions had been present for 30 years. By courtesy of R.A.
Marsden, MD, St George's Hospital, London, UK.
Fig. 7.18
Ulcerative lichen planus: there is marked atrophy of the skin around this crusted
ulcer. By courtesy of the Institute of Dermatology, London, UK.
Fig. 7.19
Ulcerative lichen planus: the digits are often affected. This variant is associated with
a slightly increased risk of squamous cell carcinoma. By courtesy of R.A. Marsden,
MD, St George's Hospital, London, UK.
­immunodeficiency virus (HIV), combined with the well-recognized relationship
to numerous drugs, adds support to this hypothesis.81–83
Lichen planus is associated with a variety of liver cell abnormalities including
aberrant liver function tests and serology.84,85 An increased incidence of chronic
active hepatitis, primary sclerosing cholangitis and primary biliary cirrhosis has
also been recorded.86–91 Not all documented series, however, have confirmed
these observations, suggesting that the reported relationship may be dependent
upon the background level of hepatitis B virus infection.89 Lichen planus has
also followed hepatitis B vaccination.92–95 More recently, lichen planus (particu-
larly oral disease) has been linked to hepatitis C virus and chronic liver disease.
The incidence of hepatitis C virus in patients with lichen planus is, however,
very variable, ranging from effectively zero in some populations, including the
United Kingdom, India, and Slovenia, to as high as 100% in Japan.96–101
Evidence of other disorders including thyroid disease, dyslipidemia, and
impaired carbohydrate metabolism including overt diabetes mellitus has also
been documented in lichen planus, particularly the oral variant.102–110 A recent
study from Japan suggests a possible association of hepatitis C infection with
both diabetes and lichen planus.109
A significant association between lichen planus and human leukocyte anti-
gen (HLA)-DR1 and HLA-DQ1 has been noted by a number of authors.111–117
This association pertains to patients with or without mucosal lesions but does
not extend to patients with the drug-induced variant. It is suggested that this
association relates to antigen presentation by HLA-DR1+ cells to T-helper
cells with the resultant development of an autoimmune response.111
Although it is generally accepted that the pathogenesis of the basal cell
damage in lichen planus primarily involves the cellular immune response, the
precise mechanism(s) require further elucidation. It is unlikely that autoan-
tibody and immune complex-mediated damage have a significant role in the
lichenoid tissue reaction.79,80
The initial event in the evolution of the lichen planus papule is destruction
of the basal epidermal layer (keratinocytes and melanocytes).118,119 In the ear-
liest stage of development, increased numbers of Langerhans cells are present
within the epidermis and it is believed that these cells process modified epi-
dermal antigens for presentation to T lymphocytes.120 Keratinocytes express
HLA-DR and this is likely to be of pathogenetic importance. Subsequent
migration with resultant CD8+ T-cell activation results in basal keratinocyte
death due to the combined effects of interferon-gamma (IFN-γ), interleukin
(IL)-6, granulocyte-macrophage colony stimulating factor (GM-CSF), and
tumor necrosis factor alpha (TNF-α).81–83,121 The expression of FasR/FasL by
the basal keratinocytes suggests that apoptosis is an important mode of cell
death in lichen planus.122 The dermal infiltrate consists predominantly of Ia+,
CD4+ lymphocytes.120,123 CD8+ lymphocytes are also present in close appo-
sition to the dermoepidermal junction adjacent to foci of basal keratinocyte
necrosis and are said to predominate in early lesions.121,123–125 B lymphocytes
are scarce and plasma cells are characteristically absent in cutaneous lesions,
except in the hypertrophic variant.
 Lichenoid dermatoses 225

Development of the typical papule appears to be due to a combination

of continued keratinocyte destruction and regenerative activity, with the lat-
ter depending upon the migration of epithelium from the edge of the lesion
and from adjacent eccrine ducts, rather than from increased mitotic activ-
ity. There is little uptake of tritiated thymidine at the site of basal cell dam-
age, but conspicuous uptake at the edges of the lesion and, as a reflection
of regeneration, keratin 17 expression is also up-regulated in the suprabasal
epithelium.126 The typical features of lichen planus therefore depend upon a
variable interplay between basal cell liquefactive degeneration and irregular
epidermal regeneration.
The earliest identifiable change in lichen planus is the presence of cytoid
bodies and associated pigmentary incontinence. Cytoid bodies (colloid or
Civatte bodies) are round or oval, homogeneous, eosinophilic bodies identifi-
able within the basal epithelium and the papillary dermis (Fig. 7.20). They
display diastase-resistant periodic acid-Schiff (PAS) positivity, and may be
identified within papules, perilesional skin, and even apparently uninvolved
skin. Although they may be seen in a variety of dermatoses (including lupus
erythematosus, graft-versus-host disease, and poikiloderma) and seemingly
normal skin, where their presence, if either in large numbers or in a cluster,
suggests lichen planus. Fig. 7.21
Lichen planus: this scanning view is characteristic and highlights the hyperkeratosis,
Ultrastructurally, cytoid bodies are composed of tightly arranged aggre-
hypergranulosis, and irregular acanthosis. Note the typical bandlike inflammatory
gates of filaments 6–8 nm in diameter; immunocytochemically they are com-
cell infiltrate and pigment incontinence.
posed of keratin.
Characteristic histological features of an established papule can usually
be recognized at scanning magnification (Fig. 7.21). They comprise hyper-
keratosis, typically wedge-shaped hypergranulosis (clinically presenting as
Wickham's striae) related to the intraepidermal components of sweat ducts
and hair follicles, and irregular acanthosis (Figs 7.22, 7.23). The acantho-
sis often has a saw-toothed appearance (Figs 7.24, 7.25). The presence of
prominent parakeratosis argues strongly against a diagnosis of lichen planus.
Lymphocytes and histiocytes may sometimes be seen in the epidermis and
very occasionally satellite cell necrosis is a feature. Liquefactive degeneration
of the basal layer of the epithelium is characteristic and often subepidermal
clefts are present (Max Joseph spaces). Pigmentary incontinence is common
(Fig. 7.26). A lymphohistiocytic bandlike infiltrate occupies the upper dermis
and obscures the dermoepidermal junction. Hyperkeratosis persists in resolv-
ing lichen planus, but the acanthosis regresses, leaving a flattened epidermis
(Fig. 7.27); there may be focal scarring and the dermal infiltrate is less con-
spicuous (Fig. 7.28).
Lesions may become completely atrophic and histologically there is flat-
tening of the epidermis, variable number of colloid bodies, and pigment
incontinence with almost no inflammation. If colloid bodies are rare, distinc-
tion from poikiloderma may be very difficult. Fig. 7.22
Lichen planus: note the hyperkeratosis, hypergranulosis, and irregular acanthosis.

Fig. 7.20 Fig. 7.23

Lichen planus: this view shows characteristic eosinophilic cytoid bodies associated Lichen planus: the hypergranulosis is clearly related to the acrosyringium. There is
with basal cell liquefactive degeneration and a lymphohistiocytic infiltrate. marked basal cell liquefactive degeneration. Note the fibrin deposition.
226 Lichenoid and interface dermatitis

Fig. 7.24 Fig. 7.27

Lichen planus: the acanthosis is irregular and often has a saw-toothed appearance. Atrophic (resolving) lichen planus: there is hyperkeratosis, epidermal flattening, and
a slight residual lymphohistiocytic infiltrate.

Fig. 7.25
Lichen planus: close-up view of Figure 7.24 showing basal cell liquefactive
degeneration and cytoid bodies.
Fig. 7.28
Atrophic (resolving) lichen planus: in addition to the lymphohistiocytic infiltrate,
there are excessive numbers of fibroblasts and increased papillary dermal collagen.

In lesions of annular lichen planus the typical histologic features are only
seen in the periphery at the advancing edge of the lesion.
In micropapular lichen planus the changes are so focal that the diagnosis
may be missed if serial sections are not examined.
Lichen planopilaris in its early stages shows an infiltrate surrounding the
lower hair follicle and papilla, follicular dilatation, and keratin plugging (Fig.
7.29).52,54 The adjacent interfollicular epithelium may or may not show a typ-
ical lichenoid infiltrate (Fig. 7.30). Basal cell hydropic degeneration, cytoid
body formation, and pigmentary incontinence are also sometimes evident. In
advanced scalp lesions, the hair follicles are destroyed and replaced by ver-
tically orientated fibrous scars, reminiscent of the fibrous streamers seen in
pseudopélade of Brocq.
Lichen planoporitis represents a rare variant in which lichenoid/interface
changes are centered on the acrosyringium and eccrine sweat duct as it enters
the epidermis. Squamous metaplasia of the ductal lining epithelium may be
a feature.127
Fig. 7.26 In lichen planus actinicus, the annular borders of the macules show typi-
Lichen planus: melanin pigment is present within macrophages (pigmentary cal features of lichen planus. In the center of the lesions, however, the epithe-
incontinence). lium is atrophic, thin, and flattened, although the lymphohistiocytic infiltrate
 Lichenoid dermatoses 227

A B

Fig. 7.29
Lichen planopilaris: (A, B) there is marked follicular dilatation and plugging accompanied by a bandlike folliculocentric infiltrate. This patient presented with scarring alopecia
and typical lichen planus lesions elsewhere.

B
A

Fig. 7.30
Lichen planopilaris: (A, B) there is a strikingly folliculocentric bandlike infiltrate associated with keratin plugging. The interfollicular epidermis is unaffected.

remains. Foci of parakeratosis and eczematization within the follicular epi-

thelium have also been described. Lichen nitidus-like lesions may sometimes
be seen (see below).
Lichen planus pigmentosus is characterized by epidermal thinning accom-
panied by basal cell vacuolization, pigmentary incontinence, and a superficial
dermal lichenoid lymphohistiocytic infiltrate.4
Hypertrophic lichen planus is characterized by more marked hyperkera-
tosis and acanthosis, with the epithelium sometimes showing pseudoepithe-
liomatous hyperplasia such that misdiagnosis as squamous cell carcinoma is
a distinct possibility, particularly if clinical information is not available (Figs
7.31–7.33).73 A number of changes not seen in ordinary lichen planus may be
observed and include parakeratosis, spongiosis, necrotic keratinocytes above
the basal cell layer, and eosinophils and plasma cells in the dermal infiltrate.
These changes may raise the possibility of a lichenoid drug eruption. The dif-
ferential diagnosis is not difficult, as lichenoid drug eruptions tend to be more
generalized and are not usually associated with hypertrophic changes.
The oral lesions of lichen planus, although often displaying the classical
features, may show parakeratosis; occasionally, alternate foci of both are Fig. 7.31
evident. In contrast to the cutaneous lesions, the epithelium is sometimes Hypertrophic lichen planus: note the hyperkeratosis, focal wedge-shaped hypergranulosis,
rather thin and the saw-toothed pattern indistinct. There is typically basal very marked irregular acanthosis, and superficial dense bandlike infiltrate.
228 Lichenoid and interface dermatitis
Fig. 7.32
Hypertrophic lichen planus: there is very marked irregular acanthosis. Note the
hypergranulosis.
Fig. 7.33
Hypertrophic lichen
planus: there is basal cell
liquefactive degeneration
with cytoid bodies.
cell hydropic degeneration. Basement membrane thickening due to the depo-
sition of fibrin-rich eosinophilic amorphous material is commonly present.
The cellular infiltrate, in addition to lymphocytes and histiocytes, frequently
contains plasma cells. Dysplasia may be seen.
Unlike skin involvement, esophageal lesions show parakeratosis. Variable
epithelial atrophy and/or mild thickening are usually seen and the saw-toothed
pattern of acanthosis is not a feature.28,32–34 As with oral lesions, plasma cells
often accompany the lymphocytic infiltrate.
Vesicular or bullous lesions are subepidermal and occur due to excessive
edema developing in association with the basement membrane zone damage
complicating basal cell hydropic degeneration (Fig. 7.34).
Fig. 7.34
Bullous lichen planus: oral lesion showing separation of the squamous epithelium
from the lamina propria. Note the bandlike infiltrate.
Fig. 7.35
Lichen planus: brilliant
green fluorescence
indicates the presence
of fibrin. By courtesy
of the Department of
Immunofluorescence,
Institute of Dermatology,
London, UK.
Direct immunofluorescence studies on skin biopsies from patients with
lichen planus usually reveal a linear fibrillar band of fibrin at the dermoepi-
dermal junction (Fig. 7.35). The cytoid bodies may be highlighted non-
­specifically by the use of antisera, mainly to IgM, but also to IgG, IgA and C3
(Fig. 7.36). A lichen planus ‘specific antigen’, which is present in the prickle
cell and granular cell layers, has been demonstrated by indirect immunofluo-
rescence of patients' serum with fetal skin.128 Whether this is of pathogenetic
significance is unknown. Direct immunofluorescence of lichen planopilaris
reveals follicular, linear basement membrane zone labeling with immunoglob-
ulin (primarily IgG or IgA).129 Fibrin may also be present. The nosological
implications of this observation are uncertain. Indirect immunofluorescence
for circulating antibasement membrane zone antibodies is negative.
 Lichenoid dermatoses 229

i­nterferon-alpha therapy.8,9 Occasionally, papules may be encountered on the

palms and soles.3–12 Familial cases have been rarely described.13,14 Lichen niti-
dus can spontaneously resolve within a few months or persist indefinitely.2
Mucous membrane involvement presenting as grayish-yellow papules has
also been described.4 Nail involvement, which is extremely rare, presents as
thickening with ridges, rippling, terminal splitting, striations, and pits.2,4
Keratodermic, vesicular, hemorrhagic, purpuric, and perforating variants
may rarely be encountered.2,15–19 Perforating lichen nitidus shows a predilec-
tion for the forearms and fingers and may be trauma related.17,20
Actinic lichen nitidus refers to the development of lichen nitidus on sun-
exposed sites, usually during the summer months. In some cases, involvement
is predominantly facial and it may present in black patients.21 It shows con-
siderable overlap with actinic lichen planus (see above).22,23

Fig. 7.36
Lichen planus: cytoid
bodies labeled positively
for IgM. By courtesy
of the Department of
Immunofluorescence,
Institute of Dermatology,
London, UK.

Differential diagnosis
Lichen planus should be differentiated from other diseases showing a
lichenoid infiltrate and hydropic degeneration of the basal layer of the epi-
thelium.130 Thus lichen planus may be indistinguishable from lichenoid Fig. 7.37
keratosis and their distinction is entirely dependent on clinicopathological Lichen nitidus: numerous tiny papules are present on the chest of a young child.
correlation. In many cases of lichenoid keratoses, there are other associated By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
changes including focal spongiosis and parakeratosis. Atrophic lesions may
be confused with poikiloderma and chronic discoid lupus erythematosus. A
lichen planus-like morphology is typical of the early stages of chronic graft-
versus-host disease (GVHD).
Poikiloderma shows epidermal atrophy, with loss of the ridge pattern and
no tendency to a saw-toothed appearance. In those examples associated with
mycosis fungoides, the lichenoid infiltrate contains variable numbers of atypi-
cal lymphocytes and mycosis fungoides cells.
Chronic discoid lupus erythematosus is associated with epidermal atro-
phy and follicular plugging. The inflammatory cell infiltrate is patchy with a
tendency to periappendageal location. A positive lupus band test is a helpful
discriminator.
Lichen planus may easily be mistaken for a lichenoid drug reaction, par-
ticularly in the absence of clinical information. Histological features favoring
the latter include high-level cytoid bodies and eosinophils within the dermal
infiltrate.

Lichen nitidus
Clinical features
Lichen nitidus is a rare but distinctive dermatosis, which shows an equal sex
incidence.1 Children and young adults are predominantly affected. It presents Fig. 7.38
clinically as an eruption of pinhead-sized, flesh-colored, shiny, flat-topped Lichen nitidus: numerous
tiny papules are present
or dome-shaped papules and shows a predilection for the arms, chest, abdo-
on the penis. The genitalia
men, and genitalia (Figs 7.37, 7.38).1–5 A positive Koebner's phenomenon are commonly affected.
is typically present.5 The condition is usually localized and asymptomatic, From the collection of the
although occasionally there may be mild or even intense pruritus.2 Rarely, late N.P. Smith, MD, the
generalized lesions have been described.2,6,7 An association with generalized Institute of Dermatology,
lesions and Down's syndrome has been documented, as has been a case after London, UK.
230 Lichenoid and interface dermatitis

Histological features
Lichen nitidus is recognizable by a characteristic histology in many cases. The
classic papule is sharply circumscribed and occupies the space of only four
or five dermal papillae. It is often depressed in the center and composed of
atrophic epidermis, frequently covered by a parakeratotic tier and overlying
a cellular infiltrate (Figs 7.39–7.42). Clawlike extensions of epidermal ridges
mark the lateral boundaries of the lesion. The epithelium shows basal cell
hydropic degeneration, and cytoid bodies may be a feature. The inflamma-
tory component consists of lymphocytes, histiocytes, and variable numbers
of epithelioid cells. Giant cells are sometimes a feature and true granulomata
may occasionally be found, although caseation is never present.24 In addition
to red blood cell extravasation, purpuric variants may show increased vascu-
larity with vessel wall thickening and hyalinization.18 In rare cases, a promi-
nent lymphocytic inflammatory infiltrate can extend down the hair follicle
and eccrine glands, making the distinction from lichen striatus challenging.24
A follicular variant of lichen nitidus may be seen and mimics lichen spinulo-
sus histologically.25 However, rarely, lichen nitidus and lichen spinulosus may
coexist clinically.26
Fig. 7.41
Lichen nitidus: the infiltrate consists of lymphocytes, histiocytes, and epithelioid
cells. Ill-defined noncaseating granulomata are not uncommon.

Fig. 7.39
Lichen nitidus: scanning view showing a typical small, circumscribed lesion occupying
only a couple of dermal papillae. Note the clawlike epidermal lateral borders.
Fig. 7.42
Lichen nitidus: there are multiple lesions of lichen nitidus with an associated
granulomatous component. The patient also had typical lichen planus lesions. By
courtesy of R. Margolis, MD, St Elizabeth's Hospital, Boston, USA.

Palmar lesions may be identical to those seen elsewhere or show a more

diffuse bandlike upper dermal lymphohistiocytic infiltrate with associated
giant cells and focal parakeratosis.3,10–12,27
Fibrin can be detected at the basement membrane zone by immunoflu-
orescent techniques, but immunoglobulin deposition is not a feature.28,29
Immunophenotypic studies show that there is a marked excess of CD4+
cells (helper/inducer T cells) over CD8+ cells (cytotoxic/suppressor T cells).28
Langerhans cells are conspicuous.30 These findings are similar to those
described for lichen planus.
Ultrastructural examination reveals rather non-specific findings includ-
ing epidermal intercellular edema, subepidermal edema, colloid bodies,
decreased numbers of desmosomes, and disruption or reduplication of the
lamina densa.31–33 Perivascular electron-dense deposits (the nature of which is
unknown) have been described in purpuric variants.8

Comment
Lichen nitidus may coexist with lichen planus or predate it and lichen niti-
Fig. 7.40 dus-like lesions may be found in patients with typical lichen planus, but it is
Lichen nitidus: note the parakeratosis and bandlike infiltrate. unlikely that the conditions are closely related.34,35 Wickham's striae are not
 Lichenoid dermatoses 231

a feature of lichen nitidus and mucosal involvement is exceptional.2,4 Lichen
nitidus is associated with parakeratosis and epidermal atrophy, in contrast
to the orthohyperkeratosis and acanthosis seen in lichen planus. The saw-
toothed appearance of the lower border of the epidermis seen in lichen planus
is not a feature of lichen nitidus and immunofluorescence for immunogloblins
is negative. Epithelioid cells and giant cells are characteristic of lichen nitidus
and are not typically a feature of lichen planus. Three patients with Crohn's
disease were reported to develop lichen niditus; however it remains to be
seen if lichen nitidus is truly an extragastrointestinal finding of this disease.36
Another patient developed lichen nitidus after hepatitis B vaccine injection.37
The significance of this is uncertain.
Lichenoid keratosis
Clinical features
Lichenoid keratosis (benign lichenoid keratosis, lichen planus-like keratosis,
solitary lichen planus) is not uncommon and usually presents as a solitary,
0.3–2-cm diameter, sharply demarcated, erythematous, violaceous, tan or
brown papule or plaque (Fig. 7.43).1,2 Occasionally, multiple lesions may
be present.2,3 It is usually of short duration and shows a predilection for the
face (particularly the cheeks and nose), neck, upper trunk (especially the pre-
sternal area), forearm, and dorsum of the hand.2,4–8 The surface is often scaly.
Lesions are commonly asymptomatic, but mild pruritus has sometimes been
documented.8 Patients are frequently Caucasian, but occasionally blacks are
affected.2,7,8 Females develop these lesions more commonly than males, usu-
ally in their fourth to seventh decades.2,5
Lichenoid keratosis is often clinically misdiagnosed as a seborrheic ­keratosis,
superficial basal cell carcinoma, squamous cell carcinoma, actinic keratosis or
Bowen's disease.5
expression, suggesting the absence of localized antigenic stimulation as seen
in lichen planus.2,12 These studies suggest that lichenoid keratosis is an entity
distinct from lichen planus despite the similarities in histology.
Despite this, histologically, as its name suggests, the features are similar to
those of lichen planus. Thus there is hyperkeratosis, wedge-shaped hypergran-
ulosis, variable acanthosis, and basal cell liquefactive degeneration sometimes
accompanied by lymphocytic exocytosis (Figs. 7.44, 7.45).2,3,5 Foci of parak-
eratosis are also frequently seen.1,2 Although the saw-toothed acanthosis of
lichen planus is sometimes evident, more often the epithelium merely shows
broadened, widened, and irregular epidermal ridges.4 The basal epidermal
layers may sometimes show very minor degrees of cytological atypia, includ-
ing cellular and nuclear enlargement with conspicuous nucleoli, but these
changes represent regenerative phenomena.3 Dysplasia as seen in lichenoid
actinic keratosis is not a feature of a lichenoid keratosis. Colloid bodies are
usually conspicuous in both the epidermis and dermis and pigmentary incon-
tinence is often marked (Figs 7.46–7.48).1,2,7 Apoptotic keratinocytes can
be prominent and may be associated with inatraepidermal blister formation
with subepidermal vesiculation. Epidermal pallor and dermal edema can be
seen in cases with only slight or no acanthosis and an interface population of
lymphocytes along the junction with vacuolar degeneration. Foci of atrophy
can be occasionally encountered.2 In some cases a combination of lichenoid
and spongiotic changes may be seen.

Pathogenesis and histological features

The precise nature of lichenoid keratosis is uncertain. In the past, it was
regarded as a solitary lesion of lichen planus or thought to have an actinic
pathogenesis.9–11 It was also proposed to represent an immunological or regres-
sive response to a pre-existent epidermal lesion similar to the phenomenon
encountered with a ‘halo’ nevus.2 The frequent association of solar lentigines
or, less commonly, seborrheic keratoses in the adjacent epithelium has been
cited as evidence in favor of this hypothesis.4–6,8 Recent studies have shown
that the lymphocytic infiltrate in lichenoid keratosis to be immunophenotypi-
cally distinct from lichen planus. The lymphocytes in lichenoid keratosis are
predominantly CD8-reactive in contrast to lichen planus. More CD20-positive
B cells are usually seen in lichenoid keratosis. Furthermore, the lymphocyte Fig. 7.44
infiltrate in lichenoid keratosis lacks the cutaneous ­lymphocyte antigen (CLA) Lichenoid keratosis: scanning view showing hyperkeratosis, hypergranulosis,
irregular acanthosis, and a bandlike chronic inflammatory infiltrate.

Fig. 7.43 Fig. 7.45

Lichenoid keratosis: there is scaling overlying a slightly raised erythematous plaque. Lichenoid keratosis: in this field there is basal cell liquefactive degeneration. Cytoid
By courtesy of the Institute of Dermatology, London. bodies are present.
232 Lichenoid and interface dermatitis
A dense chronic inflammatory cell infiltrate is typically present in the
superficial dermis. Although this characteristically has a lichenoid distri-
bution, on some occasions it may be more discrete and predominantly
perivascular in location.4,7 The infiltrate consists largely of lymphocytes and
histiocytes, but small numbers of plasma cells and eosinophils are occasion-
ally present. Exceptionally, a few atypical lymphocytes (enlarged with hyper-
chromatic, irregular, contoured nuclei) which are CD30 and CD3 reactive
can be also seen.2 The adjacent dermis sometimes shows lentigo and solar
elastosis, which is usually mild if present. Features suggestive of mycoses
fungoides such as Pautrier abscesses, dermal–epidermal tagging and mild
lymphocytic atypia have been rarely noted in benign lichenoid keratosis.13
Clinicopathological correlation and careful follow-up are essential in such
cases to avoid misdiagnosis.
Immunofluorescence findings, which are similar to those of lichen planus,
comprise deposits of IgM and, less commonly, IgG outlining cytoid bodies.5
Differential diagnosis
Many conditions show lichenoid histology and therefore come into the differ-
ential diagnosis. Most prominently, these include lichen planus and lichenoid
drug reactions.
If clinical information is available, differentiation from lichen planus
should present little difficulty. Lichen planus is characterized by large num-
bers of lesions in contradistinction to the single papule or plaque of lichenoid
Fig. 7.46
Lichenoid keratosis: in this early lesion, there is more uniform acanthosis.
Fig. 7.47
Lichenoid keratosis: there is interface change with cytoid bodies.
Fig. 7.48
Lichenoid keratosis: basal cell liquefactive degeneration is evident in addition to
cytoid bodies. Note the parakeratosis.
keratosis. In addition, lichen planus is usually itchy. Parakeratosis and dermal
plasma cells with eosinophils are not a feature of lichen planus, but are typi-
cal of lichenoid keratosis.7
Both actinic keratoses and squamous cell carcinoma in situ may some-
times show a lichenoid inflammatory cell reaction. Dysplasia by definition
is not a feature of lichenoid keratosis.1,2 Inflamed seborrheic keratosis and
porokeratosis can have a prominent lichenoid reaction. The absence of
horn cyst formation, squamous epidermal eddies, and laminated stratum
corneum keratin helps distinguish these lesions from seborrheic keratosis,
while the absence of cornoid lamella excludes porokeratosis. Melanocytic
lesions with halo phenomenon can become a diagnostic consideration and
require examination of the dermis and dermoepidermal junction for mel-
anocytic nests. In difficult cases, additional step sections or S-100 protein
immunohistochemical study can prove useful. Finally, the presence of scat-
tered CD30-positive lymphocytes in some cases of lichenoid keratosis may
raise the histological differential diagnosis of lymphomatoid papulosis.
However, the paucity of these enlarged CD30-positive cells, the absence of
a deep infiltrate, and the clinically history of a solitary lesion is reassuring
for lichenoid keratosis.2
Lichen striatus
Clinical features
Lichen striatus (Blaschko linear acquired inflammatory skin eruption
(BLAISE)) is an uncommon, usually asymptomatic, dermatosis of unknown
etiology, affecting the limbs or neck in which lesions typically follow Blaschko's
lines.1–8 Infrequently, the condition is pruritic.6–9 It is self-limiting, normally
disappearing within months to a year of onset. It shows a female predomi-
nance (2–3:1) and, although it may occur at any age, it most often presents
in children aged 5–15 years.2,5,7,8 Rarely, lichen striatus has been described
in adults (adult Blaschkitis, see below).4,10,11 Occurrence during pregnancy is
very rare.12 A family history is rarely encountered, suggesting a genetic pre-
disposition and/or a common environmental etiology in such cases.2,6,8,13,14 It
is associated with seasonal variation with most series reporting the majority
of patients presenting in spring and summer,2,7 with the exception of one large
series where the majority of patients presented in the winter 8,13 Case cluster-
ing has been documented.2
Lesions, usually solitary and unilateral, present as erythematous or flesh-
colored lichenoid or sometimes psoriasiform scaly papules, which coalesce
into a continuous or interrupted linear or curved band, 1–3 cm wide and
often covering the whole length of a limb, either lower or upper extremi-
ties (Figs 7.49, 7.50).2,8 Occasionally, multiple lesions have been recorded,
as has bilaterality.8,15,16 Presentation at two different sites and at multiple
 Lichenoid dermatoses 233

sites may exceptionally occur.17 Nail changes, which may affect a single nail,
include onycholysis, longitudinal ridging, splitting, and nail loss.8,1,18,19 An
exceptional case of lichen striatus with bilateral nail dystrophy has been
described.20 Lichen striatus is not associated with Koebner's phenomenon.
Hypo- or hyperpigmentation sometimes follows resolution, which may be
marked in people with pigmented skin.8 Lichen striatus is associated with
atopy in up to 60% of patients.1,6–8

Pathogenesis and histological features

The etiology of this condition is unknown although case cluster-
ing and seasonality raises the possibility of an environmental or infec-
tive basis in conjunction with an abnormal host response.2,21 The
development of lesions along Blaschko's lines also raises the possi-
bility of a cell-mediated autoimmune reaction to an abnormal clone
of cells. Blaschko's lines are believed to represent the direction along
which epidermal growth centers expand during early skin develop-
ment.1 It has been suggested that the distribution of lesions in lichen
striatus may reflect a postzygotic abnormality such as somatic mutation
affecting localized stem cells.1 An intriguing case following trauma in
an adult has been reported.22 Further exceptional cases associated with
solarium use, varicella infection, and hepatitis B vaccine have been
described.23–25
The histological features of lichen striatus may be non-specific and show
changes of mild chronic non-specific dermatitis.26 In an established lesion,
however, the changes often consist of an admixture of spongiotic dermatitis
with lichenoid and interface features (Fig. 7.51).27 Thus, there is often par-
akeratosis with a normal or slightly acanthotic epidermis accompanied by Fig. 7.50
intercellular edema, lymphocytic exocytosis, and keratinocyte necrosis (Figs Lichen striatus: the arms
are sometimes affected.
7.52–7.54). Satellite cell necrosis may sometimes be a feature and transepi-
The condition most often
dermal elimination of keratinocyte debris (perforating lichen striatus) has presents in children. By
occasionally been documented.4,28 Intraepidermal Langerhans cell vesicles courtesy of the Institute
have exceptionally been described.27 A heavy lymphohistiocytic infiltrate is of Dermatology, London,
present in the superficial dermis and also surrounds the vessels of the superfi- UK.
cial and deep vascular plexuses and sometimes also the cutaneous adnexae.4,27
Eosinophils and plasma cells are uncommon.27

Some biopsies may be indistinguishable from lichen planus. In those

cases where there is follicular involvement, the features can resemble
those of lichen planopilaris, and old lesions sometimes simulate lichen
nitidus.
By immunohistochemistry, the majority of the intraepidermal lympho-
cytes are of a CD8+ cytotoxic phenotype.4,27 The dermal lymphocytes
consist of an admixture of CD4+ and CD8+ subtypes. CD7 is typically
conserved.25 Intraepidermal Langerhans cells may be normal, increased or
decreased.27
Nail changes include slight spongiosis with exocytosis, focal hyper-
granulosis, dyskeratosis, and a bandlike lymphohistiocytic infiltrate
affecting the proximal nail fold, nail bed, and nail matrix dermis.18

Adult Blaschkitis
Clinical features
Adult Blaschkitis (acquired relapsing self-healing Blaschko dermatitis) is a
rare, relapsing linear eruption with a mean age of onset of 40 years, predomi-
nantly affecting males.1–14 Lesions, which are pruritic papules and vesicles,
Fig. 7.49 affect multiple sites, particularly the trunk, following Blaschko's lines and
Lichen striatus: a typically resolve in days or weeks.1 The condition, which may be unilateral or
linear band of scaly more commonly bilateral, recurs over the ensuing months or years.
hyperpigmented papules
is present on the inner Pathogenesis and histological features
aspect of the leg, a
commonly affected
The etiology is unknown. Abnormalities in chromosome 18 in cells from
site. By courtesy of involved skin in comparison to normal-appearing skin has been described
R.A. Marsden, MD, in a female patient with adult Blaschkitis, supporting a link with cutaneous
St George's Hospital, genetic mosaicism.13 Association with a drug has been cited in one case and
London, UK. emotional stress has been reported to precede relapses.11,12
234 Lichenoid and interface dermatitis

Fig. 7.51 Fig. 7.53

Lichen striatus: scanning view showing hyperkeratosis, focal parakeratosis, and Lichen striatus: there is
irregular acanthosis. A heavy inflammatory cell infiltrate is present in the upper spongiosis and marked
dermis. There is conspicuous pigmentary incontinence. Case courtesy of S. Lyle, lymphocytic exocytosis.
MD, Beth Israel Deaconess Medical Center, Boston, USA. Case courtesy of S.
Lyle, MD, Beth Israel
Deaconess Medical
Center, Boston, USA.

Fig. 7.52 Fig. 7.54

Lichen striatus: note the
Lichen striatus: in this field, there is parakeratosis, hyperkeratosis, spongiosis, and
spongiosis, basal cell
interface change. Note the pigment incontinence and intense chronic inflammatory
liquefactive degeneration,
cell infiltrate. Case courtesy of S. Lyle, MD, Beth Israel Deaconess Medical Center,
and pigmentary
Boston, USA.
incontinence. Case
courtesy of S. Lyle, MD,
Beth Israel Deaconess
Medical Center, Boston,
USA.

Histologically, adult Blaschkitis is characterized by spongiotic changes;

lichenoid features are absent and no deep involvement of adnexal structures
is seen.6,8 A rare case with interface changes has been reported.10
Differential diagnosis
It resembles lichen striatus and it has been suggested that there is no justifi-
cation for separating the two entities.15 However, it differs clinically by the
presence of vesicles, its truncal distribution, and relatively rapid resolution.
Relapsing courses are typical. Pruritus is rare in lichen striatus. Lichen stria-
tus predominantly affects young children although rare cases similar to adult
Blaschkitis but affecting children have been described.
Keratosis lichenoides chronica
Clinical features
Keratosis lichenoides chronica (Nekam's disease, lichen ruber verrucosus et
reticularis) is a very rare, chronic inflammatory dermatosis that combines
the features of a seborrheic dermatitis-like eruption of the scalp and face
with a progressive lichenoid papulonodular dermatosis affecting the trunk,
buttocks, and limbs.1–6 Patients usually present in the third to fifth decades
although exceptionally reports of pediatric involvement have been docu-
mented, some with possible familial association.7–9 It is usually persistent and
 Lichenoid dermatoses 235

typically does not respond to treatment although improvement in the summer

may sometimes be seen.5
Facial and scalp lesions are erythematous, greasy and scaly, and bear no
resemblance to those found on the trunk and extremities, which are ery-
thematous or violaceous lichenoid scaly papules in a confluent, reticulate,
or linear distribution. The latter may suggest Koebner's phenomenon (Figs
7.55, 7.56). Papulonodular and infiltrated plaques are sometimes also pres-
ent. Lesions are typically bilateral, symmetrical, and usually asymptomatic
although rarely pruritus may be intense. Scarring is not a feature. Associated
features include oral papules and ulceration, ocular lesions (blepharitis, con-
junctivitis, anterior uveitis, and iridocyclitis), laryngeal nodules, palmoplantar
keratoderma, and nail changes including yellow discoloration and dystro-
phy (longitudinal ridging, nail plate thickening, onycholysis, and paronychia)
(Fig. 7.57).1,10–14 Genital involvement including penile and scrotal papules,
chronic balanitis, and phimosis has been documented.6,10,11
Keratosis lichenoides chronica has been described in association with a
number of systemic diseases including chronic infections (toxoplasmosis,
tuberculosis, and viral hepatitis), kidney disease, and lymphoma.3,15–17

Pathogenesis and histological features

Although the precise nature of keratosis lichenoides chronica is uncertain,
some authors regard it as a variant of hypertrophic lichen planus.10,18
Histologically, the lichenoid eruption is characterized by hyperkeratosis
and parakeratosis, variable acanthosis, and epidermal atrophy associated
with a bandlike lymphohistiocytic infiltrate in the superficial dermis, often
with conspicuous melanophages.11 Neutrophils may be prominent in the
stratum corneum. Perifollicular/acrosyringotropic and perivascular chronic
inflammation may also be evident. Epidermal basal keratinocytes show Fig. 7.56
hydropic degeneration, and cytoid body formation has been described.11,18 Keratosis lichenoides chronica: close-up view of solitary lichenoid papules and a
confluent plaque. By courtesy of R.A. Marsden, MD, St George's Hospital,
Many necrotic keratinocytes are present.1 Exceptionally, amyloid deposition
London, UK.
has been documented.19
The dermal infiltrate consists of lymphocytes, histiocytes, and variable
plasma cells and eosinophils.11
Direct immunofluorescence highlights the cytoid bodies.18
The scalp and facial lesions show the features of a chronic dermatitis,
namely spongiosis with exocytosis and patchy parakeratosis. A perivascular
chronic inflammatory cell infiltrate of lymphocytes, histiocytes, and plasma
cells may be present in the upper dermis.5

Fig. 7.55
Keratosis lichenoides
chronica: there
are erythematous
hyperkeratotic lichenoid
lesions in a linear and
reticular distribution. By Fig. 7.57
courtesy of R.A. Marsden, Keratosis lichenoides chronica: plantar involvement showing disfiguring exophytic,
MD, St George's Hospital, hyperkeratotic verrucous plaques. By courtesy of R.A. Marsden, MD, St George's
London, UK. Hospital, London, UK.
236 Lichenoid and interface dermatitis

Erythema dyschromicum perstans

Clinical features
Erythema dyschromicum perstans (dermatosis cenicienta, ashy dermatosis) is
an acquired, usually asymptomatic, disfiguring dermatosis which occurs par-
ticularly in Latin American (especially Mexican) populations and in Asians.1–7
It was originally named dermatosis cenicienta after the clinical appearance of
affected patients – los cenicientos (the ash-colored ones).1 However, white-
skinned races may rarely be affected.8 It is of unknown etiology, shows a
female predilection, and can develop at any age although the majority of
patients are in their first three decades.2,9 Presentation in infancy has been
documented.10
Patients develop oval, irregular or polycyclic, gray macules with ery-
thematous, indurated, inflammatory borders of 1–2 mm. The lesions extend
peripherally, show a tendency to coalesce, and often affect large areas of the
integument (Figs 7.58–7.60). With progression, the eruption develops a gray-
blue color and loses the erythematous border, which is sometimes replaced by
a hypopigmented periphery. It is usually symmetrical, and particularly affects
the trunk, proximal extremities and, to a lesser extent, the face and neck.2 Fig. 7.58
Erythema dyschromicum
The palms and soles, scalp, nails, and mucous membranes do not appear to
perstans: this patient
be involved.6 shows irregularly
distributed gray
macules. By courtesy
Pathogenesis and histological features of R.A. Marsden, MD,
The etiology is unknown. Cases have followed HIV infection and there is a St George's Hospital,
report of simultaneous development of vitiligo and erythema dyschromicum London, UK.
perstans. The significance of these observations is doubtful.11,12 Increased sus-
ceptibility with HLA-DRB1*0407 in Mexican patients has been reported.13
Sections from the inflammatory border show hyperkeratosis and an epi-
dermis of normal thickness or somewhat atrophic, accompanied by basal cell
hydropic degeneration and cytoid body formation (Fig. 7.61). Pigmentary
incontinence is marked and a mild perivascular or lichenoid inflamma-
tory cell infiltrate is present in the superficial dermis (Fig. 7.62). Sections
from the central gray area show epidermal atrophy, follicular hyperkera-
tosis, and pigmentary incontinence. The dermal inflammatory infiltrate is
composed of both CD4 and CD8 T cells, usually with CD8 forms slightly
predominating.14
Direct immunofluorescence reveals non-specific staining of the cytoid
bodies with IgG, IgM, and C3.15–17 Fibrinogen may be present at the der-
moepidermal junction.16 The immunocytochemical studies are therefore simi-
lar to lichen planus. The epidermal keratinocytes express Ia antigen and the
­lymphocytic population comprises both helper/inducer and suppressor/cyto-
toxic phenotypes similar to lichen planus.17,18
Ultrastructural findings are non-specific, comprising intra- and interepi-
dermal edema with cytoplasmic vacuolation, separation of keratinocytes,
retraction of desmosomes, cytoid body formation, focal gaps in the kera-
tinocyte basal lamina, and pigment-laden histiocytes in the papillary
dermis.16,19,20

Differential diagnosis
The precise relationship of erythema dyschromicum perstans to lichen
planus is uncertain. The histological, immunological, and ultrastructural
findings certainly suggest that they are closely related.15,16 Typical lichen Fig. 7.59
Erythema dyschromicum perstans: in this patient there is extensive involvement of
planus may precede the development of erythema dyschromicum per-
the face, neck, and trunk. By courtesy of J. Tschen, MD, Baylor College of Medicine,
stans and sometimes the two conditions have presented simultaneously, Houston, USA.
although some of the documented cases may have represented lichen
planus pigmentosus.21,22

Lichenoid and granulomatous dermatitis
Clinical features
These lesions were described in 2000 by Magro and Crowson to have features
of both lichenoid and granulomatous dermatitis.1 There is a slight female
predominance (21:15) affecting a broad range of ages (5–86 years old).
The extremities and trunk are most often involved, followed by the head and
neck region. Clinically, the lesions present as lichenoid papules
Pathogenesis and histology
Various etiologic agents included drug, coexisting medical illnesses, and
infections have been implicated. Similar to any lichenoid disorder, there is a
 Interface dermatoses 237

Fig. 7.60
Erythema dyschromicum
perstans: in this patient
with more advanced
Fig. 7.62
disease, there is a
Erythema dyschromicum
generalized bluish
perstans: note the
discoloration. By
hydropic degeneration,
courtesy of the Institute
cytoid body, and pigment
of Dermatology, London,
incontinence.
UK.

Fig. 7.61
Erythema dyschromicum perstans: there is hyperkeratosis and marked pigmentary
incontinence.
bandlike infiltrate of lymphocytes and histiocytes. The histiocytes are vari-
ably described as loosely aggregated and superficially located, cohesive gran-
ulomata, diffuse interstitial granulomatous inflammation, scattered solitary
giant cells, and granulomatous vasculitis.1 Cases associated with drugs also
may display parakeratosis, keratinocyte necrosis, acrosyrinogeal accentua-
tion, red cell extravasation, granulomatous vasculitis, eosinophils, and plas-
macellular infiltrate sparing the deep dermis.1,2 Lymphocyte atypia may also
be a feature in examples associated with cutaneous lymphoma or lymphoma-
tous drug reactions.1
Interface dermatoses
Definitions
There is such considerable variation in the literature as to the exact defini-
tions and interrelationships between erythema multiforme (particularly the
‘major’ variant), Stevens-Johnson syndrome, and toxic epidermal necroly-
sis that it is often difficult or impossible to be certain to which disease the
authors are actually referring!1–5 The consensus paper published in 1993 by
Bastuji-Garin is used as a basis for classification since the authorship included
most of the major players at that time in this difficult subject.1
Classification of an individual patient depends upon the precise morphol-
ogy and pattern of individual lesions and the extent of skin involvement
(detached and detachable epidermis) as a percentage of total body surface
area at the worst stage of the illness.
• Target lesions are defined as sharply demarcated and round, less than
3.0 cm in diameter and comprising three distinct zones, namely a central
erythematous or purpuric disc with or without a blister, surrounded
by a raised edematous ring, in turn bordered by an erythematous rim
(Fig. 7.63).1 Target lesions are typically distributed in an acral location,
are often seen following a herpetic infection, and are characteristic of
erythema multiforme. Typical target lesions are not seen in patients with
widespread epidermal detachment.
• Raised atypical target lesions are ill-defined, round, palpable lesions
with only two zones including a central raised edematous area with an
erythematous border.
• Flat, atypical target lesions are ill-defined, round lesions with only two
nonpalpable zones. The center may be blistered (Fig. 7.64).
• Macules with or without blisters are defined as nonpalpable,
erythematous or purpuric macules with irregular shape and size and
often confluent. Blisters often occur on all or part of the macule.
This lesion is characteristically seen in patients with widespread
epidermal detachment who have a history of drug ingestion.
Working on this basis, the following definitions have been proposed:1
• Bullous erythema multiforme is characterized by < 10% detachment,
typical target lesions, and sometimes raised atypical target lesions.
238 Lichenoid and interface dermatitis
Fig. 7.63
Target lesion: characterized by a central blister surrounded by an edematous ring
and an outer erythematous border. By courtesy of R.A. Marsden, MD, St George's
Hospital, London, UK.
• Stevens-Johnson syndrome is characterized by > 10% detachment, flat
atypical target lesions, and erythematous macules in addition to blisters
and erosions affecting one or more mucous membranes.
• Overlap Stevens-Johnson syndrome/toxic epidermal necrolysis is
characterized by 10–30% detachment, atypical target lesions, and flat
erythematous macules.
• Toxic epidermal necrolysis is characterized by > 30% detachment with
flat atypical target lesions and/or erythematous macules. Rarely, toxic
epidermal necrolysis may develop as large epidermal sheets in the absence
of erythematous macules.
Erythema multiforme
Clinical features
Erythema multiforme is a relatively common condition, which predominantly
affects younger individuals (particularly in their second to fourth decades),
Fig. 7.64
Flat atypical target lesion: characterized by only two components, a central
edematous area or blister surrounded by a zone of erythema, these lesions may
be seen in erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal
necrolysis. By courtesy of the Institute of Dermatology, London.
including children, and shows a slight male predilection.1–8 All races may
be affected. It is self-limiting and commonly recurrent (recurrent erythema
multiforme), although rarely continuous episodes of erythema multiforme
have been described (persistent erythema multiforme).9–13 Very occasionally,
­epidemics are seen, as for example in military camps.4 The eruption shows
seasonal variation with many patients developing the condition in spring and
summer.
It presents as symmetrically distributed, fixed, discrete erythematous
round maculopapules 1–2 cm in diameter which appear in crops on the
acral regions, particularly the elbows, the knees, and extensor aspects of
the extremities (Figs 7.65–7.67). Sometimes, the face, palms and soles,
flexural extremities, and perineum (Fig. 7.68) are affected.2 The scalp is
rarely involved.14 Typically, the center of the lesions becomes ischemic to
produce a bluish discoloration (the classic iris or target lesion) which may
eventually blister. Although lesions are often present for up to 7 days, the
entire episode is usually over by 6 weeks or less.14 Lesions often number
a hundred or more. Resolution may be associated with postinflammatory
hyperpigmentation.
Oral lesions are common and are usually mild, typically presenting as mul-
tiple ulcers, which may involve the entire oral cavity, or predominantly affect
the buccal mucosa and tongue (Figs 7.69, 7.70).15 Target lesions on the lips
may also be encountered.
In many patients, episodes of erythema multiforme are recurrent, develop-
ing as often as five times each year. Such cases are almost invariably due to
herpes simplex infection. Particular clinical features of this variant include a
positive Koebner's phenomenon, photodistribution, grouping of lesions over
the elbows and knees, and nail fold involvement.8
In the older literature, a variant of erythema multiforme was recognized
(erythema multiforme major) in which patients developed severe mucosal dis-
ease including oral, ocular, and anogenital lesions. In keeping with the current
thinking on this complex topic, such cases are now included in the spectrum
of Stevens-Johnson syndrome.1,2
Rarely, patients (usually females) may develop erythema multiforme in asso-
ciation with discoid or systemic lupus erythematosus – Rowell syndrome.
Pathogenesis and histological features
The etiology in the overwhelming majority of cases is past or present infec-
tion with herpes simplex virus (HSV) types I and II. In many patients, dis-
ease is subclinical. In some studies the relationship is strongest in patients
with recurrent disease. Occasionally, Mycoplasma infection is of etiological
importance. Although many other viral and bacterial infections have also
Fig. 7.65
Erythema multiforme: multiple lesions on the hand, a typical site of presentation.
From the collection of the late N.P. Smith, MD, the Institute of Dermatology,
London, UK.
 Interface dermatoses 239

Fig. 7.66 Fig. 7.68

Erythema multiforme: multiple ulcerated lesions on the hands. From the collection Erythema multiforme: note the presence of erythema and erosion on the labium
of the late N.P. Smith, MD, the Institute of Dermatology, London, UK. minus. By courtesy of P. Morgan, MD, London, UK.

Fig. 7.69
Erythema multiforme: multiple erosions are present on the labial mucosa. By
courtesy of P. Morgan, MD, London, UK.

Fig. 7.67
Erythema multiforme: more extensive involvement in an adult with large
erythematous lesions. The blisters have ruptured. By courtesy of the Institute of
Dermatology, London.

been implicated including orf, cowpox, Epstein-Barr virus, streptococcus,

meningococcus, Histoplasma, and various childhood illness immunizations,
it is uncertain whether these truly represent erythema multiforme or whether
they might be better classified as some other dermatosis, including Stevens-
Johnson syndrome.4,14,16 Erythema multiforme has also been described as
a side effect of a number of drugs including sulfonamides, trimethoprim-
sulfamethoxazole combinations, penicillin, barbiturates, the oral con-
traceptive pill, TNF-α antagonists, bortezomib, sorafenib, and anti- Fig. 7.70
retroviral drugs in HIV patients.4,1,17–20 An interesting association with Erythema multiforme: there is a large ulcer on the buccal mucosa. By courtesy of
ciprofloxacin after alcohol ingestion has been described.21 The antineoplastic P. Morgan, MD, London, UK.
240 Lichenoid and interface dermatitis

drug ­paclitaxel has not only been associated with erythema multiforme but
may ­trigger a photosensitive variant of the disease.22 Furthermore, the erup-
tion has also been associated with photocontact dermatitis to ketoprofen.23
A single association with HPV vaccination has been reported.24 A localized
contact dermatitis to a henna tattoo has also triggered the disease.25 Erythema
multiforme has also been associated with internal malignancy, including
lymphoma, and may follow radiotherapy.26,27
Although cultures of skin lesions in erythema multiforme are generally
negative for herpes simplex, viral DNA has been identified within the epi-
dermis of skin lesions by polymerase chain reaction (PCR); in situ hybrid-
ization and immunohistochemistry detecting viral components are often
positive.13,16,28–35 Viral DNA is absent from healed lesions.31 Viral gene
expression correlates with lesion development.29 Since there is no evidence
of a viremia, it is thought that viral DNA is transported to the skin within
circulating lymphocytes rather than directly through the bloodstream or
via centrifugal neuronal spread.31,34 Why it localizes to specific sites in the
skin is unknown but this may be related to ultraviolet (UV) exposure. It is
likely that an episode of erythema multiforme develops as a delayed hyper-
sensitivity (and/or cytotoxic) reaction to herpes viral antigens including
DNA polymerase expressed on the surface of keratinocytes. The identifi- Fig. 7.71
Erythema multiforme: early lesion showing hyperkeratosis, basal cell hydropic
cation of IFN-γ in active skin lesions suggests a delayed hypersensitivity
degeneration, and occasional cytoid bodies.
reaction with involvement of variable cytokines recruiting additional lym-
phocytes and macrophages to amplify the inflammatory reaction.35,36 It
has been postulated that HSV DNA polymerase might also be associated
with increased expression of transforming growth factor-beta (TGF-β) and
p21waf, thereby accounting for cell growth arrest and apoptosis.37 Viral
antigens do not persist in lesional skin after resolution of the eruption and
therefore in patients with recurrent disease, repeat transportation of viral
DNA to the skin must occur.
Erythema multiforme is associated with an increased incidence of
HLA-B15 (B62), HLA-B35, and HLA-DR53, particularly in recurrent
disease.38–41 Patients with limited mucosal involvement show an increased
frequency of HLA-DQB1*0302 compared with patients in whom
mucosal lesions predominate, when HLA-DQB1*0402 is more com-
monly identified.41
Erythema multiforme is characterized by a combination of basal cell
hydropic degeneration and keratinocyte apoptosis accompanied by a heavy
superficial dermal lymphohistiocytic infiltrate associated with lymphocytic
exocytosis and satellite cell necrosis.16,42–46 An exceptional case in which the
predominant cells were histiocytes mimicking Kikuchi's disease has been
described.47
Apoptotic keratinocytes are rounded, intensely eosinophilic, and often
anucleate, although residual pyknotic forms may be present (Figs 7.71, Fig. 7.72
7.72). Their distribution may be focal, involving only an occasional and often Erythema multiforme: close-up view of basal cell hydropic degeneration.
basally located keratinocyte, or it can affect the entire epidermis, thereby
resembling toxic epidermal necrolysis (Lyell's syndrome) (Fig. 7.73). Marked
basal cell hydropic degeneration sometimes results in subepidermal clefting
or vesiculation (Fig. 7.74). Intra- and intercellular intraepidermal edema is
evident and spongiotic vesiculation can be a feature (Fig. 7.75).
In biopsies from early lesions, the changes may be predominantly dermal
with marked edema of the papillary dermis accompanied by a chronic inflam-
matory cell infiltrate and red cell extravasation (Fig. 7.76), thereby account-
ing for the clinical appearance of purpura.
The inflammatory cell infiltrate in erythema multiforme usually comprises
lymphocytes and histiocytes; neutrophils are sparse or absent. Eosinophils
may sometimes also be present.48 Leukocytoclasis is not seen.
Histological features, similar to those of the skin lesions, typify involve-
ment of the mucous membranes with spongiosis and intracellular edema.
These lesions tend to be more obvious and, therefore, intraepithelial blisters
are sometimes conspicuous.
With immunohistochemistry, the infiltrate consists predominantly of
helper (CD4+ Vβ2+) lymphocytes with a lesser number of cytotoxic lym-
phocytes and admixed macrophages.49,50 Keratinocytes express intracellu-
lar adhesion molecule-1 (ICAM-1) and HLA-DR, the latter thought to be
induced by IFN-γ of activated CD4+ T-helper 1 (Th1) cell derivation.49,51
TNF-α is not expressed in HSV-associated lesions.37 Circulating soluble Fas is Fig. 7.73
thought to be an mediator of apoptosis, as in toxic epidermal necrolysis and Erythema multiforme: marked apoptosis has resulted in intraepidermal vesiculation.
 Interface dermatoses 241

S­ tevens-Johnson syndrome. Autantibodies to desmoplakin 1 and 2 may also

play a role in erythema multiforme major.16

Differential diagnosis
Erythema multiforme shows considerable overlap with Steven-Johnson
syndrome and toxic epidermal necrolysis. In erythema multiforme, how-
ever, there are commonly more marked inflammatory changes than seen in
Stevens-Johnson syndrome and toxic epidermal necrolysis in which the epi-
dermal changes of widespread apoptosis are the predominant feature.
Erythema multiforme may also on occasion be confused with fixed drug
eruption, acute graft-versus-host disease (GVHD), and connective tissue
diseases such as systemic or subacute cutaneous lupus erythematosus and
dermatomyositis. Presence of mucin and evidence of chronicity such as hyper-
keratosis and parakeratosis are useful clues for connective tissue disease. The
presence of conspicuous eosinophils would be in favor of a drug reaction.
Focal interface change combined with an absence of significant eosinophils
and follicular involvement is thought helpful for distinguishing between
GVHD and erythema multiforme. None of the findings is considered abso-
lutely pathognomonic of any entity and clinicopathological correlation will Fig. 7.76
most often ensure their distinction with ease. Erythema multiforme: early lesion showing interface change and marked upper
dermal edema.

Toxic epidermal necrolysis and

Stevens-Johnson syndrome
The original description of toxic epidermal necrolysis included two unrelated
conditions:1
• the scalded skin syndrome seen in infants and young children and due to
staphylococcal infection with toxin production,
• a drug hypersensitivity reaction, predominantly affecting adults, now
regarded as the sole representative of this entity.

Clinical features
Classification of a blistering disorder as toxic epidermal necrolysis (Lyell's
syndrome) or Stevens-Johnson syndrome is based upon the extent of detached
or detachable skin at the worst stage of the illness.2 In the former condition,
30% or more skin is involved whereas in the latter less than 10% is affected
(Figs 7.77, 7.78). An intermediate category where 10–30% of the skin is
involved has also been recognized.3–5
Toxic epidermal necrolysis and Stevens-Johnson syndrome are very rare
conditions, with reported incidences ranging from 0.93 to 1.3 cases per mil-
Fig. 7.74
Erythema multiforme: in this example, subepidermal vesiculation is present. lion population in Europe and 0.5 in the United States.6–9 They represent
severe drug hypersensitivity reactions except for those instances in which
GVHD develops a toxic epidermal necrolysis-like appearance.7,10 While prior
studies have shown there is no racial predilection, there is some evidence
of genetic susceptibility to this condition. Patients with HLA-B*1502 and
HLA-B*5801 are associated with carbamazepine-induced Stevens-Johnson
syndrome and allopurinol-induced Stevens-Johnson syndrome among the
Han Chinese, respectively. 5,11,12 The elderly are predominantly affected, but
the condition may present at any age, including children, infants, and the
newborn.13–15 In the last group, mucosal lesions may sometimes be the sole
manifestation of the disease.16 Prior studies have shown that females are
affected more often than males (2:1) but more recent reports suggest that this
may be changing, with more male and HIV/AIDS patients being reported.4,15
In children the sex ratio is equal.
Patients typically present with a short prodromal illness of pyrexia, sore
throat, muscle ache, headache, anorexia, nausea, vomiting, and burning
eyes, soon followed by the development of a painful rash most often start-
ing on the face, neck, and shoulders before becoming more generalized with
trunk and proximal limb accentuation.4,5,15–18 The eruption consists of irregu-
lar, erythematous, and sometimes purpuric or necrotic, flat, atypical target
lesions. In some patients, an exanthematous, morbilliform eruption is initially
Fig. 7.75 seen.19 Occasionally, typical target lesions overlapping with erythema multi-
Erythema multiforme: early lesion showing spongiosis, lymphocytic exocytosis, and forme may be a feature.9 In any event, this early stage is soon followed by the
cytoid bodies. development of flaccid, fluid-filled bullae (Fig. 7.79). These rapidly ulcerate,
242 Lichenoid and interface dermatitis
Fig. 7.77
Stevens-Johnson syndrome: this patient developed Stevens-Johnson syndrome
following sulfonamide therapy. By courtesy of R.A. Marsden, MD, St George's
Hospital, London, UK.
Fig. 7.78
Stevens-Johnson syndrome: this condition is distinguished from toxic epidermal
necrolysis by there being less than 10% of the skin involved. Note the tense
blisters. By courtesy of the Institute of Dermatology, London, UK.
l­eaving painful raw erosions similar to scalding (Figs 7.80–7.83). Nikolsky's
sign is positive. Eventually, the whole body, with the exception of the hair-
bearing scalp, may become affected.
Toxic epidermal necrolysis/Stevens-Johnson syndrome is a multisystem
disease. The mucous membranes are affected in all patients and sometimes
represent the presenting manifestation.17 The oropharynx, eyes, genitalia,
and anus show particular involvement, in descending order of frequency.4,5,19
Ocular lesions are especially important, as they are a cause of significant long-
term morbidity in 40–50% of survivors.4,20 Patients may manifest conjunctivi-
tis, synechiae, the sicca syndrome, trichiasis, and keratitis.19 Gastrointestinal
Fig. 7.79
Toxic epidermal necrolysis: early stage showing multiple large fluid-filled blisters.
By courtesy of R. Reynolds, MD, Harvard Medical School, Boston, USA.
Fig. 7.80
Toxic epidermal necrolysis: there is widespread erythema and numerous blisters
are evident. By courtesy of I. Zaki, MD, and S. Dalziel, MD, University Hospital,
Queen's Medical Centre, Nottingham, UK.
lesions, esophageal stricture, hepatitis, and pancreatitis are occasional man-
ifestations.21–23 Tracheobronchial involvement is fairly common and adult
respiratory distress syndrome is an important and potentially life-threatening
complication.17 Anemia and leukopenia are typically seen.
The mortality of Stevens-Johnson syndrome is approximately 5%, whereas
the more extensive skin involvement in toxic epidermal necrolysis is reflected
in a higher mortality of up to 40%.17,22,24–26 Causes of death include sepsis
(particularly due to Staphylococcus aureus and Pseudomonas aeruginosa),
heart failure, pulmonary embolism, septic shock, disseminated intravascular
coagulation, and gastrointestinal bleeding.19 Increased age, a high proportion
of skin loss, deteriorating renal function,22 and extensive involvement of the
bronchial epithelium4 are all associated with a poor prognosis.

Fig. 7.81
Toxic epidermal necrolysis: note the generalized blistering resembling scalding.
By courtesy of I. Zaki, MD, and S. Dalziel, MD, University Hospital, Queen's Medical
Centre, Nottingham, UK.
Fig. 7.82
Toxic epidermal necrolysis: this is a serious potentially life-threatening condition.
This is a particularly severe example. From the collection of the late N.P. Smith, MD,
the Institute of Dermatology, London, UK.
Pathogenesis and histological features
Toxic epidermal necrolysis/Stevens-Johnson syndrome almost always represents
an adverse drug reaction.13,17,27 However, in children, infection with Mycoplasma
pneumoniae has sometimes been implicated in the latter condition.5,16 Etiological
agents include sulfonamides, anticonvulsants (phenytoin, barbiturates, and
carbamazepine), antibiotics (aminopenicillins, quinolones, and cephalosporins),
nonsteroidal antiinflammatory agents (phenylbutazone, oxyphenbutazone,
isoxicam, and piroxicam), and allopurinol.17,19 HIV antiretroviral agents have also
been implicated.28 Patients with such adverse reactions may show a positive patch test
to the offending drug and lymphocyte transformation may be demonstrable.27,29
Interface dermatoses 243
Fig. 7.83
Toxic epidermal necrolysis: healing is commonly followed by postinflammatory
hyperpigmentation. From the collection of the late N.P. Smith, MD, the Institute of
Dermatology, London, UK.
Toxic epidermal necrolysis may also evolve in the setting of acute
GVHD. Although some of these cases are undoubtedly due to an adverse
drug reaction, a proportion represents a specific and severe manifestation
of acute GVHD. This is associated with a very poor outlook and high
mortality.10,30
Toxic epidermal necrolysis/Stevens-Johnson syndrome is an important
complication of HIV infection and is seen in up to 1 in 1000 acquired immu-
nodeficiency syndrome (AIDS) patients per year.31 The high incidence relates
in part to the frequent use of sulfonamides in these patients.32 Patients with
systemic lupus erythematosus are also particularly at risk.15
Exceptionally, toxic epidermal necrolysis has been documented in adults fol-
lowing an infection including hepatitis A and Mycoplasma pneumoniae.4,33,34
The precise mechanisms involved in the pathogenesis of toxic epidermal
necrolysis are unclear. Affected patients in sulfonamide-related cases are com-
monly slow acetylators, and detoxification of resultant reactive drug metabo-
lites is impaired.17,35,36 Although the condition may result from a direct action
in some cases, it is thought to be more likely that drug metabolites function
as haptens and induce an indirect cellular immune reaction to keratinocytes.
Patients with AIDS are deficient in glutathione and, as a result, persistence of
such reactive metabolites may explain the increased incidence of this disease
in these patients.36
Toxic epidermal necrolysis is associated with an increased incidence of
HLA-B12: 50% compared with 26% in the normal population.37 As men-
tioned above, specific HLA types are associated with Stevens-Johnson syn-
drome in certain racial populations.
Although the exact pathogenesis of the disease is not clear, it has been
demonstrated that the inflammatory cells in the blisters are cytotoxic T lym-
phocytes and natural killer cells.38 The main cytotoxic protein expressed is
granulysin and this protein seems to be a major player in the induction of
disseminated keratinocyte necrosis. When the protein is injected into the skin
of mice, blisters closely simulating those seen in toxic epidermal necrolysis/
Stevens-Johnson syndrome develop.38
The histological features are those of variable epidermal apoptosis associ-
ated with basal cell hydropic degeneration or subepidermal vesiculation (Figs
7.84–7.87).39,40 Lymphocytic exocytosis may be present and satellite cell
necrosis is sometimes apparent.41,42 Sweat duct epithelium is also involved,
and hair follicles may also be affected, although much less often (Fig. 7.88).13
A light, predominantly perivascular infiltrate of lymphocytes, macrophages,
and melanophages is present in the superficial dermis, which also is com-
monly edematous (Figs 7.89, 7.90). Small numbers of eosinophils may be
present.
244 Lichenoid and interface dermatitis

With immunohistochemistry, the dermal infiltrate consists predomi-

nantly of CD4+ T-helper cells, whereas in the epidermis CD8+ cells are most
numerous.41,43,44 Histiocytes may be conspicuous.45 Langerhans cells are
depleted. Keratinocytes express HLA-DR. Keratinocyte cell death is thought
to result from the combined effects of cytolytic enzymes including perforin
and cytokines such as soluble TNF-α and IL-6.18,39,45–47 Fas ligand-mediated
apoptosis is believed to be of major importance in the final development of
necrolysis.4,5,18,39,45–47

Differential diagnosis
Staphylococcal scalded skin syndrome is an important clinical differential
diagnosis. The typical histological finding of a subcorneal pustule in this con-
dition makes the distinction easy. In addition, staphylococcal scale skin syn-
drome does not demonstrate full-thickness necrosis.
Toxic epidermal necrolysis/Stevens-Johnson syndrome may sometimes be
indistinguishable from severe erythema multiforme. Marked lymphocytic
exocytosis, apoptosis predominantly affecting the lower epidermis, intense,
lichenoid dermal chronic inflammation with extension along the superficial
and deep vascular plexuses, and prominent erythrocyte extravasation are
Fig. 7.86
more in favor of erythema multiforme.40,48 This histological distinction is also Toxic epidermal necrolysis: this field shows the floor of the blister. There are no
mirrored to some extent by the etiology. Thus, those cases that result from an inflammatory cells in this example.

Fig. 7.87
Toxic epidermal necrolysis: medium-power view showing necrosis of the full
Fig. 7.84 thickness of the roof of the blister.
Toxic epidermal necrolysis: low-power view showing subepidermal blistering.

Fig. 7.88
Fig. 7.85 Toxic epidermal necrolysis: follicular involvement showing basal cell hydropic
Toxic epidermal necrolysis: the roof of the blister is completely necrotic. degeneration and apoptosis.
 Interface dermatoses 245

poikiloderma. Histologically, poikiloderma is characterized by hyperkerato-

sis, epidermal atrophy with basal cell liquefactive degeneration, pigmentary
incontinence, telangiectasia, and a variable superficial dermal lymphohistio-
cytic infiltrate (Figs 7.91, 7.92).

Poikiloderma of Civatte
Poikiloderma of Civatte (poikiloderma of head and neck, Derbyshire neck) refers
to a fairly common progressive and irreversible disorder in which typical poiki-
loderma presents in a photodistribution, predominantly affecting the sides of the
face and neck and the ‘V’ of the chest (Fig. 7.93).1–4 Middle-aged and elderly
women, menopausal females, are predominantly affected. Possible etiological
factors include hormonal effects, phototoxicity or photoallergy possibly due to
perfumes or fragrances.4–6 Recently, familial cases have been documented.4

Histological features
In addition to the typical features of poikiloderma, solar elastosis is often very
marked.3 In some biopsies, however, the appearances can be very non-specific.
Fig. 7.89
Toxic epidermal necrolysis: there is a perivascular lymphohistiocytic infiltrate.

Fig. 7.91
Poikiloderma: there is basal cell hydropic degeneration and a very light perivascular
Fig. 7.90 lymphohistiocytic infiltrate.
Toxic epidermal necrolysis: note the apoptosis and pigment incontinence.

infection tend to be more inflammatory than those that represent an adverse

drug reaction, in which the changes are predominantly epidermal.48 The pres-
ence of eosinophils does not seem to distinguish between drug- and infection-
related causes within this histological spectrum.40
Toxic epidermal necrolysis resulting from an adverse drug effect and that
presenting in a background of severe GVHD are indistinguishable.

Paraneoplastic pemphigus
Erythema multiforme-like histological features are an integral feature of para-
neoplastic pemphigus.

Poikiloderma
Poikiloderma (Gr. poikilos, spotted, mottled, varied) is a clinical descriptive
term applied to skin showing slight scaling, atrophy, variable pigmentation,
and telangiectasia. It is a feature of a number of conditions including lupus
erythematosus, dermatomyositis, large plaque parapsoriasis, poikiloderma
of Civatte, poikiloderma congenitale, Bloom's syndrome, Cockayne's syn- Fig. 7.92
drome, dyskeratosis congenita, and DNA mitochondrial syndrome-associated Poikiloderma: close-up view.
246 Lichenoid and interface dermatitis

Mitochondrial DNA syndrome-associated
poikiloderma
Photodistributed poikiloderma has been documented in a number of mito-
chondrial DNA syndromes, particularly Pearson's syndrome, which also
includes failure to thrive, exocrine pancreas insufficiency, severe renal tubule
dysfunction, and bone marrow suppression.1 Other dermatological manifes-
tations of mitochondrial DNA syndromes include acrocyanosis, dry brittle
hair, vitiligo, hyperpigmentation, and anhidrosis.2–7
hands.6 While occasionally reported, mental retardation is not usually a fea-
ture of this syndrome.1 The disease is associated with the development of
cutaneous squamous cell carcinoma and more rarely basal cell carcinoma.2,4
Bowen's disease has also been described.7
There is also an increased risk of internal malignancies, particularly tib-
ial osteosarcoma and multicentric osteosarcoma (7–32%).1,2,8–10 An associa-
tion with duodenal stenosis and annular pancreas has been described in one
patient.11 The life span of the patient, however, is generally normal.

Rothmund-Thomson syndrome
Clinical features
This rare syndrome, which has been described in Asians and blacks as well as
Caucasians, has an autosomal recessive mode of inheritance. In contrast to the
earlier finding of an equal sex incidence, the more recent literature suggests a
predilection for males (2:1).1,2 It usually presents between the third and sixth
months of life (hence the term ‘poikiloderma congenitale’) as a reticulated,
erythematous rash – sometimes described as marmoreal (L. marmor, marble) –
on the face, which eventually spreads to involve the extremities and the but-
tocks (Figs 7.94–7.96).2 The trunk and flexural aspects are usually spared.1
Affected infants are photosensitive and, therefore, there is often a history of
sun exposure before the development of skin lesions.3,4 This is later replaced
by reticular, linear, or punctate foci of atrophy.4 Telangiectasia is present and
areas of hypo- and hyperpigmentation may be noted. The poikilodermatous
change is seen most frequently at sun-exposed sites.1
Fig. 7.94
A variety of other manifestations may be observed, including variable alo- Rothmund-Thomson
pecia particularly involving the scalp, eyebrows and eyelashes, and seen most syndrome: there is
often in females. This is present in up to 80% of patients.1 Gastrointestinal a marked mottled
problems including chronic emesis and diarrhea may be seen in infancy.2 hyperpigmentation
Juvenile, subcapsular (unilateral or bilateral) cataracts are common and skel- predominantly affecting
etal abnormalities include short stature, osteopenia, pathological fractures, the peripheries. By
dislocations, irregular metaphyses, abnormal trabeculation, and stippled ossi- courtesy of the Institute
fication of the patellae.2 Small hands with shortened digits are frequently of Dermatology, London,
seen.5 Frontal bossing, saddle nose, and prognathism are characteristic.1 UK.
Absent or malformed radii are seen in 10–20% of patients and bifid or absent
thumb may also be present.1,2,6 Nail dystrophy, dental abnormalities (par-
ticularly conical-shaped teeth with caries), and hypogonadism may also be
detected. Hyperkeratotic warty or verrucous lesions sometimes develop on
the extensor surfaces, particularly overlying joints and especially the feet and

Fig. 7.95
Rothmund-Thomson
syndrome: there is
symmetrical involvement
of the legs. By courtesy
Fig. 7.93 of the Institute of
Poikiloderma of Civatte: note the mottled hyperpigmentation in a characteristic Dermatology, London,
distribution. By courtesy of the Institute of Dermatology, London, UK. UK.

Fig. 7.96
Rothmund-Thomson syndrome: there is atrophy in addition to hyperpigmentation.
By courtesy of the Institute of Dermatology, London, UK.
Pathogenesis and histological features
Rothmund-Thomson syndrome, in some patients at least, has been shown
to be associated with a mutation in the RECQL4 gene, a member of the
DNA helicase family (see Bloom's syndrome).9,12–15 Cytogenetic analysis has
revealed mosaicism in a subpopulation including trisomy 8.2 The underlying
defect in Rothmund-Thomson syndrome is unknown. While most investiga-
tions have failed to demonstrate abnormal sensitivity to UVA or UVB, there
have been occasional recent reports of reduced unscheduled DNA synthesis
following irradiation of cultured fibroblasts with UVB and UVC.3,16 More
recent studies suggest a role for RECQL4 in repairing DNA induced by UV
irradiation.17 Other investigations have demonstrated that RECQL4 is also
involved in DNA replication.18–20
No recognized diagnostic test for this disorder is available and diagnosis
is based primarily on the polioderma rash.15 Mutational screening for the
RECQL4 gene is possible and can correlate with certain aspects of the syn-
drome, but additional genes may also be involved.21
The histological features of poikiloderma include hyperkeratosis, epi-
dermal atrophy, liquefactive degeneration of the basal epidermal cells, and
telangiectasia. Pigmentary incontinence may be present and a perivascular
chronic inflammatory cell infiltrate is sometimes evident in the superficial
dermis. The latter sometimes also shows elastic tissue fragmentation and
depletion or absence of cutaneous appendages.1 The squamous cell carcino-
mas show typical features.
An examination of scalp has revealed hypopigmented vellus hairs without
cortices.6
Bloom's syndrome
This rare chromosomal instability syndrome (also known as congenital
telangiectatic erythema with dwarfism) has an autosomal recessive mode of
inheritance and is particularly seen in East European (Ashkenazi) Jews. When
found in non-Jews, there is a high incidence of parental consanguinity. It rep-
resents a genetically homogenous single locus disease unassociated with any
apparent heterogeneity.1
Clinical features
There is a characteristic appearance with microcephaly, dolichocephaly, and
small, narrow ‘pinched’ facies, and stunted growth leading to severe dwarf-
ism.2,3 An erythematous rash with telangiectasia develops predominantly on
the face (in particular the ‘butterfly’ area) and is exacerbated by sunlight
(Fig. 7.97).4 The rash may also affect the backs of the hands and forearms
Interface dermatoses 247
and typically develops in infancy. Café-au-lait spots are a common manifes-
tation and discrete areas of hypopigmentation are usual.3 A peculiar high-
pitched, squeaky (so-called '’Mickey Mouse’) voice is sometimes a feature.5
Male infertility is common.3 Patients may suffer impaired concentration,
short-term memory, and general mental organizational disability.5
Bloom's syndrome is typified by an inherent propensity to chromosomal
abnormalities, in particular, sister chromatid exchange. There is an associ-
ated increased incidence of most malignancies, especially acute leukemia,
non-Hodgkin's lymphoma, colon carcinoma, breast carcinoma, and cutane-
ous squamous cell carcinoma. Patients are prone to develop multiple primary
tumors, which often develop at an early age (third decade). As a result, death
by age 30 usually occurs due to cancer.4,6 They may also suffer immunode-
ficiency (diminished IgG, IgA, IgM) and are therefore at an increased risk
of childhood infections, pulmonary infections, and chronic lung disease.5,7
There is also an elevated risk of adult onset-like diabetes mellitus.8
Pathogenesis and histological features
The gene for Bloom's syndrome, BLM, which has been mapped to 15q21.3,
is a member of the RecQ helicase protein family, responsible for unwinding
DNA and RNA.9–15 It has been identified as representing part of the BRCA1-
associated genome surveillance complex, which is mutated in families with
hereditary breast cancer.16 The protein functions as a 3′-5′ DNA helicase and
may be involved specifically in allowing sister chromatid separation during
mitosis.12,17 DNA helicases have essential roles in genetic recombination,
transcription, DNA replication, and repair.15 Mutation of the BLM gene
results in genomic instability. Bloom's syndrome is associated with increased
sensitivity to alkylating agents, increased spontaneous chromosome breakages,
increased interchromatid exchange (including sister chromatid exchange,
6–10-fold), increased somatic cell mutation frequency, and reduced replication
fork elongation rate.4,11 Mutations include missense, nonsense, frameshift,
and genomic deletions, most of which result in premature translation
terminations and resultant defective Bloom's syndrome protein with impaired
function.14 Multiple defective nuclear enzymes including DNA ligase I have
been identified.18 Monosomy 7 and deletions of the long arm of chromosome
7 are found in the majority of patients with myeloid leukemia.19 A mouse
model recapitulates many aspects of the human disease syndrome, including
hematopoietic malignancies.20
Fig. 7.97
Bloom's syndrome:
characteristic facies
includes ‘pinched’
features. Marbled
erythema of the cheek
and crusted lesions
involving the lower
lip. By courtesy of D.
Atherton, MD, Institute
of Dermatology and
Children's Hospital at
Great Ormond Street,
London, UK.
248 Lichenoid and interface dermatitis

The cutaneous lesions are typified by a lupus erythematosus-like histol-

ogy. There is epidermal atrophy accompanied by liquefactive degeneration
of the basal layer with cytoid body formation. A lymphohistiocytic infil-
trate is present in the superficial dermis. Telangiectatic blood vessels are
evident.

Cockayne's syndrome
This is a very rare disorder with an autosomal recessive mode of inheritance
and a male predominance (4:1) with the majority of cases reported to be of
British ancestry. It is a multisystem disease associated with premature aging and
particularly affects the skin, teeth, eyes, skeleton, and central nervous system.1

Clinical features
Children appear to be normal at birth and have an unremarkable early devel-
opment. However, usually in the second year of life, they show photosensi-
tivity and acquire a ‘butterfly’ rash (as in lupus erythematosus) on the malar
region, which with time is associated with scarring and hyperpigmentary
changes. These features, in association with prognathism, sunken eyes, loss of
subcutaneous fat, and nasal atrophy (‘beaked’ nose), give the children a char-
acteristic progeria-like or bird-headed appearance (Fig. 7.98).2–4 Fine hair
and anhidrosis may also be evident.1
Ocular lesions include corneal opacity, cataract, retinal degeneration, and
optic atrophy with resultant blindness.1 ‘Salt and pepper’ pigmentation of the
fundus is characteristic.2
Patients usually suffer from progressive sensorineural deafness.1 The patients
are dwarfs and have disproportionately long limbs with enlarged hands and
feet.2 Microcephaly is common and radiological examination reveals thick-
ening of the skull bones. Kyphosis, ankylosis, and flexion contractures are
frequent complications, and dental abnormalities include malocclusions and
caries. Involvement of the central nervous system presents as microcephaly,
normal pressure hydrocephalus, mental subnormality, ataxia, choreoatheto-
sis, spasticity, myoclonus, and gait disturbance.1,2,5 Renal function is usually
impaired.6
Patients with Cockayne's syndrome have an increased incidence of infec-
tions and usually die within the third decade.
An unusually severe form with early onset and quick death associated with
abnormal thymidine dimer repair (and hence showing overlap with xero-
derma pigmentosum) has recently been described.5,7
Prenatal diagnosis of Cockayne's syndrome is now possible.8
Pathogenesis and histological features
The two genes responsible for Cockayne's syndrome (CSA and CSB) have
been cloned, with most cases due to mutations in CSB.9–11 CSA encodes a
WD (Trp-Asp) protein, which interacts with a number of proteins including
p44 protein, a subunit of transcription/DNA repair factor IIH (TFIIH).12 CSB
belongs to the yeast SNF2/SW12 protein family, which is of importance in
gene transcriptional activation.12 Unlike CSA, CSB is devoid of helicase activ-
ity. CSB protein interacts with CSA and excision repair enzyme XPG. It may
also have a role in response to hypoxic injury and in chromatin structure.11
A mouse model of this syndrome has been developed.13
Patients with Cockayne's syndrome have an impaired DNA excision/
repair mechanism and are hypersensitive to the effects of UV radiation with
an inability to promote normal levels of DNA and RNA synthesis following
UV irradiation.14–17 The specific defect resides within repair of mutations in
transcriptionally active genes rather than in excision/repair mechanisms in
general.18,19 There are five complementation groups identifiable by cell fusion
studies: CSA, CSB, XPB, XPD, and XPG.5,11 XPB, XPD, and XPG differ from
groups CSA and CSB by showing an increased incidence of skin cancer.12
Cockayne's syndrome may also coexist with trichothiodystrophy.20
Biopsy of the malar rash shows epidermal atrophy associated with basal
cell hydropic degeneration. A chronic inflammatory cell infiltrate is present
in the superficial dermis.
Fig. 7.98
Cockayne's syndrome: the features include prominent ears, prognathism, a
‘beaked’ nose, and flexion contractures.By courtesy of D. Atherton, MD, Institute of
Dermatology and Children's Hospital at Great Ormond Street, London, UK.
The cerebral lesions are characterized by loss of white matter, cerebellar cor-
tical atrophy, hydrocephalus, and widespread calcification.5,21 Histologically,
there is demyelination and gliosis. Iron-laden neurons, neurofibrillary tan-
gles, and giant, bizarre astrocytes have also been reported.21,22 Severe athero-
sclerosis resulting in occasional strokes can occur. 21
The kidney shows global sclerosis due to marked basement membrane (type
IV) collagen deposition associated with tubular atrophy and interstitial fibrosis.6
Dyskeratosis congenita
Clinical features
This is a rare, but important, systemic illness with poor prognosis and high
mortality. It has a predominantly X-linked recessive mode of inheritance
and occurs mainly in males (6:1), although both autosomal dominant
and recessive variants are also recognized.1–5 The condition consists
predominantly of a complex triad of skin pigmentation, nail, and mucosa
abnormalities. There is also an increased incidence of malignancy including
hematological and solid tumors.1,2,6
The skin acquires a widespread reticular pigmentation with associated
poikiloderma, which at first appears most prominently on the face, neck,
and the ‘V’ neck region of the upper chest, but later becomes generalized
(Fig. 7.99).1,4 During childhood the nails become dystrophic and are often
lost (Fig. 7.100). There may also be palmoplantar hyperkeratosis associated
with hyperhidrosis, development of epiphora, early loss of dentition, caries,
poor growth, sparse hair, bullous eruptions, lacrimal duct stenosis, and men-
tal subnormality.1–3,7 A reduced diffusion capacity develops from pulmonary
fibrosis.2
Premalignant leukoplakia involving particularly the mouth and anus is an
important complication, with a significant risk of squamous cell carcinoma
developing in these lesions.2,5 The urethra and vagina may also be affected.
Hematological manifestations include thrombocytopenia, aplastic anemia,
pancytopenia, myelodysplasia, and acute myeloid leukemia.7–9

The grave outlook of dyskeratosis congenita relates particularly to the
development of infections complicating aplastic anemia, malignancy, and
pulmonary complications.2,10
The clinical features of this disease are most severe in males with the
X-linked variant. There is considerable variation in autosomal variants and
in some of these patients symptoms may be very mild, allowing a normal life
expectancy.2
Pathogenesis and histological features
Dykeratosis congenita is characterized by mutations in genes involved in
telomere function, with the effected gene depending on the mode of inheri-
tance.6 X-linked recessive dyskeratosis congenita is due to mutations of the
DKC1 gene, which has been mapped to Xq28.11 The mutations, which are
predominantly missense, result in single amino acid substitutions in dyskerin,
a nucleolar protein believed to be responsible for site-specific pseudouridy-
lation of ribosomal RNA. It is also associated with mutations in the TERC,
TERT, NOP10, and NHP2 genes involved in telomere function.12,13 Not all
cases have a known genetic cause. There is marked chromosomal ­instability
Fig. 7.99
Dyskeratosis congenita: typical poikilodermatous pigmentation on the neck. By
courtesy of D. Atherton, MD, Institute of Dermatology and Children's Hospital at
Great Ormond Street, London, UK.
Fig. 7.100
Dyskeratosis congenita: there is dystrophy of the nails with marked atrophy of the
surrounding skin. By courtesy of D. Atherton, MD, Institute of Dermatology and
Children's Hospital at Great Ormond Street, London, UK.
Interface dermatoses 249
with a striking predisposition to develop rearrangements.2,14 Dyskeratosis
congenita therefore appears to result from defective telomerase activity with
resultant impaired stem cell turnover or proliferative activity.4,15 This is sup-
ported by the finding that telomeres are markedly shortened and that this
develops at an early age.6,16
The autosomal dominant variant has similarly recently been shown to be
associated with a mutation of the RNA component of telomerase TERC,
telomerase enzyme TERT – both part of the shelterin telomere protection
complex TIN2.4,6
Finally, the autosomal recessive variant has been associated with mutation
in the NOP10/NHP2 genes that regulate telomerase.6
The histological features of the pigmentary changes are non-specific, show-
ing only pigmentary incontinence.
Biopsies of the mucosal lesions show an acanthotic epithelium with or
without dysplastic changes. In the latter case, great care must be taken to
exclude the presence of squamous cell carcinoma.
Graft-versus-host disease
Clinical features
Graft-versus-host disease (GVHD) represents a complex multisystem major
complication of organ transplantation, usually bone marrow, that particu-
larly affects the skin, intestine, and liver. It develops when transplanted immu-
nocompetent donor T lymphocytes are activated, proliferate, and respond
to foreign host major histocompatibility complex (MHC)-histoincompatible
antigens in a background of recipient immunosuppression.1–9 In the context
of identical class I HLA antigens, as may be seen in sibling donors, class II
HLA antigens (HLA-DR, -DP, and -DQ) and minor histocompatibility anti-
gens are of major pathogenetic significance.1,2 These latter HLA antigens are
expressed on host epithelial cells following pregraft irradiation or chemother-
apy, thereby focusing the donor lymphocyte immune response on the skin,
liver, and intestinal tract.1,10,11
GVHD is a very serious complication of allogeneic bone marrow trans-
plantation and morbidity and mortality is very high.12 It may also follow
solid organ transplantation, develop in severely immunodepressed patients
after transfusion of nonirradiated blood or blood products, or complicate
transplacental transfer of maternal lymphocytes into an immunodeficient
fetus.13–15
The clinical features of GVHD develop as a consequence of donor
T lymphocyte-mediated reactions to host tissues. Successful bone marrow
transplantation is dependent upon compatibility of the ABO system blood
groups and histocompatibility antigens (HLA). The D locus (HLA class II)
is of particular importance; successful transplantation has occurred in the
presence of identical D loci with dissimilarities at the A and B loci. However,
the development of GVHD is not totally dependent upon HLA incompatibility
as it can develop in 35% of cases with identical A, B, and D loci, suggesting the
additional importance of the minor histocompatibility antigens (miH).2,16
Development of acute GVHD appears to be a consequence of HLA dis-
parity, sex mismatch, increasing patient age, and the presence of infection.7
While the skin is a major target organ in GVHD and one of the first involved
organs, the liver and gastrointestinal tract are also affected.9,17 Manifestations
include malaise, nausea and vomiting, diarrhea, malabsorption, and abnor-
mal liver function. Additionally, patients with GVHD have an increased risk
of opportunistic infections, which are an important cause of morbidity and
mortality.
Historically, GVHD was conventionally subdivided into two subgroups by
time after transplantation:
• Acute GVHD occurs within the first 3 months following transplantation
(most often presenting between 2 and 6 weeks).2,17–19
• Chronic GVHD presents after the third month.
However, changing transplantation practices have resulted in delayed
and even atypical presentations of GVHD. In 2005, the National Institutes
of Health Consensus Development Project on Criteria for Clinical Trials in
Chronic Graft-versus-Host Disease proposed new criteria to standardize the
diagnosis of chronic GVHD and also account for these new GVHD presenta-
tions, dividing it into four groups:17,19–21
250 Lichenoid and interface dermatitis

• Classic acute GVHD: acute GVHD presenting within 100 days after
HCT or donor leukocyte infusion,
• Persistent, recurrent or late onset acute GVHD: acute GVHD occurring
more than 100 days after transplation without chronic GVHD
symptoms,
• Classic chronic GVHD: chronic GVHD without features of acute GHVD
regardless of timing from transplantation,
• Overlap syndromes: both acute and chronic GVHD features present
regardless of timing from transplantation.
The classical features of acute and chronic GVHD are presented below.
The other two categories show similar features and are defined by the clinical
context in which they occur, that is their timing relative to transplantation.

Acute GVHD
Acute GVHD develops in between 6% and 90% of patients who undergo
bone marrow transplantation.22 The incidence relates particularly to HLA
mismatch, the age of the patient, and the conditioning regimen protocols
used.1,2 Additional risk factors of importance include sex mismatch, i.e., when
the donor is a female (particularly if multiparous) and the recipient is male,
use of radiation and/or high dosage chemotherapy prior to transplantation,
prior blood transfusions, prior splenectomy, viral infections, and inadequate
immunosuppression.2
It presents with the sudden onset of fever and malaise, which are rap-
idly followed by cutaneous signs including facial erythema and a gener-
alized morbilliform, maculopapular rash characteristically affecting the
palms and soles (Figs 7.101, 7.102). Mucosal lesions may also be a feature Fig. 7.101
(Fig. 7.103). The skin lesions particularly affect the upper half of the body Acute graft-versus-host disease: chest and arm showing widespread macular
and the back of the neck; ears and shoulders are sites of predilection.1,7,18,19 erythema with fine telangiectasia and mild scaling. By courtesy of R. Touraine, MD,
Lichen planus-like features may sometimes supervene. Additional cutane- Hôpital Henri Mondor, Paris, France.
ous lesions include purpura, petechiae, desquamation, and a folliculitis-like
appearance.7,19
More severe variants include erythroderma or even a toxic epidermal
necrolysis-like reaction. The latter has a poor prognosis and may be a mani-
festation of a drug reaction or represent a true component of acute GVHD.
It usually affects a large surface area, shows mucosal involvement, and is
associated with severe liver and gastrointestinal lesions.23,24 Mortality is very
high (50% and higher, especially if untreated), related to the effects of ther-
apy in addition to the lesions themselves.12,25 In the event of survival of acute
GVHD, the rash may resolve completely or merge into the features of chronic
GVHD. It is often difficult on clinical grounds (and histologically) to dif-
ferentiate between acute GVHD, viral disorders, and cytotoxic/adverse drug
reactions.
The clinical manifestations of acute GVHD are traditionally divided into
four stages:1,2,17,18
• Stage I: Maculopapular eruption affecting up to 25% of surface area.
Bilirubin levels of 2–3 mg/dL and diarrhea in excess of 500 mL/day.
• Stage II: Maculopapular erythema affecting 25–50% of surface area.
Bilirubin levels of 3–6 mg/dL and diarrhea in excess of 1000 mL/day.
• Stage III: Generalized erythroderma. Bilirubin levels of 6–15 mg/dL and
diarrhea in excess of 1500 mL/day. Fig. 7.102
• Stage IV: Toxic epidermal necrolysis. Bilirubin levels of 15 mg/dL or more Acute graft-versus-host disease: this vivid palmar erythema is characteristic.
and diarrhea exceeding 1500 mL/day. By courtesy of R. Touraine, MD, Hôpital Henri Mondor, Paris, France.

Chronic GVHD
Chronic GVHD develops in 10% of all patients undergoing allogeneic bone
marrow transplantation and in 30–70% of all long-term survivors.26 Systems
involved include the skin, eyes, mouth and esophagus, liver, genitalia, muscle,
and peripheral and central nervous systems.7 Virtually all chronic GVHD
patients exhibit skin manifestations and 90% develop oral lesions.2 Some
develop chronic GVHD de novo (30%); others show a gradual progression
of continuous acute GVHD into the chronic variant (32%).2 Occasionally,
chronic GVHD may follow a period of resolution of acute GVHD, after an
interval of quiescence (36%).2 Chronic GVHD can occur as a lichen planus-
like eruption or show features of a poikilodermatous or sclerodermatous reac-
tion.27–29 A discoid lupus erythematosus-like reaction is rare. Polymyositis and
fasciitis have also been described.30–32 In addition, a variety of presentations
have been reported which can be subtle, especially in the early phase. These
include xerosis, ichthyosis, follicular prominence, pityriasiform, eczematous,
psoriasiform lesions, annular lesions similar to urticaria or erthyema annu-
lare centrifigum, a morbilliform papulosquamous rash, and even erythro-
derma.33 Risk factors for developing chronic GVHD include prior episode of
acute GVHD, increasing age, sex mismatch, i.e., when the donor is a female
(particularly if multiparous) and the recipient is male, and use of non-T-cell
depleted bone marrow.2,34
Although early in chronic GVHD the lesions are typically lichenoid and later
sclerodermatous, in some patients these features may appear ­simultaneously.2
 Interface dermatoses 251

Fig. 7.103 Fig. 7.104

Acute graft-versus-host disease: note the erosions on the buccal mucosa. By Early chronic graft-versus-host disease: there are widespread, almost confluent
courtesy of R. Touraine, MD, Hôpital Henri Mondor, Paris, France. hyperpigmented lichenoid papules. Associated erosion of the epidermis gives an
appearance similar to toxic epidermal necrolysis (Lyell's syndrome). By courtesy of
R. Touraine, MD, Hôpital Henri Mondor, Paris, France.

UV irradiation, trauma, and infection with herpes zoster virus or Borrelia can
precipitate chronic GVHD.2
The early chronic GVHD lesion commonly has a classic lichenoid appear-
ance with typical erythematous or violaceous polygonal papules sometimes
showing Wickham's striae (Fig. 7.104). The periorbital region, ears, palms,
and soles are sites of predilection.2 Oral mucosal lesions include typical net-like
lacy white lesions, and ulcerated areas may also develop (Figs 7.105–7.107).
The cheeks, tongue, palate, and lips are sites of predilection.2 Symptoms of
Sjögren's syndrome are also often present. Onycholysis and cicatricial alope-
cia may be features. The rash is sometimes less typical, appearing as a desqua-
mative active dermatitis or as follicular hyperkeratosis. As mentioned above,
the findings can sometimes be subtle, such as xerosis.33
The late phase of chronic GVHD is typically sclerodermatous and usu-
ally presents 8–18 months after transplantation (Figs 7.108–7.110). The
development of a poikilodermatous rash is followed by induration, atro-
phy, and sclerosis.30 The resultant features resemble morphea or systemic
sclerosis; chronic ulceration, particularly involving pressure points, can
be an unpleasant complication. Blisters may occasionally develop.30 The
development of cutaneous squamous cell carcinoma has occasionally been
documented.31,32
Chronic GVHD has a mortality of up to 40%. Causes of death include Fig. 7.105
Early chronic graft-versus-host disease: there are diffuse widespread lichenoid
infection, cachexia, and liver failure.2
changes of the lips. By courtesy of R. Touraine, MD, Hôpital Henri Mondor,
Systemic features include chronic hepatitis, diarrhea with malabsorption,
Paris, France.
bronchiolitis obliterans, peripheral entrapment neuropathy, and polymyosi-
tis.2 Opportunistic infections are also of major importance.

Pathogenesis and histological features
GVHD is mediated by the combined effects of donor T lymphocytes (CD4+
T cells responding to MHC class II antigens and CD8+ T cells to class I anti-
gens) and cytokines including IL-1, TNF-α, IFN-γ and GM-CSF.1,2,11,35–43 The
development of acute GVHD depends upon a complex interplay between
host immunosuppression, tissue damage as a result of pregraft induction
therapy, and donor lymphocyte proliferation and activation with consequent
injury and death of susceptible host tissues.1
The lymphocytes may be of CD4+ or CD8+ immunophenotype and com-
monly there is an admixture. Both Th1 and Th2 CD4+ subtypes are rep-
resented. The former produce IL-2 and IFN-γ and are thought to promote
GVHD, the latter produce IL-4, IL-6 and IL-10 and are believed to be pro-
tective, although this has been contested.44 Natural killer (NK) cells may also
be of importance although their presence appears to be variable.45 B cells are
absent. Activated keratinocytes following induction chemotherapy or irradia-
tion produce TNF-α and IL-1 and express ICAM-1 and HLA-DR.46 This may
result in increased recognition of histoincompatible MHC antigens by donor
T-cells.1 The superficial dermal endothelial cells express E-selectin, α4β1
integrin, αLβ2 integrin, ICAM-1, platelet endothelial cell adhesion mole-
cule-1 (PECAM-1), and vascular cell adhesion molecule-1 (VCAM-1) which
mediate lymphocyte adhesion to the endothelium and facilitate recogni-
tion, activation, and response to MHC molecules.1,47–49 The mechanisms
of cell injury and death result from both cytotoxic T cell and possibly NK
cell-mediated cytotoxic effects and the actions of cytokines. The former
includes cytolytic actions mediated by perforin and granzyme B, and apop-
tosis through the Fas-Fas ligand pathway.50,51 IL-1, IL-2, IL-6 and TNF-α are
thought to be of particular importance in mediating cytotoxicity.1 Raised
serum TNF-α correlates with GVHD and antibodies to TNF-α or its recep-
tor protect against the disease.1,52–54 Recently, regulatory T cells (Treg) have
been postulated to play a role in GVHD. Treg are decreased in patients with
GVHD and their role remains to be elucidated.17 Studies suggest a role for
B cells in GVHD.55
252 Lichenoid and interface dermatitis
Fig. 7.106
Early chronic graft-versus-host disease: florid reticulate white striae on the buccal
mucosa are evident. By courtesy of R. Touraine, MD, Hôpital Henri Mondor, Paris,
France.
Fig. 7.107
Early chronic graft-versus-host disease: there are erosive changes on the tongue.
By courtesy of R. Touraine, MD, Hôpital Henri Mondor, Paris, France.
Deposition of IgM and C3 at the dermoepidermal junction and around
the superficial vasculature in up to 39% of patients with acute GVHD sug-
gests that humoral responses play a significant role in the pathogenesis of
GVHD.56
The development of chronic GVHD is dependent on a variety of factors
including, antihost tissue activity of donor T cells and the development of
autoimmunity.2,57 The infiltrate consists predominantly of CD8+ T cells; NK
cells are usually absent.2 As with acute GVHD, TNF-α and IL-1 are the major
cytokines implicated.2
Fig. 7.108
Late chronic graft-versus-host disease: note the grossly hyperpigmented sclerotic
limb. By courtesy of R. Touraine, MD, Hôpital Henri Mondor, Paris, France.
Fig. 7.109
Late chronic graft-versus-host disease: hyperpigmented sclerotic plaques are present
on the back. By courtesy of R. Touraine, MD, Hôpital Henri Mondor, Paris, France.
The acute lesion of GVHD is characterized by focal or diffuse basal cell
hydropic change (Figs 7.111–7.114).58 Apoptotic and dyskeratotic ­keratinocytes,
at all levels of the epidermis and associated with adjacent lymphocytes (satellite
cell necrosis), are characteristic.17,59,60 Isolated cytoid bodies are also frequently
evident. Lymphocytic exocytosis is invariably present and spongiosis is sometimes
a feature. Microvesiculation at the dermoepidermal ­junction occasionally occurs.
Follicular involvement is a common feature and the hair bulge region is typically
affected.61,60 Langerhans cells are often reduced in number. Vascular changes include
endothelial cell swelling with sloughing, and intimal and ­perivascular lymphocytic
 Interface dermatoses 253

Fig. 7.110 Fig. 7.112

Late chronic graft-versus-host disease: there is mottled hypo- and hyperpigmentation Acute graft-versus-host disease: high-power view showing basal cell liquefactive
with gross atrophy and scaling. By courtesy of R. Touraine, MD, Hôpital Henri degeneration. Diagnosis is entirely dependent on the clinical history.
Mondor, Paris, France.

infiltration. Blood vessel proliferation has also been described. Perivascular edema
and nuclear dust may additionally be present and mast cells are also conspicu-
ous.62,63 Eosinophils are sometimes present and this finding does not necessarily
indicate a drug reaction. Therefore, the histologic presentation of GVHD is broad
and no finding can be considered pathognomonic for GVHD.12,19
The toxic epidermal necrolysis-like lesions are characterized by severe
epidermal necrosis in association with subepidermal vesiculation. Evidence
of sweat gland involvement is commonly present.64,65 Keratinous plugging
of the acrosyringium may therefore be seen and the excretory ducts often
show cytopathic-degenerative and proliferative changes.65 The former com-
prises basal cell hydropic degeneration, lymphocytic infiltration, and apop-
tosis. Follicular involvement is a not uncommon additional manifestation.66
The histological features of acute GVHD may be subdivided into four stages,
which have prognostic significance (Table 7.1).66–68
The histology of chronic GVHD is typically lichenoid in appearance and is
indistinguishable from idiopathic lichen planus (Fig. 7.115). These features
are hyperkeratosis, hypergranulosis, irregular acanthosis, basal cell hydropic
degeneration, cytoid body formation, pigmentary incontinence, and a ban- Fig. 7.113
Acute graft-versus-host disease: high-power view lesion showing parakeratosis,
basal cell hydropic degeneration, and apoptosis.

Fig. 7.111
Acute graft-versus-host disease: evolving lesion showing basal cell hydropic Fig. 7.114
degeneration and scattered apoptotic keratinocytes. The dermis contains dilated Acute graft-versus-host disease: high-power view showing parakeratosis, apoptosis,
blood vessels and a light perivascular chronic inflammatory cell infiltrate. and satellite cell necrosis.
254 Lichenoid and interface dermatitis
Table 7.1
Grading of acute graft-versus-host disease
Grade Feature
I Focal or diffuse vacuolar alteration of basal cells
II Vacuolar alteration of basal cells; spongiosis and
dyskeratosis of epidermal cells
III Formation of subepidermal cleft in association with
dyskeratosis and spongiosis
IV Complete loss of epidermis
Reproduced with permission from Lerner et al. (1974) Transplantation Proceedings, 6,
367–371.
Fig. 7.115
Early chronic graft-versus-host disease: the hyperkeratosis, hypergranulosis,
irregular acanthosis, and basal cell hydropic degeneration are indistinguishable from
idiopathic lichen planus.
dlike lymphohistiocytic infiltrate obscuring the dermoepidermal interface.
In contrast to idiopathic lichen planus, satellite cell necrosis is often present
in the early phase of chronic GVHD and the infiltrate sometimes contains
plasma cells and eosinophils. Squamous metaplasia of the eccrine sweat ducts
has been described.60,65
The late stage of chronic GVHD is characterized by epidermal atrophy
with abolition of the ridge pattern and scarring of the superficial and deep
dermis, with loss of the adnexal structures (Fig. 7.116) imparting a scle-
rodermoid feature including eosinophilic fasciitis, panniculitis, morphea-like
changes, and lichen sclerosus.60,69,70 Features of the early stage of chronic
GVHD, i.e., hydropic basal cell degeneration, cytoid body formation, and
a chronic inflammatory cell infiltrate, may or may not be evident. Dermal
mucin deposition has also been documented.71
Hepatic changes include bile duct atypia with necrosis, periportal inflam-
mation, focal hepatocyte necrosis, and cholestasis.9 Gastrointestinal lesions
show individual crypt cell necrosis accompanied by a mild chronic inflamma-
tory cell infiltrate.60,72,73
Differential diagnosis
The features of acute GVHD can be reproduced by cytotoxic drugs such as
cyclophosphamide and by radiotherapy. Viral infections also enter the dif-
ferential diagnosis, as does an adverse drug reaction, for example, to anti-
biotic therapy. Although the presence of conspicuous eosinophils argues to
Fig. 7.116
Late chronic graft-versus-
host disease: there is
dense fibrosis of the
dermis with tethering of
the subcutaneous fat.
Appendages are absent.
These appearances
are reminiscent of
scleroderma.
some extent in favor of an adverse drug reaction, in reality there are no real
discriminators between adverse drug reactions and acute GVHD.74 In short,
the regular practice of skin biopsy to differentiate between GVHD, drug reac-
tions, chemotherapy effect, and viral infection is extremely difficult and of
dubious clinical value in some cases.
Acute GVHD may be indistinguishable from erythema multiforme and,
in more severely affected patients, toxic epidermal necrolysis. Recently,
the intriguing report of bile pigment deposition in the stratum corneum in
patients with GVHD offers a possible line of approach to making this impor-
tant distinction.75
The early changes of chronic GVHD may be indistinguishable from lichen
planus. However, the dermal infiltrate is usually less conspicuous than that
in lichen planus and sometimes contains plasma cells and eosinophils. The
presence of satellite cell necrosis may be a diagnostic pointer towards chronic
GVHD.
In the absence of clinical information it is usually not possible to dis-
tinguish the features of late chronic GVHD from morphea or systemic
sclerosis.
The histological features of the eruption of lymphocyte recovery are indis-
tinguishable from acute GVHD. The differential diagnosis of acute GVHD
includes engraftment syndrome. This syndrome can occur 10–14 days after
transplantation but before peripheral lymphocytes are seen. It presents with
a fever, hepatitis, intestinal symptoms, and an erythmatous maculopapular
eruption similar to acute GVHD. Some also require the presence of weight
gain and pulmonary edema. Whether or not this represents a hypoacute
GVHD is uncertain. The etiology is unknown although it is postulated that
the damage may be caused by cytokines released from recovering and degran-
ulating neutrophils. G-CSF, GM-CSF, female gender, breast cancer, and other
hematopoietic and drugs have been implicated as risk factors for developing
this condition.17,76
In summary, no histological feature is pathognomonic for graft-versus-
host disease and clinical correlation is essential. Therefore, in the appropri-
ate clinical population, a positive biopsy can be very predictive despite subtle
­non-specific histologic findings. A negative biopsy is less reassuring. Some
have advocated the use of a four-tier diagnostic system of no GVHD, possible
GVHD, consistent with GVHD, and definite GVHD, a practical proposal
that reflects the realities of daily practice.60
 Interface dermatoses 255

Pityriasis lichenoides orrhagic and ultimately develop necrosis and ulceration (Fig. 7.120).
Healing is usually associated with the development of superficial varioli-
form scars. Postinflammatory hyper- or hypopigmentation is not uncommon
Clinical features (Fig. 7.121).9,11 The rash is often polymorphic, individual patients having
Pityriasis lichenoides (Gr. pityron, bran + iasis; lichen; Gr. eidos, form) lesions at varying stages of evolution. Patients may be pyrexic and sometimes
is an uncommon dermatosis of unknown etiology, although a hypersen- lymphadenopathy is present.1
sitivity reaction to a number of infectious agents including adenovirus, The chronic lesions are typified by numerous, lichenoid, brownish-red,
toxoplasmosis, Epstein-Barr virus, and Mycobacterium pneumoniae have scaly papules, 3–10 mm across, the scale being most noticeable peripher-
been proposed.1–4 The condition has also been documented in association ally, sometimes referred to as the mica scale (Figs 7.122, 7.123). These
with a range of autoimmune conditions such as rheumatoid arthritis, hypo- lesions usually heal without scarring, but are sometimes associated with
thyroidism, and pernicious anemia.3,4 Two cases of pityriasis lichenoides hypopigmentation, which may be the most prominent feature in dark-
chronica (PLC) associated with adalimumab therapy for Crohn's disease skinned races.
and a case induced by infliximab have been described.5,6 The term includes
a spectrum of disease manifestations, ranging from the acute ulcerone-
crotic lesions of pityriasis lichenoides et varioliformis acuta (PLEVA, also
known as Mucha-Haberman disease or acute guttate parapsoriasis) to the
more chronic scaly papules of pityriasis lichenoides chronica (chronic gut-
tate parapsoriasis); there is often clinical overlap.7–10 In addition, a febrile,
ulceronecrotic variant (febrile ulceronecrotic Mucha-Habermann disease)
is recognized.3–8
Pityriasis lichenoides in more recent studies lacks strong sex ­predominance
in adults. However, some studies have shown more of a male predominance in
pediatric populations.11–14 It most often occurs in childhood (5–10 years of
age) and early adulthood, second or third decade.11–14
Lesions show a propensity to involve the arms, legs, trunk, and buttocks
(Fig. 7.117). The upper limbs appear to be involved more often than the
lower and the flexor more commonly than the extensor surfaces. They can
begin as small macules that progress to papules. PLC is typically asymp-
tomatic while PLEVA is associated with burning and pruritis.9 The onset
is usually insidious and the course fluctuating and episodic, patients expe-
riencing recurrent crops of lesions, with the exception of the ulcronecrotic
variant which is rapid. Duration of the rash is quite variable: although
many patients are free of lesions by 3–6 months, others show great per-
sistence of the disease, often for many years.11 The disease shows some
seasonal variation, with lesions worsening in winter and showing improve- Fig. 7.118
ment in sunlight. Although pityriasis lichenoides is traditionally divided Pityriasis lichenoides acuta: typical lesions with pustulation are present on the arm,
into acute and chronic variants, not uncommonly both types of lesions can a commonly affected site. By courtesy of the Institute of Dermatology, London, UK.
be seen in the same patient, indicating a possible connection between PLC
and PLEVA.9
In the more acute form of the disease, the initial lesions are crops of
pink papules (Figs 7.118, 7.119). These may become vesicular or hem-

Fig. 7.119
Pityriasis lichenoides
acuta: early lesions
are erythematous and
Fig. 7.117 papular. By courtesy
Pityriasis lichenoides acuta: erythematous papules and crusted lesions are present of the Institute of
on the buttocks and thighs. In severe cases, lesions may be very extensive. Dermatology, London,
By courtesy of the Institute of Dermatology, London, UK. UK.
256 Lichenoid and interface dermatitis

Fig. 7.121
Pityriasis lichenoides acuta: healed lesion showing scarring and hypopigmentation.
By courtesy of the Institute of Dermatology, London, UK.

Fig. 7.122
Pityriasis lichenoides chronica: widespread scaly papules are present on the
chest and arms. From the collection of the late N.P. Smith, MD, the Institute of
B Dermatology, London, UK.

Fig. 7.120
Pityriasis lichenoides acuta: (A) necrotic and ulcerated lesions are present;
(B) close-up view. By courtesy of the Institute of Dermatology, London, UK.

Although there are case reports of lymphoma (mycosis fungoides) devel-

oping in patients with pityriasis lichenoides, this is a rare event; however, see
below.15–17
The rare febrile ulceronecrotic variant is associated systemic features
including fever, muscle weakness and pain, malaise, lymphadenopathy, arthri-
tis, myocardial involvement, and neuropsychiatric manifestations.3–8,11,18,19
Widespread cutaneous manifestations include large 2–6-cm ulceronecrotic
lesions, hemorrhagic and necrotic papules, and erythema multiforme-like
lesions.3,4,11

Pathogenesis and histological features

Immunofluorescence examination of biopsies from fresh purpuric lesions
commonly detects IgM and C3 in the walls of the superficial dermal blood
vessels and along the dermoepidermal junction in both the acute and chronic Fig. 7.123
forms of the disease.20–22 A high proportion of patients have elevated cir- Pityriasis lichenoides chronica: the characteristic mica scale. By courtesy of the
culating immune complexes.23,24 Cytotoxic suppressor T cells constitute the Institute of Dermatology, London, UK.
 Interface dermatoses 257

majority of the infiltrate in pityriasis lichenoides acuta et varioliformis.25,26

Lesser numbers are seen in pityriasis lichenoides chronica. These (and the
overlying keratinocytes in addition to nearby endothelial cells) have been
shown to express HLA-DR.26 In contrast to lymphomatoid papulosis, the
Ki-1 (CD30) activation antigen is generally not expressed in pityriasis
lichenoides acuta except perhaps in overlap cases.27 Macrophages are also
numerous. Langerhans cells are diminished in number. Clonal T-cell receptor
gene ­rearrangements have been described in small numbers of patients with
pityriasis lichenoides acuta raising the possibility of overlap with cutaneous
T-cell lymphoma.28,29 Exceptionally, pityriasis lichenoides acuta may progress
to cutaneous T-cell lymphoma.11,30,31 As a result, some have suggested that
PLEVA may represent a host response to a developing T-cell lymphoprolifera-
tive disorder in some cases.11
The histopathological features of pityriasis lichenoides are similar in both
variants, although in the acute form the changes are usually more severe.
Both are characterized by varying proportions of epidermal and dermal
changes.32–35
The chronic lesions of pityriasis lichenoides are characterized by par-
akeratosis in which there are sometimes small collections of lymphocytes
reminiscent of the Munro microabscesses of psoriasis (Figs 7.124, 7.125). Fig. 7.125
Pityriasis lichenoides chronica: note the parakeratosis, acanthosis, and perivascular
The epidermis may show slight acanthosis and usually small numbers of
and interstitial chronic inflammatory cell infiltrate.
necrotic keratinocytes are present accompanied by a hint of interface change
(Fig. 7.126). Spongiosis is often a feature. There is a perivascular chronic
­inflammatory cell infiltrate in the superficial dermis (Fig 7.127). Red cell
extravasation is often present but is usually not marked.
The acute lesions of pityriasis lichenoides show similar epidermal features,
but on a much exaggerated scale. Marked inter- and intracellular edema
accompanied by keratinocyte necrosis and interface change frequently result
in vesiculation and ulceration (Figs 7.128, 7.129). Exocytosis is usually
prominent and intraepidermal red blood cells are characteristic. The upper
dermis is edematous and contains a chronic inflammatory cell infiltrate (Fig.
7.130). This is usually perivascular and varies from sparse to dense; typically,
it has a wedge-shaped appearance, extending deeply into the reticular
dermis, although this is only seen in biopsies from established lesions. The
infiltrate consists of lymphocytes with an admixture of histiocytes. Red cell
extravasation is usually conspicuous. The blood vessels of the superficial
dermis are dilated and congested. Although the endothelial cells are often
blurred or swollen, fibrinoid necrosis indicating necrotizing vasculitis is
rarely seen (Fig 7.131).

Fig. 7.126
Pityriasis lichenoides chronica: high-power view showing basal cell hydropic
degeneration.

Fig. 7.124 Fig. 7.127

Pityriasis lichenoides chronica: scanning view showing hyperkeratosis with Pityriasis lichenoides chronica: in this high-power view there is a lymphohistiocytic
parakeratosis and acanthosis. infiltrate and melanophages are present.
258 Lichenoid and interface dermatitis
Fig. 7.128
Pityriasis lichenoides acuta: this low-power view shows an ulcerated papule with
overlying crust.
Fig. 7.129
Pityriasis lichenoides acuta: there is basal cell hydropic degeneration and apoptosis.
In febrile ulceronecrotic Mucha-Habermann disease, the features are those
of very severe pityriasis lichenoides acuta and are often accompanied by the
changes of leukocytoclastic vasculitis.11,36–38
In the earlier literature, patients having clinical and histological features
of both pityriasis lichenoides et varioliformis acuta and ­lymphomatoid
Fig. 7.130
Pityriasis lichenoides acuta: this high-power view shows a lymphohistiocytic
infiltrate. Red cell extravasation can also be seen.
Fig. 7.131
Pityriasis lichenoides acuta: high-power view showing fibrinoid necrosis affecting
the dermal vasculature.
papulosis were documented.2 In the light of our current understanding of
these two conditions, it is now apparent that such patients clearly were suf-
fering from lymphomatoid papulosis.
 Superficial and deep perivascular Chapter

See
www.expertconsult.com
for references and
additional material
inflammatory dermatoses
8
Chronic superficial dermatitis 259 Tumid lupus erythematosus 269 Pregnancy prurigo 277
Toxic erythema 261 Perniosis 270 Urticarial vasculitis 278
Erythema annulare centrifugum 261 Chilblain lupus erythematosus 272 Tumor necrosis factor receptor-associated
periodic syndrome 280
Erythema gyratum repens 263 Pigmented purpuric dermatoses 273
Eosinophilic, polymorphic and pruritic
Lymphocytic infiltrate of the skin 264 Lichen aureus 275
eruption associated with radiotherapy 280
Reticular erythematous mucinosis 265 Pruritic urticarial papules and plaques of
Viral exanthemata 280
pregnancy 276
Polymorphous light eruption 267

Chronic superficial dermatitis

Clinical features
Chronic superficial dermatitis (digitate dermatosis, superficial scaly ­dermatitis,
small-plaque parapsoriasis, persistent superficial dermatitis) is a not uncom-
mon condition, which presents as erythematous scaly persistent patches,
showing a predilection for the limbs and trunk. While the lesions may be
round or oval, they often have a finger-like appearance, hence the alternative
designation of digitate dermatosis (Figs 8.1, 8.2).1 The patches are ­usually
a few centimeters in greatest dimension, but may sometimes be much larger.
They are associated with a fine ‘cigarette-paper’ scale that often has a pale
white, tan or yellowish color (Fig. 8.3). The disorder is most commonly
encountered in middle-aged adults and shows a predilection for men. The
patient is usually otherwise asymptomatic. Coexistence with ulcerative colitis
has been reported in one patient.2 Lesions tend to chronicity, often persisting
for many years. While development of mycosis fungoides has been reported
in a patient with chronic superficial dermatitis, it is most likely that these
­represent separate disease processes rather than disease progression.3
Fig. 8.1
Chronic superficial dermatitis: this patient shows digitate erythematous lesions in a
Histological features characteristic distribution. By courtesy of the Institute of Dermatology, London, UK.
Biopsy shows a superficial perivascular lymphocytic infiltrate (Figs 8.4, 8.5).
The infiltrate is of variable density but is often very sparse. Cytological aty-
the changes described above do not represent chronic ­superficial ­dermatitis.
pia is absent. The epidermis often shows foci of spongiosis. A confluent lin-
Delayed-type hypersensitivity reactions are more ­commonly ­associated with
ear band of parakeratosis spanning multiple rete ridges is a characteristic
these histological appearances. Many other ­diseases ­similarly cause such
finding.
non-specific biopsy findings including viral exanthems and ­connective tissue
The infiltrate is largely composed of CD4+ T lymphocytes with a minor
­disease. Therefore, clinical correlation is necessary to e­ stablish the diagnosis.
population of CD8+ T-suppressor cells (Fig. 8.6).2 In a small series, the CD4
The main clinical differential diagnosis is with mycosis fungoides and,
to CD8 ratio ranged from 2 to 4.4. The T cells are generally reactive for
accordingly, most biopsies are obtained to exclude this possibility. The
CD2, CD3, and CD5 (Fig. 8.7). CD7 expression is variable and may be
patches in chronic superficial dermatitis tend to be uniform in size, shape, and
absent. Scattered CD68 reactive macrophages and CD1+ Langerhans cells
color, contrasting vividly with the greater variability of those of mycosis fun-
can be seen.
goides. The presence of spongiosis favors a diagnosis of chronic superficial
dermatitis; however, mycosis fungoides may also be associated with signifi-
Differential diagnosis cant spongiosis and this feature does not reliably distinguish these disorders.
The histological features in chronic superficial dermatitis are entirely ­non-­specific. In Diagnostic pointers favoring early mycosis fungoides include the presence of
fact, the constellation of histological findings is among the most often encountered atypical lymphocytes, epidermotropism, and lymphocytes aligned along the
by the dermatopathologist. Certainly, the vast ­majority of biopsies that show basal cell layer of the epidermis (‘tagging’).
260 Superficial and deep perivascular inflammatory dermatoses
Fig. 8.2
Chronic superficial
dermatitis: these uniform,
linear lesions had been
present for many years.
By courtesy of the
Institute of Dermatology,
London, UK.
Fig. 8.3
Chronic superficial dermatitis: closer examination shows that the lesions appear
somewhat wrinkled and have a fine scale. By courtesy of R.A. Marsden, MD,
St George's Hospital, London, UK.
Immunohistochemistry should be viewed with caution. Loss of T-cell
expression may support a diagnosis of mycosis fungoides provided there
are histological features in favor of the diagnosis and if the clinical con-
text is appropriate. Loss of CD7 expression, however, may be seen in reac-
tive conditions and this feature is therefore not reliable. Occasionally, only
careful review of the clinical information, taken in conjunction with the
histological features of previous biopsies (if available) allows for defini-
tive diagnosis. It is important to note that some investigators have dem-
onstrated cases of chronic superficial dermatitis with clonal T-cell gene
rearrangements by polymerase chain reaction (PCR).4 One case with a
clonal T-cell population resolved, underscoring the growing appreciation
that clonality and malignancy are not necessarily synonymous.4 Therefore,
it appears that demonstration of a clonal T-cell population may not suf-
fice to reliably distinguish chronic superficial dermatosis from early myco-
sis fungoides in all cases. In the past, others have concluded that chronic
Fig. 8.4
Chronic superficial dermatitis: there is parakeratosis, acanthosis, and a superficial
perivascular infiltrate.
Fig. 8.5
Chronic superficial
dermatitis: there is very
slight intercellular edema.
The infiltrate consists
of lymphocytes and
histiocytes.
superficial dermatitis is mycosis fungoides.5 The observation that chronic
superficial dermatitis rarely, if ever, evolves into (or declares itself as) frank
mycosis fungoides has led some authors to cast doubt on this view.6 More
recent publications have asserted that chronic persistent dermatitis does
not progress to mycosis fungoides.7 It is perhaps more likely that some
cases of very early mycosis fungoides cannot be reliably distinguished from
chronic superficial dermatitis. Recently, clonal T-cell gene rearrangements
have been demonstrated in circulating lymphocytes in blood but not in skin
of patients with digitate dermatitis.8 Clearly, long-term follow-up studies
are necessary to resolve the significance of clonality in putative cases of
chronic superficial dermatitis.
Pityriasis lichenoides may also be confused with chronic superficial der-
matitis. Spongiosis without interface changes favors the latter. Pityriasis
lichenoides is associated with either vacuolar or lichenoid interface changes
in the absence of spongiosis.9

Fig. 8.6
Chronic superficial
dermatitis: the infiltrate is
composed predominantly
of CD4+ T-helper cells.
Fig. 8.7
Chronic superficial
dermatitis: in this
example, there is no
significant loss of CD7
expression.
Toxic erythema
Toxic erythema, annular erythema, and gyrate erythema are terms used by
dermatologists to describe a number of diseases that share common clinical
and histological appearances. Clinically, the terms imply annular erythema-
tous lesions. Pathologists often also use these same terms (particularly gyrate
erythema) in a generic manner to describe an inflammatory lesion with a
‘cuffed’ perivascular lymphocytic infiltrate. Although such nomenclature
may be used as a descriptor (as one might use terms such as ‘lichenoid’, for
­example), it should not be taken to imply a specific disease. It is likely that the
Toxic erythema 261
earlier literature frequently classified different diseases together under these
appellations.1 Therefore, to avoid confusion, it is encouraged that these terms
are not used in referring to specific diseases.
Erythema annulare centrifugum
Clinical features
Erythema annulare centrifugum has an incidence of 1 per 100 000 and may
be associated with certain underlying factors, including:
• Connective tissue disorders, e.g., Sjögren's syndrome,1,2
• Drugs, e.g., penicillin, salicylates, amytriptyline, etizolam, gold, sodium
thiomoalate, hydroxychloroquine sulfate, piroxicam, finasteride,
hydrochlorothiazide and thiacetazone,3–11
• Bacterial infections, e.g., Mycobacteria, Streptococcus, Escherichia coli,12
• Viral infection, e.g., Epstein-Barr virus, HIV, herpes simplex and zoster,
molluscum contagiosum,13–16
• Fungal infection, e.g., dermatophytoses, Candida,17–19
• Parasites, e.g., helminthes,20
• Arthropods,21
• Sarcoidosis,22
• Hypereosinophilic syndrome,23
• Bullous dermatosis, e.g., linear IgA dermatosis,24,25
• Autoimmune disease, e.g., polyglandular autoimmune disease type 1 as well
as autoimmune progesterone dermatitis and autoimmune hepatitis,26–28
• Pregnancy.29,30
Many of these associations are likely to be coincidental and, in most
cases, no underlying etiology is identified.31–35 It is unclear whether erythema
annulare centrifugum is a distinctive entity or simply represents the clinical
expression of a number of inflammatory dermatoses such as hypersensitivity
reactions sharing common histological features.36
Mahood and colleagues emphasized that many earlier reports of neopla-
sia associated with erythema annulare centrifugum are questionable since
different subtypes of annular erythemas were often classified together.31,37,38
However, more recent cases have documented erythema annulare cen-
trifugum in patients with underlying malignancy, once again raising the issue
of an association with neoplasia. Erythema annulare centrifugum in patients
with non-small cell lung carcinoma, carcinoma of breast, colon and prostate,
chronic lymphocytic leukemia, and Hodgkin's lymphoma have been reported
in the last decade.14,39–44 In a recent large series, carcinoma was present in 6
of 66 (13%) patients.45 Of these, two had leukemia (acute myelogenous and
acute lymphoblastic); one patient had non-Hodgkin's lymphoma; and three
cases were associated with carcinoma (lung, rectal, and hepatocellular).45
Erythema annulare centrifugum has been reported in all age groups, includ-
ing infants and neonates, but is most commonly seen in young adults.46,47 A
recent large series found that the lower extremities, particularly the thighs,
were the most frequent site of involvement.45 Nearly 50% of patients in this
series had lower extremity involvement. The trunk was affected in 28% of
patients and the upper extremity in 16%. The hands, feet, and face are usu-
ally spared. Head and neck involvement was seen in only 8% of patients.
Laboratory investigation sometimes reveals a peripheral eosinophilia.31
Although individual lesions persist for weeks to a few months before resolv-
ing, a course of relapses and remissions over months to years is common and
an annually and seasonally recurring form has recently been reported.48 Kim
et al. found that lesions lasted from 3 days to 18 years with a mean duration
of 2.8 years.45
The lesions take the form of annular erythematous bands, which may
spread outwards or remain stationary (Figs. 8.8, 8.9). They are well cir-
cumscribed with raised edges, and slight scaling that tends to trail behind the
advancing margin.49 With time, central clearing is seen. Arcuate and polycy-
clic variants are therefore occasionally evident.31 Lesions may be mildly pru-
ritic. Vesiculation is rare.32
Some authors have divided the disease into two distinct subtypes: superfi-
cial and deep gyrate erythema.45
• The superficial variant is associated with pruritus and has a trailing scale.
• The deep variant is characterized by erythematous annular lesions with
indurated borders but lack a scale.
262 Superficial and deep perivascular inflammatory dermatoses
Fig. 8.8
Erythema annulare centrifugum: bilateral annular lesions are present on the
buttocks. From the collection of the late N.P. Smith, MD, The Institute of
Dermatology, London, UK.
Fig. 8.9
Erythema annulare centrifugum: close-up view. From the collection of the late N.P.
Smith, MD, The Institute of Dermatology, London, UK.
Histological features
A spectrum of non-specific histological findings is seen in erythema annulare
centrifugum. As noted above, deep and superficial variants are recognized.45
In the superficial variant, a well-demarcated perivascular infiltrate of
lymphocytes and histiocytes, often described as having a ‘coat sleeve'’ or
­‘pipe-stem’ appearance, is confined to the superficial dermis (Figs 8.10, 8.11).
The overlying epidermis often may be normal; however, epidermal changes
including mild spongiosis, slight and focal basal layer vacuolar degeneration,
mounds of parakeratosis or hyperkeratosis are encountered in approximately
50% of patients.14,45
In the deep subtype of erythema annulare centrifugum, the perivascular
infiltrate involves both the superficial and deep plexuses.14,32–34,45 Epidermal
changes are usually absent or minimal.
In both variants, the degree of inflammation is variable; however, the
­density of inflammation tends to be greater in the deep variant. The vast
majority of cells are lymphocytes; however, a minor component of histiocytes
and eosinophils may be seen.
Fig. 8.10
Erythema annulare
centrifugum: the
superficial and deep
vasculature is surrounded
by a dense infiltrate.
Fig. 8.11
Erythema annulare centrifugum: the infiltrate is composed of mature lymphocytes
and histiocytes.
Differential diagnosis
Given that the histological features of erythema annulare centrifugum are not
distinctive, it is critical to correlate the biopsy and clinical findings. Clinical
information is necessary to distinguish this disorder from other gyrate
­erythemas, pityriasis rosea, hypersensitivity reactions, lupus erythematosus,
viral exanthemata, and Jessner's lymphocytic infiltrate. In cases with significant
­epidermal changes, a silver stain to exclude a fungal infection is also advised.
Clinically, erythema annulare centrifugum may resemble psoriasis. The presence
of ­parakeratotic mounds associated with neutrophils would favor a diagnosis
of psoriasis. In contrast to cutaneous lupus erythematosus, interface changes
are not usually well developed and immunofluorescence studies are negative.
Erythema chronicum migrans also enters the differential diagnosis. The ­presence
of plasma cells would be in favor of the latter condition. Histochemical stains
for spirochetes may be positive but are cumbersome and difficult to interpret.
PCR is a more realiable and easy test to confirm the diagnosis.
 Toxic erythema 263

Erythema gyratum repens

Clinical features
Erythema gyratum repens (L. repens, to crawl or creep) is an extremely rare
and clinically distinctive figurate eruption usually associated with an under-
lying malignancy. The most commonly associated neoplasm is carcinoma
of the lung; other affiliated tumors include carcinoma of the uterus and
­cervix, esophagus, stomach, kidney, and breast as well as essential thrombo-
cythemia.1–11 Treatment of the cancer may be associated with remission of the
cutaneous eruption, while tumor recurrence or metastases can be accompa-
nied by a relapse.2 Rarely, the condition develops in the absence of an under-
lying malignancy.12–17 It may disclose underlying pulmonary tuberculosis. In
one patient with no evidence of malignancy, the rash resolved a few days after
removal of a cavitary tuberculoid lung lesion.14
Ichthyosis may accompany erythema gyratum repens.18 A report of a
patient with transitional cell carcinoma of the kidney who developed erythema
gyratum repens and ichthyosis comes as no surprise since both conditions are
associated with malignancy. The combination of ichthyosis, palmoplantar
keratosis, and erythema gyratum repens, in the absence of malignancy, has Fig. 8.13
also been reported.19 Erythema gyratum repens: the eruption may sometimes have a bizarre appearance.
Erythema gyratum repens-like eruptions have also been described in the By courtesy of R. Cerio, MD, The London Hospital, London, UK.
presence of connective tissue diseases. Typical erythema gyratum repens devel-
oped in a patient with cutaneous subacute lupus ­erythematosus ­following are usually spared.33 Postinflammatory hyperpigmentation may be a feature.1
hydroxychloroquine treatment.20,21 The authors of this report ­concluded that Hyperkeratosis of the palms and soles is also sometimes present.3,12 Males are
the patient's rash represented a peculiar pattern of involvement by ­subacute affected twice as commonly as females.3 Patients are usually in their seventh
lupus which they designated subacute lupus gyratum repens. An erythema gyra- decade.20
tum repens-like eruption has also been described in association with Sjögren's
syndrome, neutrophilic dermatosis, leukocytoclastic ­vasculitis, in patients with Pathogenesis and histological features
lupus erythematosus, and in the setting of u­ rticarial vasculitis.22–25 Erythema gyratum repens may have an immunological pathogenesis, since
Caputo et al. reported linear IgA dermatosis, erythema, and an erup- granular deposits of IgG and C3 have been found at the basement mem-
tion resembling erythema gyratum repens in a patient without malignancy.26 brane zone of both involved and uninvolved skin in a patient with associ-
Bullous pemphigoid may be associated with erythema gyratum repens and ated bronchial carcinoma and in involved non-sun-exposed skin in another
an erythema gyratum repens-like eruption has been documented in a patient unassociated with neoplasia.16,34–36 In a separate patient, although basement
with treated and resolving psoriasis and with epidermolysis bullosa acquisita membrane zone immunofluorescence was negative, epidermal nuclear label-
accompanied by ulcerative colitis.27–31 ing was identified.37 Caux et al. reported one patient with squamous cell car-
Erythema gyratum repens has been described in patients with hypereo- cinoma of the lung who had immunoreactants at the basement membrane of
sinophilic syndrome, also with no evidence of neoplasia.32 involved and normal non-sun-exposed skin. In addition, this patient showed
The eruption, which may precede the malignancy by months, takes the staining of IgG, IgM, and C3 along the basement membrane of the bron-
form of concentric bands of erythema in an annular or gyrate arrange- chus.35 However, the immunoreactants did not localize to the tumor.
ment (Figs 8.12, 8.13). These bands have been described as having a ‘tim- The appearances in erythema gyratum repens are not diagnostic. They
ber grain’ or ‘zebra-like’ pattern and they move (up to about 1 cm) daily.33 include hyperkeratosis, parakeratosis, acanthosis, and spongiosis, together
Scaling occurs and there may be pruritus. Lesions often commence on the with a superficial perivascular lymphohistiocytic infiltrate in the papillary
arms and legs, but frequently become generalized.1 The hands, feet, and face dermis (Figs 8.14, 8.15).2

Fig. 8.12
Erythema gyratum repens:
the presence of annular
erythematous parallel
bands with scaling is
characteristic. From the
collection of the late N.P.
Smith, MD, The Institute Fig. 8.14
of Dermatology, London, Erythema gyratum repens: there is hyperkeratosis, acanthosis and a mild perivascular
UK. chronic inflammatory cell infiltrate.
264 Superficial and deep perivascular inflammatory dermatoses
Fig. 8.15
Erythema gyratum repens: spongiosis is present.
Differential diagnosis
As noted above, the histological features are non-specific and vary from
patient to patient. Fortunately, the clinical features are so distinctive that con-
fusion with other disorders is unlikely. Obviously, any patient with features
of erythema gyratum repens should be very carefully evaluated for an under-
lying neoplasm.
Lymphocytic infiltrate of the skin (Jessner)
Clinical features
Jessner's lymphocytic infiltrate of the skin is an uncommon dermatosis of
unknown etiology, although a relationship with sun exposure, at least in the
early stages, is occasionally documented.1 Lesions, which may be single or
more often multiple, occur most often on the face, neck, back, and upper
chest, and present as 1–2-cm diameter, asymptomatic, discoid or annular, ery-
thematous or brownish papules or plaques that often show central clearing to
produce circinate lesions (Figs 8.16, 8.17).1–4 Familial cases have occasion-
ally been documented.5–8
In contrast to discoid lupus erythematosus, with which it is sometimes
confused, there is no hyperkeratosis, telangiectases or follicular plugging,
and scarring is not a feature. Rarely, however, the two diseases appear to
Fig. 8.16
Jessner's lymphocytic infiltrate: there are multiple erythematous plaques on this
young man's cheek. By courtesy of the Institute of Dermatology, London, UK.
Fig. 8.17
Jessner's lymphocytic infiltrate: central clearing has resulted in this circinate lesion.
By courtesy of the Institute of Dermatology, London, UK.
coexist.1 The disease tends to affect adults, particularly in the third to fifth
decades. Although some authors have found a predilection for males, 54%
of patients in a large series were female and the overall gender distribution
appears to be equal.1,3 Rarely, the condition presents in children.9–11 Lesions
often resolve within weeks or months, but relapses are not uncommon and, in
many patients, the disorder persists for years. The eruption is not character-
ized by seasonal variation. The evidence available suggests that lymphocytic
infiltrate of the skin is a distinctive dermatosis. It does not evolve into lupus
erythematosus, polymorphous light eruption or lymphoma.1
Pathogenesis and histological features
The etiology of this curious condition is unknown. Although some patients
notice a relationship with sun exposure, many do not, and lesions not uncom-
monly develop on covered sites.
Braddock and coauthors found that natural killer cell lytic activity and anti-
body-dependent cell-mediated cytotoxicity was decreased.10 This same group
identified increased levels of circulating immune complexes in patients with
lymphocytic infiltrate of skin. In two patients immune complexes decreased
to normal levels following treatment but became elevated during recurrence
of disease following treatment.10,11 Based on these observations, these inves-
tigators concluded that immune defects might be important in the pathogen-
esis of Jessner's lymphocytic infiltrate. Of interest, similar findings have been
observed in patients with reticular erythematous mucinosis. Clearly, further
study is necessary to determine the pathogenesis of this disease.
The epidermis is typically unaffected. Within the superficial and mid der-
mis is a perivascular and, much less commonly, a perifollicular infiltrate of
mature lymphocytes (Figs 8.18, 8.19). Occasional histiocytes and scattered
plasma cells may also be present and sometimes there is an increase in dermal
ground substance.12 Lymphoid follicles are not a feature.
The infiltrate consists predominantly of T cells, most often of the CD4+
helper subtype (Fig. 8.20). Occasionally, however, CD8+ suppressor T cells
constitute the majority of cells.3,13–16 Leu 8 is commonly expressed but human
leukocyte antigen (HLA)-DR is not present. B cells are relatively sparse in
number or are absent.
Differential diagnosis
Lymphocytic infiltrate of the skin differs from discoid lupus erythematosus
by the absence of epidermal changes, scarring, and a negative lupus band
test. Immunohistochemistry may sometimes be helpful. The infiltrate in lym-
phocytic infiltrate is HLA-DR negative in contrast to discoid lupus erythe-
matosus in which the lymphocytes and often the keratinocytes are HLA-DR
positive.17 Leu 8 (immunoregulatory T-cell) expression is also more frequently
seen in lymphocytic infiltrate.13,18 In one study, the average percentage of Leu
 Reticular erythematous mucinosis 265

8 ­positive lymphocytes was 65% in lymphocytic infiltrate of skin and only

15% in discoid lupus erythematosus.18 The presence of CD20+ B cells favors
lupus erythematosus, which tends to be composed of a mixture of B and T
cells. In contrast, T cells predominate in lymphocytic infiltrate of skin.14,19,20
One group of investigators has suggested that the presence of plasmacytoid
monocytes favors a diagnosis of lymphocytic infiltrate of skin over lupus ery-
thematosus. They found plasmacytoid monocytes to be present in 58% of
patients with lymphocytic infiltrate of skin but only in 7% of patients with
discoid lupus erythematosus.21 Others, however, have not been able to cor-
roborate this finding.19 The presence of significant dermal mucin would sup-
port lupus erythematosus. Reliable distinction between lymphocytic infiltrate
of the skin and tumid lupus erythematosus may be difficult and frequently
impossible since lymphocytic infiltrate may sometimes be accompanied by
excess dermal mucin. It has therefore been speculated that these entities rep-
resent a continuous disease spectrum rather than different diseases.22 The
finding that a subset of patients with lymphocytic infiltrate of the skin also
had a confirmed diagnosis of lupus erythematosus lead one group to specu-
late whether lymphocytic infiltrate of the skin could represent a variant of
lupus erythematosus.4
Fig. 8.18 Epidermal Langerhans cells are often increased in lymphocytic infil-
Lymphocytic infiltrate of Jessner: a heavy chronic inflammatory cell infiltrate cuffs
trate whereas they are frequently reduced in number in discoid lupus
the vessels in the superficial and mid dermis.
erythematosus.13
Lymphocytic infiltrate may often be distinguished from chronic lympho-
cytic leukemia/lymphocytic lymphoma by careful evaluation of cellular mor-
phology. The benign lymphocytic infiltrate is composed of non-neoplastic
lymphocytes with small, regular, and hyperchromatic nuclei. In chronic lym-
phocytic leukemia/lymphocytic lymphoma the nuclei are larger, irregular, and
paler staining, and a nucleolus may be visible. Regardless of these subtle cyto-
logical differences, if the possibility of low-grade lymphoma exists, immuno-
histochemical studies should be performed. Most often, well-differentiated
lymphomas are of B-cell lineage.
Lymphocytic infiltrate is usually histologically indistinguishable from poly-
morphous light eruption although early lesions of the latter may show edema
of the papillary dermis. It should be noted, however, that sometimes the two
conditions may coexist. In cases where the diagnosis is in doubt, phototesting
may be necessary. One group of investigators has found the presence of plas-
macytoid monocytes to favor lymphocytic infiltrate of the skin over polymor-
phous light eruption.21 However, this has not been confirmed (see above).
Histologically, lymphocytic infiltration of Jessner also shows some over-
lap with reticular erythematous mucinosis. Mucin deposition, however, is
not generally a feature of lymphocytic infiltrate of the skin, although it may
Fig. 8.19 be evident. Furthermore, the infiltrate in reticular erythematous mucinosis is
Lymphocytic infiltrate of Jessner: the infiltrate is composed almost entirely of small usually mild.
lymphocytes.

Reticular erythematous mucinosis

Clinical features
This rare chronic dermatosis, which shows a female predominance (2:1), has
been described worldwide.1 Although it may affect a wide age range, it most
frequently develops in the second to fourth decades.2 Rarely, it is encoun-
tered in children.2 Familial presentation is exceptional.3 It usually presents
as a persistent, reticulate, urticated, macular, and sometimes papular, ery-
thema with an irregular, but well-defined border. The lesions typically occur
on the central chest and upper back (Figs 8.21–8.23).4–6 Less commonly,
they can be found on the face, arms, abdomen, and groins, but the peripher-
ies are spared.1,7,8 Patients frequently notice an exacerbation in the sun, but
the relationship between sunlight and the disease (if any) is not well under-
stood.2,6–11 Although patients are usually asymptomatic, some report pruritus
or burning following exposure to sunlight. There is no evidence of systemic
involvement.
Occasional patients have more infiltrated papules and plaques; this was
originally described as plaquelike cutaneous mucinosis, but is now accepted
as a variant of reticular erythematous mucinosis.12,13 Of particular interest,
Fig. 8.20 the plaquelike form of the disease has been documented in association with
Lymphocytic infiltrate of Jessner: the majority of lymphocytes express CD4 (T-helper carcinoma of the breast and colon and one patient suffered from essential
cells). thrombocytosis in addition to carcinoma of the lung.13,14
266 Superficial and deep perivascular inflammatory dermatoses
Fig. 8.21
Reticular erythematous mucinosis: erythematous reticular eruption in a characteristic
distribution in a young woman. By courtesy of the Institute of Dermatology, London, UK.
Fig 8.22
Reticular erythematous mucinosis: location in the lower back is unusual. From the
collection of the late N.P. Smith, MD, The Institute of Dermatology, London, UK.
Patients with this condition have an increased risk of thyroid disease,
arthritis, and diabetes mellitus.2 In a series of nine patients, one patient
had evidence of Hashimoto's disease while another had hyperthyroidism.13
A patient with reticular erythematous mucinosis and myxedema in the setting
of Hashimoto's thyroiditis has also been described.15
Reticular erythematous mucinosis in patients with human immuno-
deficiency virus (HIV) infection has also been documented.16,17 Of inter-
est, other cutaneous mucinoses that have been described in association
with HIV infection include scleredema and lichen myxedematosus.17
Furthermore, deposition of mucin in the bone marrow of patients with
acquired immunodeficiency syndrome (AIDS) is a common finding.18 The
pathogenetic ­relationship between these various forms of mucin deposition,
Fig. 8.23
Reticular erythematous mucinosis: closer view of previous figure. Macular elements
predominate. From the collection of the late N.P. Smith, MD, The Institute of
Dermatology, London, UK.
if any, has not been defined. It is, of course, tempting to postulate that they
are related but data to support such a conclusion are not yet established.
The presence of monoclonal IgG (kappa) paraproteinemia has been
reported in one patient.19
Pathogenesis and histological features
The pathogenesis of reticular erythematous mucinosis is not well understood.
Phototoxicity likely plays some role in the disease, either directly or indi-
rectly. Braddock and coauthors found that natural killer cell lytic activity
and antibody-dependent cell-mediated cytotoxicity were decreased.20 This
same group found increased levels of circulating immune complexes. Of
interest, two patients were observed to have circulating immune complexes
that decreased with treatment only to become elevated during recurrence of
disease following treatment.20 Based on these observations, the investigators
concluded that immune defects may be of importance in the pathogenesis. Of
interest, similar findings have been observed in patients with Jessner's lym-
phocytic infiltrate (see above). Clearly, further study is necessary regarding
the precise pathogenetic basis of this disease.
The epidermis may be slightly flattened or appear normal. Within the der-
mis there is moderate vascular dilatation associated with a marked mono-
nuclear perivascular and often perifollicular infiltrate composed mainly of
T-helper lymphocytes (Figs 8.24, 8.25).6,13,20–22 Excess mucin (predominantly
hyaluronic acid) is usually present in the upper dermis but in more chronic
lesions it is sometimes absent (Fig. 8.26). The mucin stains positively with
Alcian blue (pH 2.5) and colloidal iron, but is usually not metachromatic with
toluidine blue. The collagen fibers are separated, but appear morphologically
normal. Fragmentation of elastic fibers is sometimes a feature.7 There is no
evidence of fibroblastic proliferation, but by immunohistochemistry increased
numbers of factor XIIIa-positive dermal dendrocytes have been identified.23
A few cases with positive direct immunofluorescence have been reported.
IgM-reactive papillary dermal cytoid bodies were documented in one case.20
Rare examples show staining for IgM along the dermal–epidermal junc-
tion.2,10,24 The significance of these findings is unclear but may be further
­evidence of an immunological basis for the pathogenesis of this condition.24
 Polymorphous light eruption (including juvenile spring eruption and lambing ears) 267

Ultrastructural studies are largely unhelpful. Other than demonstrating

conspicuous and dilated rough endoplasmic reticulum within dermal fibro-
blasts, electron microscopy merely serves to confirm the light microscopic
observation of widely separated fascicles of collagen fibers.21 In a number
of reports tubuloreticular structures were identified within the cytoplasm of
endothelial cells.7,25,26 Although at one time these were thought to represent
paramyxoviruses, more recent studies suggest that they may be derived from
infolded endoplasmic reticulum. They have also been identified in pretibial
myxedema, lupus erythematosus, dermatomyositis, malignant atrophic papu-
losis, and various lymphomas.27

Differential diagnosis
The principal clinical and pathological differential diagnoses include lupus
erythematosus and polymorphous light eruption. Distinguishing between
lupus erythematosus and reticular erythematous mucinosis may be very diffi-
cult, particularly as one condition may evolve into the other.28 Histologically,
reticular erythematous mucinosis lacks the epidermal changes of lupus ery-
thematosus and the immunofluorescent findings are usually, but not always,
negative.7–9 As noted above, there are a few reports in which granular
Fig. 8.24
Reticular erythematous mucinosis: there is a perifollicular and perivascular infiltrate
immunoglobulin deposition at the dermoepidermal junction has been iden-
in the upper and mid dermis. tified.2,10,24 The presence of several immunoreactants favors a diagnosis of
lupus erythematosus. Clinical and serological studies are also necessary to
establish a diagnosis of lupus erythematosus.
In polymorphous light eruption, mucin deposition is much less striking and
is limited to the papillary dermis.29 Perifollicular inflammation is not a feature
of polymorphous light eruption. In addition, epidermal changes of spongiosis –
sometimes with vesiculation in papular and eczematous lesions and mild basal cell
hydropic change in the plaque variant – serve as further distinguishing features.30
Polymorphous light eruption resolves once exposure to sunlight has ceased, in
contrast to reticular erythematous mucinosis where the lesions persist.
Histologically, reticular erythematous mucinosis also shows some overlap
with lymphocytic infiltrate of Jessner.2 Mucin deposition, however, is not gen-
erally a feature of the latter condition and the inflammatory cell infiltrate is
always more prominent.

Polymorphous light eruption (including

juvenile spring eruption and lambing ears)
Clinical features
Fig. 8.25 Polymorphous (polymorphic) light eruption, which is the most common
Reticular erythematous mucinosis: the infiltrate consists of mature lymphocytes ­photodermatosis, usually presents in young people as recurrent erythematous
with a lesser number of histiocytes. papules, vesicles and/or plaques following exposure to ultraviolet (UV) light
(Figs 8.27, 8.28).1–6 The face, chest, upper back, and extremities are the most
common sites of involvement.5 Most patients have multiple lesions.5 In one
study of 138 patients, the mean age at onset was 26 years.5 There is a predilec-
tion for young women, with 89% of patients being female.7,8 The vast majority
of lesions are associated with pruritus. Most patients require less than 30 min-
utes of sun exposure to elicit clinical features.5 Onset following light ­exposure
typically takes 18–24 hours. Either the UVA or UVB part of the light spectrum
may cause lesions.2,9 Lesions are caused by UVA light in 56% of cases, UVB
in 17%, and both UVA and UVB ranges in 26% of cases.2 However, some
authors have not been able to elicit lesions with UVB light.4 Exposure result-
ing in sunburn is not necessary for the development of the condition.4 Some
patients report symptoms resulting from light exposure through glass.4
Polymorphous light eruption most often occurs in patients with fair skin;
however, dark-skinned individuals can also be affected. The disease is more
common in people residing in northern latitudes. One study showed that the
prevalence rates for London (UK) and Perth (Australia) were 14.8% and
5.2%, respectively.10 In a recent retrospective analysis, however, the ­incidence
of photosensitivity reactions and polymorphous light eruption in ­particular
was found to be roughly comparable for dark-skinned and Caucasian
­individuals.11 The pinpoint papular variant of polymorphous light eruption
Fig. 8.26 has only recently been recognized and appears to be particularly common
Reticular erythematous mucinosis: increased dermal mucin (hyaluronic acid) separates on dark skin.11,12 It is characterized by numerous grouped, small, 1–2-mm
the collagen fibers (Alcian blue stain). ­papules, which may be accompanied by small vesicles in the acute phase.13
268 Superficial and deep perivascular inflammatory dermatoses
Fig. 8.27
Polymorphous light eruption: patients present with erythematous papules and
vesicles on sun-exposed skin. From the collection of the late N.P. Smith, MD,
The Institute of Dermatology, London, UK.
Fig. 8.28
Polymorphous light eruption: the eruption is typically symmetrical and is usually
pruritic. By courtesy of the Institute of Dermatology, London, UK.
It appears that the incidence of polymorphous light eruption is much more
common than is demonstrated by contact with healthcare workers. In one
survey, 21% of workers in a Swedish pharmaceutical company had symp-
toms consistent with polymorphous light eruption; however, only 3% had
sought medical attention for their symptoms.7
Biopsy of experimentally induced lesions shows similar histological fea-
tures compared to clinical lesions.4 Given the role of sun exposure in its
pathogenesis, it comes as no surprise that polymorphous light eruption is
most often seen in spring and summer.4 In addition, it is not uncommon for
the first sign of disease to manifest during a vacation to southern latitudes.
The features, which develop after a latent period of hours to days, commonly
subside completely within days and heal without sequelae.1 However, once
the disease is established, persistence for many years is common.3 Overall,
however, there is diminution of light sensitivity over time, but this process
often takes years.3 In a large study, the mean disease duration of the condition
was 10.5 years.5 Patients with a duration of up to 53 years have been stud-
ied.7 The distribution of lesions often changes with time.5
One study showed that thyroid disease was present in 14% of patients.14
This same study found lupus erythematosus in only 2 of 94 patients. The
authors concluded that the risk of lupus erythematosus was not increased in
patients with polymorphous light eruption. Authors of another study, how-
ever, have suggested that a subgroup of patients with polymorphous light
eruption may be at an elevated risk for lupus erythematosus.15
Juvenile spring eruption appears to be either a variant of polymorphous
light eruption or a closely related disorder.16–21 In one study, the prevalence was
6.7% with a male predominance.16 The lesions are characterized by erythema-
tous papules and vesicles located on sun-exposed portions of the helix of the
ear following light exposure. They tend to be pruritic. In one study, 4 of 18
patients also had lesions of typical polymorphous light eruption.17 As its name
implies, the lesions tend to occur in the spring. A positive family history is
present in some patients.19 A disorder, clinically and histologically reminiscent
of juvenile spring eruption, has also been reported to develop in farmers at the
time of lambing and calving. It is provisionally termed ‘lambing ears’.22
Pathogenesis and histological features
The pathogenesis of polymorphous light eruption is poorly understood.
Study of adhesion molecule expression has led some authors to propose that
polymorphous light eruption is immunologically mediated.23 Specifically,
vascular endothelial expression of endothelial leukocyte adhesion molecule-1
(ELAM-1), vascular cell adhesion molecule-1 (VCAM-1), and keratinocyte
and endothelial expression of intercellular adhesion molecule-1 (ICAM-1) in
biopsies of induced lesions has been documented.23 The authors noted that
their results were similar to those seen in delayed-type hypersensitivity reac-
tions. In addition, reduced skin infiltration by neutrophils following UVB
exposure was noted.24 However, the triggering antigen(s) are unknown.23 It
appears that polymorphous light eruption may be a heritable disorder. In one
study, 46% of patients reported a positive family history.7
Histologically, a perivascular lymphohistiocytic infiltrate is present in the
superficial and sometimes deep dermis (Figs 8.29, 8.30).25–27 A characteristic,
but not uniformly present feature, is papillary dermal edema, which is often
marked. The presence of massive papillary dermal edema may be associated
with subepidermal or intradermal vesicle formation.
Papular and papulovesicular lesions may show epidermal acanthosis,
spongiosis, occasional dyskeratotic cells, and lymphocyte exocytosis.25,27
Spongiosis may sometimes become so severe as to lead to intraepidermal ves-
icle formation.25 Other authors, however, have not found spongiosis to be a
significant feature.26 Basal cell vacuolization, usually mild, is found in some
cases.25,27,28 Periadnexal involvement by a chronic inflammatory cell ­infiltrate
Fig. 8.29
Polymorphous light
eruption: there is papillary
dermal edema and a
dense superficial and deep
perivascular inflammatory
cell infiltrate.

Fig. 8.30
Polymorphous light eruption: incipient subepidermal vesiculation is evident. Note
the red cell extravasation and lymphocytic infiltrate.
may be present in papular and papulovesicular lesions.25 Some authors have
reported increased eosinophils and neutrophils; however, others have not
confirmed this observation.25,26 Papillary dermal erythrocyte extravasation
is commonly present.25 Finally, features secondary to scratching, such as
­hyperkeratosis and acanthosis, may be seen.27
Immunofluorescence studies have shown that immunoreactants (C3, IgG,
and IgM) may be present along the basement membrane zone.3 However,
when staining is evident, it is usually weak.3
Juvenile spring eruption of the ears is characterized by a perivascular lym-
phohistiocytic infiltrate often associated with subepidermal vesicle formation.20
In early lesions, helper-inducer T lymphocytes predominate and increased
numbers of dermal Langerhans cells are present.26 With chronicity, cytotoxic
suppressor T cells become more conspicuous.
Differential diagnosis
It should be noted that there is considerable variability in both the clini-
cal and histological descriptions of polymorphous light eruption. This has
led some authors to suggest that polymorphous light eruption likely repre-
sents a group of related disorders rather than a single entity.25,26 Phototesting,
therefore, is probably the best ‘gold standard’ for establishing the diagnosis.
Compared with reticular erythematous mucinosis, mucin deposition is absent
or much less prominent in polymorphous light eruption. Clinically, polymor-
phous light eruption resolves once exposure to sunlight has ceased in contrast
to the persistent lesions of reticular erythematous mucinosis.
Histologically, polymorphous light eruption also shows some overlap with
other causes of gyrate erythema such as lymphocytic infiltration of Jessner.
The presence of marked papillary dermal edema, when present, favors poly-
morphous light eruption. A clinical history of documentation of resolution
of lesions with cessation to light exposure may sometimes be the only way to
distinguish these entities. In cases where the diagnosis is in doubt, phototest-
ing may often be necessary.
The histological features of lupus erythematosus are sometimes difficult
to distinguish from polymorphous light eruption, particularly when the lat-
ter is associated with positive immunofluorescence. However, most cases of
polymorphous light eruption are negative with immunofluorescence testing.
When immunoreactants are present, usually only weak staining is observed.
Careful clinical and serological evaluation should resolve any confusion
between these conditions.
Actinic reticuloid is another eruption associated with exposure to UV light.
Compared with polymorphous light eruption, actinic reticuloid is more typi-
cally associated with a dense cellular interstitial infiltrate involving the pap-
illary and reticular dermis, and ­sometimes extending into the subcutaneous
fat. It is composed of lymphocytes, histiocytes, variable numbers of eosino-
phils, and plasma cells. The presence of multinucleate stellate myofibroblasts
Tumid lupus erythematosus 269
and giant cells is a conspicuous feature that favors actinic reticuloid. Finally,
the finding of large atypical, hyperchromatic cerebriform lymphoid cells and
blast forms is characteristic of actinic reticuloid.
Tumid lupus erythematosus
Clinical features
Lupus erythematosus is discussed in detail in Chapter 17 and the reader is
referred there for a comprehensive discussion of the disease. In this section
only the tumid variant of lupus erythematosus is discussed.
Tumid lupus erythematosus (lupus erythematosus tumidus) is a rare mani-
festation of lupus that some authors believe to be sufficiently characteristic
to justify classification as a distinctive subtype of chronic cutaneous lupus
­erythematosus.1 However, the lack of an agreed-upon diagnostic gold stan-
dard makes this designation somewhat controversial. Further study and
refinement of criteria for inclusion into this subtype of lupus and to allow for
reliable distinction from other inflammatory dermatoses is necessary.
Raised erythematous plaques, which have been described as ‘succulent’,
characterize the clinical lesions.1 Follicular plugging is not a feature.2 Annular
and gyrate forms are seen in some patients.1 The sun-exposed areas such
as the face, chest, arms, and shoulders are most commonly affected.1–4 In
the largest series published to date, patients with this clinical appearance
accounted for 16% of the total number of patients seen in a large cutane-
ous lupus clinic.1 Approximately equal numbers of male and female patients
are affected, in contrast to the preponderance of females affected by other
subtypes of cutaneous lupus.2,4 In this variant, young adults are most often
encountered but presentation in childhood is rare.4,5 In most patients, lesions
can be reproduced by exposure to UVA or UVB light.1,3,6 Development of
tumid lupus erythematosus has also been reported following highly active
antiretroviral therapy in the setting of HIV as a manifestation of immune
restoration as well as in the setting of estrogen and infliximab treatment.7–9
Unusual and rare presentations include unilateral distribution in addition to
symmetrical involvement of both elbows.10,11
Histological features
Biopsy shows a superficial and perivascular ‘cuffed’ lymphocytic infiltrate
(Fig. 8.31).12 Periadnexal involvement is also seen in many cases. Abundant
dermal mucin is commonly present (Fig. 8.32).2,12,13 In contrast to other
­variants of lupus erythematosus, epidermal changes (e.g., follicular plugging,
­vacuolar interface changes, and thickened basement membrane) are generally
not apparent.1,2,12
Fig. 8.31
Tumid lupus erythematosus: there is a perivascular lymphocytic infiltrate. The
collagen fibers are separated by excess dermal mucin. By courtesy of J. Cohen,
MD, Dermatopathology Laboratory, Tucson, Arizona, USA.
270 Superficial and deep perivascular inflammatory dermatoses

As can be seen from the above discussion, tumid lupus erythematosus is

a controversial entity. To some extent, the problem is a matter of seman-
tics and definitions. Indeed, some authors have taken the position that
reticular erythematous mucinosis and Jessner's lymphocytic infiltrate of
the skin would be more appropriately regarded as tumid lupus.18 Clearly,
further studies are necessary to more clearly define the clinicopathologi-
cal features of tumid lupus erythematosus and its distinction from similar
entities.

Perniosis, atypical chilblains and cold

equestrian panniculitis
Clinical features
Perniosis (chilblains) is characterized by sensitivity to cold, damp weather
and is therefore seen during the cold months of the year. The disease seems to
be more common in environments where inadequate heating is problematical
for a few months of the year and is less common in localities characterized by
Fig. 8.32 harsh frigid winters where adequate home heating is the norm.1 Exposure to
Tumid lupus erythematosus: the mucin is Alcian blue positive. By courtesy of
cold water sometimes appears to play a role.2
J. Cohen, MD, Dermatopathology Laboratory, Tucson, Arizona, USA.
Patients present with painful, erythematous nodules on the ­distal extremi-
ties, especially the fingers and the toes (Fig. 8.33).1,3 Other exposed sites,
Direct immunofluorescence staining fails to demonstrate reactivity.1 such as the nose and ears, may also be affected (Fig. 8.34). Lesions may be
The infiltrate cell infiltrate consists of a mixture of CD4+ and CD8+ reac- ­complicated by blister formation or ulceration. In most patients, the ­condition
tive T lymphocytes.2,14 remits during summer but often recurs during winter months. Patients with
anorexia nervosa may be at increased risk of developing perniosis.4,5
Differential diagnosis Horse-riding enthusiasts who wear tight clothing during cold weather may
The concept of tumid lupus erythematosus has been expanded in a recent develop similar lesions on the thighs (Fig. 8.35). This disease is associated
large series of patients.1 Whether there is justification for classification of with panniculitis and has been termed ‘equestrian cold panniculitis’.6
the disorder in these patients as a variant of lupus erythematosus or not is Patients with lesions that persist into warmer seasons appear to be at a
debatable. None met the criteria for lupus erythematosus and most did not higher risk of developing lupus erythematosus.7 One group has designated
have significantly elevated antinuclear antibodies (ANA). However, occa- patients with some criteria, but not meeting diagnostic thresholds for con-
sional patients have been shown to develop skin lesions consistent with dis- nective tissue diseases such as lupus erythematosus, as having ‘atypical
coid lupus erythematosus, including prominent e­ pidermal changes.13,15 ­chilblains’.7 This subset of patients appears to be at higher risk of developing
In addition to patients similar to those described by Kuhn et al.,1 patients unequivocal features of connective tissue disease. It is reasonable to evaluate
that do fit the criteria for discoid lupus erythematosus (DLE), subacute cuta- all patients with perniosis for evidence of lupus erythematosus. Occasionally,
neous lupus erythematosus (SCLE) or systemic lupus erythematosus (SLE) patients with perniosis who present without clinical manifestations of
rarely develop lesions that show a dense superficial and deep perivascular and ­connective ­tissue disease eventually develop SLE.8
periappendigeal infiltrate in the absence of significant epidermal changes.16
Distinction of these subgroups of tumid lupus from lymphocytic infiltrate of
Jessner and polymorphous light eruption based on histological examination
alone may be difficult if not impossible.17 Some authors have suggested that
some cases reported as lymphocytic infiltrate of Jessner or reticular erythema-
tous mucinosis, in fact, represent tumid lupus.18
The histological features of tumid lupus erythematosus may be difficult to
distinguish from polymorphous light eruption. The latter condition, which is
the most common photodermatosis, usually presents in young ­people, par-
ticularly females, as recurrent, erythematous papules, vesicles and/or plaques
following exposure to UV light. Lesions, which develop after a latent period
of hours to days, commonly subside completely within days and heal with-
out sequelae.19 A dense perivascular lymphohistiocytic infiltrate, often
associated with papillary dermal edema, is present in the superficial and
sometimes deep dermis.20 The presence of significant papillary dermal edema
favors polymorphous light eruption. Furthermore, the latter often has focal
­epidermal changes, particularly spongiosis and lacks dermal mucin.
Lymphocytic infiltrate of the skin (Jessner) may be difficult to distinguish from
tumid lupus erythematosus.3 In such cases, immunocytochemistry may some-
times be helpful. The infiltrate in lymphocytic infiltrate is HLA-DR negative in
contrast to lupus erythematosus in which the lymphocytes and often the kera-
tinocytes are HLA-DR positive.21 Leu 8 (immunoregulatory T-cell) expression Fig. 8.33
Perniosis: erythematous
is also more frequently seen in lymphocytic infiltrate.21 Epidermal Langerhans
nodules are present over
cells are often increased in number in lymphocytic infiltrate whereas they are the fingers. From the
frequently reduced in discoid lupus.22 The presence of significant amounts of collection of the late N.P.
dermal mucin favors a diagnosis of tumid lupus erythematosus. Smith, MD, The Institute
Erythema annulare centrifugum differs from tumid lupus by the lack of of Dermatology, London,
significant dermal mucin. UK.
 Perniosis, atypical chilblains and cold equestrian panniculitis 271

Fig. 8.36
Perniosis: there is hyperkeratosis, acanthosis, and a heavy lymphocytic infiltrate.
Note the marked subepidermal edema.
Fig. 8.34
Perniosis: in this patient,
the nose is affected.
From the collection of the
late N.P. Smith, MD, The
Institute of Dermatology,
London, UK.

Fig. 8.37
Perniosis: there is marked subepidermal edema and red cell extravasation.

Fig. 8.35
Equestrian cold
panniculitis: tender
erythematous lesions on
buttock and thigh.
By courtesy of the
Institute of Dermatology,
London, UK.

Pathogenesis and histological features

The pathogenesis of perniosis is not well understood. Clearly, cold is
a requirement for development of symptoms. Tight clothing may play a
role in the development of perniosis at nonexposed sites. In some patients,
particularly children, the presence of cryoproteins may play a role in the
disease.9
Biopsy reveals a cuffed perivascular lymphocytic infiltrate with ­variable
vascular fibrinoid change (Figs 8.36–8.38). The inflammatory ­infiltrate Fig. 8.38
may be superficial but often extends into the deep dermis and ­subcutaneous Perniosis: the infiltrate consists largely of lymphocytes.
272 Superficial and deep perivascular inflammatory dermatoses
Fig. 8.39
Perniosis: this example shows a heavy mural infiltrate consistent with lymphocytic
vasculitis.
a­ dipose tissue. In some cases it is difficult to demonstrate strict criteria for
lymphocytic vasculitis (Fig. 8.39). In other examples, however, fibrinoid
­vascular damage with thrombi is extensive. Papillary dermal edema, which
may be marked, is often present.10 Interface changes, either vacuolar interface
or lichenoid dermatitis, may sometimes be seen.11 A chronic inflammatory
infiltrate around sweat glands has occasionally been noted.7
Biopsy of cold panniculitis shows a perivascular chronic inflammatory
infiltrate that tends to be prominent at the dermal–subcutaneous tissue
junction.6
The inflammatory infiltrate is mostly composed of CD3+ T cells with a minor
subpopulation of CD20+ B cells and scattered CD68+ macrophages.11,12
Differential diagnosis
The biopsy findings are non-specific and other diseases causing cuffed
perivascular lymphocytic reactions and lymphocytic vasculitis enter into the
differential diagnosis. The diagnosis is rendered only after careful clinical cor-
relation. Patients often have some features of, but fail to meet criteria for,
connective tissue disease.7 Also, lesions very similar, or identical, to perniosis
may be seen in patients with cutaneous or systemic lupus erythematosus.8,11,13
Frank lymphocytic vasculitis and interface changes appear to be more com-
mon in patients with chilblain lupus erythematosus than in idiopathic chil-
blains; however, the presence or absence of these findings may not be reliable
discriminators.7,11 A positive lupus band test or antinuclear antibodies favors
a diagnosis of chilblain lupus erythematosus.7
Chilblain lupus erythematosus
Clinical features
Lupus erythematosus is discussed in detail in Chapter 17 and the reader is
referred there for a comprehensive discussion of the disease. In this section,
only chilblain lupus erythematosus (lupus pernio) will be discussed.
Chilblain lupus erythematosus may be a manifestation of either discoid
or systemic lupus erythematosus and shares many clinical and ­histological
­similarities with idiopathic chilblains (Fig. 8.40). It develops almost
­exclusively in females during the winter months.1 Lesions are characterized
by itchy, ­painful, erythematous or blue-purple papules, plaques, and nodules
on the fingers, heels, and soles of the feet; the hands, calves, knees, knuckles,
elbows, nose, and ears are less often affected.2 Hyperkeratotic fissured lesions
and ulcers are also sometimes present.3 Patients may develop chilblains many
years after the typical discoid rash, or lesions may develop simultaneously.
Occasionally, chilblains are the sole manifestation.3 While the majority of
cases are sporadic, familial disease with an autosomal dominant inheritance
has also been reported.4–7
Fig. 8.40
Chilblain lupus erythematosus: resolving perniosis involving the tips of the thumb, ring,
and little fingers. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
Approximately 15% of patients develop SLE, particularly those who
develop discoid and perniotic lesions simultaneously and those with DLE-
erythema multiforme-like syndrome in addition to perniosis.1,2,8 Patients with
severe chilblains that persist into warmer seasons appear to be at higher risk
of lupus erythematosus compared to those with the idiopathic form.9 Patients
with some criteria, but not meeting diagnostic thresholds for connective ­tissue
disease, have been designated as having ‘atypical chilblains’.9 These individ-
uals appear to be at higher risk of eventually developing frank connective
­tissue disease.9 Based on the above observations, it is clear that patients with
perniosis should be evaluated for evidence of lupus erythematosus.
Pathogenesis and histological features
While the pathogenesis of sporadic disease remains elusive, mutations in the
DNA exonuclease TREX1, located on chromosome 3, have recently been
reported in the autosomal dominant familial form of chilblain lupus.4–7 The
function of TREX1 is the digestion of single-stranded DNA. Recent work has
shown that lack of TREX1 function may lead to accumulation of reverse tran-
scribed DNA with subsequent stimulation of interferon production, which
ultimately may be a trigger for autoimmunity.10,11 Mutations in TREX1 have
also been reported in other autoimmune disorders such as Aicardi-Goutieres
syndrome, an encephalopathy characterized by basal ganglia calcification and
white matter alterations.6,12 The development of chilblains is not infrequently
seen in patients with this syndrome with clinical and histological findings
similar to chilblain lupus erythematosus.13,14
Biopsy reveals a cuffed perivascular lymphocytic infiltrate with edema, red cell
extravasation, and variable vascular fibrinoid change (Fig. 8.41). Some biopsies
show frank lymphocytic vasculitis. The inflammatory infiltrate often extends into
the deep dermis and subcutaneous adipose tissue. Interface epidermal changes,
ranging from focal vacuolar changes to a lichenoid tissue reaction, are often
­present.2,15 Chronic inflammation around sweat glands is sometimes seen.9
The infiltrate is mostly composed of T cells, occasional macrophages, and
scattered B cells.
Differential diagnosis
Other diseases associated with a ‘cuffed’ perivascular lymphocytic infiltrate
and lymphocytic vasculitis must be considered in the differential diagnosis.
The diagnosis is rendered only after careful clinical and serological corre-
lation. Distinction from idiopathic chilblain perniosis is not possible based
on histological features alone. The presence of lymphocytic vasculitis and
interface changes appears to be more common in chilblain lupus compared
with idiopathic chilblains, but these features are not reliable discriminators.9
A positive lupus band test and the presence of antinuclear antibodies favor a
diagnosis of chilblain lupus erythematosus.
 Pigmented purpuric dermatoses 273

Fig. 8.42
Fig. 8.41 Majocchi's disease: characteristic brown plaques on the backs of the knees in a
Chilblain lupus male. By courtesy of R.A. Marsden, MD, St George's Hospital, London, UK.
erythematosus: there is
subepidermal edema with
red cell extravasation and
a superficial perivascular
lymphocytic infiltrate.

Pigmented purpuric dermatoses including

Majocchi's disease, Schamberg's disease,
pigmented purpuric lichenoid dermatitis
of Gougerot and Blum and itching purpura
Clinical features
The term pigmented purpuric dermatoses (purpura simplex, chronic capil-
laritis) encompasses a number of clinical syndromes characterized by orange/
brown pigmentation (due to hemosiderin deposition likened to ­cayenne
­pepper), interspersed with fine pinpoint purpura (due to extravasated red
blood cells).1–4 All are of unknown etiology. These disorders may show Fig. 8.43
overlapping clinical and histological features. Indeed, some authors no lon- Schamberg's disease: a localized area of capillaritis showing characteristic cayenne
ger consider their classification to have nosological value. In addition to pepper speckling over the lateral malleolus of a male. By courtesy of R.A. Marsden,
the ­disorders listed below, unusual clinical presentations include unilateral MD, St George's Hospital, London, UK.
­disease, ­zosteriform distribution, and concomitant morphea in addition to
familial disease.5–9
• In Majocchi's disease, the lesions tend to be discrete and annular, vary
from one to several centimeters in diameter, and are associated with
telangiectases (Fig. 8.42).
• Schamberg's disease is characterized by purpura and petechiae with
conspicuous pigmentation; there is a marked preponderance of males and
presentation in childhood is unusual (Figs 8.43, 8.44).10 Lesions, usually
irregular in shape and occurring predominantly on the lower limbs, may
remain for 10 years or longer. In some cases, the findings may mimic
those of chronic venous insufficiency. The lesions are asymptomatic in
most cases. However, some patients complain of pruritus.
• In pigmented purpuric lichenoid dermatitis of Gougerot and Blum,
patients, predominantly males, develop lichenoid papules in addition to
purpuric lesions, most often on the legs.
• Itching purpura (pruriginous angiodermatitis) also shows a male
predominance and is associated with an acute onset of widely distributed
orange macules (Figs 8.45, 8.46). It commonly begins on the dorsal
surface of the feet or ankles, but soon spreads to affect the thighs,
buttocks, trunk, and arms. This variant is associated with a shorter Fig. 8.44
duration than the others, with most patients being free from lesions by Schamberg's disease: in this patient, the bilateral distribution over the malleoli mimics
1 month. The itching, which is of unknown etiology, is usually severe. the effects of venous stasis. By courtesy of R.A. Marsden, MD, St George's Hospital,
Similar appearances may be caused by drug sensitivity. London, UK.
274 Superficial and deep perivascular inflammatory dermatoses

Fig. 8.47
Fig. 8.45 Pigmented purpura: there is an upper dermal heavy perivascular lymphocytic infiltrate.
Itching purpura: these
small macules are widely
distributed over both legs.
By courtesy of J. Newton,
MD, St Thomas' Hospital,
London, UK.

Fig. 8.48
Pigmented purpura:
the infiltrate consists
of lymphocytes and
histiocytes. Note the red
cell extravasation.
Fig. 8.46
Itching purpura: close-up
view of a typical orange
macule. By courtesy of J. the later stages they may not be present when hemosiderin-laden macrophages
Newton, MD, St Thomas' become conspicuous (Fig. 8.49). An iron stain is useful to demonstrate
Hospital, London, UK. ­hemosiderin. Recently, cases of pigmented purpuric dermatosis associated
with ­granulomatous inflammation have been described and designated granu-
lomatous pigmented purpuric dermatoses.13,14 Some cases of granulomatous
Since lichen aureus has more distinctive features, it is discussed separately ­pigmented dermatosis appear to be associated with hyperlipedemia.15
(see below).
Differential diagnosis
Histological features It should be emphasized that extravasated red blood cells and hemosid-
All variants show similar histopathological features. A perivascular lympho- erin associated with a lymphocytic capillaritis are non-specific findings.
cytic infiltrate is associated with reactive endothelial changes and extravasated The ­differential diagnosis is broad and includes other forms of ­perivascular
red blood cells (Figs 8.47, 8.48).11 The lymphocytes are predominantly of the ­lymphocytic infiltrates and lymphocytic capillaritis. Careful clinical cor-
T-helper subset.12 The density of the infiltrate is highly variable. The Gougerot- relation is necessary to establish a correct diagnosis. Progression of lesions
Blum variant is often associated with a dense lichenoid lymphocytic infiltrate. mimicking ­pigmented purpuric dermatoses to mycosis fungoides has been
Extravasated red blood cells are usually appreciated in early lesions, while in documented.16,17 However, this appears to be an uncommon event and
 Lichen aureus 275

Fig. 8.49 Fig. 8.50

Pigmented purpura: there Lichen aureus: golden-
is abundant hemosiderin red-brown plaques on the
deposition as revealed ankle. By courtesy of M.
with the Perl Prussian blue Price, MD, St Thomas'
stain for iron. Hospital, London, UK.

it is more likely that these cases represent examples of purpuric cutane- fashion immediately below the epidermis (Figs 8.51, 8.52). In contrast
ous T-cell ­lymphoma from the beginning. The absence of epidermotropism to lichen planus, however, there is no evidence of basal cell hydropic
and ­cytological atypia favors pigmented purpuric dermatitis over a T-cell degeneration and cytoid bodies are not usually found. A Grenz zone is
­lymphoproliferative disorder. However, in rare cases, distinction may be sometimes present, although the infiltrate may abut the overlying epi-
­difficult or ­impossible and ­ancillary investigations such as immunohistologi- dermis. Lymphocytic exocytosis is sometimes present. Scattered within
cal and T-cell gene rearrangement studies may be indicated. Adding to this the infiltrate are increased numbers of blood vessels. Hemosiderin-laden
occasionally difficult distinction, cases of pigmented purpuric dermatoses macrophages are present in the deeper aspect of the infiltrate or in the
with clonal T-cell gene rearrangements have been reported.13,18 Therefore, it adjacent noninfiltrated dermis. Purpura is a variable feature and there is
appears that the results of gene rearrangement studies may not always ­reliably no evidence of frank vasculitis.
aid in this differential diagnosis. All information – clinical, ­histological, immu-
nohistological, and genetic – should be evaluated in context.
Differential diagnosis
There may be some histological overlap with the Gougerot-Blum variant of
Lichen aureus pigmented purpuric lichenoid dermatitis but lichen aureus tends to be more
localized.
Clinical features
Lichen aureus (lichen purpuricus) is a rare variant of the pigmented purpu-
ric dermatoses. It may be differentiated from the other forms by virtue of
its distinctive clinical and histological features.1–4 It is, therefore, discussed
separately.
Lichen aureus shows a male predilection (2:1) and tends to affect the
younger age group, with a peak incidence in the fourth decade. Children
may occasionally be affected.3 Lesions are usually asymptomatic, although
pruritus is an occasional feature. The disease is characterized by discrete
or confluent lichenoid macules and papules, which may be golden yellow,
bronze, purple, or dark brown, and may resemble a bruise (Fig. 8.50).
Sometimes a purpuric element is evident. The lesions of lichen aureus are
characteristically very persistent, although occasionally spontaneous reso-
lution is a feature. They occur most often on the lower legs, but may affect
quite a wide variety of sites, including the arms, hands, trunk, thighs, and
vulva.5,6 Lesions are usually unilateral and limited to only one or two sites;
they consist of either solitary ovoid maculopapules 3–5 cm in diameter or
irregular plaques up to 20 cm across. Rarely, a zosteriform pattern has been
described.7

Histological features
The epidermis is structurally normal. A dense lymphohistiocytic infil- Fig. 8.51
trate is present in the upper dermis, usually distributed in a bandlike Lichen aureus: there is a dense bandlike infiltrate in the upper dermis.
276 Superficial and deep perivascular inflammatory dermatoses

Fig. 8.52 Fig. 8.53

Lichen aureus: the infiltrate consists of lymphocytes and histiocytes. Note the marked Pruritic urticarial papules and plaques of pregnancy: there is focal spongiosis. Note
red cell extravasation. the perivascular upper dermal infiltrate.

Pruritic urticarial papules and plaques

of pregnancy
Clinical features
Pruritic and urticarial papules and plaques of pregnancy (PUPPP, also known
as polymorphic eruption of pregnancy, toxemic rash of pregnancy, toxic ery-
thema of pregnancy, late onset prurigo of pregnancy) is a common dermatosis
of uncertain etiology with an estimated incidence of 0.5%.1,2 The disorder is
most frequently seen in the primigravida.3,4 Characteristically, it presents late in
pregnancy, towards the end of the third trimester with an average time of onset
in the 36th week.3,4 Rarely, presentation during the postpartum period has been
documented.3–5 In a recent study, the male to female infant ratio in affected
patients was 2:1.6 In one large series, 76% of patients were primigravidas.3,4
As its name indicates, urticarial papules and plaques are associated with
vexatious pruritus. Patients frequently complain that pruritus interferes with
sleep.3 At onset, papules are often localized to the abdomen along lines of
stria distensae. This pattern is seen in approximately 50% of patients.1,3 Small
vesicles are occasionally present.3 With time, the papules spread to involve the
proximal limbs and torso and coalesce to form plaques.4 The distal extremi-
ties are rarely affected.4,7 Sparing of the face is a helpful diagnostic clinical
clue. Typically, the lesions resolve shortly after delivery. Importantly (see dif- Fig. 8.54
ferential diagnosis section below), PUPPP does not usually recur with subse- Pruritic urticarial papules
quent pregnancies. and plaques of pregnancy:
One group found PUPPP was associated with increased maternal weight high-power view showing
gain and increased newborn weight compared with a control population.8,9 spongiosis.
Some studies suggest a relationship between PUPPP and twin gestation with
two such reports documenting 10% and 16% of cases, respectively, associated
with twin gestations.3,8–10 These data have led some authors to postulate that biopsies had eosinophils in the infiltrate. However, other authors report con-
abdominal distension may play a role in the pathogenesis of PUPPP.8 Other trary experience, with most biopsies showing eosinophils. It is our experi-
reported association include hypertensive disorders and induction of labour.11 ence that most biopsies show at least rare eosinophils if multiple sections are
Rarely, congenital abnormalities have been noted in association with PUPPP examined.
but this may be due to small statistical sampling. In one report, one child had The lymphohistiocytic infiltrate is also variable in density, ranging from
hypoplastic dental enamel, while another developed congenital laryngomal- modest numbers of cells to a dense infiltrate with a tightly ‘cuffed’ perivas-
acia requiring surgical intervention.3 In this same series, another child was cular distribution.3 Mild papillary dermal edema is a common finding but
reported to have a ventriculoseptal defect. Most authors, however, believe that marked edema is rarely seen.3 The additional feature of spongiotic vesicula-
there is no direct association between PUPPP and congenital abnormalities. tion characterizes later lesions. Less common manifestations include eosino-
philic spongiosis, and rarely eosinophil-rich subepidermal blistering.
Histological features
Early lesions (urticarial papules) of polymorphic eruption of pregnancy show Differential diagnosis
epidermal and upper dermal edema accompanied by a perivascular lympho- As can be deduced from the above histological description, the biopsy findings
histiocytic infiltrate with variable numbers of eosinophils (Figs 8.53–8.55). are non-specific. The main differential diagnosis includes urticaria, hypersen-
Often, the number of eosinophils is modest and in one series only 17% of sitivity reactions, and pemphigoid gestationis. Usually, clinical examination
 Pregnancy prurigo 277

pregnancy suggested that there is significant clinical and histological overlap

between eczema of pregnancy, pruritic folliculitis of pregnancy and prurigo
of ­pregnancy and that they should be regarded as a single disease complex
termed ‘atopic eruption of pregnancy’.6
The histological features are not specific, comprising mild spongiosis,
lymphocytic exocytosis, and a superficial perivascular lymphohistiocytic
infiltrate with occasional eosinophils (Figs 8.56 and 8.57). Frequently, his-
tological features of excoriation are present. Immunofluorescence studies are
negative.

Differential diagnosis
The histological features are non-specific and clinical correlation is necessary
to render a firm diagnosis. The diagnosis is perhaps best approached as one of
exclusion, and underlying etiologies should be sought. The major differential
diagnosis includes hypersensitivity reactions (drug eruption, insect bites, etc.)
with superimposed prurigo nodularis.

Fig. 8.55
Pruritic urticarial papules and plaques of pregnancy: the infiltrate consists of
lymphocytes, histiocytes, and eosinophils.

and history will allow distinction from hypersensitivity reactions, which

may show identical histological features. Urticaria can be distinguished by
the presence of neutrophils. In our experience, distinction between the pre-
bullous phase of pemphigoid gestationis and PUPPP is the most common rea-
son for which the clinician performs a biopsy. Distinction is important since
pemphigoid gestationis, but not PUPPP, may be associated with significant
fetal morbidity. The presence of a subepidermal vesicle or marked papillary
dermal edema favors pemphigoid gestationis; however, some early lesions
will lack these features. Furthermore, PUPPP is frequently associated with
mild papillary dermal edema. Immunofluorescence studies are often neces-
sary for definitive diagnosis. Pemphigoid gestationis is associated with base-
ment membrane staining for C3 and sometimes IgG. Most cases of PUPPP
show negative immunofluorescence results.12 However, it should be noted
that there have been a few purported cases of PUPPP in which weak C3 Fig. 8.56
Pregnancy prurigo: there is a superficial perivascular inflammatory cell infiltrate.
staining in a linear pattern along the basement membrane was reported.3 In
some laboratories, granular deposits along the basement membrane have also
been described in cases of PUPPP.3,13 However, PUPPP is not associated with
positive strong linear immunofluorescence staining along the basement mem-
brane – a result that would strongly favor pemphigoid gestationis.13 As men-
tioned above, in contrast to pemphigoid gestationis, PUPPP does not tend to
recur during subsequent pregnancies.

Pregnancy prurigo
Clinical features
Pregnancy prurigo (prurigo gravidarum, prurigo gestationis) affects 1 in
300 pregnancies, presenting as pruritic, erythematous, 0.5–1.0-cm papules
and nodules with a predilection for the extensor surfaces of the extremities
and the abdomen.1–8 Superimposed features of excoriation with scale-crust
may be seen. Lesions usually present during the third trimester but may
present at all stages of pregnancy.6 The condition usually disappears fol-
lowing delivery, but in some cases it persists into the puerperium. Blistering
is not a feature. Fetal and maternal health does not appear to be adversely
affected.5

Pathogenesis and histological features

The pathogenesis of pregnancy prurigo is unknown. It has been suggested
that the condition represents pruritus gravidarum in a background of Fig. 8.57
atopic dermatitis.1,5 Patients often have a history of atopy.5 Serum IgE may Pregnancy prurigo:
be elevated in patients regardless of whether or not there is a positive his- the infiltrate consists
tory of atopy.5 Of interest, eczematous dermatitis appears to be common in of lymphocytes with
­pregnancy.5 Furthermore, a recent comprehensive analysis of dermatoses of occasional eosinophils.
278 Superficial and deep perivascular inflammatory dermatoses

Urticarial vasculitis
Clinical features
Urticarial vasculitis is an uncommon condition characterized clinically by
chronic urticaria and histologically by leukocytoclastic venulitis.1–3 In some
patients, urticarial vasculitis is associated with antibody–antigen complexes –
a type III hypersensitivity reaction.4,5 In many patients, however, no underly-
ing cause is discovered.
Patients may have, in addition to urticarial skin lesions, angioedema, arth-
ralgia, gastrointestinal symptoms, and evidence of renal involvement. The
spectrum of illness ranges from mild symptoms to a serious systemic illness,
for which treatment with corticosteroids is sometimes necessary.6
The disease shows a female predominance (2:1) and is most often seen in
the third, fourth or fifth decade. It is rare in children.7 The cutaneous lesions
are urticarial in appearance, but usually last 24–72 hours (Figs 8.58–8.60).8
Pruritus, a burning sensation, or pain, are common complaints. The fre-
quency of attacks varies from daily to monthly. The skin lesions are edem-
atous, raised, and erythematous, and are associated with nonblanchable
purpura.
Systemic manifestations/associations include joint pain, stiffness and swell- Fig. 8.59
ing, particularly of the hands, elbows, feet, ankles, and knees. Frank arthri- Urticarial vasculitis: in
this patient, there is an
tis is extremely rare but may be associated with the development of valvular
extensive urticarial plaque.
heart disease.9,10 Proteinuria and hematuria may be seen in some patients.
By courtesy of J. Newton,
Many patients are hypocomplementemic.4,11 Rarely, renal biopsy reveals the MD, St Thomas' Hospital,
features of focal or diffuse proliferative glomerulonephritis. Crescentic glom- London, UK.
erulonephritis, and mesangial and membranous nephropathy have also been
documented.6,12–14 Abdominal pain associated with nausea, vomiting, and
diarrhea is a feature in some patients.
The erythrocyte sedimentation rate (ESR) is raised in many cases and in
about 50% of patients there is hypocomplementemia. The presence of the lat-
ter correlates with systemic involvement.6,15 There may also be depression of
the early classical pathway components C1q, C4, and C2. Patients with hypo-
complementemic urticarial vasculitis have a high prevalence of autoantibodies
to endothelial cells and antibodies against C1q are invariably present.16–18 The
term ‘Schnitzler's syndrome’ has been applied to patients with urticarial vas-
culitis and monoclonal IgM gammopathy.19–24 Hepatosplenomegaly, elevated
ESR, elevated white blood cell count, fever, and joint pain are ­characteristic

Fig. 8.60
Urticarial vasculitis:
note the bizarre annular
purpuric urticarial plaque.
By courtesy of J. Newton,
MD, St Thomas' Hospital,
London, UK.

features and renal insufficiency has also been documented.20–22,25 An underly-

Fig. 8.58
Urticarial vasculitis: note
the urticaria with a livid
hue. By courtesy of J.
Newton, MD, St Thomas'
Hospital, London, UK.
ing lymphoproliferative disorder is present in a minor subset of patients.19
Importantly, urticarial vasculitis (especially the hypocomplementemic vari-
ant) is often associated with, or heralds the onset of, a variety of systemic dis-
eases, including SLE, arthritis, interstitial lung disease, pericarditis, systemic
sclerosis, mixed connective tissue disease, relapsing polychondritis, inflam-
matory myositis, hepatitis, inflammatory bowel disease, serum sickness, pol-
yarteritis nodosa and Wegener's granulomatosis, viral infections, Sjögren's
syndrome, cryoglobulinemia, polycythemia rubra vera, adverse reaction to
drugs, and as a response to sunlight.6,15,26–44 In one study, more than 50% of
 Urticarial vasculitis 279

patients had uveitis, scleritis, conjunctivitis or episcleritis.6 It appears that

patients with hypocomplementemia have more severe disease.26 Some authors
have postulated that hypocomplementemic urticarial vasculitis represents a
form of systemic lupus erythematosus.45 Others, however, have shown no
significant difference in the association with lupus in patients with normo-
complementemic compared with hypocomplementemic urticarial vasculitis.6
A diagnosis of urticarial vasculitis in any patient should initiate an evaluation
for underlying disease. Fortunately, urticarial vasculitis usually has a benign
outcome.6
Urticarial vasculitis has been documented in association with malig-
nancy.6,46–51 Given the rarity of this association, it may well be coincidental.

Histological features
In urticarial vasculitis, vascular damage is superimposed on a background
of dermal edema and inflammation typical of urticaria. The vasculitis affects
the superficial vascular plexus. Extravasation of red blood cells is evidence
of vascular damage. The vasculitis shows features of leukocytoclastic vas-
culitis except that the histological features tend to be subtle and are easily­
Fig. 8.63
Urticarial vasculitis: there is a heavy lymphocytic and eosinophil infiltrate. In this
example, there are conspicuous flame figures.

overlooked (Figs 8.61–8.63). Mild or focal fibrinoid changes associated with

few neutrophils and sparse karyorrhexis are typical. In our experience, the
vasculitis is usually low grade in nature. Others have shown that endothe-
lial necrosis is unusual.52 Nevertheless, more impressive necrotizing vasculitis
may sometimes be encountered (Fig. 8.64). Urticarial vasculitis appears to
­represent a spectrum of disease ranging from urticaria with very mild ­vascular
injury to frank necrotizing vasculitis.53–55

Differential diagnosis
Clinical correlation is necessary to distinguish urticarial vasculitis from
other forms of leukocytoclastic vasculitis. Although urticarial vasculitis
is often associated with subtle, low-grade vascular injury, this pattern
should not be relied upon in the distinction from other forms of vasculi-
tis. In short, the pathologist's role in diagnosis is to confirm the presence
of vasculitis.

Fig. 8.61
Urticarial vasculitis: in this example of an early lesion, there is a conspicuous
perivascular eosinophil infiltrate. There is no evidence of vessel wall damage.

Fig. 8.64
Urticarial vasculitis: this
Fig. 8.62 biopsy of a purpuric lesion
Urticarial vasculitis: in this field, there is marked edema accompanied by a mixed shows features of florid
lymphocytic and eosinophil infiltrate. vasculitis.
280 Superficial and deep perivascular inflammatory dermatoses
Tumor necrosis factor receptor-associated
periodic syndrome (familiar Hibernian fever)
Clinical features
Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is a rare
autosomal dominant condition with a predilection for individuals of Irish and
Scottish descent.1–5 Other terms used to describe this disorder include familial
Hibernian fever, benign autosomal dominant familial periodic fever, and auto-
somal dominant periodic fever with amyloidosis. Patients usually present in
infancy or early childhood with prolonged episodes of fever accompanied by (in
descending order of frequency) abdominal pain, cutaneous manifestations, myal-
gia, headache, arthralgia, and pleuritic chest pain.3 Rare associations include
central nervous system involvement due to a ­demyelinating disorder, IgA neph-
ropathy, and small vessel vasculitis with concomitant relapsing panniculitis.6–8
Cutaneous manifestations include migratory asymptomatic, nonscaly
­erythematous macules and plaques, annular and serpiginous lesions measur-
ing up to 28 cm in diameter.2,3 The trunk and extremities are predominantly
affected with lesions presenting proximally and migrating distally.3 Patients
may also develop conjunctivitis and periorbital edema.2 Amyloidosis is an
occasional complication.9
Pathogenesis and histological features
TRAPS is due to a mutation of the TNFRSF1A gene which encodes the tumor
necrosis factor receptor.3 The gene has been localized to chromosome 12p13.4
More than 60 mutations have been identified in the TNFRSF1A gene so far
but the precise disease mechanism remains elusive.10
Histologically, the skin lesions are characterized by dermal edema and a
superficial and deep perivascular and interstitial infiltrate of lymphocytes and
a lesser number of macrophages.1–3 There is no evidence of vasculitis. Small
numbers of neutrophils or plasma cells may occasionally be present.3
The infiltrate consists of CD3+ T lymphocytes and CD68+ macrophages.
CD4+ T-helper and CD8+ T-suppressor forms are both represented. CD20+
B lymphocytes are not present.
Eosinophilic, polymorphic and pruritic
eruption associated with radiotherapy
Clinical features
Rueda and coworkers have recently documented a polymorphic cutaneous erup-
tion which develops in females undergoing radiotherapy for cancer (eosinophilic,
polymorphic, and pruritic eruption associated with radiotherapy, EPPER).1–6
Although a wide spectrum of tumors may be present, cervical squamous carci-
noma is by far the most common. The cutaneous lesions are intensely pruritic and
include excoriations, erythematous papules, vesicles, blisters, and panniculitis-
like lesions. The extremities, particularly the legs, are predominantly affected.
Pathogenesis and histological features
The pathogenesis of this condition is unknown.
Histologically, the eruption is characterized by a superficial and deep
lymphohistiocytic infiltrate accompanied by conspicuous eosinophils. The
epidermis is hyperkeratotic and there is mild acanthosis frequently accom-
panied by spongiosis. Other manifestations include eosinophilic spon-
giosis, bullous pemphigoid-like subepidermal blistering, and eosinophilic
panniculitis.
Direct immunofluorescence may disclose perivascular deposits of C3 and
IgM. Indirect immunofluorescence studies are negative.
The lymphocytes are of the CD3+ T-cell phenotype with a predominance
of CD4+ T-helper cells over CD8+ T-suppressor cells. B cells are absent.
Viral exanthemata
A variety of viral infections may present with cutaneous eruptions (Table 8.1).
Although some viruses are associated with an eruption with distinc-
tive ­clinical features, others are affiliated with a non-specific maculo-
papular ­dermatosis. Exceptionally, exanthemata may represent a primary
­cutaneous infection. More commonly, the clinical features are a manifes-
tation of an immune response, such as an immune complex disease or a
­cell-mediated hypersensitivity reaction, to an infection at an extracuta-
neous site.
Biopsy of a viral exanthem often shows a superficial perivascular lym-
phocytic infiltrate. Some cases may show epidermal pathology such as inter-
face changes with dyskeratotic cells. The histological features are entirely
­non-­specific and distinction from hypersensitivity reactions (e.g., a drug erup-
tion) is impossible without clinical (often including serological ­investigation)
­correlation. Viruses that infect cutaneous sites may be ­visualized by light
microscopy including immunohistochemistry, or demonstrated by viral ­culture,
immunological testing, PCR or DNA hybridization. Skin ­manifestations of
viral infections are described in detail in Chapter 18.
Table 8.1
Viruses associated with cutaneous eruptions
Cytomegalovirus
Enterovirus (coxsakievirus, echovirus)
Epstein-Barr virus
Hepatitis B virus
Human immunodeficiency virus
Paramyxovirus
Parvovirus
Roseola (human herpesvirus-6)
Rubella
Rubeola (measles)
Toga virus
 Granulomatous, necrobiotic and Chapter

See
www.expertconsult.com
for references and
additional material
perforating dermatoses
9
Sarcoidosis 281 Necrobiotic xanthogranuloma 306 Granulomata in congenital
immunodeficiency syndromes 314
Granuloma annulare 288 Palisaded neutrophilic and granulomatous
dermatitis 308 Aluminum granuloma 315
Necrobiosis lipoidica 295
‘Metastatic’ Crohn's disease 309 Perforating disorders 316
Rheumatoid nodule 300
Granulomatous cheilitis 310 Reactive perforating collagenosis 316
Pathogenesis and histological features 301
Perforating folliculitis 318
Differential diagnosis 301 Acne agminata 310
Elastosis perforans serpiginosa 319
Elastolytic granulomata 302 Perioral dermatitis 310 Hyperkeratosis follicularis et parafollicularis in
Annular elastolytic giant cell granuloma 302 cutem penetrans 321
Demodicosis 311 Perforating pseudoxanthoma elasticum 322
Actinic granuloma (O'Brien) 302
Atypical facial necrobiosis lipoidica 304 Infective granulomata 311 Necrotizing infundibular crystalline
Granuloma multiforme 304
Foreign body granulomata 311 folliculitis 323
Rheumatic fever nodule 306
Granulomatous contact dermatitis 313 Chondrodermatitis nodularis chronica
helicis 324

Sarcoidosis
Clinical features
Sarcoidosis (Gr. sarkos, flesh; eidos, form), so-named because its histological
features were originally thought to resemble a sarcoma (Boeck), is a common
systemic disease of unknown etiology. It is characterized and defined by the
presence of noncaseating granulomata, usually (but not invariably) affecting
multiple organ systems.1–10 Manifestations are variable. Patients may present
with:
• an acute and usually self-limiting variant,
• a chronic form exclusively affecting the skin (up to between 20%
and 40% of patients with cutaneous sarcoidosis do not have systemic
involvement),
• a serious systemic chronic variant with widespread lesions, which affects
multiple systems, is associated with high morbidity, and may occasionally
be fatal.
Sarcoidosis is more commonly encountered in industrialized countries and
shows particularly high incidences in northern Europe (including the UK),
Fig. 9.1
the USA, and New Zealand, where as many as 20/100 000 of the population
Sarcoidosis: this patient presented with multiple plaques with raised margins
may be affected. It presents particularly in people in their third and fourth on the neck. From the collection of the late N.P. Smith, MD, the Institute of
decades and shows a female predominance.11 In the USA, sarcoidosis is com- Dermatology, London, UK.
mon among blacks and there is a similar tendency in the UK (Figs 9.1, 9.2).
An epidemiological study of sarcoidosis in the Detroit, Michigan, area found
that African-Americans living there had a 3.8 times greater risk of developing children and occurring mainly during teenage years presents with a multisys-
the disease compared with Caucasians.12 The disease is rare in Asians.13 First- temic disease similar to that seen in adults. Younger children under the age of
and second-degree relatives of patients with sarcoidosis seem to have a sig- 4 present with a cutaneous rash, arthritis, and uveitis.18 Infantile sarcoidosis
nificant risk of developing the disease compared to the normal population.14 should not be confused with Blau's syndrome. This disease is inherited in an
The disease is rare in children, presents mainly in teenagers and although the autosomal dominant fashion and is characterized by sarcoidal granulomata
manifestations are usually similar to those seen in adults, infants may present in the skin, uveal tract and joints but with no pulmonary involvement.19,20
with symptoms simulating juvenile rheumatoid arthritis (Fig. 9.3).15–17 Two Despite the similarities between both diseases, no genetic linkage has been
forms of sarcoidosis have been identified in children. A variant affecting older identified.
282 Granulomatous, necrobiotic and perforating dermatoses

form of sarcoidosis is associated with a good prognosis, with most patients

­experiencing resolution within 6 months of onset of symptoms.25–27 In one
study, however, 16% of patients who presented with erythema nodosum
developed chronic disease.26
A not uncommon mode of presentation is the development of a wide-
spread, usually asymptomatic, maculopapular eruption. Individual lesions
are erythematous or violaceous, 3–6 mm in diameter, and most commonly
seen on the face (particularly in a periorbital distribution), the trunk, the
extensor aspects of the extremities, and the neck (Figs 9.4, 9.5). In this
­variant the patient may also develop acute lymphadenopathy and uveitis, and
a chest X-ray examination can reveal features of early respiratory involve-
ment. Spontaneous resolution sometimes occurs. Occasionally, micropapular
lesions are seen, particularly on the face and limbs (Fig. 9.6). Rarely patients
develop sheets of pinhead-sized lichenoid papules on the trunk and limbs.
The onset is abrupt and lesions may appear in crops. Some patients develop
nodules and plaques, which may occur anywhere on the body, but most
often affect the face, extremities, buttocks, and shoulders (Figs 9.7–9.11).
Annular or serpiginous lesions are also encountered and sometimes there is a
prominent telangiectatic component (angiolupoid sarcoid) (Figs 9.12, 9.13).10
Fig. 9.2 Rarely, epidermal changes result in a psoriasiform or even ­ichthyosiform
Sarcoidosis: papules are present on both upper and lower lips. From the collection
of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.

Fig. 9.4
Fig. 9.3 Sarcoidosis: widespread erythematous plaques on the upper arm, some with
Sarcoidosis: the condition
an annular appearance. By courtesy of R.A. Marsden, MD, St George’s Hospital,
is rare in children.
London, UK.
There are widespread
micropapules on this
child’s face. By courtesy
of C.T.C. Kennedy, MD,
Bristol Royal Infirmary,
Bristol, UK.

Rarely, sarcoidosis presents in monozygotic twins.21 Coexistence with

common variable immune deficiency is also a rare occurrence.22
Cutaneous lesions occur in 20–35% of patients with systemic sarcoido-
sis and may be classified into non-specific (erythema nodosum) and spe-
cific (granulomatous) subtypes.10 Cutaneous sarcoidal granulomata appear
to be associated with a poorer prognosis and an increased incidence of pul-
monary fibrosis and uveitis. Chronic facial lesions have been shown to be
more commonly associated with involvement of the lungs, sinuses, and
eyes.23 Erythema nodosum occurs quite commonly in sarcoidosis, reported
incidences varying from 11% to 31%.24 There is a significant female pre-
dominance (3:1). Interestingly, erythema nodosum appears to be relatively
uncommon in both African-Americans and Caucasians in the USA. It pres-
ents as erythematous, tender, subcutaneous nodules, usually on the anterior
tibial regions. Erythema nodosum may be associated with pyrexia, polyarth- Fig. 9.5
ralgia (wrists, knees, and ankles), a very high erythrocyte sedimentation rate Sarcoidosis: characteristic mauve plaque on the malar area with an infiltrative
(ESR) and bilateral hilar lymphadenopathy (Lofgren's syndrome). This acute appearance. By courtesy of R.A. Marsden, MD, St George’s Hospital, London, UK.
 Sarcoidosis 283

Fig. 9.6
Sarcoidosis: micropapular variant. Note the tiny lichenoid papules. By courtesy of Fig. 9.8
the Institute of Dermatology, London, UK. Sarcoidosis: erythematous
plaque adjacent to the
eye. From the collection
of the late N.P. Smith,
MD, the Institute of
Dermatology, London, UK.

Fig. 9.7
Sarcoidosis: there is extensive facial involvement, a commonly affected site. From
the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.

appearance.28 An exceptional case mimicking lipodermatosclerosis has been

described.29 Chronic skin lesions are associated with pulmonary fibrosis, ocu-
lar, and bone involvement.
Most characteristic of sarcoidosis, however, is lupus pernio. This chronic
violaceous plaque most often affects the nose, cheek, and ears, but lesions
also sometimes affect the fingers and knees (Fig. 9.14). It is a particularly dis-
figuring variant and resolution is especially complicated by marked scarring.
Lupus pernio is often associated with lesions in the upper respiratory tract
and can be followed by nasal obstruction and septal perforation. Patients also
have severe pulmonary fibrosis, bone cysts, and ocular lesions. This variant
has an insidious onset and is associated with a prolonged course and poor
prognosis.15
Patients with sarcoidosis not uncommonly develop lesions in scar tis-
sue30,31 and also in relation to trauma at the sites of desensitizing injections,
­tattoos, venipuncture, surgery, laser, cosmetic fillers, and BCG (Fig. 9.15).32–37
A single case attributed to copper-containing earrings has been described.38
Sarcoidal granulomata in association with foreign bodies do not necessarily
imply a diagnosis of sarcoidosis. However, a small number of patients with
sarcoidal granulomata in association with silica and tattoo pigment may have
systemic sarcoidosis or the latter may develop subsequently.39 Awareness of
this problem is important as such cutaneous granulomata may be the first
Fig. 9.9
Sarcoidosis: the
extremities are commonly
affected. From the
collection of the late N.P.
Smith, MD, the Institute of
Dermatology, London, UK.
manifestation of the disease. Sarcoidosis has also been documented present-
ing in a tattoo in association with interferon-alpha (IFN-α) treatment for
chronic hepatitis C.40 Interestingly, sarcoidosis has also been reported rarely
in patients receiving interferon and ribavirin for chronic hepatitis C,41,42 and
in rare patients on interferon-alpha therapy for melanoma.43,44 Sarcoidosis in
patients with chronic hepatitis C may present concomitantly with the disease
and unrelated to medication, or more often triggered by treatment, mainly
ribavirin and interferon-alpha.45
Hypopigmented lesions may be seen in black patients.46 Unusual cuta-
neous manifestations include subcutaneous nodules, ichthyosiform lesions,
284 Granulomatous, necrobiotic and perforating dermatoses
Fig. 9.10
Sarcoidosis: these grouped nodules are present on sun-damaged skin of the upper
chest. By courtesy of the Institute of Dermatology, London, UK.
Fig. 9.11
Sarcoidosis: small nodules on the anterior aspect of the neck. By courtesy of R.A.
Marsden, MD, St George’s Hospital, London, UK.
­erythroderma, scarring and nonscarring alopecia, lymphedema, nail dystro-
phy in the absence of underlying bone changes, verrucous lesions, generalized
atrophy, leonine facies, palmar erythema, and leg ulcers with or without gran-
ulomatous vasculitis.47–61 Lesions of scarring alopecia may clinically mimic
discoid lupus erythematosus.62 Subcutaneous nodules are rare and present as
persistent, freely mobile, often painful lesions measuring 5–15 mm in diam-
eter. It has been suggested that subcutaneous lesions are more often associ-
ated with systemic disease.63 In a further study the subcutaneous involvement
occurred at the beginning of the disease and the associated systemic disease
was not severe.64 Oral and genital involvement is rare but disease restricted to
the vulva has been documented.65–67 Sarcoidosis has also been described pre-
senting as a testicular mass.68
Ninety percent of patients with sarcoidosis have pulmonary involvement.27
Bilateral hilar lymphadenopathy is the commonest intrathoracic manifesta-
tion of sarcoidosis and together with pulmonary involvement forms the most
frequent lesion. Intrathoracic manifestations in sarcoidosis are classified into
five subgroups: 6,10
• Stage 0: normal chest X-ray,
• Stage I: bilateral hilar and/or paratracheal lymphadenopathy with no
pulmonary involvement,
• Stage II: lymphadenopathy with pulmonary infiltrates,
Fig. 9.12
Sarcoidosis: annular
lesions on the ankle. By
courtesy of the Institute of
Dermatology, London, UK.
Fig. 9.13
Sarcoidosis: close-up view of an annular lesion. Note the beaded appearance.
By courtesy of the Institute of Dermatology, London, UK.
• Stage III: pulmonary infiltrates, but no lymphadenopathy,
• Stage IV: irreversible fibrosis and bullae, cysts, emphysema.
Stage I disease is frequently associated with spontaneous resolution; pro-
gression to stage II disease is uncommon. Severe pulmonary involvement as
seen in stage III patients correlates with deep chronic plaque lesions and lupus
pernio. Patients have interstitial fibrosis and eventual cor pulmonale, which
may prove fatal.
Systemic vasculitis involving small- to large-caliber vessels has been found
in some adults and children with sarcoidosis.69 This manifestation tends to be
more common in African-American and Asian patients.69
Ocular lesions develop in about 20% of patients with sarcoidosis. Acute
anterior uveitis is the most common manifestation; it is frequently bilateral
and shows a predilection for females. It correlates with a benign outcome and
erythema nodosum. Chronic uveitis also affects the anterior chamber and if
untreated may progress to glaucoma and blindness. Other lesions include
retinal vein perivasculitis, disc edema, and neovascularization. Conjunctival
 Sarcoidosis 285

Peripheral lymphadenopathy develops in about 30% of patients. However,

histological examination of peripheral lymph nodes will reveal ­granulomata
in about 75% of patients with sarcoidosis. Although splenomegaly is only
present in 10–25% of patients, granulomata are present in about 50%
of cases. Splenic disease is usually asymptomatic, but patients may have
­abdominal pain, hypersplenism and, very rarely, splenic rupture. Splenic
­disease ­correlates positively with a high frequency of intrathoracic sarcoido-
sis. Liver function test abnormalities are quite common and about 20% of
patients have hepatomegaly; 60% of patients have hepatic granulomata on
­histological examination.
Cardiac lesions are uncommon, but are of particular importance due to
the associated mortality.6 In a recent autopsy series, 50% of all deaths were
due to cardiac disease.72 This same study found that the clinician often does
not appreciate the presence of cardiac involvement – the antemortem diag-
nosis of cardiac lesions was made in only 29% of patients.72 Granulomata
may occur at any site, but appear to show a predilection for the ­conduction
­system. Clinical manifestations include ventricular tachycardia, complete
heart block, congestive cardiac failure, pericardial effusion, and myocardial
infarction. Sarcoidal granulomata may affect small and large blood vessels, in
particular the pulmonary vasculature.
Fig. 9.14 Muscle involvement is usually asymptomatic. Histological examination of
Sarcoidosis: lupus pernio.
random muscle biopsies reveals granulomata in as many as 50% of patients.
The nose shows typical
Rare features include asymptomatic palpable nodules and a polymyositis-like
scaly violaceous swelling.
By courtesy of the syndrome.
Institute of Dermatology, Although a rare complication, patients with sarcoidosis appear to be more
London, UK. prone to develop cryptococcosis than other infections.73
Radiologically demonstrable bone lesions occur in about 15% of
patients. Early lesions consist of osteoporosis, cortical thinning, and ­mottled
­rarefaction. Established lesions are cystic and are sometimes associated
with pathological fractures. The hands and feet are predominantly affected
(Fig. 9.16). Destruction of the nasal bones can result from direct infiltration
in patients with lupus pernio.
Hypercalcemia and, particularly, hypercalcuria are important complica-
tions of sarcoidosis. This is possibly due to increased intestinal absorption of
calcium and abnormal production of 1,25-dihydroxyvitamin D.74 It is more
often transitory, but in a small proportion of patients it is persistent and
sometimes complicated by the development of renal failure due to nephrocal-
cinosis. Granulomata are found on histological examination of the kidney in
up to 40% of patients.
Laboratory investigations reveal a wide variety of abnormalities of the
immune system (see below). Patients may demonstrate elevated levels of
serum angiotensin-converting enzyme (ACE). Unfortunately, this finding is
not specific for sarcoidosis, increased values also being found in patients with
diabetes mellitus, alcoholic liver disease, and leprosy. It is sometimes of value

Fig. 9.15
Sarcoidosis: tattoo
reaction. There are
multiple dome-shaped
nodules. By courtesy
of the Institute of
Dermatology, London, UK.

granulomata may be present in up to 30% of patients; therefore biopsy can

be a useful and relatively safe method of establishing the diagnosis. The lacri-
mal gland is also sometimes affected.
Neurological involvement occurs in 5–15% of patients with systemic sar-
coidosis. Clinical manifestations include facial nerve palsy, Guillain-Barré
syndrome, optic nerve disease, meningitis, seizure, and encephalopathy.6,70,71
In one study, neurosarcoidosis was the presenting symptom in 31% of
patients.70 The combination of uveitis, facial nerve palsy, fever, and swelling
of the parotid gland is known as uveoparotid fever (Heerfordt's syndrome).
This condition is often associated with central nervous system involvement. Fig. 9.16
Hypothalamic and pituitary lesions are rare and may manifest as diabetes Sarcoidosis: there is marked swelling of the distal interphalangeal joints. By courtesy
insipidus or panhypopituitarism. of R.A. Marsden, MD, St George’s Hospital, London, UK.
286 Granulomatous, necrobiotic and perforating dermatoses
in monitoring the level of disease activity in patients known to have sarcoido-
sis. Patients may also display increased levels of serum and urinary lysozyme,
serum beta-2-microglobulin, and collagenase.
The Kveim test was used in the past to aid in diagnosis. A homogenate of
known sarcoid tissue is injected intradermally at a marked (India ink) site, and
4–6 weeks later the injection site is biopsied. A positive result depends upon
the detection of an epithelioid cell granuloma. False-positive reactions may
occur with other diseases including Crohn's disease, infection ­(mycobacterial,
fungal), berylliosis, silicosis, asbestosis, and lymphoma. The stimulatory
­‘sarcoidal’ antigen of the Kveim reagent has not been identified.75 The Kveim
test is almost never used nowadays because of difficulties in obtaining the
homogenate of sarcoid tissue.
Although sarcoidosis is associated with a high morbidity, the mortality ­rate
is low, being of the order of 3–6%. Causes of death include cardiac involve-
ment and respiratory or renal failure. The prognosis is better in females and
appears to be improved in those with a positive purified protein derivative
(PPD) skin test and normal serum immunoglobulin levels. The severity of dis-
ease is greater in blacks and Asians compared with Caucasians.76 Of interest,
despite the very marked upset in immunological phenomena, patients do not
seem to have an associated greatly increased risk of opportunistic infections
except as a consequence of therapy (e.g., corticosteroids).
The association between sarcoidosis and a number of systemic diseases
is probably coincidental. Sarcoidosis has been documented in association
with vitiligo, pernicious anemia, autoimmune thyroiditis, Graves' disease,
chronic hepatitis, Addison's disease, Sjögren's syndrome, diabetes mellitus
and ulcerative colitis, lymphoma, human immunodeficiency virus (HIV)
infection, and primary biliary chirrosis.77–88 Interestingly, patients with
acquired immunodeficiency syndrome (AIDS) usually develop manifesta-
tions of sarcoidosis after antiretroviral therapy is started. This phenome-
non is the result of the immune restoration syndrome.85,89 Associations with
cutaneous autoimmune disease include dermatitis herpetiformis and linear
IgA disease.90,91 A single case of trachyonychia associated with sarcoidosis
has been reported.92
Pathogenesis and histological features
The pathogenesis of sarcoidosis is poorly understood. The demonstration of
familial clustering suggests hereditary susceptibility to sarcoidosis in at least
a subset of patients.14,93
Despite intensive studies, the etiology and pathogenesis of sarcoidosis
remains elusive.94,95 It is likely, however, that sarcoidosis represents a reaction
pattern that may develop in a predisposed patient on exposure to one or more
infective agents or other antigens.
The role of mycobacteria in the pathogenesis of sarcoidosis is a controver-
sial topic. Attempts at detection of mycobacterial DNA by polymerase chain
reaction (PCR) have produced conflicting results. While some authors have
failed to detect mycobacterial DNA, others have identified DNA of various
strains of tuberculous and nontuberculous mycobacteria.96–100 In one study,
although amplified mycobacterial DNA was detected by PCR in 38% of sar-
coidosis patients, mycobacterial DNA was also detected in tissue in 44% of
control patients.101 Furthermore, most studies published in the literature fail
to report more than 6% positivity for Mycobacterium tuberculosis DNA in
patients with sarcoidosis.102 In another interesting study, cell wall deficient
acid-fast bacteria (L forms) were cultured from the blood of 19 of 20 patients
with sarcoidosis but not from controls.103 In summary, these mixed results
between laboratories have not clarified the role of mycobacteria in the patho-
genesis of sarcoidosis. It seems, however, that mycobacteria may be of etio-
logical importance in at least a subset of cases.
Propionibacterium acnes DNA has also been identified in tissues of
patients with sarcoidosis, including involved lymph nodes.104,105 The signifi-
cance of this finding remains uncertain. Human herpesvirus 8 DNA has not
been demonstrated in tissues of patients with sarcoidosis.105
The occasional association with known autoimmune diseases, such as pro-
gressive systemic sclerosis and systemic lupus erythematosus (SLE), has inevi-
tably led to the proposal of an autoimmune pathogenesis. Although many
familial cases have been reported in the literature, no consistent pattern of
inheritance has emerged. The results of human leukocyte antigen (HLA)
typing have shown associations with particular features of the disease; for
example, HLA-A1 and HLA-B8 are associated with arthritis, HLA-A1 is
also associated with uveitis, and HLA-B13 may be associated with a chronic
refractory variant.10 Patients with HLA-DR17 have a better prognosis.106 One
study has shown that patients with sarcoidosis have an increased frequency of
a glutamine residue at position 69 of the B1 chain of the HLA-DPB molecule
compared with a control population.107 This is particularly interesting since
a similar polymorphism has been documented in patients with chronic beryl-
lium disease, a disorder also characterized by granulomata and which shares
some pathological features in common with sarcoidosis.
Immunological investigations in patients with sarcoidosis have produced
an immense wealth of data, which reveal that there is clearly an associated
state of abnormal immunological hyperactivity. There are alterations of both
cell-mediated and humoral immunity. Despite great efforts to clarify the
immunobiology of sarcoidosis, particularly with regard to the precise anti-
gens that may facilitate the disease, we still do not have a clear understand-
ing of the disease process. Sarcoidosis, at least in part, appears to be due
to a hyperactive T-helper cell proliferation with lymphokine production.108
Increased T-helper (Th1, Th2) cells are present in the alveolar lung paren-
chyma. Several studies have demonstrated selective activation of certain oli-
goclonal T-cell subsets.109–112 In one study, there was a correlation between
the particular oligoclonal T-cell subsets and disease activity.109 Th1 lympho-
cytes (T cells expressing interleukin (IL)-2 and IFN-γ) preferentially accumu-
late in pulmonary parenchyma and the alveolar space compared with Th2
lymphocytes (T cells expressing IL-4 and IL-5).113 Compared with T-cells in
peripheral blood, T cells obtained by bronchoalveolar lavage show greater
expression of IFN-γ and tumor necrosis factor alpha (TNF-α).106 Of interest,
patients with HLA-DR17 show a muted cytokine response, a finding that is
perhaps related to the better prognosis observed in this subset of patients.107
T lymphocytes, in turn, stimulate B cells. Abnormalities of humoral
immunity include a non-specific polyclonal hypergammaglobulinemia and
circulating immune complexes in acute forms of the disease, particularly in
association with erythema nodosum.
The paramount puzzle in unraveling the pathogenesis of sarcoidosis is
identifying the initial event(s) that lead to the disease. Despite our increas-
ing knowledge of the immunobiology of sarcoidosis, we seem no closer to
answering this key question.
Histologically, sarcoidosis is characterized by a dense, noncaseating
granulomatous infiltrate in the dermis (Figs. 9.17, 9.18), which sometimes
extends into the subcutaneous fat. The granulomata are discrete and strik-
ingly uniform in size and shape. They are composed of epithelioid histiocytes
with abundant eosinophilic cytoplasm and oval or twisted vesicular nuclei
often containing a small central nucleolus (Fig. 9.19). Variable numbers of
Langhans giant cells are present and sometimes a scattering of lymphocytes
is seen at the peripheral margin of the granuloma (Fig. 9.20). Discrete small
Fig. 9.17
Sarcoidosis: the dermis is replaced by uniform circumscribed nests of non-
caseating granulomata.
 Sarcoidosis 287

central foci of fibrinoid necrosis are sometimes present but caseation ­necrosis
is rare (Fig. 9.21).114,115 Transepidermal elimination is sometimes seen.116
The epidermis is usually normal although occasional cases display acantho-
sis and sometimes the granulomata are focally lichenoid. A predominantly
lichenoid pattern may exceptionally be seen.117 Exceptional cases of sarcoido-
sis may display histologic findings that focally overlap with granuloma annu-
lare, palisading neutrophilic and granulomatous dermatitis, and interstitial
­granulomatous dermatitis.118 Further histologic findings described include
elastophagocytosis, perineural granulomas resembling leprosy, mucin deposi-
tion, and an infiltrate rich in plasma cells.115
In some cutaneous lesions, inclusion bodies are present, although much
less frequently than in lymph nodes. The Schaumann body, a basophilic,
­laminated, rounded, conchoidal structure composed of calcium carbonate, cal-
cium oxalate, phosphate, iron, and dolomite, is not specific for sarcoidosis and
is seen in a number of other granulomatous conditions including ­tuberculosis
and berylliosis (Fig. 9.22).119–121 The asteroid body is a small intracytoplasmic
eosinophilic star-shaped structure; it is not specific for ­sarcoidosis, being seen
also, for example, in tuberculosis, tuberculoid leprosy, ­berylliosis, and atypi-
cal facial necrobiosis. It is also commonly found in necrobiotic xanthogran-
Fig. 9.18 uloma.122 Initial studies suggested that the asteroid body was ­composed of
Sarcoidosis: note the paucity of lymphocytes and absence of necrosis.
collagen but more recent reports, using ­immunohistochemistry, suggest that

Fig. 9.19
Sarcoidosis: the epithelioid cells are composed of pink cytoplasm with a central oval Fig. 9.21
or sometimes twisted vesicular nucleus containing a small basophilic nucleolus. Sarcoidosis: occasionally small foci of ‘fibrinoid’ necrosis may be seen in the center
The granuloma also contains lymphocytes and occasional fibroblasts. of the granuloma, but cellular detail is not lost.

Fig. 9.20 Fig. 9.22

Sarcoidosis: in this example the granulomatous reaction is associated with abundant Sarcoidosis: in this lymph node biopsy specimen, fragmented, laminated
foreign material. Schaumann bodies are seen. They are very rarely a feature of cutaneous sarcoidosis.
288 Granulomatous, necrobiotic and perforating dermatoses

it is a product of the microtubular system.123,124 The presence of foreign mate-
rial in sarcoidal granulomata does not exclude the diagnosis of sarcoidosis. In
fact, polarizable material has been found in up to 5% of cases.125–127
It has been shown that the gli-1 oncogene is consistently and abnormally
expressed in the cells forming the granulomata not only in sarcoidosis but
also in granuloma annulare and necrobiosis lipoidica. This observation raises
the possibility of trials using inhibitors of gli-1 signaling to treat this group of
granulomatous disorders.128
The visceral lesions are characterized by an identical histology of nonca-
seating granulomata, which may be accompanied by significant scarring, for
example in the lung, where advanced cases are characterized by interstitial
fibrosis and sometimes honeycomb lung formation. In the liver, granulomata
are most commonly found in the portal tracts or in relation to central veins.
Splenic lesions are randomly distributed and are not usually associated with
significant fibrosis.
Differential diagnosis
Sarcoidosis must be approached as a diagnosis of exclusion and has to be
distinguished from the numerous conditions that may be associated with a
noncaseating granulomatous histology, including some forms of tuberculo-
sis, tuberculoid leprosy, berylliosis, fungal infections, Crohn's disease, and
foreign body granulomatous reactions.129 Therefore, the use of special stains,
including the Ziehl-Neelsen preparation for mycobacteria and the periodic
­acid-Schiff (PAS) and methenamine silver reactions for fungi, is mandatory
before diagnosing sarcoidosis. Depending on the clinical context, culture
may also be required to exclude an infective etiology. Tuberculoid leprosy
is characterized by nerve involvement, a feature that is usually absent in
sarcoidosis.
Some of the granulomata seen in a variety of primary immunodeficiency
syndromes closely mimic those found in sarcoidosis and histological distinc-
tion may be impossible. A study comparing granulomata in sarcoidosis to
those seen in primary immunodefiencies found a much lower rate of CD4+/
CD8+ cells in the former as opposed to the latter.130
Labial and gingival involvement may be histologically mistaken for
Crohn's disease and granulomatous cheilitis (Miescher). It is worth noting
that in rare cases oral involvement in Crohn's disease may precede systemic
manifestations by several years. Metastatic Crohn's disease may be difficult
to distinguish from sarcoidosis. The former often show nonsuppurative gran-
ulomata in a diffuse pattern and surrounded by a thin cuff of lymphocytes.
Further frequent findings include the presence of numerous eosinophils and
ulceration, findings not often seen in sarcoidosis.131
Granulomatous lesions that have been described in exogenous ochronosis
appear to be related to sarcoidosis.132 However, similar lesions have also been
described as showing changes mimicking actinic granuloma.133
Other documented associations of granuloma annulare include morphea,
chronic hepatitis C infection, autoimmune thyroiditis, secondary hyperpara-
thyroidism, sarcoidosis, Plummer's disease, myelodysplastic syndrome, met-
astatic carcinoma, and a bee sting.25–33 Granuloma annulare has also been
described after vaccination for tetanus and diphtheria, hepatitis B and tuber-
culosis (BCG), and after mesotherapy.34–38 It may also develop in the scars
of herpes zoster.39–42 It is important to highlight that most patients with the
condition heal after variable periods of time, and long follow-up has not
revealed consistent associations with any systemic diseases.43 A further study
has found no consistent relationship between malignant neoplasms and gran-
uloma annulare.44 However, it has been suggested that elderly patients with
lesions that do not have typical features of granuloma annulare but display
microscopic findings resembling granuloma annulare should be investigated
for an underlying malignancy, especially lymphoma.44
Granuloma annulare has developed during treatment with allopurinol,
amlodipine, daclizumab, and antitumor necrosis factor.45–48 Interferon-alpha
has been associated with generalized interstitial granuloma annulare.49 It is
most likely, however, that granuloma annulare-like eruptions secondary to drug
administration often represent interstitial granulomatous drug eruptions.
Localized granuloma annulare
The localized variant is the commonest type. It usually presents in the first
three decades and is associated with a female preponderance (2.25:1). Lesions
consist of one or several papules, which may be skin-colored, red or viola-
ceous, and are typically distributed to form an annular or arcuate lesion 1–5
cm in diameter (Figs 9.23–9.27). About 50% of patients have solitary lesions.
The acral sites are most commonly affected, in particular the knuckles and
dorsum of the fingers. In a small proportion of patients, lesions are present
on both the upper and lower limbs, and occasionally the trunk is affected.
Lesions on the palms are exceptional.50 Facial involvement appears to be
uncommon.51,52 In a reported case, lesions were restricted to the area involved
by a Becker's nevus.53 Although lesions may be persistent, approximately 50%
of patients can anticipate resolution by about 2 years from onset. However,
recurrences are, unfortunately, quite common. Patients in which the disease
arises earlier in life appear to have earlier resolution of lesions.54 Interestingly,
on occasion lesions regress spontaneously after biopsy.55 In one case, spon-
taneous resolution resulted in mid-dermal elastolysis.56 Rarely, granuloma
annulare has been reported in families and in monozygotic twins.57 A case has
been documented in which the lesions recurred seasonally with sun-exposed
areas.58 There has only been a single case report of cutaneous granuloma
annulare with similar lesions in an intra-abdominal location.59 In one case,
granuloma annulare was the first sign of adult T-cell leukemia/­lymphoma and

Granuloma annulare
Clinical features
Granuloma annulare is a common, usually asymptomatic, dermatosis of
unknown etiology.1,2 It may be divided into six clinical subsets:
• localized,
• generalized,
• perforating,
• subcutaneous,
• papular,
• linear.
Unusual clinical variants include pustular follicular lesions and presenta-
tion with patches.3,4 A single case presenting as contact dermatitis has been
reported.5 Granuloma annulare (often with widespread disseminated lesions)
has been described in patients with HIV infection and sometimes may be the
presenting sign.6–18 Granuloma annulare, mainly the generalized variant (see Fig. 9.23
below), has also been reported in association with both Hodgkin's and non- Localized granuloma annulare: a typical annular lesion over the knuckle. Stretching
Hodgkin's lymphoma.19–22 Exceptionally, anterior uveitis and concomitant of the skin reveals a translucent beaded margin. By courtesy of R.A. Marsden, MD,
skin lesions have been described.23,24 St George’s Hospital, London, UK.

Fig. 9.24
Localized granuloma annulare: in this patient multiple lesions are present on the feet.
From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.
Fig. 9.25
Localized granuloma annulare: this arm lesion shows a characteristic beaded margin.
From the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.
Fig. 9.26
Localized granuloma annulare: close-up view of annular lesions. By courtesy of the
Institute of Dermatology, London, UK.
Granuloma annulare 289
Fig. 9.27
Localized granuloma annulare: in this patient there is a large plaque on the ankle
with a hint of central clearing. By courtesy of the Institute of Dermatology,
London, UK.
in a further patient it was associated with angioimmunoblastic T-cell lym-
phoma.60,61 Very rarely, acral, localized granuloma annulare may present as
an acute and painful eruption.62
Generalized granuloma annulare
Generalized lesions occur in approximately 15% of patients with granuloma
annulare.2,63 As with the localized form, there is an increased incidence in
females; however, the median age differs the majority of cases occurring in
patients in the fourth to seventh decades, with the rest appearing during the
first decade. Patients with generalized granuloma annulare have an increased
incidence of HLA-Bw35.64 Generalized granuloma annulare is defined as
lesions occurring on at least the trunk and either upper or lower extremities,
or both.2 Most lesions are papules, which may be distributed in an annular
pattern, but maculopapules and nodules also occur. They vary in hue from
flesh-colored or red, to tan, brown or yellow. Numbers vary from several
dozen to hundreds (Figs 9.28 to 9.30). A single patient has been documented
with generalized disease accompanied by marked swelling of the hands and
another patient developed the disease following erythema multiforme.65,66
Lesions may be asymptomatic or pruritic.2 As with the localized form, the
Fig. 9.28
Generalized granuloma annulare: innumerable papules are present on this patient’s
arms. By courtesy of J. Williams, MD, Brigham and Women’s Hospital, Boston, USA.
290 Granulomatous, necrobiotic and perforating dermatoses
Fig. 9.29
Generalized granuloma annulare: there are widespread papules and plaques.
By courtesy of the Institute of Dermatology, London, UK.
Fig. 9.30
Generalized granuloma
annulare: in this patient
numerous annular lesions
are present. From the
collection of the late
N.P. Smith, MD, the
Institute of Dermatology,
London, UK.
disease is persistent, but some patients experience resolution within 4 years.
Anetoderma has been exceptionally reported as a complication of general-
ized granuloma annulare.67 A remarkable association with giant cell arteri-
tis, gastrointestinal stromal tumor, and other internal malignancies including
ovarian and gastric cancer has been reported.68–70 Tuberculous lymphaden-
its was an association in one case.71 In two instances, the condition was the
initial manifestation of chronic myelomonocytic leukemia.72 An association
with lymphoma, including Hodgkin's disease, has also been described.73
A patient with hepatitis B developed generalized granuloma annulare, and viral
DNA was detected in the skin lesions by PCR.74 A further case presented in a
photosensitive distribution and healed with scarring and milia formation.75
Perforating granuloma annulare
Perforating granuloma annulare is distinguished by the presence of tran-
sepidermal elimination of necrobiotic collagen.10,18,76–79 Clinically, the lesion
­presents as a group of papules with an umbilicated crust usually located on
Fig. 9.31
Perforating granuloma annulare: the extremities are most often affected. Necrotic
debris and crust can be seen. From the collection of the late N.P. Smith, MD, the
Institute of Dermatology, London, UK.
the extremities, often the dorsum of the hands (Fig. 9.31). Presentation of
lesions on the ears has exceptionally been described, as has a generalized vari-
ant.80–82 It may affect both children and adults, and both localized and gener-
alized forms exist. Spontaneous resolution sometimes occurs within months
or years of onset. An exceptional case of perforating granuloma annulare
which developed following tattooing has been reported.83
Subcutaneous (deep) granuloma annulare
The subcutaneous variant is synonymous with the pseudorheumatoid nod-
ule of childhood and deep granuloma annulare.84–87 Lesions may present
de novo or arise in association with typical cutaneous papules. It occurs
in childhood, often affecting the underlying periosteum and involving pre-
dominantly the lower legs (particularly the tibia), feet, buttocks, hands,
and head.88 Lesions may also present on the penis or eyelid.89,90 An excep-
tional case of numerous lesions limited to the scalp of a child which
regressed spontaneously has been reported.91 A further patient presented
with a periorbital subperiostal lesion and in another patient the lesion was
congenital.92,93 In one study of 47 patients, the mean age was 4.3 years.88
In some instances, there is a past ­history of trauma. By definition, such
children do not have rheumatoid arthritis or rheumatic fever. The lesion
usually regresses after several years. However, recurrences appear in 19%
of patients.88
Papular granuloma annulare
Papular granuloma annulare presents as flesh-colored or hypopigmented,
1–3-mm diameter papules on the dorsal aspect of the hands, usually in male
children. Occasional lesions may be umbilicated or generalized (Figs 9.32,
9.33).94
Linear granuloma annulare
The linear variant is very rare and may have a bilateral distribution.95,96
Rarely, it may follow Blaschko's lines.97 This variant overlaps and may in
some cases be the same as the condition described as interstitial granuloma-
tous dermatitis.
Pathogenesis and histological features
The cause of granuloma annulare is unknown. The original concept that it
represented a tuberculid has long since been discounted. Although it has been
reported at the site of previous herpes zoster infection and verruca vulgaris,
it is unlikely that an infectious pathogenesis exists. Borrelia has been dem-
onstrated by focus-floating microscopy in a number of biopsies of patients

Fig. 9.32
Papular granuloma annulare: widespread papules are present on this patient’s back
and shoulders. By courtesy of the Institute of Dermatology, London, UK.
Fig. 9.33
Papular granuloma annulare: numerous small, scaly papules are present.
By courtesy of the Institute of Dermatology, London, UK.
with granuloma annulare raising the possibility of a pathogenetic role for
the organism in some cases of the disease.98 However, a study based on PCR
found no association between granuloma annulare and Borrelia infection.99
There is a wide variety of currently possible pathogenetic mechanisms, most
of which have some merit, but none of which satisfactorily clarifies the pre-
cise mechanism by which the lesions of granuloma annulare develop.100
Particularly popular are an immune complex vasculitic process and a cell-
mediated delayed hypersensitivity reaction. Evidence in favor of the former
has been the detection, by direct immunofluorescence, of immunoreactants
(IgM and complement) in blood vessel walls in some patients.100 Elevated lev-
els of circulating immune complexes have also been recorded.101 The histology
may reveal features suggestive of a vasculitic process, including endothelial
swelling, vessel wall thickening (due to the deposition of PAS-positive mate-
rial), vascular occlusion, and necrosis (Fig. 9.34).102 All of the latter changes
may, of course, develop as a consequence of the inflammatory process rather
than cause it. A recent study of serial sections of 38 biopsies in 35 patients
found no evidence of a vasculitic process in any of the cases.103
In favor of a cell-mediated delayed hypersensitivity reaction are:
• the finding of activated T-lymphocytes in lesions of granuloma annulare
on electron microscopic examination,
Granuloma annulare 291
Fig. 9.34
Granuloma annulare: view through the edge of a necrobiotic focus. In the center a
small blood vessel shows fibrinoid necrosis with occlusion. This is an uncommon
finding.
• the predominance of T-helper inducer cells in the infiltrate,
• the histopathological resemblance of the infiltrate to that of conditions of
known delayed hypersensitivity pathogenesis, including sarcoidosis and
tuberculosis.104
It has been suggested that Th1 lymphocytes expressing interferon-gamma
induce a delayed hypersensitivity reaction leading to macrophages becoming
aggressive effector cells that express tumor necrosis factor-alpha and matrix
metalloproteinases.105 If tumor necrosis factor alpha plays a role in the induc-
tion of the disease, then agents that block this cytokine may be useful in
treating the condition. Although some patients respond to these agents other
do not and the reason for this is not clear. Monozygotic twins with general-
ized granuloma annulare and the 8.1 ancestral haplotype, a genotype that
leads to increased production of tumor necrosis alpha, have responded well
to adalimumab.106
Patients with granuloma annulare may have raised serum migration
inhibition factor activity.87 Defective neutrophil migration has also been
reported.107,108 Other proposed pathogenetic mechanisms include collagen
damage by macrophage lysosomal hydrolytic enzymes as the initial event,
or a primary disorder of collagen leading to an allergic or nonallergic tissue
reaction. The increased incidences of diabetes mellitus and HLA-B8 may
also be of pathogenetic significance (compare with necrobiosis lipoidica).109
In a study of a group of pediatric patients with multiple lesions of granu-
loma annulare it was found that they had significantly lower serum insulin
values than the control group and showed mild impairment of glucose tol-
erance.110 However, these children, often had a family history of diabetes
mellitus.
Although there are reports of generalized granuloma being associated with
sunlight, this appears to be of doubtful significance.2
It has been shown that the glioma-associated oncogene homologue ­gli-1,
a member of the vertebrate zinc finger transcription factor genes of the gli
superfamily is highly expressed in a number of granulomatous disorders
including granuloma annulare.111 The relevance of this in the pathogene-
sis of granuloma annulare is not clear but it raises the possibility of using
inhibitors of gli-1 signaling in the treatment of granulomatous noninfectious
diseases.
The most characteristic histological lesion seen in granuloma annulare is
the palisading granuloma (Figs 9.35–9.38). This consists of a central core of
degenerate (necrobiotic) collagen, surrounded by an often radially arranged
infiltrate of lymphocytes, histiocytes, and fibroblasts. Elastic tissue may be
absent within these foci and there can be phagocytosis of elastic fibers by
giant cells at the periphery of the granuloma (Fig. 9.39).112 However, altered
elastic fibers are not a constant finding. Solar elastosis is not a feature of
granuloma annulare. In some lesions the altered collagen has a somewhat
292 Granulomatous, necrobiotic and perforating dermatoses
Fig. 9.35
Localized granuloma annulare: the characteristic appearance of a well-circumscribed
palisading granuloma consisting of a necrobiotic center surrounded by a cellular
infiltrate.
Fig. 9.36
Localized granuloma annulare: the collagen is fragmented and in part granular. Note
the peripheral palisade of histiocytes, occasional lymphocytes, and fibroblasts.
basophilic appearance due to the presence of acid mucopolysaccharides, but
more commonly there is eosinophilia, due in part to fibrin deposition (Fig.
9.40). Heparin sulfate is an important component of the mucin in granuloma
annulare but not of other cutaneous diseases associated with mucin deposi-
tion (Fig. 9.41).113
Occasionally, sparse karyorrhectic debris is present in the center of the
lesion and sometimes the necrobiotic foci contain lipid droplets. More
often, however, the collagenous degeneration is not organized into a nod-
ular pattern, but affects isolated fibers in a random pattern, an appear-
ance often best appreciated on low-power examination (Fig. 9.42).114 In
this so-called diffuse or interstitial form of granuloma annulare, affected
fibers, which are swollen and intensely eosinophilic, alternate with appar-
ently normal fibers to give a rather disorganized appearance (Figs. 9.43,
9.44). Necrobiosis is minimal or absent. Characteristically, the collagen
fibers are separated by mucin, which stains positively with Alcian blue at
pH 2.5. Histiocytes are often seen infiltrating around and between affected
fibers, and this feature may be a helpful clue to the diagnosis in early
Fig. 9.37
Localized granuloma
annulare: this lesion is
from the palm of the
hand, an uncommonly
affected site. There is a
sharply delineated focus
of necrobiosis in the deep
reticular dermis.
Fig. 9.38
Localized granuloma annulare: the necrobiosis is advanced, presenting as eosinophilic
granular debris. The histiocytic palisade is well established.
cases when the collagen changes are inconspicuous and should, therefore,
encourage examination of additional sections to detect more typical features
(Fig. 9.45).
An almost inevitable feature of granuloma annulare is the presence of a
perivascular chronic inflammatory cell infiltrate, both within the lesion and
in the adjacent tissue. Well-formed sarcoidal granulomata with associated
giant cells are seen in some cases. Significant numbers of eosinophils may be
encountered.115 In one study, eosinophils were present in 66% of biopsies, of
which 14% showed more than 10 eosinophils per high-power field.115 Plasma
cells are rare and this is useful in the differential diagnosis with necrobiosis
lipoidica (see below). Neutrophils are a rare finding and when present, par-
ticularly in association with changes of vasculitis, it is likely that there is an
association with systemic disease.116
 Granuloma annulare 293

Fig. 9.39 Fig. 9.42

Localized granuloma annulare: there is loss of elastic tissue within the granuloma. Diffuse granuloma annulare: the collagen bundles are arranged haphazardly. Note
Elastic-van Gieson. the circumferential lymphocytic infiltrate.

Fig. 9.40 Fig. 9.43

Localized granuloma annulare: the red-staining material in the center of the Diffuse granuloma annulare: individual fibers are swollen and intensely eosinophilic.
granuloma is fibrin. Martius scarlet blue. The apparent separation of the fibers is due to increased mucin.

Fig. 9.41 Fig. 9.44

Localized granuloma annulare: in this example there is abundant mucin in the Diffuse granuloma annulare: higher-power view showing the dense interstitial
center of the necrobiotic focus. Alcian blue stain. histiocytic infiltrate.
294 Granulomatous, necrobiotic and perforating dermatoses

Fig. 9.45 Fig. 9.47

Diffuse granuloma annulare: high-power view. Perforating granuloma annulare: close-up view showing the dermal perforation and
transepidermal elimination of collagenous debris.

Fig. 9.46
Perforating granuloma annulare: scanning view showing widespread typical Fig. 9.48
granuloma annulare (in the upper-right quadrant degenerate collagen is undergoing Subcutaneous granuloma annulare: within the subcutaneous fat and involving the
transepidermal elimination). fascia is a massive necrobiotic nodule.

Although the relationship with Borrelia infection is debatable, it has been

suggested that formation of pseudorosettes in granuloma annulare may sug-
gest infection with the organism.117
In perforating granuloma annulare the necrobiotic debris is present in
close proximity to the epidermis and may be seen to be engulfed by the latter
to form a perforating channel by which the necrotic material is extruded to
the surface (Figs. 9.46, 9.47). If serial sections are performed, the perforation
is often shown to occur through a hair follicle.
The subcutaneous lesions are much larger than the superficial ones
(Figs. 9.48, 9.49) and are frequently composed of multiple nodules. There is
­usually massive necrobiosis and abundant mucin; on occasions, lipid droplets
are evident. Mucin, however, may be minimal or not apparent and if fibrin
deposition is present, distinction from rheumatoid nodule is impossible.
A dense rim of lymphocytes, histiocytes, and fibroblasts surrounds the necro-
biotic center. Multinucleate giant cells are common and eosinophils are often
present. The latter appear to be more common in this variant than in ordinary
granuloma annulare. Fibrosis of the surrounding tissue may be marked. In
up to 25% of cases of subcutaneous granuloma annulare, changes of classic
granuloma annulare may be seen in the dermis.118 Fig. 9.49
Papular and linear variants show histological features similar to those Subcutaneous granuloma annulare: note the intensely eosinophilic necrobiosis and
described for typical granuloma annulare. surrounding fibrosis.
 Necrobiosis lipoidica 295

Differential diagnosis
Granuloma annulare must be distinguished from necrobiosis lipoidica,
­rheumatoid nodule, actinic granuloma, and granuloma multiforme. Points of
­distinction are summarized in Table 9.1.
Granuloma annulare-like lesions with the added features of vasculitis and
a significant component of acute inflammatory cells may be encountered in
the setting of systemic disease.116,119 This pattern of disease is discussed in
detail in the section on palisaded neutrophilic and granulomatous dermatitis
and related disorders.
Granuloma annulare-like drug eruptions have been reported. The ­presence
of associated interface changes favors a drug eruption.10,120
Very rarely, scleromyxedema may focally mimic interstitial granuloma
annulare histologically.121 However, the changes simulating granuloma annu-
lare are focal, and elsewhere in the biopsy there are more typical features of
scleromyxedema including fibrosis and increase in fibroblasts.
Occasionally, infection by Mycobacterium marinum may mimic intersti-
tial granuloma annulare. The microscopic features may be so similar that the
diagnosis can only be made by special stains and culture.122
Although epithelioid sarcoma, with its associated geographic necrosis,
may bear a superficial resemblance at low-power examination to granuloma
annulare, the degree of nuclear atypia and pleomorphism in the former con-
dition should afford their distinction in the majority of cases. In addition,
epithelioid sarcoma often shows perineural tumor infiltration. It should be
noted, however, that mitotic activity may be encountered in granuloma annu-
lare.123 In difficult cases, keratin, epithelial membrane and, in up to 60% of
cases, CD34 antigen immunoreactivity in epithelioid sarcoma should assist in
this differential diagnosis.
Rare cases of mycosis fungoides may be associated with a tissue reac-
tion resembling granuloma annulare.124,125 The presence of interstitial
­lymphocytes with nuclear atypia and epidermotropism, a feature not seen
in granuloma annulare, should resolve this differential diagnosis. However,
in difficult cases, immunophenotyping and gene rearrangement studies may
be required.
Necrobiosis lipoidica
Clinical features
Necrobiosis lipoidica is a disease of unknown etiology which shows a strong
association with diabetes mellitus.1–6 Although the affiliation is likely to
have pathogenic implications, the precise mechanism by which the lesions
of necrobiosis lipoidica develop is, nevertheless, unknown and the nature
of the relationship between the two diseases is unclear. Therefore, although
the diagnosis of diabetes is most often established before the onset of the
skin lesions, on occasion, typical plaques may precede the apparent onset
of ­diabetes ­mellitus by several years. The course of the cutaneous disease
does not appear to be related to the hyperglycemia, and treatment of diabetes
does not affect the outcome of the cutaneous lesions. In one study, proteinu-
ria, retinopathy, and smoking were more common in patients with necro-
biosis ­lipoidica compared with patients with diabetes but no skin disease.7
Interestingly, however, only a minority of patients with necrobiosis lipoidica
has diabetes mellitus. It has been shown that 11% of patients with necrobio-
sis lipoidica have diabetes mellitus and a further 11% develop the disease or
altered glucose tolerance on follow-up.8
Necrobiosis lipoidica may develop in both juvenile (type I) and ­maturity-onset
(type II) diabetes. Interestingly, the condition improves in ­diabetic patients
after pancreatic transplant.9 Necrobiosis lipoidica has been ­documented in
patients with endocrine disorders other than diabetes such as hypo- and
hyperthyroidism, and also in association with inflammatory bowel disease
and vasculitis.10 One nondiabetic patient with necrobiosis lipoidica and
ataxia telangiectasia has been reported.11 Exceptionally, necrobiosis lipoidica
and granuloma annulare have presented simultaneously.12,13 The ­disease has
also been documented in association with sarcoidosis.14,15
Necrobiosis lipoidica shows a marked female preponderance (3.3:1) and,
although a wide age range may be affected, patients present most often in the
fourth decade (those associated with diabetes mellitus) or fifth decade (those
not associated with diabetes mellitus). The condition is rare in childhood

Table 9.1
Differential diagnosis of palisading granulomata and variants

Granuloma Subcutaneous Necrobiosis Rheumatoid Actinic Granuloma

annulare (GA) GA Perforating GA lipoidica (NL) Atypical NL nodule granuloma multiforme
Epidermis Normal Normal Transepidermal Normal or Normal Normal Normal or Normal
elimination atrophic or atrophic
acanthotic
Location of Superficial Deep dermis Superficial Deep dermis Upper and Deep dermis Upper and Upper and mid
lesion dermis and subcutis dermis and subcutis mid dermis and subcutis mid dermis dermis
Necrobiosis Circumscribed Massive sharp Circumscribed Diffuse and Rarely Massive Absent Focal
or ill defined border marked present sharp margin
Mucin Common Abundant Common Variable Absent Common Absent Present
Lipid Occasional Variable Variable Common Absent Variable Absent Absent
Fibrosis Absent Marked Absent Common; may Absent Common Usually Slight
be marked absent
Loss of elastica Yes Yes Yes Yes Yes Yes Very marked Yes
Vascular Common Variable Minimal Common Absent Variable Absent Absent
thickening
Capillary Absent Common Absent Variable Absent Common Absent Absent
hyperplasia
Giant cells Relatively few Common Relatively few Common Common Relatively Abundant; Common
few contain elastica
Asteroid bodies Absent Absent Absent Absent Present Absent Not Absent
uncommon
Palisading of Common Common Common Variable Absent Common Infrequent Inconspicuous
histiocytes degree in

Reprinted from Muhlbauer JE. Granuloma annulare. J Am Acad Dermatol 3:217–230; Copyright Elsevier 1980, with permission from the American Academy of Dermatology, Inc.
296 Granulomatous, necrobiotic and perforating dermatoses

and is often associated with diabetes mellitus. It also appears to be related to

underlying renal and retinal disease.16–20 Familial cases may also occur, with
or without, diabetes.21–23 A case of monozygotic twins with diabetes mellitus
type 2 and necrobiosis lipoidica has been reported.24
The characteristic lesion, sometimes referred to as a sclerodermatous
plaque, is round or oval, circumscribed, and often has a slightly elevated
rim. It is typically a few millimeters to several centimeters in diameter.
Newly acquired lesions are often red-brown in color, but with progression
the center of the lesion becomes yellowish and the peripheral border may
acquire a violaceous hue. Larger plaques are usually irregular and more
variably shaped. Scaling and telangiectasia may become evident. Ulceration
appears to be relatively frequent and has been reported in up to 13% of
patients.25–27 Perforating necrobiosis lipoidica is very rare and may be seen
very exceptionally in children.28,29 In perforating cases, the clinical appear-
ance may consist of a focal scaly depression or comedone-like lesions.
Atypical forms may also be found: patients sometimes manifest papules
and nodular lesions, and occasionally plaques resembling granuloma annu-
lare are seen. (It should be noted, however, that rarely these two conditions
appear to coexist.)12,30 Clinical presentations with papulonecrotic and nod-
uloulcerative lesions mimicking gummata or erythema induratum have been Fig. 9.51
documented, albeit exceptionally.25 The lesions may be solitary or multiple, Necrobiosis lipoidica:
often symmetrical, and show a predilection for the lower extremities, in typical lesion with an
erythematous border.
particular the pretibial area (Figs 9.50–9.53). They can also occur on the
From the collection of the
arms, hands, fingers, abdomen, nipples, and back; rarely the face or scalp
late N.P. Smith, MD, the
is affected, in which case diabetes is seldom present.31 Generalized lesions Institute of Dermatology,
may exceptionally occur.32 London, UK.
It is doubtful whether the so-called atypical necrobiosis lipoidica of the
face and scalp represents a variant of necrobiosis lipoidica. The name was
chosen because of the coexistence of typical lesions of necrobiosis lipoid-
ica on the shins of one of the patients in the original series. However, most
patients do not present with classic lesions of necrobiosis lipoidica elsewhere
and the microscopic findings do not resemble the latter entity.33
Involvement of the penis with lesions resembling chronic balanitis has been
described.34–36 Rarely, lesions are associated with Koebner's phenomenon.37–39
Necrobiotic and silicotic granulomata developing within phlebectomy scars
have also been reported.40
The disease tends to chronicity. It is of interest that necrobiosis lipoid-
ica has been reported to be associated with cutaneous hypo- or complete
anesthesia in both diabetic and nondiabetic patients.41,42 One study found

Fig. 9.52
Necrobiosis lipoidica: lesion on shin showing atrophy and telangiectasia.
From the collection of the late N.P. Smith, MD, the Institute of Dermatology,
London, UK.

loss of nerves within lesions and, based on this finding, the authors pos-
tulated that destruction of nerves might explain the sensory loss that is
observed in some patients.42,43 Hypohidrosis and partial alopecia have also
been reported.44
Rarely, squamous carcinoma may arise in longstanding lesions.45–49
One such case developed in association with perforating necrobiosis
lipoidica.50
Fig. 9.50
Necrobiosis lipoidica: Pathogenesis and histological features
characteristic, bilateral,
symmetrical lesions.
The precise pathogenesis of necrobiosis lipoidica is unknown. Of primary
From the collection of the importance is the temporal relationship between collagen degeneration and
late N.P. Smith, MD, the the inflammatory infiltrate.51 The close association of necrobiosis lipoidica
Institute of Dermatology, and diabetes mellitus suggests a causal relationship, but the exact mechanism
London, UK. is uncertain. In the past, some 60% of patients with necrobiosis ­lipoidica were
 Necrobiosis lipoidica 297

Gli-1, the glioma-associated oncogene homologue, has been found to be

Fig. 9.53
Necrobiosis lipoidica:
chronic lesion with
ulceration and crusting.
From the collection of the
late N.P. Smith, MD, the
Institute of Dermatology,
London, UK.
expressed in a number of granulomatous skin disorders including necrobiosis
lipoidica.64 The explanation for this is not clear but it suggests that inhibitors
of gli-1 may be used in the treatment of the disease.
Recently, spirochetal microorganisms, likely to be Borrelia, have been
identified in lesions of necrobiosis lipoidica in patients from central Europe.65
The significance of this finding is unclear.
The histopathological features are variable, depending to some extent on
the presence or absence of coexistent diabetes mellitus.66,67 The palisading
granuloma with necrobiosis is more typical of the diabetes-related variant,
whereas a granulomatous sarcoidal type of reaction is more often a feature
of nondiabetes-related necrobiosis. Nevertheless, there is very considerable
overlap and in the majority of cases one cannot predict, on histological
grounds alone, which cases are, and which are not, diabetes-related.
The epidermal changes are usually inconspicuous or absent. There may,
however, be acanthosis or atrophy, and hyperkeratosis is not uncommon.
The hallmark of necrobiosis lipoidica is the palisading necrobiotic granu-
loma. Large, often confluent areas of necrobiosis are present, usually centered
in the lower dermis, although the superficial dermis and subcutaneous fat may
also be affected (Figs 9.54–9.56). When the subcutaneous fat is involved,
the changes are seen mainly in the septa. The foci of necrobiosis consist of

reported as having coexistent diabetes mellitus.2,4,52,53 However, its reported

prevalence in diabetes is only of the order of 3/1000.51 Furthermore, a recent
study has found that only a minority of patients with necrobiosis lipoidica
have diabetes.8
It has been suggested that the lesions develop as a consequence of diabetic
microangiopathy: the vessel walls in lesions of necrobiosis lipoidica are typi-
cally thickened by a diastase-resistant PAS-positive material. This does not
explain the development of necrobiosis lipoidica in nondiabetic patients or
the absence of the disease in patients with established microvascular lesions.
An association with venous insufficiency and hypercholesterolemia has been
suggested in a very small group of patients.54 The significance of this finding is
therefore unclear. Study of microcirculation by Doppler flowmetry and ­oxygen
partial pressure in necrobiosis lipoidica lesions in nondiabetics has demon-
strated an altered microcirculation.55 Low oxygen and high carbon dioxide
pressures, presumably reflecting ischemia, characterize necrobiotic plaques.56
Such vascular changes, although possibly causal, could equally well develop as
a consequence of the necrobiotic changes. Aberrant platelet aggregation may
also play a role in pathogenesis. Platelet survival times are markedly reduced
in patients with necrobiosis lipoidica.57 Whether this is of pathogenic impor-
tance is uncertain.
Autoantibodies against cytoskeleton proteins have been observed in sera
from patients with necrobiosis lipoidica. These autoantibodies (IgG anti-
troponin, antidesmin, antikeratin, anti-insulin, antitrinitrophenol, and IgA
and IgM antikeratin) were found to be elevated in patients with necrobiosis
lipoidica compared with diabetic patients without evidence of necrobiosis
lipoidica.58 What role, if any, these autoantibodies play in the pathogen-
esis of necrobiosis lipoidica is unclear. Synthesis of collagen by fibroblasts
cultured from lesions is decreased compared with fibroblasts from normal
skin.59
Also of uncertain significance is the reported detection, by immunofluo-
rescence, of immunoreactants (IgM and C3) in blood vessel walls in some
cases of necrobiosis lipoidica.60,61 Epidermal dendritic S-100-positive cells are
increased in number.62 Whether this reflects an immunological aspect to the
development of necrobiosis lipoidica has yet to be determined.
Glut-1 (the human erythrocyte glucose transporter) is expressed by the
fibroblasts in areas of sclerotic collagen from biopsies of patients with necro-
biosis lipoidica.63 This raises the possibility of an altered transport of glucose Fig. 9.54
in the affected areas contributing to the histopathological features seen in this Necrobiosis lipoidica: the epidermis is unaffected; there is extensive necrobiosis in
disease. the reticular dermis. A heavy chronic inflammatory cell infiltrate is present.
298 Granulomatous, necrobiotic and perforating dermatoses

e­ osinophilic, swollen or degenerate collagen, often appearing hyalinized with

a surrounding infiltrate of variable numbers of lymphocytes and histiocytes
(Fig. 9.57). Aggregates of lymphoid cells, with or without germinal center
formation, are frequently found.68 Plasma cells are almost invariably ­present.
In a single case, the plasma cell infiltrate was mononclonal, and ­further
­investigations revealed an underlying monoclonal gammopathy.69 The necro-
biotic foci sometimes contain mucin. Palisading is variable, being more con-
spicuous in those instances associated with a heavy inflammatory cell infiltrate.
The areas of necrobiosis are associated with loss of elastic tissue (Fig. 9.58).
Usually, epithelioid histiocytes and giant cells are evident and sometimes there
are well-formed granulomata resembling the sarcoidal type of necrobiotic his-
tological reaction (see below) (Fig. 9.59). Very rarely, asteroid bodies are iden-
tified.70 Lipid droplets, best seen with oil red O or Sudan IV staining on frozen
tissue, are almost invariably present in the necrobiotic foci. Usually, a mild to
moderate perivascular lymphocytic infiltrate is seen in the adjacent dermis.
Cholesterol clefts are rare and only exceptionally may be prominent.71,72
A careful search often reveals vascular changes in necrobiosis lipoidica. These
consist of blood vessel wall thickening, with intimal proliferation and narrow-
ing of the lumen. Occasionally thrombi are noted. Sometimes increased num-
Fig. 9.55 bers of vessels are a feature. The vascular changes are more obvious in patients
Necrobiosis lipoidica: the lesion extends down to the subcutaneous fat.

Fig. 9.56 Fig. 9.58

Necrobiosis lipoidica: high-power view of Figure 9.54. Necrobiosis lipoidica: note the complete absence of elastic tissue. Elastic-van
Gieson.

Fig. 9.57 Fig. 9.59

Necrobiosis lipoidica: the degenerate collagen is surrounded by a palisade of Necrobiosis lipoidica: there is a granulomatous infiltrate with conspicuous
histiocytes, lymphocytes, and fibroblasts. multinucleate giant cells.
 Necrobiosis lipoidica 299

with associated diabetes mellitus or other systemic disease. These changes are
particularly severe in those cases where necrobiosis is very marked. One study
also showed that neutrophilic and granulomatous vasculopathies correlated
with systemic disease.73 In addition, telangiectatic superficial venules are a com-
mon feature. Cases with necrobiosis-like features and significant vasculitis and
neutrophilic infiltrates in the setting of systemic disease are discussed in detail
in the section on palisaded neutrophilic and granulomatous dermatitis associ-
ated with systemic disease. In lesions with anesthesia, S-100 shows destruction
of nerve fibers in the areas of necrobiosis.42,43
In the diffuse variant there is very widespread necrobiosis with a mini-
mal inflammatory cell response; such cases are usually associated with dia-
betes (Fig. 9.60). Sometimes linear infiltrates of histiocytes between collagen
fibers are a feature, as in granuloma annulare. Lipomembranous fat necrosis
is noted in occasional cases.74
In the sarcoidal type of necrobiosis lipoidica, which is more often noted
with the nondiabetes mellitus-associated variant, the appearances are those
of naked ­epithelioid cell granulomata, particularly in the lower dermis
(Fig. 9.61). Langhans and foreign body giant cells are usually ­conspicuous
and a ­lymphocytic and plasma cell infiltrate may be evident (Fig. 9.62).
Necrobiosis is usually ­minimal; multiple levels may have to be examined Fig. 9.61
Necrobiosis lipoidica (granulomatous variant): well-defined noncaseating granulomata
before its ­presence is ­confirmed (Fig. 9.63). The sarcoidal type of necrobiosis
replace the reticular dermis. Necrobiosis is present to the left of center.
lipoidica in patients without ­diabetes mellitus has in the past been described as
Miescher's granuloma.
Perforating necrobiosis lipoidica is associated with transepidermal
­elimination of necrobiotic collagen and also degenerated elastotic material
(Figs 9.64–9.66).71,75,76

Differential diagnosis
Necrobiosis lipoidica must be distinguished from granuloma annulare, rheu-
matoid nodule, actinic granuloma, and granuloma multiforme. Points of
­distinction are summarized in Table 9.1. The presence of massive necrobio-
sis associated with numerous cholesterol clefts, bizarre multinucleated giant
cells, and Touton-type giant cells distinguishes necrobiotic xanthogranu-
loma from necrobiosis lipoidica. As noted above, prominent cholesterol cleft
­formation, which is a feature that usually suggests necrobiotic xanthogranu-
loma, may rarely be seen in necrobiosis lipoidica.66,67 Small punch ­biopsies
may not be adequate for definitive evaluation and sampling bias may be
­misleading. Clinical correlation should be taken into consideration before
making a final diagnosis.

Fig. 9.62
Necrobiosis lipoidica (granulomatous variant): the naked granulomata are very
reminiscent of sarcoidosis. Note the multinucleate giant cells.

Fig. 9.60
Necrobiosis lipoidica
(diffuse variant): a
broad band of confluent Fig. 9.63
necrobiosis has destroyed Necrobiosis lipoidica (granulomatous variant): higher-power view of the necrobiotic
the entire reticular dermis. focus seen in Figure 9.61.
300 Granulomatous, necrobiotic and perforating dermatoses
Fig. 9.64
Perforating necrobiosis lipoidica: there is widespread hyperkeratosis and crusting.
A perforating channel is seen on the right side of the picture.
Fig. 9.65
Perforating necrobiosis:
close-up view of the
perforating channel.
Rheumatoid nodule
Clinical features
Rheumatoid nodules are subcutaneous lesions that develop at sites of trauma
or at pressure points in approximately 30% of adults with rheumatoid arthri-
tis.1–3 They are most commonly found on the extensor aspect of the forearms
and elbows (particularly the olecranon process), the feet, knees, knuckles,
buttocks, scalp, and back (Figs 9.67, 9.68).4 They have also been described
involving a wide variety of other sites, including the abdominal wall, heart
(pericardium, myocardium, and valves), larynx, lungs, pleura, splenic cap-
sule, peritoneum, mesenterium, eye, bridge of nose, pinna, ischial tuberosity,
thyrohyoid membrane, and Achilles tendon.5,6 Lesions are often fixed to the
underlying periosteum or deep fascia. They present as firm, asymptomatic,
dome-shaped masses in the subcutaneous fat or deeper tissues and measure
Fig. 9.66
Perforating necrobiosis:
the dermis immediately
beneath the site of
perforation shows severe
necrobiotic change.
Fig. 9.67
Rheumatoid nodules: lesions on the knuckles are commonly seen in rheumatoid
arthritis. By courtesy of Dr J.C. Pascual, MD, Alicante, Spain.
from several millimeters to 5 cm in diameter. Numbers may vary from one to
over a hundred. Ulceration sometimes occurs. Intrapulmonary rheumatoid
nodules have been exceptionally associated with leflunomide in a patient with
rheumatoid arthritis.7 A case of large cavitary pulmonary lesions in a patient
with HIV has been reported.8
Rheumatoid nodules are more commonly found in patients with severe
rheumatoid arthritis and are associated with a high titer of rheumatoid fac-
tor, joint erosions, and an increased incidence of rheumatoid vasculitis.9
They are not, however, specific for rheumatoid arthritis, being found in
approximately 5–7% of patients with SLE (although in this condition they
tend to be localized about the hands) and occasionally in seronegative anky-
losing spondylitis.10,11 Clinically similar lesions have also been reported in
patients with scleroderma. Presentation of multiple rheumatoid nodules on
the fingers in association with little or no arthritis has been described as
rheumatoid nodulosis.12–14 This, however, can be associated with destruc-
tive arthritis.15 A similar name (cutaneous nodulosis) has been given to the
 Rheumatoid nodule 301

Fig. 9.68 Fig. 9.69

Rheumatoid nodule: close-up view. By courtesy of Dr J.C. Pascual, MD, Alicante, Rheumatoid nodule: there is massive necrobiosis with adjacent scarring and a
Spain. dense lymphocytic infiltrate. Rheumatoid nodules characteristically occur in the soft
tissues.

development of multiple small nodules at different sites during methotrexate

therapy for rheumatoid arthritis.16 Etanercept has been linked to the excep-
tional development of extensive pulmonary nodulosis while infliximab and
the aromatase inhibitor letrozole are associated with accelerated cutaneous
nodulosis.17–19

Pathogenesis and histological features

Although these lesions develop at sites of pressure and trauma (implying
pathogenetic significance), there is some evidence in support of an immune
complex-mediated pathogenesis, as both IgG and IgM have been detected
by immunofluorescence in the walls of blood vessels adjacent to rheumatoid
nodules.20 Similarly, both rheumatoid factor and complement have been dem-
onstrated within the substance of rheumatoid nodules. Localization of IgM
rheumatoid factor and terminal complement complexes C5b-9 has been dem-
onstrated on the luminal surface of endothelial cells in rheumatoid nodules.21
C4d has been shown in association with palisading macrophages and in areas
of fibrinoid necrosis, further supporting the role of complement activation in
the pathogenesis of the lesions.22 Proinflammatory cytokines and cell adhe-
sion molecules (TNF-α, IL-1β, IL-Ra RNA, E-selectin) have been shown in
rheumatoid nodules and are likely to play a role in mediating injury.23 The Fig. 9.70
Rheumatoid nodule: in this example, tendon can be seen on the right side of the
expression of cytokines in the rheumatoid nodule is very similar to that in
field.
the synovial lining in rheumatoid joints and suggests that the pathogenesis of
both is very similar and driven by Th1 lymphocytes.24 The cytokines involved
include IFN-γ, IL-1beta, TNF-α, IL-12, IL-18, IL-15, and IL-10.23 Although
massive central necrosis is predominant, apoptosis has been demonstrated
Differential diagnosis
throughout the nodule.25 In some cases of deep granuloma annulare the histological changes are similar
Rheumatoid nodules are typically located in the subcutaneous fat or to rheumatoid nodule. Deep granuloma annulare (‘pseudorheumatoid nod-
soft tissues although they may extend into the deeper reticular dermis. This ule’) tends to have more mucin deposition and less fibrin than typical rheu-
is in contrast to the more superficial location of both granuloma annu- matoid nodules.28 Therefore, the latter are referred to as ‘red’ granulomas
lare and necrobiosis lipoidica. They are multinodular and associated with and the former as ‘blue’ granulomas.29 However, some rheumatoid nodules
very extensive necrobiosis (Figs 9.69, 9.70). Fibrin deposition is often seen do contain mucin. Clinicopathological and serological correlation is advised
in the center of the nodule.26 Immunoglobulin, lipid, glycosaminoglycans, before establishing a definitive diagnosis.
and nucleoproteins may also be present. Old lesions are sometimes associ- Compared to rheumatoid fever nodule, rheumatoid arthritis nodules tend
ated with cyst formation due to liquefactive degeneration of the contents of to be better circumscribed and surrounded by a well-defined palisade of his-
the nodules. A well-developed palisade of histiocytes and occasional giant tiocytes. In addition, the fine fibrinoid strands that form the center of a rheu-
cells characteristically surrounds necrobiotic foci and fibrinoid material matic fever nodule contrast with the more dense sheet-like areas of necrobio-
(Fig. 9.71). Asteroid inclusions are not a feature. The outer layer is com- sis and fibrin deposition in the rheumatoid arthritis nodule.
posed of vascular granulation tissue, and in older lesions marked fibrosis Patients combining the features of severe rheumatoid arthritis with pali-
is a frequent accompaniment. An inflammatory cell infiltrate of lympho- sading granulomata accompanied by a neutrophilic infiltrate and leukocyto-
cytes, plasma cells, and eosinophils is often present. Leukocytoclastic vas- clastic vasculitis have been described.9 These lesions are discussed under the
culitis has occasionally been reported to affect the blood vessels in and rubric of palisaded neutrophilic and granulomatous dermatitis with vasculi-
around early nodules. A rare case with perforation of the epidermis has tis. In short, lesions showing these features may be associated with a number
been documented.27 of systemic diseases, including rheumatoid arthritis.
302 Granulomatous, necrobiotic and perforating dermatoses
Fig. 9.71
Rheumatoid nodule: the necrobiotic connective tissue is surrounded by a well-
developed histiocytic palisade.
Fig. 9.72
Rheumatoid nodule: the palisading histiocytes may sometimes show mitotic
figures which may lead the unwary to consider epithelioid sarcoma.
Although epithelioid sarcoma, with its associated geographic necrosis,
may bear a superficial resemblance at low power to rheumatoid nodule, the
degree of nuclear atypia and pleomorphism in the former should allow easy
­distinction between these conditions (Fig. 9.72). However, in difficult cases,
keratin and epithelial membrane antigen immunoreactivity in epithelioid
­sarcoma should assist in the differential diagnosis.
Elastolytic granulomata
This is a controversial group of diseases, the prototype of which is the actinic
granuloma. Other entities that probably belong to this group include atypical
facial necrobiosis lipoidica and granuloma multiforme (see below). It has been
suggested that all these conditions represent examples of granuloma annulare
occurring in different clinical settings.1–4 However, the clinicopathological
features are distinctive and the pathological process clearly relates to the pri-
mary destruction of elastic fibers by a granulomatous infiltrate. In granuloma
annulare, as in diseases such as sarcoidosis, destruction of ­elastic fibers does
not always occur and when it does, it tends to occur focally, ­developing as a
secondary phenomenon.5
Annular elastolytic giant cell granuloma
Clinical features
The term ‘annular elastolytic giant cell granuloma’ has been used to describe
not only cases of actinic granuloma but also lesions in which destruction of
elastic fibers occurs in the absence of solar elastosis.6 In fact, some cases pres-
ent at sites with little sun exposure and the disease may also occur in chil-
dren.7 Thus, although the terms actinic granuloma and elastolytic giant cell
granuloma have been used interchangeably in the literature, the latter term
should be reserved for elastolytic granulomata occurring in skin without solar
elastosis.8
Lesions usually present on the trunk and neck and rarely on proximal limbs.
They vary in size but tend to be large. Despite the name annular, some cases
present with papules or reticular erythema.9 In those that are annular there is
an advancing raised border which may be papular. Rarely, lesions are general-
ized.10 Spontaneous resolution is rare.9 A reported case describes a lesion that
developed at the site of an old burn scar and spread after trauma.11
Elastolytic granulomata have rarely been described in association with
adult T-cell leukemia lymphoma, primary cutaneous CD4-positive small/
medium-sized pleomorphic T-cell lymphoma, acute myelogenous leukemia,
and monoclonal gammopathy.12–14 Elastolytic granulomata have also been
documented in internal organs.15 The latter, however, probably represents
sarcoidosis with prominent elastolysis.
Pathogenesis and histological features
Elastic fibers become altered through an unknown mechanism and appear
to induce factor XIIIa-positive cells and CD68-positive macrophages to form
granulomata.16
Histological features may be identical to those of actinic granuloma (see
below) except for the absence of solar elastosis. Ideally, in annular lesions the
biopsy should be a wedge including the center, the advancing edge, and nor-
mal skin for comparison purposes. This is not always possible, particularly
in lesions that do not have an annular configuration. The center of the lesion
is completely devoid of elastic fibers and there is usually no inflammation.
The loss of elastic fibers appears to be irreversible.17 In the advancing margin
there is a granulomatous reaction with fragmentation and phagocytosis of
elastic fibers. In one case, histology showed features of mid-dermal elastolysis
­leading the authors to suggest that annular elastolytic giant cell granuloma
may possibly represent a prodromal or inflammatory stage of the disease.18
Differential diagnosis
Many granulomatous reactions, including infections, often display elas-
tophagocytosis. However, in these conditions the change is mild and focal.
In granuloma annulare, there is usually very little or no elastophagocytosis,
while in annular elastolytic giant cell granuloma there is no necrobiosis or
palisading granuloma.19
Actinic granuloma (O’Brien)
Clinical features
Actinic granuloma develops on the sun-damaged skin of the neck, face, upper
chest or arms of middle-aged patients.1–5 It may also affect the conjunc-
tiva, and a single case affecting the upper lip has been reported.6–9 A further
case presented as alopecia.10 The incidence is equal in men and women, and
­individuals with blond hair and freckled skin are predisposed, particularly
those living in sunny climates. An association with the longstanding use of
sunbeds and with doxycycline phototoxicity has also been described.11,12
Lesions present as one or more skin-colored or pink papules, which
enlarge to form annular or arcuate plaques up to 1 cm in diameter. The edge
of the lesion is somewhat raised, forming a border 0.2–0.5 cm in width.
These annular plaques enlarge slowly and the center may gradually clear to
appear ­relatively normal or slightly atrophic with variable depigmentation.
Lesions are asymptomatic and there is no evidence of anesthesia. They do not
develop on nonsun-damaged skin. Spontaneous resolution may take place
after months or years.
 Elastolytic granulomata 303

Bilateral periocular actinic granulomata have been documented in a patient

with renal failure.13 Other rare associations include relapsing polychondritis,
cutaneous amyloidosis, and giant molluscum contagiosum.14–16

Pathogenesis and histological features

The pathogenesis of actinic granuloma is poorly understood. It has been sug-
gested that the antigenic stimulus for the formation of granulomata in both
actinic granuloma and temporal arteritis is actinically degenerated elastic
tissue.17,18 Interestingly, phototesting in a single case failed to reproduce the
lesions of actinic granuloma.19
The features are best appreciated by examination of a radial biopsy
through the edge of a lesion and including uninvolved skin.20,21 The epidermis
may be normal or atrophic. The peripheral unaffected skin shows gross solar
(actinic) elastosis (Figs 9.73–9.75). Within the rim of the lesion there is a for-
eign body giant cell reaction in association with, and engulfing, fragmented
elastotic material (elastoclasis) (Figs. 9.76, 9.77).20,21 The granulomatous
reaction is centered in the zone of solar elastosis and, accordingly, tends to be
confined to the superficial dermis.22 The giant cells may contain asteroid bod-
ies. There is an accompanying chronic inflammatory cell infiltrate composed
Fig. 9.75
of histiocytes, lymphocytes, and plasma cells. Necrobiosis is not a feature Actinic granuloma: the granulomatous infiltrate is associated with degenerate
elastic fibers.

Fig. 9.73 Fig. 9.76

Actinic granuloma: a granulomatous reaction is present the superficial dermis Actinic granuloma: elastotic material is seen in the cytoplasm of the giant cell in the
surrounding an ill-defined necrobiotic process. Solar elastosis is evident. centre of the field.

Fig. 9.74
Actinic granuloma: in addition to solar elastosis, this example also shows interface Fig. 9.77
change with conspicuous cytoid bodies. Actinic granuloma: high-power view of basophilic degenerate elastic fibers.
304 Granulomatous, necrobiotic and perforating dermatoses

of this condition. Palisading of histiocytes is either absent or minimal and,

if present, is related to the elastotic debris. Dermal mucin does not appear
to be increased.22 Fibroblasts are scant and fibrosis is minimal. In the actinic
granuloma, blood vessels appear normal. Within the central zone the collagen
appears relatively normal, although it is more obviously horizontally aligned
and may appear more closely packed than normal. Slight scarring is present
in the central area where elastic tissue is absent.22

Differential diagnosis
The facial location, presence of elastophagocytosis, and absence of necro-
biosis aid in distinguishing actinic granuloma from other granulomatous
lesions. The absence of dermal mucin, necrobiosis, and palisading granu-
loma and the presence of marked elastoclasis and mild scarring help to distin-
guish actinic granuloma from granuloma annulare, the disorder that it most
resembles.14,23

Atypical facial necrobiosis lipoidica

Clinical features Fig. 9.79
This variant of necrobiosis lipoidica deserves separate mention because of its Atypical facial necrobiosis lipoidica: a dense granulomatous infiltrate occupies the
dermis.
unusual clinical features and distinctive histology.1–5 Atypical facial necro-
biosis lipoidica, which predominantly affects females (9:1), usually develops
in the absence of diabetes mellitus, and manifests most often in the fourth
decade. Patients present with one or more annular, nonscaling plaques on the
upper face and scalp, which typically have slightly raised, relatively uniform
borders and measure 1–5 cm in diameter (Fig. 9.78). Although early lesions
are erythematous with a brown border, older lesions are characterized by cen-
tral depigmentation. Atrophy, however, is minimal or absent. Patients may,
in addition, show involvement of other sites, including the arms, hands, and
trunk. Very rarely, patients have concomitant typical necrobiosis lipoidica on
the shins. It is for this reason that the name was originally coined. We now
believe, however, that the condition probably has no relationship whatsoever
to necrobiosis lipoidica. It is much more likely that it represents a variant of
an annular elastolytic granuloma.

Histological features
The condition is characterized by a dense granulomatous infiltrate, with con-
spicuous giant cells, involving the dermis (Figs 9.79, 9.80). The infiltrate has
a rather irregular distribution, being dispersed between individual collagen
bundles. Occasional circumscribed granulomata may sometimes be a feature.
Asteroid bodies are often found in the cytoplasm of giant cells. Typically,
there is loss of elastic tissue in the areas of granulomatous inflammation.
Fig. 9.80
Atypical facial necrobiosis lipoidica: close-up view of the granulomata. Note the
conspicuous giant cells.

Rarely, ill-defined foci of necrobiosis are noted (Fig. 9.81), but well-defined
palisading granulomata are not present. In cases with coexistent necrobiosis
lipoidica, biopsies from the affected areas on the shins show the typical histo-
logical features of this condition.

Differential diagnosis
In contrast to actinic granuloma with which this condition is often confused,
the surrounding skin does not show evidence of significant solar elastosis and
elastoclasis.

Fig. 9.78
Atypical facial necrobiosis lipoidica: atrophic plaque on forehead with a well-defined
edge. From the collection of the late N.P. Smith, MD, the Institute of Dermatology,
London, UK.
Granuloma multiforme
Clinical features
This dermatosis of unknown etiology is of particular importance because clin-
ically it can be confused with leprosy; however, it is not associated with cuta-
neous anesthesia.1,2 Granuloma multiforme, which shows a marked female
predominance, is seen most often in Central Africa, especially eastern Nigeria.
It has also been documented in the Congo, Uganda, India, and Tunisia.3–6
The disease is very common in some villages. It particularly affects patients
 Elastolytic granulomata 305

Fig. 9.81 Fig. 9.83

Atypical facial necrobiosis lipoidica: an ill-defined focus of necrobiosis is present. Granuloma multiforme: there are multiple large irregular plaques. By courtesy of the
Institute of Dermatology, London, UK.

over 40 years of age. Lesions, which tend to chronicity, are found on the
upper and exposed parts of the body. They commence as small, flesh-colored,
indurated, pruritic papulonodules, 1–8 mm in diameter and raised 1–3 mm
above the skin surface, which extend peripherally and coalesce to form annu-
lar lesions and plaques (Figs 9.82, 9.83). Very large lesions become irregular
and develop scalloped or gyrate borders. Central healing may be associated
with residual hypopigmentation.

Histological features
The epidermis is normal. Situated within the dermis is an ill-defined, irregu-
lar, necrobiotic lesion (Fig. 9.84).7 In general, this affects individual collagen
fibers, producing a rather haphazard picture of abnormal fibers interspersed
with unaffected ones and associated with a histiocytic infiltrate (Fig. 9.85).
Only rarely is a well-defined palisading granuloma seen. In addition to his-
tiocytes, giant cells are commonly found and the tissues show a perivascular
lymphocytic infiltrate with variable numbers of plasma cells and eosinophils.

Fig. 9.84
Granuloma multiforme: there is extensive necrobiosis.

Fig. 9.82
Granuloma multiforme:
typical annular lesions
with raised borders in a
child. By courtesy of R.A.
Marsden, St George’s Fig. 9.85
Hospital, London, UK. Granuloma multiforme: necrobiosis is seen in the center.
306 Granulomatous, necrobiotic and perforating dermatoses
Fig. 9.86
Granuloma multiforme: note the complete loss of elastic tissue. Elastic-van Gieson.
The giant cells do not contain asteroid bodies. Perineural involvement is not
a feature.1 The adjacent vasculature is normal. Loss of elastic tissue is typical
in relation to the inflammatory infiltrate and healed areas are characterized
by absence of elastic tissue and mild superficial scarring (Fig 9.86).1
Differential diagnosis
The exact nosological position of granuloma multiforme is unknown. It is
probably a clinicopathological variant of elastolytic granuloma. An associa-
tion with sun exposure has been suggested.8 The granulomata do not show
a perineural distribution, thus helping to distinguish granuloma multiforme
from leprosy. Nevertheless, since infection must be excluded before giving a
definitive diagnosis, stains for organisms (especially mycobacteria and fungi)
must be performed to exclude this possibility. Culture should also be per-
formed when clinically appropriate.
Rheumatic fever nodule
Clinical features
Fortunately, effective antimicrobial therapy has relegated rheumatic fever to
a rare pediatric infection. As a consequence, complications of rheumatic fever
are only rarely encountered in dermatology practice. In older studies, approx-
imately one-third of patients with rheumatic fever develop papules that had a
tendency to occur over bony prominence of the knee, elbows, fingers, ankles,
spine, scalp, and rarely at other sites.1–3 Most patients had multiple nodules.
In one report, the number of nodules ranged from 1 to 108.1 Lesions per-
sisted from days to several months. Interestingly, in a more recent study of
44 patients with rheumatic fever, only one had a single subcutaneous nodule.4
Histological features
Biopsy shows central gossamer fibrin associated with variable numbers of
neutrophils, lymphocytes, plasma cells, and karyorrhexis. The lesions are
often not well circumscribed and histiocytes surround the lesion, forming a
poorly defined palisade.
Differential diagnosis
The histological features of the rheumatic fever nodule are not pathog-
nomonic. Clinical correlation is required to establish a definite diagnosis.
The rheumatic fever nodule can be classified under the rubric of ‘palisaded
neutrophilic and granulomatous dermatitis associated with systemic dis-
ease’. Rheumatic fever nodule is discussed separately, however, because of
its historic interest and its longstanding recognition as a distinct clinical
entity. The differential diagnosis is therefore that of palisaded ­neutrophilic
and ­granulomatous dermatitis. Other systemic diseases, including con-
nective ­tissue disease, infection, ­vasculitis, neoplasia, and inflammatory
bowel ­disease, may be associated with lesions with similar histology. The
reader is referred to this section for a more detailed discussion of this
group of disorders. In short, a diagnosis of rheumatic fever nodule should
only be made in the setting of confirmed rheumatic fever. In the absence
of such history, a careful search for other underlying systemic diseases is
necessary.
Rheumatoid arthritis nodules tend to be better circumscribed and sur-
rounded by well-defined palisade of histiocytes. In addition, the fine fibrinoid
strands that form the center of a rheumatic fever nodule contrast with the
more dense sheetlike areas of necrobiosis in the rheumatoid arthritis nodule.
Necrobiotic xanthogranuloma
Clinical features
Necrobiotic xanthogranuloma (necrobiotic xanthogranuloma with parapro-
teinemia) is an extremely rare condition of unknown etiology.1–3 It occurs
equally in men and in women, in the late middle aged and elderly (average
age at presentation is 56 years). The disease is characterized by the develop-
ment of nodules and plaques, which show a predilection for the face, neck,
trunk and, less commonly, proximal limbs. The facial lesions are charac-
teristically periorbital (most often infraorbital) in distribution and consist
of papules that progress to nodules, and plaques that may form irregular
ulcers (Fig. 9.87). Although periorbital involvement is fairly constant, in
some patients this feature is absent.4,5 Scarring and telangiectasia are com-
mon. Lesions are sharply demarcated and have a distinctive xanthomatous
appearance. Ocular complications are common and include episcleritis,
­keratitis, proptosis, uveitis, and iritis.6 Some patients report pain but this is
not a usual feature.2
The lesions on the trunk and limbs are irregular, well-demarcated, bright
yellow, dermal and subcutaneous plaques measuring up to 25 cm across
(Fig. 9.88). They may be complicated by ulceration, hemorrhage, scarring,
central atrophy, and telangiectases, and typically have a peripheral inflam-
matory border. Violaceous and flesh-colored nodules are sometimes pres-
ent, particularly over the trunk. Unusual presentations include a solitary
nodular lesion mimicking a tumor and, exceptionally, the absence of skin
involvement.7,8 A lesion presenting at the site of a blepharoplasty scar and a
further lesion presenting in the scar of a burn have been reported.9,10
Involvement of myocardium, lung, larynx, kidneys, salivary gland,
and skeletal muscle has been documented.11–16 Patients may have arthritis,
chronic obstructive pulmonary disease, neuropathy or hypertension.2 Other
Fig. 9.87
Necrobiotic xanthogranuloma: indurated yellow plaques are present around both
eyes and on the eyelids. By courtesy of the Institute of Dermatology, London, UK.
 Necrobiotic xanthogranuloma 307

Fig. 9.88 Fig. 9.89

Necrobiotic xanthogranuloma: there are multiple yellow plaques around the shoulders Necrobiotic xanthogranuloma: there is a dense infiltrate extending throughout the
and overlying the clavicles. By courtesy of the Institute of Dermatology, London, UK. dermis into the subcutaneous fat.

reported cases include one associated with Graves' disease, another with
­linear ­morphea, one with scleroderma and one with lichen sclerosus.2,17–19 In
another patient there was an association with syncitial giant cell hepatitis.20
Nodular transformation of the liver is a feature noted in rare patients.14,21
Laboratory investigations reveal anemia, leucopenia, and a raised ESR.
Most patients with necrobiotic xanthogranuloma have an associated mono-
clonal paraproteinemia, usually IgG kappa type. Few present with a lambda
paraprotein and an exceptional case has been documented with two mono-
clonal paraproteins. Some patients have multiple myeloma or B-cell lym-
phoma.22–26 A case with associated Hodgkin's lymphoma has also been
reported.27 Diabetes mellitus is sometimes present and occasionally hyper-
lipidemia. Other associations that may be encountered include low serum
complement levels and cryoglobulinemia.

Pathogenesis and histological features

The pathogenesis of necrobiotic xanthogranuloma is unknown. The plasma
cells in the infiltrate are consistently polyclonal, supporting a reactive pro-
cess.3 Direct immunofluorescence has shown IgM, C3, and fibrinogen deposi-
Fig. 9.90
tion in blood vessel walls.6 It has more recently been suggested that activation
Necrobiotic xanthogranuloma: there is extensive necrobiosis and a dense histiocytic
of monocytes is responsible for the intracellular accumulation of lipoprotein- infiltrate with conspicuous giant cells.
derived lipids and the hypocholesterolemia.28 Focus-floating microscopy of
six cases demonstrated the presence of Borrelia.29 The significance of this
finding is unclear.
Necrobiotic xanthogranuloma has a very distinctive histological appear-
ance.6,26 Large areas of marked necrobiosis alternate with foci of xanthogran-
ulomatous infiltration throughout the reticular dermis with extension into
the subcutaneous fat (Fig. 9.89).4 Exceptionally, necrobiosis is absent.30
Involvement of the subcutaneous fat is predominantly in a septal distribution
and can mimic panniculitis.31 The necrobiotic collagen appears as amorphous
eosinophilic debris (Fig. 9.90). The granulomatous infiltrate is composed of
epithelioid and foamy histiocytes in addition to conspicuous giant cells, many
of which are of the Touton type (Figs 9.91, 9.92). Foreign body giant cells
are also present. Lymphocytes and plasma cells are often prominent and for-
mation of germinal centers is sometimes seen. A characteristic feature is the
presence of large and bizarre angulated giant cells with considerable numbers
of nuclei irregularly grouped together within copious eosinophilic cytoplasm
in the tissue immediately adjacent to foci of necrobiosis (Fig. 9.93). Asteroid
bodies, which are often found in the cytoplasm of giant cells, have been sug-
gested as a useful diagnostic finding.32 Frozen sections and oil red O staining
for fat may reveal focal lipid droplets. Cholesterol clefts and lipid vacuoles
are sometimes seen within the foci of necrobiosis and xanthogranulomatous Fig. 9.91
inflammation (Fig. 9.94). In rare cases, however, lipid deposition and giant Necrobiotic xanthogranuloma: in this field, there are conspicuous xanthomatized
cells are inconspicuous.33 The granulomatous and necrobiotic process may histiocytes.
308 Granulomatous, necrobiotic and perforating dermatoses

affect muscular arteries. Staining for elastic fibers reveals their absence in the
necrobiotic areas; Alcian blue staining may reveal small amounts of inter-
stitial mucin. As with most necrobiotic disorders, transepidermal elimina-
tion of necrobiotic collagen is sometimes a feature.34 A case with prominent
elastophagocytosis has been described.35The lungs and heart may show giant
cells, granulomata, necrobiosis or a combination of these features in patients
with systemic disease.12

Differential diagnosis
The clinical and histological features are distinctive: the presence of ­massive
necrobiosis associated with numerous cholesterol clefts, bizarre multinucle-
ated giant cells, and Touton-type giant cells distinguishes necrobiotic xan-
thogranuloma from necrobiosis lipoidica and other necrobiotic dermatoses.
It should, however, be noted that prominent cholesterol cleft formation may
rarely be seen in necrobiosis lipoidica.36 Small punch biopsies may not be ade-
quate for definitive evaluation and sampling bias may be misleading. Clinical
correlation should be taken into consideration before making a definitive
diagnosis.
Fig. 9.92
Necrobiotic xanthogranuloma: Touton giant cells are sometimes prominent.
Palisaded neutrophilic and granulomatous
dermatitis
Clinical features
Palisaded neutrophilic and granulomatous dermatitis (interstitial granu-
lomatous dermatitis) is a term that has been applied to a reaction pattern
of necrobiotic and granulomatous inflammation encountered in the setting
of systemic disease.1 Other terms that have been applied to similar, overlap-
ping and, in some cases, probably identical lesions, include interstitial granu-
lomatous dermatitis with arthritis, rheumatoid papules, superficial ulcerating
rheumatoid necrobiosis, cutaneous extravascular necrotizing granuloma, and
Churg-Strauss granuloma.1–6 Myriad underlying systemic diseases have been
purported to be associated with these lesions including rheumatoid arthri-
tis, lupus erythematosus, systemic sclerosis, Sjögren's syndrome, thyroiditis,
Raynaud's syndrome, hepatitis, inflammatory bowel disease, lymphoprolif-
erative disorders, myelodysplastic syndrome, vasculitis (Wegener's granulo-
matosis, Churg-Strauss syndrome, Takayasu's arteritis, periarteritis nodosa),
hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, mixed
cryoglobulinemia, drug reactions (especially sulfonamides), carcinoma, diabe-
tes, and infections (streptococcal, HIV, Epstein-Barr virus, parvovirus).1–4,7–12
Fig. 9.93 In most cases an underlying systemic disease is found, and it is rare that an
Necrobiotic xanthogranuloma: angulated giant cells with darkly staining nuclei are underlying disease is not detected.13
commonly present. The lesions are mainly located on the extremities and less commonly the
trunk in an adult.1 Children are seldom affected.14,15 The disease is character-
ized by papules and nodules, which are often arranged in a linear pattern.
These linear lesions may be confluent and have been described as linear bands
or cords with a ‘ropelike’ consistency (the so-called rope sign). Plaques have
also been described.6

Pathogenesis and histological features

Fig. 9.94
Necrobiotic xanthogranuloma: cholesterol clefts are a characteristic feature.
The pathogenesis of palisaded neutrophilic and granulomatous dermatitis
most likely depends on the associated/underlying disease. In a number of
cases autoantibodies, particularly anti-DNA in type, are found.16 It has been
suggested that the disease is mediated by immune complexes.17 Direct immu-
nofluorescence studies have demonstrated fibrin and IgM in the vasculature
of some patients.1
A variety of histological patterns have been described. These patterns may
be seen in the same or different biopsies from the same patient, emphasizing
the fact that they are not separate diseases.18 Some biopsies resemble the inter-
stitial variant of granuloma annulare without a well-defined palisade, loosely
organized histiocytes, and variable numbers of neutrophils with nuclear dust.
Fibrin is also seen. In fact, some would label these lesions as falling within the
spectrum of granuloma annulare.4 However, mucin deposition is not as marked
as seen in granuloma annulare and the changes are more ill defined. In other
­samples, ­palisaded histiocytes surround individual collagen bundles and in

Fig. 9.95
Palisaded neutrophilic and granulomatous dermatitis: an interstitial inflammatory
cell infiltrate is present in the center of the field, mimicking diffuse granuloma
annulare.
Fig. 9.96
Palisaded neutrophilic and granulomatous dermatitis: close-up view showing
necrobiosis, histiocytes, and neutrophils associated with karyorrhexis.
the ­background there is a neutrophilic infiltrate with karyorrhexis (Figs 9.95,
9.96). In late stages, fibrosis may be seen. The various changes described are
more likely to represent the evolution of the lesions. Variable numbers of eosino-
phils may be noted and, when present, appear to occur mostly in patients with
a peripheral eosinophilia. Frank leukocytoclastic vasculitis is present in some
cases.18 A few cases may resemble necrobiosis lipoidica.4
Differential diagnosis
From the above discussion it can be seen that a number of different terms
have been proposed to describe lesions resembling granuloma annulare or
rarely necrobiosis lipoidica but with the added features of acute and eosino-
philic inflammation, karyorrhexis and neutrophils with leukocytoclasia and
rarely with leukocytoclastic vasculitis. Some authors include these changes
within the spectrum of granuloma annulare and necrobiosis lipoidica.4 The
precise terminology preferred by the dermatopathologist is probably not
important. More significant than any nosological nuances is issuing a report
that alerts the clinician to the possibility that the patient may have underly-
ing systemic disease and that, when such lesions are encountered, appropriate
clinical evaluation is necessary.10
‘Metastatic’ Crohn’s disease 309
‘Metastatic’ Crohn’s disease
Clinical features
Patients with Crohn's disease may present with cutaneous and oral lesions,
the most frequent of which are aphthous stomatitis, pyoderma gangrenosum,
and erythema nodosum.1 Metastatic cutaneous lesions in Crohn's disease are
rare and defined as the presence of sterile granulomatous lesions that occur
at sites not contiguous with the gastrointestinal tract. They predominantly
involve the skin of the lower limbs, genitalia, perineum, perianal region, and
lips. One review of the literature showed that approximately 50% of patients
with cutaneous Crohn's disease have involvement of the lower extremi-
ties.2 Most affected patients are adults but lesions may rarely be seen in chil-
dren.3 The lesions present as single or multiple papules, plaques, nodules,
and ulcers.2–12 Vulval tumor-like masses, vulval or penile swelling, and herpes
virus-like lesions have occasionally been described.10,13,14 Penile lesions may
sometimes occur.15 Colostomy site involvement has also been documented.
One patient has been reported as presenting with an erysipelas-like erup-
tion involving the lip and nasolabial region and a further patient presented
with involvement of the nipple.5,16 In some patients, mucocutaneous lesions
precede evidence of bowel involvement.7,17,18 Of uncertain significance is the
finding that cutaneous Crohn's disease seems to be highly associated with
involvement of the large bowel.13 The duration of lesions is variable, typically
lasting from months to years.
Pathogenesis and histological features
The pathogenesis of mucocutaneous Crohn's disease is not understood.
Histologically, lesions are usually manifest as ill-defined, noncaseating,
and nonsuppurative granulomata present in the superficial (often papil-
lary) dermis; however, granulomata may also involve the deep dermis and
even ­subcutaneous adipose tissue.19,20 The granulomata are surrounded by
a small cuff of lymphocytes.20 In addition, there is a superficial and deep,
perivascular, mixed inflammatory cell infiltrate. The granulomata resemble
those seen in the bowel. Necrobiotic collagen has been described in a num-
ber of cases.19 Lymphocytes and plasma cells are also commonly present and
eosinophils can be prominent.20 Ulceration of the epidermis may be seen.20
Recently, the histological features of metastatic Crohn's disease have been
expanded to include the findings of significant necrobiosis with leukocyto-
clasis, and vasculitis (see palisaded neutrophilic and granulomatous derma-
titis, above).19,21
Differential diagnosis
Since the histological features of cutaneous Crohn's disease are non-specific,
a definitive diagnosis requires clinical confirmation of the presence of asso-
ciated bowel disease. Therefore, endoscopy, evaluation of gastrointestinal
biopsies, and review of clinical findings all play a role in confirmation of this
diagnosis. Sarcoidosis may be indistinguishable from metastatic Crohn's dis-
ease; however, the granulomata of the former tend to be more discrete and
compact. Eosinophils may be prominent in metastastic Crohn's disease and
are rare in sarcoidosis.20 Mycobacterial infection is also an important differ-
ential diagnosis; therefore liberal use of special stains for microorganisms is
essential. Culture should be performed as deemed clinically appropriate.
As noted above, cutaneous granulomata may precede evidence of bowel
involvement.7,16,17 Therefore, patients with granulomatous skin disease of
uncertain etiology should be followed up carefully for evidence of bowel
disease.
Granulomatous cheilitis may also show identical histological features.
Studies have documented patients presenting with granulomatous cheili-
tis who subsequently developed clinical manifestations or pathological evi-
dence (without gastrointestinal symptoms) of Crohn's disease.20,22–27 One
group study described a patient in whom granulomatous cheilitis antedated
development of Crohn's disease by 7 years.28 It appears, therefore, that some
patients with granulomatous cheilitis are at risk for development of Crohn's
disease and require gastrointestinal evaluation and careful clinical follow-up.
Similarly, vulval Crohn's disease precedes development of bowel involvement
in 25% of cases.13
310 Granulomatous, necrobiotic and perforating dermatoses

Granulomatous cheilitis
Granulomatous cheilitis (cheilitis granulomatosa, Meischer's cheilitis, orofa-
cial granulomatosis) is discussed elsewhere.

Acne agminata
Clinical features
Acne agminata (lupus miliaris disseminatus faciei, acnitis, papular tuberculid) is
a rare condition originally thought to be a form of tuberculid but an association
with tuberculosis has since been excluded.1–4 Some authors consider this disease
to be synonymous with granulomatous rosacea. However, the distinctive clini-
cal presentation, and the absence of typical rosacea in patients affected by the
disease, argue against this. Recently, a new name has been suggested for the dis-
ease: facial idiopathic granulomata with regressive evolution (FIGURE).5
Clinical presentation is characterized by fairly monomorphous yellowish-
brown papules typically involving the central face with predilection for peri-
ocular areas (Fig. 9.97). The disease is limited to the eyelids in rare cases.6 Fig. 9.98
Involvement of axillae or upper limbs is an exceptional finding.7–9 There is Acne agminata: there are multiple caseating granulomata.
no sex predilection and the age range is wide although most cases occur in
young to middle-aged adults.10 An exceptional case during pregnancy has
been documented.11 Response to conventional treatment for rosacea is often
ineffective but lesions tend to regress spontaneously over a period of months
or even years, leaving mild scarring.12

Pathogenesis and histological features

As suggested by some synonyms, infection by mycobacteria has been favored
by certain authors as a potential etiological factor. This theory is no longer ten-
able due to the absence of past or present systemic tuberculosis and the ­constant
failure of isolation of bacilli. In a study from Israel, mycobacterial DNA was
not detected by PCR.1 It has been suggested that the development of lesions is
due to an unusual granulomatous reaction to ruptured hair follicles.13
The histological features vary with the stage of evolution and may be
entirely non-specific.14 A biopsy from a well-established lesion shows a ­central
area of well-defined caseous necrosis surrounded by multinucleate giant cells
and epithelioid cells (sometimes indistinguishable from tuberculous infection)
(Figs 9.98 and 9.99). Serial sections often reveal a relationship of the necrosis

Fig. 9.99
Acne agminata: close-up view. The condition is not a tuberculid. Special stains and
culture for tubercle bacilli are invariably negative.

to a destroyed hair follicle. Special stains may demonstrate a ring of elastic

fibers in the center of the necrotic focus, possibly representing the isthmus of
the hair follicle. The granulomata are not usually related to Demodex follicu-
lorum as is often the case in granulomatous rosacea. Focal vasculitis is only
exceptionally seen.

Differential diagnosis
The diagnosis is fairly easy in the presence of granulomata surrounding an
area of caseation necrosis since the latter is not usually a feature of either
granulomatous rosacea or perioral dermatitis. In biopsies showing only focal
granulomatous inflammation, establishing the diagnosis may require very
careful clinicopathological correlation.

Fig. 9.97
Acne agminata: note the
characteristic distribution
of papules on the cheek
and around the eyes.
From the collection of the
late N.P. Smith, MD, the
Institute of Dermatology,
London, UK.
Perioral dermatitis
Clinical features
Perioral dermatitis (perioral granulomatous dermatitis, periorificial derma-
titis) is a common dermatosis that may represent a variant of rosacea.1–6
It is discussed in this section since it can, on occasion, be associated with
­granulomatous histology. Patients are usually young women but the ­condition

Fig. 9.100
Perioral dermatitis: erythema and papules in a characteristic distribution. From the
collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK.
can occur in children.1,7 Presentation in identical twins is exceptional but has
been documented.8 A granulomatous variant of perioral dermatitis has been
described in children.9–11 It tends to be more common in Afro-Caribbean
children and has been labeled facial Afro-Caribbean childhood eruption
(FACE).9 Typically, perioral dermatitis consists of erythematous papules and
pustules with a characteristic distribution on the chin and nasolabial folds
(Fig. 9.100). Involvement of the inner cheeks, the skin around the nose,
forehead or periocular area is unusual. Based on the fact that some cases
show perinasal and periocular involvement, the name periorificial dermatitis
has been suggested.12 Extrafacial and generalized involvement has also been
documented.13 The clinical appearances may mimic acne but comedones are
absent.14
Pathogenesis and histological features
The pathogenesis of perioral dermatitis is not clearly understood but
the condition seems to be etiologically linked in some cases to the use of
potent topical steroids, the application of cosmetics, certain toothpastes,
epoxy diacrylates in dental composite resins, contraceptive pills, and some
moisturizing creams.15–23 In rare patients, the disease appears during preg-
nancy and may flare up before the menstrual period.23 Even inhaled cor-
ticosteroids have triggered perioral dermatitis.24 Physical sunscreens with
high sun protection factor have also been blamed for causing the disease
in children.25 Multiple dental fillings with a mercury-containing amal-
gam induced perioral dermatitis in a girl and in a further case the disease
appears to have been triggered by orthognathic surgery.26,27 An association
has also been reported in renal transplant patients on systemic steroids and
azathioprine.28
Biopsy shows mild acanthosis, focal spongiosis, and hyperkeratosis with
parakeratosis and a mild perivascular and periadnexal lymphohistiocytic
infiltrate. The appearances are almost indistinguishable from those found in
rosacea.29 Ruptured hair follicles with microabscess formation are occasion-
ally seen. Sometimes granulomata with sarcoidal features are present.30 Giant
cells have also been documented, in which case distinction from sarcoidosis
may be difficult.1,31 In most cases, clinical correlation resolves any diagnostic
difficulties.
Demodicosis
There are two species of Demodex that live in a symbiotic relationship
in human hair follicles. The mites are D. folliculorum and D. brevis.
The former is mainly found in the infundibulum of the hairs and the lat-
ter in the sebaceous glands. They are ubiquitous in the skin but there is
Foreign body granulomata 311
a ­predilection for the face. Their pathogenetic role in skin diseases has
always been ­controversial and they are often regarded as innocent bystand-
ers. However, it does seem that in a small number of cases, particularly in
immunocompromised patients, they have an important role in causation of
disease.1–4 The mites do not appear to be a primary factor in the develop-
ment of rosacea although they may play a part in the granulomatous form
of the disease. Traditionally, three facial forms of involvement have been
described: pityriasis folliculorum, rosacea-like demodicosis, and demodi-
cosis gravis. Skin eruptions attributed to the mites, however, have variable
manifestations and include a rosacea-like eruption, a perioral dermatitis-
like eruption, chronic blepharitis, follicular plugging and erythema and a
disseminated form in immunocompromised patients.1–12 Localized pustules
and even abscesses have also been reported.13 An unusual case of a patient
with demodicosis presenting as a facial plaque after ophthalmic herpes
zoster has been described. In a further case, the ­disease mimicked favus
in a child.14 Adults are mainly affected but cases in children have been
reported.9–11,15
Pathogenesis and histological features
The pathogenetic link between the mites and cutaneous disease is a matter of
controversy. In cases where there seems to be a clear link, the density of mites
is very high.4
Histologically, the findings combine suppurative and granulomatous
changes. Dilated hair follicles with multiple mites are seen and there is forma-
tion of neutrophilic pustules. This is associated with a variable, perifollicular
mononuclear cell infiltrate composed of lymphocytes and plasma cells. When
the hair follicle ruptures, focal granulomata are seen and often contain frag-
ments of the mites.
Infective granulomata
Infections, particularly fungal and mycobacterial, are often associated with
granulomatous inflammation. Conversely, the vast majority of routine
biopsies showing granulomatous inflammation are not due to an infection.
However, when faced with a specimen showing granulomatous inflamma-
tion, the pathologist must maintain a low threshold for performing stains
for organisms and for issuing recommendations for microbiology culture.
If such an approach is not taken, the vast majority of infectious causes of
granulomatous inflammation will be misdiagnosed. In addition, although
pathologists tend to associate certain patterns of granulomatous inflam-
mation with infection by specific organisms (e.g., caseating granulomatous
inflammation and Mycobacterium tuberculosis), it should be remembered
that the same organism can cause several different patterns of granuloma-
tous inflammation (e.g., Mycobacterium leprae). Similarly, mixed suppu-
rative and granulomatous inflammation may result from both atypical
mycobacteria and deep ­fungal infections. A practical corollary to this is
that the pathologist should order several special stains to evaluate for a
variety of organisms rather than relying on a single stain for the most likely
culprit.
Specific infectious causes of granulomatous inflammation are discussed in
detail in Chapter 18.
Foreign body granulomata
A wide variety of substances when present within the dermis may result in
a foreign body giant cell reaction and can mimic primary granulomatous
disorders. These are summarized in Table 9.2 and examples are shown in
Figures 9.101–9.108. Therefore, when examining specimens with granu-
lomatous inflammation of uncertain etiology, all sections should be exam-
ined with polarized light to exclude foreign material. Most foreign body
granulomatous reactions occur as a result of external foreign matter, particu-
larly suture material. It can also occur as a result of injury from sea urchin
spines, particularly on acral sites.1–4 The granulomata formed are often for-
eign body and sarcoidal, but other types of granulomata including necrobi-
otic, suppurative, and tuberculoid have been described.4 Interestingly, a study
312 Granulomatous, necrobiotic and perforating dermatoses

Table 9.2
Important causes of foreign body granulomata

Endogenous Exogenous
Keratin Silica Graphite Cactus spine
Hair shaft Beryllium Paraffin Vegetable oil
Ruptured cyst Zirconium Shrapnel Mineral oil
contents
Released lipids Talc Sutures Food particles
Urate crystals Silicone Arthropods Wood splinters
Tattoo pigment Sea urchin spine

Fig. 9.103
Foreign body granuloma:
this free hair shaft has
been partially engulfed by
foreign body giant cells.

Fig. 9.101
Foreign body granuloma: there is a florid granulomatous reaction to shrapnel.

Fig. 9.104
Foreign body granuloma: high-power view

found Mycobacterium marinum DNA using PCR in a number of sea urchin

granulomata raising the possibility that the organism may be involved in the
­pathogenesis of the ­disease.5 Foreign body granulomatous reactions second-
ary to internal foreign bodies are mainly secondary to hair shafts within the
dermis after folliculitis or to fragments of keratin as a result of ruptured epi-
dermoid or trichilemmal cysts. Another source of foreign body granuloma-
tous r­ eaction to internal material is gout.
The pathologist should be particularly aware that beryllium and zir-
conium may be associated with granulomata that mimic sarcoidosis, the
so-called ­sarcoidal ‘naked’ granuloma. It is especially important to think
Fig. 9.102 of these agents as rare possible causes of granulomata since neither is vis-
Tattoo site: foreign body ible with routine or polarization microscopy. Beryllium was once used in the
and sarcoidal responses ­manufacture of fluorescent light bulbs. Following exposure to beryllium,
may occasionally be seen patients may develop either systemic berylliosis or have cutaneous involve-
in tattoo reaction. ment only. Pulmonary lesions follow inhalation.5 Skin involvement, in the
 Granulomatous contact dermatitis 313

Fig. 9.105
Suture granuloma: suture fragments are present; note the multinucleate giant cells.

Fig. 9.107
Bioplastique and silicone
granuloma: note sclerosis
and cystic spaces.

Fig. 9.106
Suture granuloma: when viewed with polarized light, suture fragments show
birefringence.

form of papules, follows direct inoculation.6 Diagnosis of chronic beryllium
disease is based on demonstration of a cell-mediated response to beryllium by
patch testing.6 Diagnosis may also be established by laser microprobe mass
spectrometry.6,7
Zirconium was once added to antiperspirants.8 Patients developed pap-
ules at sites where the substance was used and interstitial lung disease also
occurred.9 More recently, elephantiasis following nodal involvement has
been described in patients with beryllium and zirconium exposure from min-
eral-rich soil (podoconiosis).10 Diagnosis may be made using spectrographic
analysis.6,7,11
Foreign body granulomata following esthetic microimplants are relatively
uncommon nowadays, as the material used is greatly improved. Silicone gran-
ulomata are sometimes found and occasionally one encounters foreign body
granulomata to cosmetic microimplants such as Dermalive (hyaluronic acid
and acrylic hydrogel), artecoll (PMMA-microspheres), bioplastique (polym-
ethylsiloxane), and bioalcamid.12,13 Foreign body granulomata to iron oxide
after permanent p ­ igmentation of the eyebrows have also been reported.14
A metastatic silicone granuloma mimicking acne agminata and ­associated
with the sicca complex has been reported in a silicone breast implant
patient.15
Fig. 9.108
Bioplastique and silicone granuloma: note silicone spaces resembling lipoblasts in
the left of the field. On the right there are irregular cystic space containing foreign
material.
Granulomatous contact dermatitis
Clinical features
There are rare reports of a granulomatous reaction to metals, mainly pal-
ladium and less commonly gold and a titanium alloy, particularly at the
site of ear piercing but also in relation to piercing at other body sites.1–8
Granulomata induced by titanium have also been reported after implanta-
tion of a titanium-containing pacemaker.9 Areas of swelling, induration, or
red papules and/or nodules develop at the site of piercing and this may occur
shortly after or weeks and even months after the patient starts wearing ear-
rings. Most cases have been reported in adults but similar lesions may be
seen in children.10
A granulomatous contact dermatitis to propolis has also been
described.11
314 Granulomatous, necrobiotic and perforating dermatoses

Pathogenesis and histological features

The pathogenesis is likely to be a delayed hypersensitivity reaction to the
metal. This is proven by the fact that patients usually have a positive patch
test to palladium or less frequently gold. A positive reaction to zinc has also
been found.
Throughout the dermis and sometimes extending into the subcutis, there
is a prominent, diffuse granulomatous inflammatory cell infiltrate. This
­comprises epithelioid histiocytes and scattered giant cells surrounded by
lymphocytes and sometimes plasma cells are present. Necrosis is not usually
seen. In a case report of a reaction to titanium alloy (containing titanium,
aluminium, and vanadium) brown-black particles were demonstrated his-
tologically within the cytoplasm of macrophages.8 In another example trig-
gered by gold earrings, intracytoplasmic crystalline inclusions were found
within macrophages.6

Differential Diagnosis
The differential diagnosis from sarcoidosis and other granulomatous pro-
cesses may be difficult. The clinical history of piercing and the sites affected
are useful in achieving a correct diagnosis. Fig. 9.110
Tuberculoid granulomata in agammaglobulinemia: high-power view

Granulomata in congenital
immunodeficiency syndromes
A number of inherited immune deficiency diseases may on occasion present
with noninfectious granulomata involving different organs ­including the
skin.1–4 These diseases include combined immune deficiency, chronic granu-
lomatous disease, ataxia telangiectasia, common variable ­immunodeficiency,
and X-linked infantile hypogammaglobulinemia (Figs 9.109–9.112).
In combined immune deficiency, cutaneous tuberculoid and necrobiotic
granulomata may occur and in a single instance perineural invasion was
identified, closely mimicking tuberculoid leprosy.5,6 Cutaneous granulomata
in chronic granulomatous disease may show caseation necrosis without a
detectable trigger and can also be associated with foreign bodies.7,8 In ataxia
telangiectasia, patients present with either necrobiotic or tuberculoid gran-
ulomata.9–11 In common variable immunodeficiency, tuberculoid, sarcoidal,
and caseating granulomata have been documented.12–14 In X-linked infan-
tile hypogammaglobulinemia, caseating granulomata have been reported.15
An unusual perforating neutrophilic and granulomatous dermatitis has been
reported in a patient with agammaglobulinemia.16 It is important to highlight
the fact that affected patients have an immune deficiency; therefore, every
Fig. 9.111
effort should be made to rule out an infectious process with special stains Necrotizing granuloma in agammaglobulinemia: there is very extensive dermal
and cultures. necrosis with a surrounding granulomatous infiltrate.

Fig. 9.109
Tuberculoid granulomata in agammaglobulinemia: there is a diffuse granulomatous Fig. 9.112
infiltrate throughout the dermis. Necrotizing granuloma in agammaglobulinemia: high power view.
 Aluminum granuloma 315

Aluminum granuloma
Clinical features
Aluminum granuloma refers to the persistent, sometimes painful, subcutaneous
nodules that develop at the sites of vaccination or hyposensitization with agents
containing aluminum hydroxide as an absorbing agent (Fig. 9.113).1–5 If a vac-
cine is erroneously applied intradermally, lesions may occur within the dermis.6
The term granuloma is a misnomer as lesions do not usually consist of granu-
lomatous inflammation. The lesions develop after a few weeks or years after the
injections and are thought to be secondary to a hypersensitivity reaction to alu-
minum hydroxide. Often, patients have positive patch tests to aluminum hydrox-
ide. The most common vaccine associated with this reaction is tetanus toxoid
but any vaccine containing aluminum hydroxide as an absorbent may induce the
reaction, including hepatitis A and C and human papillomavirus vaccines.7
Intramuscular vaccines induce a condition described as macrophagic myo-
fasciitis. This condition has been described both in children and adults.8,9

Pathogenesis and histological features Fig. 9.114

The occurrence of the nodules appears to be the result of a delayed hypersen- Aluminum granuloma: there is a dense inflammatory cell infiltrate within the
subcutaneous fat.
sitivity reaction to aluminum.
Four histological patterns, which can overlap, may be found:10
• A predominantly lobular panniculitis with fairly non-specific findings
including focal inflammation consisting of lymphocytes, histiocytes,
and plasma cells with fat necrosis. Loose subcutaneous collections of
histiocytes with a slightly granular, bluish cytoplasm are always found
but their number varies and the change may be subtle.
• A prominent subcutaneous, predominantly mononuclear, inflammatory
cell infiltrate with eosinophils and focal formation of germinal centers
often mimicking a marginal zone lymphoma (Figs 9.114–9.116). Plasma
cells are often prominent. Careful examination reveals scattered grouped
histiocytes with bluish granular cytoplasm.
• A deep granuloma annulare-like infiltrate with numerous histiocytes
surrounding an area of necrobiosis (Figs 9.117, 9.118). All the
histiocytes show a characteristic bluish granular cytoplasm.
• A pattern with hyaline necrosis of the subcutaneous lobule mimicking
lupus profundus. This is associated with lymphocytes, and plasma cells
and germinal centers may also be seen. Careful examination reveals the
presence of typical histiocytes with bluish granular cytoplasm.
A case with numerous mast cells and associated with urticaria has been
described.11
The material within the histiocytes represents aluminum. Confirmation of Fig. 9.115
the presence of aluminum can be done histochemically with the use of azurin Aluminum granuloma: the infiltrate consists of lymphocytes, histiocytes and plasma
stain or by energy dispersive X-ray microanalysis. cells.

Fig. 9.113 Fig. 9.116

Aluminum granuloma: multiple depressed nodules with scarring are evident. From Aluminum granuloma: the histiocytes have markedly granular cytoplasm due to the
the collection of the late N.P. Smith, MD, the Institute of Dermatology, London, UK. presence of aluminum.
316 Granulomatous, necrobiotic and perforating dermatoses

disease in the same biopsy.33 Drugs including sirolimus and indinavir have
also been associated with the disease.34,35 The inherited cases are not associ-
ated with any systemic disorder. Reactive perforating collagenosis has also
been reported in a patient with HIV/AIDS in association with end-stage renal
failure.36 Perforating collagenosis is seen in approximately 10% of patients
with renal failure.1,2,37 Patients may develop lesions either before or after dial-
ysis treatment.2 In most cases, underlying diabetes ­mellitus is also present.1,2,37
Affected individuals suffer generalized pruritus and crusting papules. A single
case with a zosteriform distribution has also been documented.38
Following mild trauma, such as a scratch or insect bite, patients develop
flesh-colored papules 1–2 mm in diameter. These enlarge, become umbili-
cated and, over the course of about 4 weeks, grow to reach a diameter of
some 5–10 mm (Figs 9.119–9.121). Rarely, giant lesions are observed.39 The
umbilicated area contains keratinous debris, which is dark brown, hard, and
leathery. It is also very densely adherent, and bleeding results if detachment is
attempted. This is followed by regression. The papules flatten, and by 6–8 weeks

Fig. 9.117
Aluminum granuloma: in this example there is a palisading granuloma surrounding
a necrobiotic nodule.

Fig. 9.119
Reactive perforating collagenosis: there are multiple pink papules, some showing
central umbilication with crusting. By courtesy of D. McGibbon, MD, St Thomas’
Hospital, London, UK.

Fig. 9.118
Aluminum granuloma: the histiocytes have finely granular cytoplasm.

Perforating disorders
Reactive perforating collagenosis
Clinical features
This is a very rare disorder of uncertain etiology in which patients are predis-
posed to develop an unusual skin reaction to mild trauma, causing damaged
collagen to be extruded through the epidermis.1–4 Although sporadic cases do
occur, in many instances reactive perforating collagenosis appears to be an
inherited condition, autosomal recessive and dominant variants having been
described.5–8 Reactive perforating collagenosis has been documented in asso-
ciation with the Treacher Collins syndrome.9 The disease shows an equal sex
incidence, most cases presenting in childhood, although lesions tend to per-
sist into adult life. In familial cases the expression of the disease is variable
and can sometimes be mild and subtle.10 Lesions may be precipitated by sun Fig. 9.120
Reactive perforating
­exposure.10 An acquired variant occurring in adulthood and associated with
collagenosis: an example
IgA nephropathy, diabetes mellitus, chronic renal failure, ­hydronephrosis, on the cheek of a young
lung fibrosis, herpes zoster infection, cytomegalovirus, scabies, lymphoma, boy. By courtesy of E.
leukemia, and carcinoma (including papillary thyroid carcinoma and hepato- Young, MD, Wycombe
cellular carcinoma) has been described.11–32 In a single patient with Mikulicz's General Hospital, High
disease, the condition showed histologic features of IgG4-related sclerosing Wycombe, UK.
 Perforating disorders 317

Fig. 9.121 Fig. 9.123

Reactive perforating collagenosis: close-up view. By courtesy of E. Young, MD, Reactive perforating collagenosis: irregular, swollen collagen fibers have penetrated
Wycombe General Hospital, High Wycombe, UK. the epidermis.

from onset all that remain are residual scars or hypopigmented areas. It is of
interest that lesions develop only after mild superficial trauma, deep penetrat-
ing wounds healing normally. A positive Koebner phenomenon is character-
istic and lesions may be induced by gentle needle scratching. Lesions tend
to be rather polymorphic: as old lesions heal, new ones develop. They are
distributed primarily on the upper and lower extremities and face, although
the trunk may be affected.40,41 Rarely, the palms and soles may be involved.
Mucosal involvement has also been described in one patient.42 The severity of
this condition seems to increase in cold weather, whereas there is a reduction
in the number of lesions in summer. Exceptionally, secondary bacterial infec-
tion within the lesions may occur.43

Pathogenesis and histological features

The pathogenesis of reactive perforating collagenosis has not been eluci-
dated.44 Transepidermal elimination of type IV collagen has been demon-
strated but the mechanism that triggers the process is not clear.45
A broadened dermal ridge containing degenerate, basophilic collagen char-
acterizes early, nonumbilicated lesions. The overlying epithelium is atrophic
and centrally is composed of a thin layer of parakeratotic material. At the lat-
eral margins there is typically acanthosis. In the fully established umbilicated
lesion the central plug is composed of parakeratotic debris, degenerate collagen,
and inflammatory cells (Figs 9.122, 9.123).46 The epidermis deep to the plug
Fig. 9.124
Reactive perforating
collagenosis: close-up
view of collagen fibers
within the epidermis.

is markedly thinned and is traversed focally by vertically orientated collagen

fibers (Figs 9.124, 9.125). Elastic fibers are not present within the extruded
connective tissue debris. On either side of the cup-shaped deformity, the epider-
mis is acanthotic and hyperkeratotic. A lymphohistiocytic infiltrate is present
in the superficial dermis. The histological appearances in reactive perforating
collagenosis and acquired perforating collagenosis are identical. Distinction
between these disorders requires clinical correlation (Figs 9.126, 9.127).

Fig. 9.122
Reactive perforating collagenosis: this is a transverse section through the center of
a lesion. Note the crust overlying multiple points of incipient perforation.
Differential diagnosis
Changes identical to those seen in reactive perforating collagenosis may be
seen following trauma in ‘normal’ patients without stigmata of the disease.
Not uncommonly, biopsies of patients with prurigo nodularis/lichen ­simplex
chronicus (but who do not meet clinical criteria for reactive perforating
­collagenosis) show transepidermal elimination of collagen in a pattern simi-
lar to that seen in perforating collagenosis. Table 9.3 highlights points of
­distinction among the perforating disorders.
318 Granulomatous, necrobiotic and perforating dermatoses

Fig. 9.125 Fig. 9.127

Reactive perforating collagenosis: transepidermal elimination is seen to better Reactive perforating collagenosis: higher-power view.
advantage with this Masson’s trichrome stain.

Perforating folliculitis
Clinical features
Perforating folliculitis is a not uncommon, usually asymptomatic, derma-
tosis of unknown etiology that superficially resembles Kyrle's disease.1–3
It shows a female predominance (2:1) and, although a wide range of age
groups may be affected, the majority of patients present in the third decade.
The disease is characterized by the development of discrete, erythematous
follicular papules, 2–8 mm in diameter, each containing a small central white
keratotic core. Lesions most often affect the extremities, with a predilection
for the hairy portions of the arms, forearms, and thighs. The buttocks may
also be involved (Figs 9.128, 9.129). Koebnerization is not usually a feature.
Duration of the rash is variable, ranging from several months to years and
remissions and exacerbation may punctuate the course. Some patients present
with features of more than one perforating disease (i.e., perforating folliculitis
and elastosis perforans serpiginosa).4
Perforating folliculitis is associated with renal failure in some patients.5–7
It has also been reported in the setting of HIV infection and recently was
Fig. 9.126 described in two dialysis patients with markedly elevated serum ­silicon
Reactive perforating collagenosis: this example developed in a patient with chronic ­levels.8,9 Primary sclerosing cholangitis may rarely be ­associated with
renal failure. ­perforating ­folliculitis.10,11 A number of medications have been ­associated with
­perforating folliculitis including sorafenib, infliximab, and etanercept.12,13
Table 9.3
Differential diagnosis of perforating disorders

Reactive perforating
Kyrle’s disease collagenosis Elastosis perforans serpiginosa Perforating folliculitis
Age of patient Average 30 years (20–60) Childhood Second decade Third decade
Sex distribution ♂=♀ ♂=♀ 4 ♂=♀ 2 ♀=♂
Site Extensor lower extremities; upper Upper and lower Side and back of neck; upper Hair-bearing portions of
extremities; head, neck and trunk extremities; face extremities; face; lower extremities arms, forearms, thighs
Koebner phenomenon Occasionally positive Positive Occasionally positive Negative
Associated diseases Diabetes mellitus; renal failure; None; (acquired variant Down’s syndrome; Ehlers-Danlos None
hepatic insufficiency; congestive renal failure) syndrome; osteogenesis imperfecta;
cardiac failure pseudoxanthoma elasticum
Mode of inheritance ? autosomal recessive
? autosomal dominant
Histology Transepidermal elimination of Transepidermal Transepidermal elimination of Intrafollicular
degenerate parakeratin and elimination of collagen abnormal elastic tissue curled- up hair;
inflammatory debris transepidermal limination
of degenerate connective
tissue
 Perforating disorders 319

The subsequent exposure of the follicular contents to the underlying ­dermis

results in necrosis of connective tissue and subsequent transepidermal
elimination.
The histopathological features of perforating folliculitis are those of a
widely dilated hair follicle containing ortho- and parakeratotic keratin, baso-
philic necrotic debris, connective tissue elements, and degenerate inflam-
matory cells (Fig. 9.130).2 A curled-up hair is sometimes found within the
keratinous plug or extruded into the perifollicular dermis. Typically, the
infundibular follicular epithelium is disrupted at single or multiple foci.
The underlying degenerate dermis, including collagen and elastic fibers, may
be seen to impinge upon the perforated follicle. The adjacent epidermis often
shows pseudoepitheliomatous hyperplasia. A foreign body giant cell reaction
is sometimes found within the superficial dermis.

Differential diagnosis
Perforating folliculitis is differentiated from Kyrle's disease by uniform fol-
licular involvement associated with infundibular epithelial perforation (com-
pared with perforation at the base of the lesion in Kyrle's disease) and the
presence of tortuous hairs. Although elastic fibers may be found within
the dilated follicle, they are neither abnormal in appearance nor increased
Fig. 9.128
in quantity as seen in elastosis perforans serpiginosa. Table 9.3 highlights
Perforating folliculitis:
discrete scaly lesions on points of distinction among the perforating disorders. Keratosis pilaris is
the buttocks and thighs. associated with keratotic plugs that tend to be folliculocentric, but perfora-
By courtesy of K. Green, tion and inflammation are not features.
MD, Lister Hospital,
Stevenage, UK.
Elastosis perforans serpiginosa
Clinical features
Elastosis perforans serpiginosa (L. serpere, to creep) is a rare dermatosis asso-
ciated with transepidermal elimination of abnormal elastic tissue.1–3 It shows
a male predominance (4:1) and presents most often in the second decade.
A case with simultaneous onset in two sisters has been reported.4 Another
unusual case has been documented in an individual with a 47 XYY karyotype
and unilateral atrophoderma of Pasini and Pierini.5
The primary lesion is a 2–5-mm flesh-colored or red keratotic papule
containing an adherent plug, removal of which is associated with ­bleeding.
Classically, the papules are arranged in an arcuate or serpiginous pattern,
although sometimes they are randomly distributed (Fig. 9.131). Most often
the lesions are confined to one site, with the back and sides of the neck being
most frequently affected. Symmetrical involvement is very rare.6 Other sites
include the upper extremities, face, lower extremities, and abdomen, in
decreasing order of frequency. The penis is very rarely involved.7 In those cases
where multiple sites are involved, symmetrical distribution is characteristic.

Fig. 9.129
Perforating folliculitis:
close-up view. By courtesy
of K. Green, MD, Lister
Hospital, Stevenage, UK.

Pathogenesis and histological features

Although the exact etiology is unknown, the frequent finding of a distorted,
curled hair within the dilated follicle, often associated with disruption of
the epithelium, and the occasional presence of hair fragments within the
adjacent dermis suggest that mechanical disruption of follicular epithelium
by hair may be the cause of this condition. The lesions of perforating fol-
liculitis occur most commonly on the extensor aspects of the extremities,
suggesting that trauma may be implicated. It has been proposed that, as Fig. 9.130
with Kyrle's disease, chronic friction leads to abnormal keratinization of Perforating folliculitis: this field shows a dilated hair follicle containing keratinous
the follicular epithelium, which eventually results in follicular ­perforation. and basophilic debris. A hair shaft is visible.
320 Granulomatous, necrobiotic and perforating dermatoses

abnormality of copper metabolism associated with reduced numbers of

elastic fibers in arterial walls. It may be, therefore, that ­penicillamine
locally depletes the dermis of copper, resulting in ­abnormally formed elastic
tissue and the subsequent development of elastosis p ­ erforans serpiginosa.
In the established lesion there is a marked increase in elastic tissue in
both the reticular and papillary dermis (Fig. 9.132). The vertically ori-
entated fibers of the latter are thicker than normal and can be seen to
penetrate the epidermis. A section through the center of the lesion shows
characteristic transepithelial perforating canals, which may be transepi-
dermal, parafollicular or transfollicular in location and straight, wavy
or screwlike in configuration (Figs 9.133, 9.134). The canal contents
­consist of a basophilic mass comprising degenerate epithelial cells, inflam-
matory debris, and numerous elastic fibers (Fig. 9.135). The superficial
plug is composed predominantly of keratinous material and basophilic
debris. Sometimes elastic fibers are ­identified in the stratum corneum. The
­epithelium on either side of the perforating canal is acanthotic and may

Fig. 9.131
Elastosis perforans
serpiginosa: typical scaly
serpiginous eruption on
the elbow. By courtesy
of M.M. Black, MD,
St Thomas’ Hospital,
London, UK.

Rarely, lesions are widely disseminated. The eruption is usually asymptomatic,

although mild pruritus is sometimes a feature. Koebnerization is occasionally
noted.
Although elastosis perforans serpiginosa may occur as an isolated phenom-
enon, in quite a high proportion of cases it develops in association with other
conditions including Down's syndrome, Ehlers-Danlos syndrome, osteogen-
esis imperfecta, Marfan's syndrome, pseudoxanthoma elasticum, cutis laxa,
acrogeria, the Rothmund-Thomson syndrome and Moya Moya disease.8–17
Rarely, elastosis perforans serpiginosa may develop as a complication of pen-
Fig. 9.132
icillamine therapy for Wilson's disease and cystinuria.9,18–23 In patients treated Elastosis perforans serpiginosa: the epidermis is markedly thickened. Multiple
with penicillamine it may be associated with pseudoxanthoma elasticum and perforating channels containing basophilic debris are present.
cutis laxa.24,25 It has also been described in a patient with juvenile rheumatoid
arthritis.9

Pathogenesis and histological features

The pathogenesis of elastosis perforans serpiginosa is not entirely under-
stood. The documentation of familial cases suggests that a genetic component
plays a role in a subset of patients.26 The common association of elastosis
perforans serpiginosa with a variety of connective tissue disorders raises the
possibility of an elastic tissue defect as being of pathogenetic ­significance.
Histochemical and enzyme studies have confirmed that it is the elastic tissue
that is undergoing transepidermal elimination: electron ­microscopic studies
have shown that the elastic fibers are increased in size and have a convoluted
and branched pattern.27 It appears that these abnormal fibers have an irritant
effect, resulting in epidermal proliferation and their eventual engulfment by
the epidermis. Following epidermal growth with consequent upward migra-
tion, the abnormal elastic tissue is expelled via perforating canals. Recently,
it has been demonstrated that the 67 kD elastin receptor is present in the
keratinocytes associated with the ­elimination of elastic material in elastosis
perforans serpiginosa.28,29 This expression varies with the stage of the disease
and suggests that the elastin-keratinocyte interaction plays an important role
in the transepidermal elimination of elastin.28,29
It is of particular interest that this condition has been described follow- Fig. 9.133
Elastosis perforans
ing the use of the copper chelating agent penicillamine.9,18,19 Tissue copper
serpiginosa: this picture is
deficiency is known to be associated with damage to the elastica of arter- taken through the center
ies in experimental animals. The Blotchy mouse, which develops fusiform of a characteristic tortuous
aortic aneurysms, has a copper metabolism defect that includes reduced perforating canal. Note the
activity of the copper-dependent enzyme lysyl oxidase which is essential degenerate elastic tissue
for cross-linking the elastin molecules. In Menkes' syndrome, there is an at the base of the lesion.
 Perforating disorders 321

Hyperkeratosis follicularis et parafollicularis

in cutem penetrans
Clinical features
Hyperkeratosis follicularis et parafollicularis in cutem penetrans (Kyrle's dis-
ease) is a very rare dermatosis of unknown etiology.1–4 It has an equal inci-
dence in men and women and an age of onset ranging from 20 to 60 years,
with an average of 30 years. The disorder is characterized by a widespread,
asymptomatic, and typically bilateral eruption of 1–8-mm papules, each con-
taining a central cone-shaped keratotic plug. Although lesions are located
most often on the extensor aspect of the lower extremities, they may also
affect the upper extremities, head, neck, and trunk (Figs 9.136, 9.137). They
may or may not be related to hair follicles. The mucous membranes, palms,
and soles are characteristically spared. Ocular changes have been ­documented
in a single kindred with the disease.5 In a further patient, there was involve-
ment of the conjunctiva and oral mucosa.6 Lesions may coalesce into plaques
and, occasionally, a Koebner-like appearance is present. There is no evidence
to suggest that Kyrle's disease has a genetic etiology. However, the disease
exceptionally can be seen in siblings and families.5,7,8 It is sometimes asso-
ciated with diabetes mellitus, renal failure, hepatic insufficiency, and con-
gestive cardiac failure.9,10 It is unclear whether Kyrle's disease is a distinct
Fig. 9.134 entity. Some cases clearly overlap with a perforating folliculitis and reports
Elastosis perforans of examples in patients with diabetes and renal failure may actually represent
serpiginosa: high-power examples of the latter condition. An overlap with Flegel's disease has also
view. been described.11

Pathogenesis and histological features

The precise pathogenesis of Kyrle's disease is unknown; however, it has been
suggested that the lesions develop as a consequence of rapid and abnormal
keratinization, which proceeds at a faster rate than epidermal proliferation,
with consequent premature and abnormal differentiation of all the epidermal
layers. In most instances, this is complicated by dissolution of the epidermal
basement membrane region, with extrusion of keratinous debris into the der-
mis and subsequent development of a foreign body granulomatous reaction.
Following this, the epithelium adjacent to the site of the breach ­proliferates
downwards and, by fusion medially, eventually walls off the inflamma-
tory debris. Subsequent epidermal proliferation deep to the debris results in

Fig. 9.135
Elastosis perforans serpiginosa: the elastic fibers stain strongly with elastic-van Gieson in
the superficial dermis, but less strongly as the fibers undergo transepidermal elimination.

manifest pseudoepitheliomatous hyperplasia. Commonly, a foreign body

giant cell reaction is present in the superficial dermis and occasionally elas-
tophagocytosis is evident.
In the penicillamine-induced variant the elastic fibers characteristically have
an irregular, serrated, saw-toothed border.7 Ultrastructur­ally, this gives the lateral
borders of the affected elastic fibers a ‘lumpy bumpy’ appearance.5

Differential diagnosis
Although elastic fibers may be found within the dilated follicle in perforat-
ing folliculitis, they are neither abnormal in appearance nor increased in Fig. 9.136
Kyrle’s disease: multiple
quantity as seen in elastosis perforans serpiginosa. Keratosis pilaris is associ-
umbilicated lesions are
ated with keratotic plugs that tend to be folliculocentric but perforation and present on the thigh. The
inflammation are not features. Kyrle's disease is differentiated from elastosis largest contains a keratin
­perforans serpiginosa by perforation of a keratin plug at the base of the lesion plug. By courtesy of M.M.
­associated with curled hairs in the former. Table 9.3 summarizes the points of Black, MD, St Thomas’
distinction among the perforating disorders. Hospital, London, UK.
322 Granulomatous, necrobiotic and perforating dermatoses

Fig. 9.137 Fig. 9.139

Kyrle’s disease: multiple keratotic lesions are present on the dorsum of the foot. Kyrle’s disease: this lesion shows a flask-shaped epidermal invagination containing
By courtesy of the Institute of Dermatology, London, UK. parakeratotic debris. In the lower-left corner of the lesion is a laminated focus of
basophilic degenerate material.

­eventual transepidermal elimination. Transepidermal elimination or perfora-

tion, it seems, is of secondary rather than primary importance in this disorder.
From this description, it follows that in early lesions there may be no evidence
of an epidermal breach.
In a single case, reported regression of the lesions was seen after treatment
with clindamycin, raising the possibility of a bacterial agent in the etiology
of the disease. However, there is very little additional evidence to suggest that
the process may be triggered by bacteria.12
The histological features of an established lesion consist of a keratotic
plug filling an epidermal invagination.13–15 The keratinous plug shows parak-
eratosis and contains basophilic cellular debris (Figs 9.138, 9.139). Elastic
tissue is absent. The epithelium deep to the plug shows parakeratosis, which
extends to the point of epidermal disruption (Figs 9.140–9.143). Where the
keratinous debris is in contact with the dermis there is often a granuloma-
tous infiltrate. In more advance cases, downward epidermal proliferation and
encirclement results in incorporation of the basophilic keratotic debris into
the lower reaches of the epidermis and hence subsequent elimination. A lym-
phohistiocytic infiltrate is often seen around the epidermal downgrowth and
the superficial blood vessels. An exceptional case with acantholytic dyskera- Fig. 9.140
Kyrle’s disease: a
tosis mimicking Darier's disease has been described.16
somewhat earlier lesion
in which perforation
has not yet occurred.
Note the thinning of the
epidermis basally. Where
parakeratosis is evident
there is absence of the
granular cell layer.

Differential diagnosis
Kyrle's disease must be distinguished from reactive perforating collagenosis
and elastosis perforans serpiginosa. In the former, collagen bundles may be
seen entering the lesion from the dermis; in the latter, the basophilic material
is elastic tissue. Kyrle's disease must also be distinguished from perforating
folliculitis (see above). Table 9.3 highlights points of distinction in the differ-
ential diagnosis of perforating disorders.

Perforating pseudoxanthoma elasticum

Pseudoxanthoma elasticum (Grönblad-Strandberg syndrome) is an inherited
Fig. 9.138 generalized degenerative disease of elastic tissue of which there are autosomal
Kyrle’s disease: scanning view through the center of an established lesion showing dominant and autosomal recessive variants. The disease is briefly discussed in
the keratin plug. this section since a perforating variant is recognized.
 Necrotizing infundibular crystalline folliculitis 323

Perforating pseudoxanthoma elasticum is seen predominantly in multipa-

rous, obese, middle-aged and frequently hypertensive black women who present
with isolated abdominal, periumbilical involvement.1–6 Whether this represents
a forme fruste or a distinct entity is not yet known (so-called acquired pseudox-
anthoma elasticum). In some cases, however, transepidermal elimination is seen
in patients with systemic manifestations (Fig. 9.144).7 The perforating variant
may be associated with renal failure.6
The perforating subtype is characterized by transepidermal elimination of
the degenerate elastic tissue.7,8

Necrotizing infundibular crystalline

Fig. 9.141
Kyrle’s disease: this high-power view shows parakeratosis of the residual epithelium.
folliculitis
Clinical features
Only three cases of this distinctive entity have been reported. The first
two cases were described as a perforating disorder under the rubric tran-
sepidermal elimination of urate-like crystals but it has more recently been
­suggested that it represents a form of folliculitis.1,2 Two patients were male
with in­volvement of the back and the third patient was a female with a rash
on the face and a previous history of acne vulgaris. They all presented with
multiple umbilicated papules with waxy keratinous material in the center.
The lesions were asymptomatic and transient, and resolved spontaneously
without any treatment.

Pathogenesis and histological features

Although the material within the umbilicated craters resembles urate crystals
(monosodium urate monohydrate), none of the patients had evidence of gout
or hyperuricemia.
Histology is characteristic and consists of a crater full of eosinophilic
­filamentous material surrounded by an amorphous matrix and bulging
into the dermis (Figs 9.145, 9.146). Focally, the filaments are distributed
in a ­parallel fashion mimicking urate crystals. The crystals are negatively
­birefringent. Although in the first two cases a relationship with the hair
­follicles was not described, in the most recent case partially destroyed hair fol-
licles were demonstrated. The residual infundibular portion of the hair folli­
cles showed ­vacuolar and filamentous degeneration. By electron ­microscopy,
the ­filamentous ­material appears to represent tonofilaments.

Fig. 9.142
Kyrle’s disease: in this example there is incipient perforation.

Fig. 9.144
Fig. 9.143 Perforating pseudoxanthoma elasticum: multiple small crusted lesions are seen in a
Kyrle’s disease: high-power view showing liquefactive degeneration of the background of typical yellow papules. By courtesy of the Institute of Dermatology,
basal layer. London, UK.
324 Granulomatous, necrobiotic and perforating dermatoses
Fig. 9.145
Necrotizing infundibular crystalline folliculitis: note a crater like area containing
filamentous material.
Fig. 9.146
Necrotizing infundibular crystalline folliculitis: filamentous material mimicking urate
crystals.
Chondrodermatitis nodularis chronica
helicis
Clinical features
Chondrodermatitis nodularis chronica helicis presents as a small, usually soli-
tary, painful dome-shaped nodule on the helix of the ear, most commonly in
males over 40 years of age (mean age 60 years) and develops as a consequence
of chronic trauma (Fig. 9.147).1–3 Bilateral involvement is very rare.4 The
process is less common in women, when it is usually located on the antihe-
lix. Cases in children are exceptional.5 The pain is typically severe enough to
wake the patient at night if the affected ear touches the pillow. In the majority
of patients, symptoms are present for 2–3 years.3
On close examination, a firm crust with a small erosion or tiny channel
underneath usually covers the nodule. Lesions measure 3–15 mm in diameter.6
After surgical treatment there is a recurrence rate of 20%. Chondrodermatitis is
frequently mistaken for squamous cell or basal cell carcinoma, but the clinical
history and auricular location should allow the diagnosis to be made without
difficulty. Nevertheless, histological confirmation is advisable. An association
with systemic sclerosis and childhood dermatomyositis has been reported.7,8
Fig. 9.147
Chondrodermatitis
nodularis: this presents
as a crusted lesion on the
helix and may be clinically
misdiagnosed as an
epithelial neoplasm.
By courtesy of R.A.
Marsden, MD, St George’s
Hospital, London, UK.
A further study described an association with systemic vascular diseases and
connective tissue diseases including lupus erythematosus and rheumatoid
arthritis in a group of younger patients, with a predilection for females.9
Pathogenesis and histological features
The etiology is multifactorial, but trauma is likely to be of primary importance.
The exposed position of the ear, together with a known history of solar or physi-
cal trauma, appears important as many patients have outdoor jobs and evidence
of solar damage elsewhere. Of historic interest, in the past there appeared to be
a high frequency of cases in telephonists and nuns (wearing a wimple), again
supporting the role of physical trauma to the ear. Other ­factors including cold,
anatomical aberrations of the ear (such as a poor ­vascular supply), and senile
degeneration of the cartilage may play a role in development.3 Recently, it has
been suggested that the process is due to arteriolar narrowing in the perichondrial
region of the pinna.10 It is most unlikely, however, that the cartilaginous changes
described below are anything other than secondary. An exceptional case described
the simultaneous occurrence of the disease in middle-aged monozygotic twins.11
The pathogenetic mechanism of chondrodermatitis nodularis has been
interpreted as representing the process of transepidermal elimination.3 This
phenomenon occurs when a disturbance in the dermis initiates an epidermal
response. Foreign material in the dermis may elicit one of three responses:
• If the material is inert, there is no response.
• If the material is an irritant, either a superficial abscess or necrosis will
develop.
• The material (in this case degenerate collagen) may be eliminated by a
gradual process of transepidermal elimination.
Ulceration, although usual, may not be seen in early lesions.3,6 The epithe-
lium on either side of the ulcer is hyperplastic and shows features of lichen
simplex chronicus (Figs 9.148, 9.149). Pseudoepitheliomatous hyperplasia
is occasionally evident.6,12 Lesions have sometimes been shown to be related
to the follicular infundibulum.6 The crateriform ulcer contains keratinous
and epidermal debris superimposed on a focus of fibrinoid necrosis of the
underlying dermal collagen (Fig. 9.150). The base and radial edges of the
lesion contain granulation tissue and a variable chronic inflammatory cell
infiltrate, comprising lymphocytes, histiocytes, and occasional plasma cells
(Fig. 9.151). Vascular thromboses and hair shaft fragments are sometimes
evident.6 Nerve hyperplasia may be found and it has been suggested that this
may explain the pain experienced by pressure.13
 Chondrodermatitis nodularis chronica helicis 325

Fig. 9.150
Fig. 9.148 Chondrodermatitis nodularis: note the fibrin and intensely eosinophilic degenerate
Chondrodermatitis nodularis: this is a section through the center of the lesion cartilage.
showing ulceration. The adjacent epithelium is hyperkeratotic, parakeratotic, and
acanthotic. There is chronically inflamed granulation tissue at the base of the lesion.
Cartilage is evident in the center field.

Fig. 9.151
Fig. 9.149 Chondrodermatitis nodularis: high-power view of granulation tissue and
Chondrodermatitis nodularis: there is abundant granulation tissue at the base and inflammation.
adjacent to the ulcer.

It is thought that the pathogenetic process at advanced stages of this dis-
ease represents the transepidermal or, occasionally, transfollicular ­elimination
of damaged collagen.3,14 There are often degenerative changes present in
the underlying cartilage, including hyalinization, tinctorial changes, and
­perichondritis. Occasionally, degenerate and fragmented cartilage may also
be seen undergoing transepidermal elimination. The adjacent dermis often
shows marked solar elastosis.3
Differential diagnosis
Punch biopsies, which show the characteristic layering of fibrin, granula-
tion tissue, and degenerating cartilage, are diagnostic and distinctive. Often,
superficial shave biopsies sample only fibrin and granulation tissue without
cartilage. Nevertheless, if the clinical setting is appropriate, the diagnosis can
still be suggested.
 Inflammatory diseases of the
10
Chapter

subcutaneous fat
See
www.expertconsult.com
for references and
additional material
Bostjan Luzar and Eduardo Calonje

Erythema nodosum 327 Crystal-storing histiocytosis 346 Familial partial lipodystrophy (Dunnigan
Erythema nodosum-like lesions in Behçet’s Gouty panniculitis 346 variant) 354
disease 332 Familial partial lipodystrophy (Köbberling
Nodular vasculitis 346 variant) 354
Weber-Christian disease 332 Familial partial lipodystrophy associated with
Subcutaneous sarcoidosis 349
α1-Antitrypsin deficiency-associated mandibuloacral dysplasia 355
Neutrophilic lobular panniculitis associated
panniculitis 333 Acquired lipodystrophy 355
with rheumatoid arthritis 349
Factitial and traumatic panniculitis 334 Acquired generalized lipodystrophy 355
Eosinophilic panniculitis 350 Acquired partial lipodystrophy 355
Cold panniculitis 337
Infective panniculitis 350 Localized lipoatrophy 356
Cytophagic histiocytic panniculitis 337 Lipoatrophic panniculitis 356
Acute infectious id panniculitis –panniculitic
Subcutaneous Whipple’s disease 339 bacterid 352 Lipophagic panniculitis of
childhood 357
Pancreatic panniculitis 339 Sclerosing panniculitis 352 Connective tissue panniculitis 357
Subcutaneous fat necrosis of the Membranous fat necrosis 353 Lupus erythematosus profundus 358
newborn 340 Scleroderma panniculitis 361
LIPODYSTROPHY 354 Dermatomyositis panniculitis 361
Sclerema neonatorum 343 Postirradiation pseudosclerodermatous
Familial lipodystrophy 354
panniculitis 361
Cutaneous oxalosis 343 Congenital generalized lipodystrophy
(Berardinelli-Seip syndrome) 354
Calciphylaxis 344

Inflammatory diseases of the subcutaneous fat are a source of considerable

confusion and often cause diagnostic difficulty to clinicians and pathologists
alike. This stems in part from the use of classifications and clinical descrip-
tions based upon time-honored but outdated literature.1–4 Inadequate biopsy
specimens are also a source of considerable difficulty, particularly the punch
biopsy specimen, which often yields no subcutaneous fat at all. Similarly,
histological subdivision into diseases that affect the lobule and those that
affect the septa is to some extent artifactual and sometimes unrewarding since
most disorders affect both.2,3,5 There is also a somewhat monotonous clinical
­presentation, with most patients complaining of deep-seated, variably tender
or painful nodules, often affecting the lower extremities.
The subcutaneous fat has a limited repertoire of responses to noxious
stimuli. Fat necrosis is a common manifestation of many forms of pannicu-
litis and as a consequence there is often considerable histological overlap.
Although there are many variants of fat necrosis – including enzymatic, crys-
talline, ­suppurative, hyalinizing and microcystic – lipophagic fat necrosis is
the ­subtype most commonly encountered and is often a secondary feature
in many forms of panniculitis (Fig. 10.1). This is characterized by a lobular
infiltrate of histiocytes, xanthomatized cells, and foreign body giant cells,
­frequently accompanied by granulomata (Fig. 10.2).
It is important to remember that the subcutaneous fat may be involved
in a secondary manner, for example, in the vasculitides, the deep cutaneous Fig. 10.1
fungal infections, by metastatic tumor, and following surgery or ­radiotherapy Lipophagic fat necrosis: numerous xanthomatized histiocytes have engulfed free
(Figs 10.3, 10.4). In this chapter the panniculitides are classified, where lipid following fat necrosis.
­possible, on an etiological basis (Table 10.1).
 Erythema nodosum 327

Table 10.1
Classification of panniculitis

• Erythema nodosum
– subacute nodular migratory panniculitis/erythema nodosum migrans
• Erythema induratum
– nodular vasculitis
• Panniculitis associated with connective tissue disease
– lupus panniculitis
– morphea profunda/scleroderma/eosinophilic fasciitis
– dermatomyositis
– connective tissue panniculitis
• Lipoatrophy
– localized (involutional; inflammatory, e.g. lipophagic panniculitis/
granulomatous lipoatrophy)
– lipodystrophy
• Factitial or traumatic panniculitis
– injection-induced (steroids, insulin, narcotics, other drugs)
– sclerosing lipogranuloma
– blunt trauma
• Cold panniculitis
– popsicle panniculitis
– equestrian panniculitis
Fig. 10.2 • Panniculitis of newborn or infants
Lipophagic fat necrosis: in this field xanthomatized multinucleated foreign body – sclerema neonatorum
giant cells are present. Such an infiltrate is a common manifestation of many forms – subcutaneous fat necrosis of the newborn
of panniculitis and merely reflects the presence of fat necrosis. • Drug-induced
– direct (local) effect, e.g. due to injection
– systemic effect or reaction
– poststeroid panniculitis
– lobular panniculitis secondary to ciprofloxacin
– Panniculitis associated with α1-antitrypsin deficiency
• Calcifying panniculitis
– renal failure
– parathyroid disease
• Pancreatic panniculitis
• Gouty panniculitis
• Panniculitis with cytophagic histiocytes
– cytophagic histiocytic panniculitis
– malignant histiocytosis
– sinus histiocytosis with lymphadenopathy
–  T-cell lymphoma
• Eosinophilic panniculitis
– parasitic infection
– Well’s syndrome
– incidental finding of eosinophils in other forms of panniculitis
• Lipomembranous panniculitis
• Non-infectious subcutaneous granulomatous disease
– granuloma annulare, necrobiotic xanthogranuloma, rheumatoid
Fig. 10.3 nodule, sarcoidosis
‘Malignant’ panniculitis: this patient had a known history of bronchial small cell
• Infectious panniculitis
carcinoma and presented with a subcutaneous nodule on the chest wall.
• Subcutaneous Whipple’s disease
• Hemorrhagic panniculitis secondary to atheromatous emboli
• Vasculitis involving the panniculus
• Periarteritis nodosa
Reproduced with permission from Peters, M.S. and Daniel Su, W.P. (1992). Panniculitis.
Dermatologic Clinics, 10, 37–57.

There is considerable histological overlap in the various types of ­panniculitis

and one must take into account all the clinical information before attempting to
reach a definitive diagnosis. In patients in whom the ­diagnosis of ­panniculitis is
suspected, a deep surgical incisional biopsy is essential (Fig. 10.5). The punch
biopsy has no role whatsoever in the diagnosis of panniculitis.

Fig. 10.4
‘Malignant’ panniculitis: high-power view showing basophilic tumor cells with
hyperchromatic nuclei. Note the crush artifact.
Erythema nodosum
Clinical features
Erythema nodosum represents the commonest form of nodular panniculitis
and is the prototype of septal panniculitis.1,2 It is, of course, a clinical ­syndrome
rather than a specific disease in its own right, representing a ­complex of
symptoms and signs with multiple and very variable etiologies.3,4 It ­typically
328 Inflammatory diseases of the subcutaneous fat

Fig. 10.5
Panniculitis: a deep surgical biopsy is essential in all cases where panniculitis is
suspected. Fig. 10.7
Erythema nodosum:
the lesions are raised
and erythematous. By
courtesy of the Institute of
Dermatology, London, UK.

Fig. 10.6
Erythema nodosum:
typical erythematous
nodule on the shins of a
young woman. From the
collection of the late N.P.
Smith, MD, the Institute of
Dermatology, London, UK.
affects young adults and shows a marked predilection for women (as high as
9:1 in some series). Children are only rarely affected.5 Patients ­present with
a sudden onset of bright red, warm, tender nodules; these typically affect
the anterior and lateral aspects of the lower legs, but the arms, face, calves,
and trunk are occasionally involved (Figs 10.6, 10.7).6,7 Involvement of the
soles of the feet is rare although it appears to be more often encountered
in children.8,9 The lesions are usually multiple, bilateral, symmetrically dis-
tributed, elevated above the skin surface, and measure 1–15 cm in diameter.7
Ulceration and scarring are not features. Subsequently, the erythema fades to
a bluish or livid hue and then to a yellow discoloration, reminiscent of a bruise
(Fig. 10.8). The duration of the illness is 3–6 weeks. Patients ­sometimes also
have pyrexia, malaise, and vague aches and pains in the joints. Laboratory
findings may include a raised erythrocyte sedimentation rate (ESR), leukocy-
tosis, and mild anemia.3
Two clinical variants have been described.
• Erythema nodosum migrans (subacute nodular migratory panniculitis,
migratory panniculitis) is similar to classic erythema nodosum, but the
lesions appear to migrate due to central clearing of established lesions
Fig. 10.8
Erythema nodosum: in
this patient the lesions
are healing and show a
characteristic bruiselike
appearance. By courtesy
of the Institute of
Dermatology, London, UK.
and the development of new nodules at the periphery.10–13 The lesions,
which may persist for months or years, are usually associated with only
mild symptoms.10 Recurrences are sometimes encountered. Scarring
is not a feature. This variant is typically asymmetrical, unilateral,
and distributed solely on the leg. It also shows a marked female
predominance (approximately 9:1), but tends to affect an older age group
than classic erythema nodosum (mean age 50 years).11
• Chronic erythema nodosum, a somewhat controversial entity, is
characterized by the presence of nodules over a course of months or even
years.14 Otherwise, the clinical features appear indistinguishable from the
more typical condition.
 Erythema nodosum 329

Pathogenesis and histological features

The etiology and pathogenesis of erythema nodosum are unknown. Despite
the very occasional finding of immunoreactants (IgM or IgG, and C3) in the
blood vessel walls, an immune complex-mediated vasculitis is not consid-
ered likely.6 It is probable that erythema nodosum represents a non-specific
hypersensitivity reaction that involves delayed hypersensitivity mechanisms
in addition to a type 3 component.
There are many known associations. Although some are certainly of sig-
nificance in the etiology of this dermatosis, many are probably coincidental
(Table 10.2).15–28 In the earlier part of the twentieth century, tuberculo-
sis was noted in up to 90% of adult patients with erythema nodosum, but
this is now found in less than 1% of cases. Today, the more frequent asso-
ciations include streptococcal infections, sarcoidosis, ulcerative colitis and
Crohn's disease, Sweet's syndrome, Behçet's disease, menstruation, preg-
nancy, estrogens and the oral contraceptive, cat scratch disease and various
drug treatments (e.g., bromides, antibiotics, and sulfonamides). Other infec-
tious conditions that have been described in association with erythema nodo-
sum include cytomegalovirus, Epstein-Barr virus, parvovirus b19, Yersinia,
Mycoplasma, Chlamydia, Brucella, Bartonella, Rickettsia, Helicobacter Fig. 10.9
pylori, hepatitis B, ­atypical mycobacterial infections (e.g., swimming pool Erythema nodosum: this example shows the classical appearance of septal inflammation
granuloma), Salmonella, Shigella, meningococcal septicemia, Q fever, lep- with spread into the immediately adjacent lobule, giving rise to a lacelike appearance.
tospirosis, ­syphilis, human immunodeficiency virus (HIV), kerion, histo-
plasmosis, blastomycosis, amebiasis, ascaris, Chlamidophila pneumonia,
and giardiasis.15,25–27,29–49 Additional drugs that have been implicated in the
development of erythema nodosum include isotretinoin, interleukin (IL)-2,
minocycline, thalidomide, echinacea, gold salts, hepatitis B vaccine, all-trans-
retinoic acid, capecitabine, azathioprine, aromatase inhibitors, cabergoline,
and lidocaine.16,50–62 Erythema nodosum has also been reported following
a variety of malignancies including Hodgkin's lymphoma, myelodysplastic
syndrome, hairy cell leukemia, acute myeloid leukemia, acute myelomono-
cytic leukemia, diffuse large B-cell lymphoma, hypernephroma, non small cell
lung carcinoma, pheochromocytoma, carcinoid tumor, hepatocellular carci-
noma, carcinomas of the colon, pancreas and uterine cervix, and after radio-
therapy.63–79 In 20–30% of patients no obvious cause is identified (idiopathic
erythema nodosum).2 Erythema nodosum in renal transplant recipients can
be related to infections, malignancies, drugs, inflammatory bowel disease or
autoimmune diseases.80
Erythema nodosum migrans seems to be particularly related to ­pregnancy,
the oral contraceptive, streptococcal infection, and thyroid disease.10–12 Many
cases, however, have no obvious associated predisposing factors or conditions.
Histologically, erythema nodosum represents the prototype of septal pan-
niculitis. It is characterized by a combination of features, including vascular Fig. 10.10
change, septal inflammation, hemorrhage, and a variable degree of acute Erythema nodosum: in the acute phase, venulitis is very occasionally present
or chronic panniculitis (Fig. 10.9). Although it is often said that erythema although many sections or levels must be examined before its presence is detected.
nodosum characteristically affects the septal component of the panniculus,
it should be noted that there is not infrequently involvement of the lobule,
in part or in whole, particularly if older lesions are biopsied. In the past,
cases of the latter might have been diagnosed as Weber-Christian disease.
Frank vasculitis is only very exceptionally encountered. When present, it
involves the small veins, and very occasionally medium-sized vessels within the
connective tissue septa.81 It may be acute and necrotizing, associated with thrombo-
sis and hemorrhage, or may manifest as chronic venular ­inflammation associated
with endothelial cell swelling (Figs 10.10, 10.11). The overlying dermis typically
shows a perivascular and periadnexal chronic inflammatory cell infiltrate.

Table 10.2
Erythema nodosum: etiology

Streptococcus Sarcoidosis
Tuberculosis Sweet’s syndrome
Chlamydophila psittaci Cat scratch disease
Crohn’s disease Yersinia infection
Drugs Ulcerative colitis Fig. 10.11
Behçet’s disease Malignancy Erythema nodosum: in this field there is a thrombosed venule associated with
marked hemorrhage.
330 Inflammatory diseases of the subcutaneous fat

In the early stages, the septal inflammation may be acute, ­characterized

by an infiltrate of neutrophil polymorphs, but this is soon replaced by
­lymphocytes and histiocytes (Figs 10.12–10.14).82,83 Eosinophils are some-
times found and rarely they can be conspicuous. Septal collections of histio-
cytes surrounding a cleftlike space (so-called Miescher's radial granuloma)
are said to be a characteristic feature, although they have been reported in
Sweet's syndrome, nodular vasculitis, and necrobiosis lipoidica (Figs 10.15–
10.17).2,84,85 Further progression leads to the development of a frankly gran-
ulomatous infiltrate in which giant cells may be conspicuous. Coagulation
and caseation-like necrosis are never seen in erythema nodosum (compare
with nodular vasculitis below). Sometimes the connective tissue in the fibrous
septa shows fibrinoid necrosis, and ­hemorrhage is almost invariably present
(Figs 10.18–10.20).
Characteristically, the septal infiltrate (lymphocytes, histiocytes,
and ­granulomata) spills over to affect the periphery of the fat lobule
to give a delicate lacy appearance, but fat necrosis is not usually pres-
ent. On occasion, however, otherwise typical erythema nodosum may be
­associated with fat necrosis and a neutrophil inflammatory cell infiltrate
(Fig. 10.21).81,86
If an older lesion is biopsied, septal fibrosis can sometimes be quite marked. Fig. 10.14
Erythema nodosum: close-up view of cellular infiltrate.
Residual granulomatous inflammation is usually present.

Fig. 10.12 Fig. 10.15

Erythema nodosum: there is septal thickening with a lymphohistiocytic infiltrate. Erythema nodosum: collections of histiocytes known as Miescher’s granulomata
are a common finding. Fibrinoid necrosis affecting a small venule is also present.

Fig. 10.13 Fig. 10.16

Erythema nodosum: this view shows the interface between the septum and the Erythema nodosum: in this example multiple small granulomata are evident in the
lobule. thickened septa.
 Erythema nodosum 331

Fig. 10.17 Fig. 10.20

Erythema nodosum: high-power view of granulomata. Erythema nodosum: in this example there is massive hemorrhage. Subsequent
breakdown with hemosiderin formation accounts for the clinical appearance of bruising.

Fig. 10.18 Fig. 10.21

Erythema nodosum: fibrinoid necrosis of the connective tissue septa is an occasional Erythema nodosum: focal fat necrosis associated with lipid-laden histiocytes.
feature.

A B

Fig. 10.19
Erythema nodosum: there is marked red cell extravasation.
332 Inflammatory diseases of the subcutaneous fat

Erythema nodosum migrans is characterized by densely scarred and

thickened interlobular septa accompanied by a conspicuous granulomatous
­infiltrate (Figs 10.22, 10.23). Numerous giant cells may be seen and often
they form a palisade along the septal borders. Granulation tissue-like ­vascular
proliferation is often a conspicuous feature. Vasculitis is absent and hemor-
rhage is not usually seen.
In chronic erythema nodosum the histological changes are similar to, but
usually milder, than those of the acute variant.11

Differential diagnosis
At scanning magnification, vasculitic processes affecting the septa of the subcu-
taneous fat may be mistaken for erythema nodosum. Occasionally, the features
of leukocytoclastic vasculitis are seen within the septa in the absence of the more
usual superficial dermal involvement.87 Such instances present as erythematous
nodules, usually affecting the lower legs. Similarly, superficial thrombophlebi-
tis presents within the subcutaneous fat septa. In this condition, however, the
vein is the focus of the inflammatory process with associated thrombosis and
there is little or no involvement of the lobule. Cutaneous polyarteritis nodosa
affects muscular arteries within the lower dermis and subcutaneous fat septa
and, therefore, should not be confused with erythema nodosum.87 Nephrogenic Fig. 10.23
Erythema nodosum migrans: close-up view showing granulomata and newly
systemic fibrosis can rarely be associated with mild septal mononuclear cell
formed blood vessels.
infiltrates and granulomata, thereby simulating erythema nodosum.88

Erythema nodosum-like lesions in

Behçet’s disease
Recurrent erythematous, tender, nodular lesions on the lower extremities
(clinically reminiscent of erythema nodosum) are a common manifestation
of Behçet's disease.1–6 Erythema nodosum-like lesions develop in more than
40% of the patients during the course of the disease.7 Erythema nodosum-like
lesions and superficial thrombophlebitis could represent predictive markers
for visceral involvement.8
The fronts of the shins are most often affected but lesions may also
occur on the arms, face, neck, and buttocks.2 Although histologically they
have been described as showing erythema nodosum-like features, more
commonly they are characterized by a lobular or mixed septal and lobular
panniculitis associated with a neutrophil-rich infiltrate, neutrophilic vas-
culitis (affecting arterioles and venules), and associated fat necrosis.2,9 Less
often, a lymphocytic vasculitis and, exceptionally, polyarteritis nodosa-
like features are encountered. Miescher's granulomata may sometimes
be present.2,10

Weber-Christian disease
As originally defined by Christian in 1928 (relapsing febrile nodular nonsup-
purative panniculitis), this disorder was characterized by recurrent attacks of
fever associated with the development of subcutaneous tender nodules (par-
ticularly over the extremities), which were histologically characterized by the
presence of nonsuppurative panniculitis which healed to leave a depressed
scar.1–4 Lesions were said to affect mainly young white females, and although
the lower extremities were predominantly affected, the upper extremities,
buttocks, abdominal wall, breasts, and face could also be involved. Arthritis,
arthralgias, and myalgias were often present.3 A systemic variant – which
was potentially fatal and affected the intestines, mesentery, lungs, heart, and
­kidneys – was also recognized.3,5
Since 1928 there have been many case reports in the literature dealing with
this so-called ‘specific disease’. In general, however, many of the (particularly
earlier) studies used imprecise clinical and histological diagnostic criteria.
Some were certainly examples of erythema nodosum. In the light of cur-
rent knowledge of the panniculitides, many cases would now be reclassified.
A Weber-Christian-like disease may be seen in erythema nodosum, fac-
titial panniculitis, lupus panniculitis, pancreatic fat necrosis-associated
­panniculitis, α1-antitrypsin deficiency-associated panniculitis, connective
Fig. 10.22 ­tissue ­diseases, subcutaneous panniculitic T-cell lymphoma, and gamma-
Erythema nodosum migrans: there is marked septal thickening with conspicuous delta T-cell ­lymphoma.6–15 The term has also been applied to cases of infective
granulomata. Granulation tissue extends into the adjacent lobule. ­panniculitis, and panniculitis following jejuno-ileal bypass surgery.16–19

It seems unlikely, therefore, that Weber-Christian disease represents a ­distinct
entity in its own right. It is proposed, therefore, to take this opportunity to bury
it once and for all. As suggested by Patterson, ‘a clinical diagnosis of Weber-
Christian disease should signal the beginning of a search for the true cause
of the disorder’.9 Likewise, the term Rothmann-Makai syndrome should be
­abandoned.20 More often than not it probably represents erythema nodosum.
a1-Antitrypsin deficiency-associated
panniculitis
Clinical features
Deficiency of α1-antitrypsin is associated with a severe and particularly
intractable form of panniculitis.1–14 Patients have recurrent episodes of pain-
ful or tender nodules which are particularly resistant to therapy. The disease
shows a slight male predominance (3:2), and although a wide age range can
be affected (7–73 years), most patients are in their fourth or fifth decade.5,7
Children, however, may occasionally be affected.5 The nodules, which are
often precipitated by trauma, develop most often on the trunk and proximal
extremities, but the buttocks, chest, back, and abdomen are sometimes also
affected (Fig. 10.24). Occasionally, the disease spreads to the genitalia and
involvement of the abdominal fat has been described.
The nodules may be erythematous and are frequently associated with
ulceration and the spontaneous discharge of clear or serosanguinous fluid.5
Deeply penetrating sinuses associated with liquefaction of the subcutaneous
tissues are an important complication.
Fever is a common accompaniment and patients often have pulmonary prob-
lems including panacinar emphysema, chronic obstructive pulmonary disease,
effusions, and embolic phenomena.5,15 Peripheral edema and ­anasarca are occa-
sional manifestations. This is a particularly severe form of panniculitis, which
has recently been successfully treated by the use of infusions of commercial
α1-antitrypsin concentrate or liver transplantation.5,9,16,17 It is thought that many of
the previously reported cases of Weber-Christian disease belong to this group.18
Panniculitis in association with α1-antitrypsin deficiency has been induced
by cryosurgery,19 pregnancy, cesarean section delivery, and clarithromy-
cin leak at the site of intravenous application.17,19–21 In one patient with
the enzyme defect, Sweet's syndrome was followed by the development of
acquired cutis laxa (Marshall's syndrome).22 An acquired α1-antitrypsin defi-
ciency ­panniculitis following liver transplantation has been reported recently,
which was successfully treated with re-transplantation of the liver.23
Pathogenesis and histological features
α1-Antitrypsin (a glycoprotein of hepatic derivation) is a serine protease inhib-
itor (PI) that greatly modifies the effects of proteolytic enzymes, account-
ing for at least 90% of serum proteolytic enzyme inhibition. In addition to
Fig. 10.24
α1-Antitrypsin deficiency-associated panniculitis: note the extensive involvement of
the buttocks in this young female. By courtesy of M.R. Pittelkow, MD, Mayo Clinic,
Rochester, New York, USA.
Weber-Christian disease 333
antitrypsin inhibition, it is also responsible for inhibition of chymotrypsin,
collagenase, elastase, factor VIII, and kallikrein.7 Its deficiency has been asso-
ciated with panacinar emphysema, noninfective (neonatal and adult) hepati-
tis, and cirrhosis. More recently, associations have also been described with
cutaneous vasculitis, atopic dermatitis, psoriasis, nodular prurigo, and cold
urticaria.24 It has been proposed that absence of the protease inhibitor is asso-
ciated with unrestrained complement activation with increased inflammatory
cell activity, endothelial injury, and resultant autolytic tissue damage.25
Immunoglobulin (IgM) and complement (C3) have been identified in
blood vessel walls in patients with this variant of panniculitis.6 The signifi-
cance of this is uncertain.
The gene for α1-antitrypsin on chromosome 14 has in excess of 75 alleles
and is inherited as an autosomal dominant.7 Deficiency occurs in between
1:3000 to 1:5000 of white North Americans.26 The MM genotype is most
common and individuals with normal activity are coded PiMM. The ZZ
genotype is associated with deficient α1-antitrypsin activity and the pan-
niculitis is usually found in PiZZ individuals.27 Instances of panniculi-
tis in PiMZ, PiSZ, PiMS, PiSS, and Null patients, however, have also been
recorded.28–31 Panniculitis may also develop as a consequence of dysfunc-
tional α1-antitrypsin.31,32 Recognition of this particular form is of importance
as serum α1-antitrypsin levels are normal and therefore the diagnosis can eas-
ily be missed.
The earliest changes consist of necrosis of the connective tissue in the retic-
ular dermis and septa of the subcutaneous fat accompanied by a neutrophil
polymorph inflammatory cell infiltrate (Fig. 10.25).33 The histological fea-
tures of an established lesion are those of a predominantly acute panniculitis
(Fig. 10.26). The changes, which affect the septa and the paraseptal aspect
of the lobule, are characteristically focal in nature. In acutely inflamed areas,
large numbers of neutrophil polymorphs infiltrate the lobule. Fat necrosis is
common and a characteristic feature is said to be the presence of normal fat
adjacent to necrotic and inflamed fat (Figs 10.27, 10.28).6,34 Special stains
often show fragmentation and loss of elastic tissue.6 Z-type α1-antitrypsin
polymers have been demonstrated in the lesional as well as unaffected fatty
tissue by immunohistochemistry in a single patient.35 Foci of hemorrhage
associated with vascular thrombosis may be present, but there is no evidence
of active vasculitis (Fig. 10.29).6 Elsewhere, a histiocytic infiltrate is conspic-
uous, involving both the deep vasculature and adjacent panniculus. Lipid-
laden foamy macrophages are sometimes evident and multinucleate giant
cells are occasionally found. Healing is by fibrous scarring.
Differential diagnosis
The clinical features may suggest traumatic or factitial panniculitis. The
heavy neutrophil infiltrate can cause diagnostic confusion with an infectious
etiology.10 In cases of doubt, special stains for microorganisms should be
performed.
Fig. 10.25
α1-Antitrypsin deficiency-associated panniculitis: early lesion showing necrosis and
acute inflammation of the deep reticular dermis. Blood vessels are also affected.
By courtesy of M.R. Pittelkow, MD, Mayo Clinic, Rochester, USA.
334 Inflammatory diseases of the subcutaneous fat
Fig. 10.26
α1-Antitrypsin deficiency-associated panniculitis: there is intense acute inflammation
extending from the septum into the edge of the lobule. Note the necrosis of the
adjacent dermal connective tissue. By courtesy of M.R. Pittelkow, MD, Mayo Clinic,
Rochester, USA.
Fig. 10.27
α1-Antitrypsin deficiency-associated panniculitis: in this field hemorrhage is evident
in addition to the inflammatory changes. By courtesy of M.R. Pittelkow, MD, Mayo
Clinic, Rochester, USA.
Fig. 10.28
α1-Antitrypsin deficiency-associated panniculitis: high-power view showing an intense
neutrophil infiltrate. By courtesy of M.R. Pittelkow, MD, Mayo Clinic, Rochester, USA.
Fig. 10.29
α1-Antitrypsin deficiency-associated panniculitis: note the organizing thrombus.
By courtesy of M.R. Pittelkow, MD, Mayo Clinic, Rochester, USA.
Factitial and traumatic panniculitis
Clinical features
Factitial panniculitis is by definition self-induced and vigorously denied, and
may be caused by mechanical, physical, or chemical means. The diagnosis is
always worth considering in those patients with bizarre clinical lesions and
inflammatory changes in the subcutaneous fat that defy ready classification.
It should be particularly sought in those patients with panniculitis who have
a known history of psychiatric illness or drug or alcohol abuse. Lesions are
most commonly found on the more accessible sites including the buttocks
and thighs.
Mechanical causes include local pressure and repeated blunt trauma; the
latter may be readily recognized by the presence of obvious bruising. Cold is
another possible cause of factitial panniculitis.
By far the most common etiology is the subcutaneous injection of chemical
substances including drugs, oily materials, and organic matter.1–4 Panniculitis
has been described as a complication of morphine and tetanus antitoxoid
injections. Similarly, repeated injections of pentazocine cause a characteris-
tic woody fibrosis of the skin and subcutaneous fat accompanied by deeply
penetrating ulcers and hyperpigmented halos.5–7 Pentazocine abuse has been
described, particularly in members of the medical profession.5 There appears
to be a relationship with a personal or family history of diabetes mellitus. It
has been suggested that peripheral ischemia may be the pathogenetic link.7
A similar problem has recently been described following injections of the
­opioid ketobemidone.8
An important cause of factitial panniculitis is the repeated injection of
oily materials including paraffin and liquid silicon (paraffinoma, scleros-
ing lipogranuloma, lipogranulomatous panniculitis) (Fig. 10.30).1,2,4,9–13
Sclerosing lipogranuloma was a condition usually seen in the male genitalia
that developed as a consequence of the injection of paraffin oil and related
compounds into the penis in the mistaken belief that this would enhance erec-
tions. Povidone (polyvinylpyrrolidone), a synthetic dispersing or suspending
agent which has been used in both pharmaceutical products and hair sprays,
may result in a particular characteristic histological variant of panniculitis.14,15
Associated features have included pulmonary lesions, lymphadenopathy, and
hepatosplenomegaly. Organic substances that have been implicated in the eti-
ology of factitial panniculitis include food matter, milk, and even feces.
Nodular cystic fat necrosis is a distinct posttraumatic lesion that is seen
­predominantly in adolescent boys and middle-aged women. Lesions, which are
usually found on the legs, are often associated with a history of trauma.16
Traumatic fat necrosis is a not uncommon condition and occurs predom-
inantly in middle-aged or elderly females with large pendulous breasts. Its
importance is that it may be clinically mistaken for a malignancy. In addition, it
can be seen to involve the arms, trunk, buttocks, and thighs of the very obese.
 Factitial and traumatic panniculitis 335

careful examination may reveal foamy histiocytes or giant cells lining the
edges of these cystic cavities (Fig. 10.32).9 There is often associated dense
fibrous scarring. Early lesions sometimes show a marked granulomatous
component.9 Similar features have been described following a grease gun
injury.29
In panniculitis due to pentazocine abuse the histological features include
dense dermal fibrosis accompanied by variable scarring of the subcutaneous
fat.5 A ‘Swiss cheese’ appearance may be evident. Small-vessel thrombosis is
frequently present.5
Povidone panniculitis is characterized by histiocytic accumulation of
gray-blue, Congo red-positive foamy material accompanied by necrosis and
hemorrhage.14
Lesions caused by blunt trauma show the features of an organizing hematoma.
Granulomata and foci of hemosiderin pigment may additionally be present.30
Nodular cystic fat necrosis is thought to have an ischemic pathogenesis.
Histologically, it is characterized by an encapsulated nodule of necrotic (anu-
cleate) fat cells (Fig. 10.33).31,32 Variable inflammation is present.
Fat necrosis with histiocytes (lipophages) and giant cells is a com-
mon histological finding in specimens taken from sites of previous sur-
Fig. 10.30 gery of the subcutaneous fat (or deeper). Zelickson and Winkelmann have
Paraffinoma: note the infiltrated plaque with foci of retraction. By courtesy of the
Institute of Dermatology, London, UK.

A number of therapeutic injections have been associated with the devel-

opment of panniculitis including interferon-beta (IFN-β),17–21 glatiramer
acetate,22–24 nadroparin-calcium25 and granulocyte colony stimulating fac-
tor.26 Aluminum granuloma may present as a panniculitis. Panniculitis
has also been documented following vitamin K1 injections27. Two patients
with factitial panniculitis caused by electroacupuncture have been recently
described.28

Pathogenesis and histological features

The histological features of factitial panniculitis are not usually specific and
depend to some extent upon the cause. In some instances, therefore, the
changes are those of acute lobular inflammation associated with fat necrosis
and a neutrophil polymorph infiltrate. In older lesions, mononuclear cells,
lipid-laden histiocytes, and foreign body giant cells become predominant and
sometimes the response becomes frankly granulomatous. On other occasions
the septa may be primarily affected, thereby mimicking erythema nodosum.
Calcification is occasionally evident.2 It is sometimes rewarding to view the
sections with polarized light, as birefractile material may be identified, raising
the possibility of the factitious nature of the condition. Fig. 10.32
Paraffinoma is characterized by the presence of round or oval spaces Paraffinoma: on high-power examination, the cystic spaces can often be seen to be
lined by lipophages.
within the dermis and subcutaneous fat (‘Swiss cheese’ pattern) (Fig. 10.31);

Fig. 10.31 Fig. 10.33

Paraffinoma: empty spaces of variable size (due to the removal of lipid during Nodulo-cystic fat necrosis: typical low-power appearance; note the encapsulated
processing) characterize this lesion. The appearance is often likened to Swiss cheese. fatty cyst, scarring, and chronic inflammation.
336 Inflammatory diseases of the subcutaneous fat

described this as lipophagic panniculitis.31 Hemosiderin deposits are also

­commonly found and in many instances fragments of suture material may
be identified.
The histological features of traumatic fat necrosis are not specific and are
characterized by fat necrosis accompanied by a variable inflammatory cell
infiltrate (Figs 10.34, 10.35). In early lesions this is predominantly composed
of neutrophils, later replaced by lymphocytes and monocytes. Aggregates of
lipophages are seen frequently and often the reaction becomes frankly granu-
lomatous. Fat cysts are a common feature. With resolution, fibrosis takes
place (Fig. 10.36). As evidence of the traumatic nature of the lesion, foci of
hemosiderin deposition are not uncommon (Fig 10.37). Occasionally, the
presence of fat necrosis is complicated by focal calcification (Fig. 10.38).
Panniculitis after subcutaneous injection of interferon-beta can mimic
histologically erythema nodosum, lupus panniculitis, and pancreatic
panniculitis.18–20
Glatiramer acetate-induced panniculitis is characterized histologically by
a predominantly lobular inflammatory infiltrate composed of lymphocytes,
plasma cells, and scattered neutrophils and eosinophils in the background of
lipophagic granulomata.23 Reactive germinal centers may also be seen.
Interferon-beta-induced panniculitis and glatiramer acetate-induced Fig. 10.36
Traumatic fat necrosis: scarring is a feature in more chronic lesions.
­panniculitis are frequently associated with subsequent lipoatrophy.18,22

Fig. 10.37
Fig. 10.34 Traumatic fat necrosis: there is marked hemosiderin deposition.
Traumatic fat necrosis: there is intense lobular inflammation with septal fibrosis and
hemorrhage.

Fig. 10.35 Fig. 10.38

Traumatic fat necrosis: collections of lipophages are characteristic. Traumatic fat necrosis: in this example there is marked granular calcification.
 Cytophagic histiocytic panniculitis 337

Cold panniculitis
Clinical features
This rare condition was originally described in infants and young children
who developed tender, warm, erythematous plaques on exposed sites, namely
the cheeks and submental region, after experiencing low temperatures,1–6 and
usually appeared within the first 72 hours after exposure.7 These plaques
resolved spontaneously after 2–3 weeks, with no residual sequelae. The appli-
cation of an ice cube to a child's skin may result in the development of simi-
lar lesions. Identical changes have also been described in infants following
the sucking of ice lollies (popsicles; ‘popsicle panniculitis’).8–11 Increased satu-
rated fat content having a higher melting point may precipitate the develop-
ment of panniculitis in children.
A similar phenomenon has been described in young women following
horse riding in cold weather (equestrian cold panniculitis); these patients
develop indurated red-violaceous plaques on the superolateral aspect of the
thighs following prolonged riding in freezing conditions (Fig. 10.39).12–14
There is a tendency to ulcerate; healing is associated with postinflammatory
Fig. 10.40
hyperpigmentation and the development of depressed scars. It is thought that
Cold panniculitis: an intense inflammatory cell infiltrate is present at the junction
these lesions occur as a result of extremely cold temperatures combined with between the dermis and subcutaneous fat. By courtesy of P.H. Cooper, MD,
the effect of noninsulated, but tight-fitting, clothes which impair the circula- University of Virginia Medical Center, USA.
tion around the thighs. Recently, two patients with cold agglutinins and this
condition have been described.13
Chilblains (perniosis) also represent localized, abnormal inflammatory
responses to the cold.15 They have an acral distribution (e.g,. dorsal surfaces
of the fingers and toes) and present as pruritic erythematous lesions, which
may blister or ulcerate.

Histological features
The features of cold panniculitis are most noticeable at the interface between
the dermis and subcutaneous fat (Fig. 10.40).3,8 The infiltrate, which con-
tains lymphocytes, histiocytes, and neutrophils, extends from a perivascular
location into the adjacent fat where it is associated with adipocyte necrosis
and the development of small cysts (Fig. 10.41). Excess hyaluronic acid may
sometimes be present. Granulomata are not usually conspicuous.16 The blood
vessels show thickening of their walls and endothelial swelling, but frank vas-
culitis is not a feature.

Fig. 10.41
Cold panniculitis: the infiltrate consists of lymphocytes and histiocytes.

The histological features of perniosis include intense papillary dermal

edema and a superficial perivascular mononuclear infiltrate. The blood ­vessel
wall characteristically shows very marked edema and often there is fibrin
deposition.15

Cytophagic histiocytic panniculitis

Fig. 10.39
Cold panniculitis: there are
ulcerated lesions on this
patient’s thigh. From the
collection of the late
N.P. Smith, MD, the
Institute of Dermatology,
London, UK.
Clinical features
Cytophagic histiocytic panniculitis (panniculitis associated with hemophago-
cytic syndrome) was originally described as a serious disorder of immune
dysregulation.1–3 It may develop in association with a number of underlying
conditions including viral infections such as cytomegalovirus and Epstein-
Barr virus.4–8 HIV infection has also rarely been incriminated.7 Bacteria,
fungi, and parasites are sometimes of etiological significance.9–11 The condi-
tion has been described as a complication of phenytoin therapy, following
bone marrow transplantation, in systemic lupus erythematosus (SLE), and as
an adverse reaction to interferon-alpha (IFN-α) therapy.12–15 Some examples
in the earlier literature were described as Weber-Christian disease.16
Of particular importance, the hemophagocytic syndrome may also be
associated with a number of malignancies, most commonly T-cell lymphoma
338 Inflammatory diseases of the subcutaneous fat
(nodal or cutaneous).8,16–18 It is likely that many of the cases of the entity
described in the past represent examples of lymphomas including subcutane-
ous panniculitis-like T-cell lymphoma, nasal-type extranodal natural killer/T-
cell lymphoma and, particularly, gamma delta T-cell lymphoma. Rarely, an
underlying systemic B-cell lymphoma has been incriminated.19 Most patients
are immunosuppressed; however, very exceptionally, the cause is unknown
(idiopathic histiocytic cytophagic panniculitis).17,20 It is, therefore, of particu-
lar importance that all patients diagnosed with this condition are investigated
to exclude an underlying lymphoma, particularly of T-cell lineage.
Clinically, the cutaneous manifestations of cytophagic histiocytic pan-
niculitis include erythematous to violaceous or hemorrhagic nodules, which
particularly affect the lower limbs and trunk (Figs 10.42, 10.43). In many
patients however, the distribution is much more widespread. Ulceration is
sometimes seen. Severe localized or generalized edema may also be a feature.18
Constitutional symptoms including pyrexia, malaise, weight loss, fatigue, and
Fig. 10.42
Cytophagic histiocytic panniculitis: an extensive, erythematous, indurated plaque
is present on the upper arm. By courtesy of M. Cook, MD, St George’s Hospital,
London, UK.
Fig. 10.43
Cytophagic histiocytic
panniculitis: in this
example the lesions
are hemorrhagic and
ulcerated. By courtesy of
M. Cook, MD, St George’s
Hospital, London, UK.
myalgia may be present. Patients commonly develop hepatosplenomegaly,
lymphadenopathy, hypertriglyceridemia, anemia, leukopenia, thrombocy-
topenia, and disseminated intravascular coagulopathy.2–4 Steatohepatitis may
complicate exacerbation of cytophagic hemorrhagic panniculitis.21
The course of the disease is variable and to some extent depends upon the
underlying cause.22–31 Some patients have a prolonged indolent disease over
many years before progressing to clinical evidence of systemic hemophago-
cytosis. Rarely, patients may present with cutaneous lesions and a relatively
benign illness; 20,25,30,32 others have a rapidly progressive condition with
hemophagocytosis and its sequelae from the outset. The mortality rate for
these last patients is high. In addition to the direct effects of bone marrow fail-
ure and disseminated intravascular coagulation, systemic infections including
opportunist bacteria and fungi are important causes of death.8
Pathogenesis and histological features
Hemophagocytosis appears to develop as a consequence of excess T-cell
cytokine production, either virally induced or as a consequence of neoplas-
tic transformation. Tumor necrosis factor-alpha (TNF-α) and IL-2 may be of
particular importance.8 Perforin gene mutation has been detected in a child
with cytophagic lymphocytic panniculitis associated with fatal hemophago-
cytic lymphohistiocytosis.33
Histologically, the lesions are characterized by an infiltrate of histiocytes
with abundant eosinophilic cytoplasm and uniform, variably hyperchromatic
or vesicular nuclei containing small nucleoli. Variable numbers of lympho-
cytes and neutrophils are also present. Although the distribution is predomi-
nantly lobular, septal involvement is usually apparent and the lower dermis
is also often involved (Fig. 10.44). Red cell extravasation is typically pres-
ent and frequently the lesions are frankly hemorrhagic. Erythrophagocytosis
is invariably a feature and phagocytosis of lymphocytes or nuclear debris is
also often evident (Fig. 10.45). The enlarged and distended histiocytes are
sometimes described as ‘bean-bag’ cells (Fig. 10.46).2,3 Giant cells and gran-
ulomata are not usually a feature unless there is concomitant fat necrosis.
Lymphoid nuclear atypia is evident in those cases in which a T-cell lymphoma
is present (see below).
Differential diagnosis
Cytophagic histiocytic panniculitis must be distinguished from other condi-
tions in which erythrophagocytosis or hemophagocytosis may be a feature
including subcutaneous T-cell panniculitic lymphoma, angiocentric lym-
phoma, and cutaneous Rosai Dorfman disease.
In subcutaneous panniculitic T-cell lymphoma, the lymphocytes show cyto-
logical atypia with karyorrhexis and mitotic activity (Fig. 10.47). Angiocentric
T-cell lymphoma is characterized by an angioinvasive and ­frequently
Fig. 10.44
Cytophagic histiocytic panniculitis: there is a cellular infiltrate associated with fat
necrosis.

Fig. 10.45
Cytophagic histiocytic panniculitis: note the histiocytes with abundant eosinophilic
cytoplasm, some of which show erythrophagocytosis.
Fig. 10.46
Cytophagic histiocytic panniculitis: in the center of the field are several multinucleated
giant cells containing phagocytosed nuclear debris (‘bean-bag’ cells).
Fig. 10.47
Subcutaneous panniculitic T-cell lymphoma: numerous histiocytes showing
hemophagocytosis are present. In addition, however, there are conspicuous
hyperchromatic and irregular atypical lymphocytes.
Pancreatic panniculitis 339
a­ ngiodestructive atypical lymphoid infiltrate usually accompanied by wide-
spread coagulative necrosis. In cutaneous Rosai-Dorfman disease, the infiltrate
is usually centered on the dermis. Lymphophagocytosis is often marked but
erythrophagocytosis is not usually present. The histiocytes are characteristically
S-100 protein positive.
Subcutaneous Whipple’s disease
Clinical features
Whipple's disease is a rare condition which most often affects males and is due
to infection with the bacillus Tropheryma whippeli.1,2 It is characterized by
small intestinal involvement leading to malabsorption accompanied by fever
and arthritis, although virtually any organ system may be affected. Cutaneous
lesions include hyperpigmentation, erythroderma, purpura, vasculitis,
­erythematous and urticarial lesions, eczematous dermatitis and lichenoid gran-
ulomatous lesions.3,4 Exceptionally, subcutaneous nodules have been described
3,5–7 with occasional symmetrical distribution on inner thighs and forearms.8
Histological features
Involvement of the subcutaneous fat presents as a predominantly septal ‘pan-
niculitis’ characterized by a mixed inflammatory cell infiltrate consisting
of lymphocytes, neutrophils, and foamy periodic acid-Schiff (PAS)-positive
histiocytes.4,8
Electron microscopy reveals degenerate bacilli within membrane-bound
vesicles in the cytoplasm of the histiocytes.3
More recently, diagnostic polymerase chain reaction (PCR) and immuno-
histochemical techniques have become available.9
Pancreatic panniculitis
Clinical features
In pancreatic panniculitis the association of subcutaneous fat necrosis (meta-
static fat necrosis) with pancreatic disease is very rare, but is of particular
importance because sometimes the underlying pancreatic lesion is clinically
silent. The pancreatic diseases include acute pancreatitis, chronic pancreatitis,
pancreatic pseudocyst, pancreatic divisum, and pancreatic neoplasms (mostly
acinar cell carcinoma, but also ductal carcinoma, neuroendocrine carcinoma,
and intraductal papillary mucinous neoplasm).1–24 Pancreatic panniculitis has
also been described as a possible adverse drug reaction following renal trans-
plantation for SLE and following simultaneous pancreas-kidney transplanta-
tion for type I diabetes.25,26 There are two additional reports of the disease
developing in a background of lupus erythematosus.27,28 Pancreatic pannicu-
litis has also been reported following L-asparaginase treatment for acute lym-
phoblastic leukemia and in a patient with nephrotic syndrome due to rapidly
progressing glomerulonephritis.29,30
Patients present with multiple, exquisitely tender nodules, which are ery-
thematous or violaceous in appearance (Figs 10.48, Figs 10.49). The lower
extremities, buttocks, and trunk are most often affected, although occasion-
ally the upper arms, thorax, and scalp are involved. Occasionally, the nodules
ulcerate and release a creamy or oily discharge (Fig. 10.50). Joint manifesta-
tions (pain and swelling) are an important feature of this syndrome, occur-
ring in approximately 54% (pancreatitis-associated) to 88% (pancreatic
carcinoma-associated) of patients.5,31–35 The ankles are most often affected,
but the knees, elbows, wrists, metacarpophalangeal, and metatarsophalan-
geal joints are occasionally involved. A single case with chondronecrosis
and osteonecrosis has been reported.36 Additional features include pleural
effusions (in 25%), ascites (in 30%) and, very occasionally, pericardial effu-
sion.4 Intramedullary fat may also be affected and intestinal involvement has
rarely been documented.1,35 Peripheral blood eosinophilia is quite a com-
mon laboratory finding (19% in pancreatitis-associated; 65% in pancreatic
carcinoma-associated). Males are affected more often than females (pan-
creatitis 2:1; carcinoma 7:1) and patients are most often in the fourth, fifth
or sixth decade. This disease is associated with a high mortality, 42% in
­pancreatitis-associated variants and up to 100% in those cases presenting
with an u­ nderlying carcinoma.4
340 Inflammatory diseases of the subcutaneous fat
Fig. 10.48
Pancreatic panniculitis:
early lesions are often
erythematous. By courtesy
of J.C. Pascual, MD,
Alicante, Spain.
Fig. 10.49
Pancreatic panniculitis: a more advanced lesion. From the collection of the late
N.P. Smith, MD, the Institute of Dermatology, London, UK.
Pathogenesis and histological features
The development of subcutaneous fat necrosis in association with pancreatic
disease is due to the release into the peripheral circulation of trypsin, lipase,
phospholipase, and amylase.7,37 It has been postulated that trypsin damages
the vasculature, particularly in dependent sites, thereby permitting lipase to
enter the surrounding tissues. In vivo evidence suggests that this may be too
simplistic a viewpoint.9 Serum lipase levels do not always correlate with sub-
cutaneous fat necrosis and examples of patients with fat necrosis and normal
serum lipase levels have been documented.10 The reports of Wilson et al. and
Simkin et al., however, provide striking in vivo evidence to support a patho-
genetic role for released pancreatic enzymes.31,32
Histologically, the features are pathognomonic and are identical to
those seen in the peripancreatic adipose tissue following an episode
of acute ­hemorrhage pancreatitis (Fig. 10.51). Although very early
changes can show features of septal panniculitis without fat necrosis or
Fig. 10.50
Pancreatic panniculitis: the nodules may ulcerate and release blood-stained fluid.
By courtesy of J.C. Pascual, MD, Alicante, Spain.
Fig. 10.51
Pancreatic panniculitis: the changes predominantly affect the lobules.
­vasculitis, most ­frequently, however, the changes are lobular in distribu-
tion and are characterized by the presence of ghost cells (Fig. 10.52).38
The ­latter are anucleate, ­composed of amorphous granular debris, and
often show a rim of eosinophilia (Fig. 10.53). Stippled basophilia due
to ­calcification is commonly found (Fig. 10.54). A neutrophil poly-
morph response is usually ­evident around the foci of fat necrosis, and
hemorrhage is an almost invariable feature (Fig. 10.55). The uninvolved
­surrounding fat is heavily infiltrated by acute and chronic inflammatory
cells ­including large numbers of macrophages, many of which have foamy
cytoplasm due to ingested lipid, and occasional multinucleate giant cells
(Fig. 10.56). There is no evidence of a vasculitis. Birefringent crystals
have been described in the mesenteric fat and within affected joints but
not in the subcutaneous fat.39,40
Subcutaneous fat necrosis of the newborn
Clinical features
This uncommon disease presents in full-term or post-term neonates in the
first few weeks of life.1–4 Affected babies develop painless subcutaneous nod-
ules measuring from a few millimeters to several centimeters in diameter.
The overlying skin may appear normal or be erythematous or violaceous.
 Subcutaneous fat necrosis of the newborn 341

Fig. 10.52 Fig. 10.55

Pancreatic panniculitis: there is extensive enzymatic fat necrosis. Note the Pancreatic panniculitis: there is a heavy neutrophil infiltrate.
characteristic ghost cells.

Fig. 10.53 Fig. 10.56

Pancreatic panniculitis: close-up view of ghost cells. Pancreatic panniculitis: as with other forms of fat necrosis, lipophages are often
evident.

Lesions are symmetrical and distributed over bony prominences, the arms,
shoulders, buttocks, thighs, and cheeks (Fig. 10.57). The nodules frequently
soften and become fluctuant, occasionally liquefying. The disease is usually
self-limiting and benign, spontaneous resolution occurring within a period of
weeks to months in the majority of cases. Occasionally, however, it is asso-
ciated with hypercalcemia, dyslipidemia, thrombocytopenia, and lactic aci-
dosis.4–11 Hypercalcemia may be asymptomatic and associated with failure
to thrive, fever, vomiting, irritability, and seizures.1,12 Calcium deposits have
been described in the kidneys, liver, inferior vena cava, and heart.4,13 Delayed
onset of hypercalcemia up to 6 months after occurrence of the subcutaneous
fat necrosis of the newborn is also possible.14 Exceptionally, this disease can
prove fatal.

Pathogenesis and histological features

Fig. 10.54
Pancreatic panniculitis: the stippled basophilia represents calcification.
The pathogenesis of the hypercalcemia is unknown. A number of theo-
ries have been proposed including calcium release from resolving plaques,
elevated parathormone and prostaglandin E2 levels, increased vitamin D
sensitivity and, most recently, lesional histiocytic production of excessive
1,25-dihydroxyvitamin D3 with resultant increased intestinal absorption of
calcium.15–23
342 Inflammatory diseases of the subcutaneous fat

Fig. 10.58
Fig. 10.57 Subcutaneous fat necrosis of the newborn: multiple foci of fat necrosis with chronic
Subcutaneous fat necrosis inflammation are present.
of the newborn: crusted,
ulcerated nodules on both
cheeks. By courtesy of the
Institute of Dermatology,
London, UK.

The cause of subcutaneous fat necrosis of the newborn is unknown, but

most cases are related to some form of fetal distress, including obstetric or other
birth trauma, cord accidents, meconium aspiration, infections, hypothermia,
placenta previa, cesarean section and neonatal asphyxia.2,4 Pre-eclampsia and
maternal diabetes have also been associated with this condition.4,7 A primary
abnormality of subcutaneous fat may be of some importance.24 Neonatal fat
is characterized by elevated levels of saturated fatty acids which have a high
melting point and are therefore susceptible to precipitation as a consequence
of neonatal hypothermia. Deficiency of brown fat has also been proposed
as a potential etiological factor.25 Although not histologically confirmed, a
case of simultaneous development of sclerema neonatorum and subcutane-
ous fat necrosis of the newborn was described in an infant following cesar-
ean section for fetal distress, hypothermia, neonatal respiratory distress, and
hypoglycemia.26
Subcutaneous fat necrosis has also been described after hypothermic car-
diac surgery, as a complication of congestive heart failure in an infant with A
ventricular septal defect and patent ductus arteriosus, associated with mater-
nal diabetes, increased blood pressure, smoking, thrombosis-related risk
­factor, a possible complication of cocaine abuse, following the in partum use
of calcium-channel blockers and as a consequence of prolonged exposure in
very cold weather.4,27–33
The histological changes are characteristic.21,34–36 The subcutaneous fat
is the scene of intense necrosis. Individual adipocytes are swollen and con-
tain abundant radially arranged eosinophilic crystalline spaces resulting
from dissolved lipid (Figs 10.58, 10.59). The crystals are largely composed
of triglycerides.35 There is a heavy inflammatory cell infiltrate comprising
polymorphs, lymphocytes, histiocytes, and numerous foreign body giant
cells (Fig. 10.60). Large numbers of eosinophils have been described in two
cases.21 Multinucleated giant cells containing eosinophilic granules in their
cytoplasm have recently been reported.37,38 The significance of these granules
is unknown, and their origin from degranulating eosinophils has been pos-
tulated.37 Older lesions may show fibrosis and foci of calcification. Systemic
involvement is sometimes present.36
B
Differential diagnosis
It is of interest to note that identical histological features were seen some years Fig. 10.59
ago in the poststeroid panniculitis syndrome.39–44 This condition occurred in (A, B) Subcutaneous fat necrosis of the newborn: individual adipocytes are swollen
children who had been treated for rheumatic fever or ­glomerulonephritis and contain characteristic, radial, eosinophilic crystals.

Fig. 10.60
Subcutaneous fat necrosis of the newborn: surrounding the foci of fat necrosis is a
chronic inflammatory infiltrate containing numerous foreign body giant cells.
with very large doses of steroids; sudden withdrawal of the steroids resulted
in the development of subcutaneous swellings up to 4 cm across on the
cheeks, arms, and trunk. The disease is now of historic interest only due to
the ­standard practice of steroid taper when withdrawing the drug. The skin
overlying the nodules was erythematous, warm, and itchy. In mild cases the
panniculitis resolved spontaneously; in more severe examples it subsided fol-
lowing the reintroduction of steroids. Poststeroid panniculitis has recently
also been reported in an adult patient.45
Sclerema neonatorum
Clinical features
Sclerema neonatorum is a very rare condition associated with high morbidity
and mortality (75–90%).1 It is sometimes confused with, and therefore must
be distinguished from, subcutaneous fat necrosis of the newborn.2–4 Infants
present in the first week of life (average age of onset, 4 days; range, birth to
70 days) with a diffuse, rapidly spreading, waxlike thickening and induration of
the subcutaneous fat, resembling lard. This usually commences about the but-
tocks, thighs, and trunk and often spreads to involve the whole body, excluding
the palms, soles, and genitalia. The fat is typically tethered to the underlying
fascia and the skin cannot be grasped between the fingers. Pitting edema is not
a feature.
Affected infants are usually hypothermic, but body temperature may be
normal or, rarely, raised.5,6 Some of the infants are premature, but they are
a minority. The children commonly have some other associated illness, such
as septicemia, pneumonia, diarrhea, dehydration, intestinal obstruction, con-
genital heart disease or other congenital malformations.7 A patient with both
sclerema neonatorum and concurrent subacute fat necrosis of the newborn
has been described.8
Pathogenesis and histological features
The etiology and pathogenesis of this condition are uncertain. It is thought
that the structural alterations of the subcutaneous fat probably predate the
development of the clinical features. Neonatal subcutaneous fat is character-
ized by a higher content of saturated fatty acids (palmitic and stearic) and a
lower content of unsaturated fatty acids (oleic) than adult subcutaneous fat.2
It also has higher melting and solidification points. It has been suggested that
infants with sclerema neonatorum have an inadequately developed enzyme
system for converting saturated to unsaturated fatty acids.2 It is thought that
this, in association with stress, might result in the precipitation of triglycerides
and consequent solidification of the subcutaneous fat. Recently, it has been
proposed that redistribution of blood flow to the systemic circulation with
resultant relative ischemia of the subcutaneous fat may be of ­pathogenetic
Cutaneous oxalosis 343
importance.9 Sclerema neonatorum is characterized by increased blood lipid
peroxidation and diminished superoxidase dismutase activity, which raises
the possibility that free radicals may play a role in its pathogenesis.10 There is
no evidence of vasculitis.
The histological features are surprisingly bland. The subcutaneous fat
is greatly thickened and the fibrous septa are broader than normal. The
adipocytes, which are increased in size, may contain radially orientated
fine crystals identical to those described in subcutaneous fat necrosis of
the newborn although often they are inconspicuous.1,11 In contrast to the
latter condition, however, there is no necrosis or significant inflammatory
cell infiltrate. Calcification is rarely a feature.1 The dermis may appear
sclerotic with hyalinization and the epidermis atrophic with loss of the rete
ridges.11
Cutaneous oxalosis
Clinical features
Oxalosis, in which there is widespread deposition of calcium oxalate in the
tissues, may represent a primary metabolic disease or a secondary phenom-
enon due to increased intake of oxalate precursors or defective excretion.1–5
Secondary oxalosis can also result from pyridoxine deficiency, glycerol
­infusion, methoxyflurane anesthesia, excessive ascorbic acid, extensive hemo-
dialysis, peritoneal dialysis, and ethylene glycol poisoning.2
Primary oxalosis, which is associated with overproduction of oxalate, is
an autosomal recessive condition and includes three subtypes:
• Type I, which is most often encountered, develops as a result of deficiency
of the hepatic enzyme alanine:glyoxylate aminotransferase with resulting
increased urinary excretion of oxalate, glycolate and glyoxylate.1–3
• Type II (L-glyceric aciduria) results from cytosolic D-glycerate
dehydrogenase and glyoxylate reductase deficiencies with associated
increased urinary excretion of L-glycerate and oxalate accompanied by
normal glycolate and glyoxylate excretion.4
• Type III develops as a result of primary small intestinal disease associated
with excessive oxalate reabsorption.5
Calcium oxalate crystal deposition occurs most commonly in the kidneys
(calcium oxalate stones and chronic renal failure).4 With the onset of the
latter, hyperoxalemia develops with resultant deposition of oxalate crystals
in the blood vessels, retina, myocardium, cardiac conducting system, central
nervous system, peripheral nerves, bones, and joints.6
Cutaneous manifestations may occur in both primary and secondary
forms.6–24 Lesions most often result from vascular involvement, patients
presenting with acrocyanosis, livedo reticularis, Raynaud's phenomenon,
and distal gangrene (Fig. 10.61).7–12 Ulceronecrotic lesions reminiscent
Fig. 10.61
Cutaneous oxalosis: this child shows gangrene with ulceration. By courtesy of
N. Saxe, MD, Groote Schuur Hospital, Cape Town, South Africa.
344 Inflammatory diseases of the subcutaneous fat

Fig. 10.62 Fig. 10.64

Cutaneous oxalosis: note the radially orientated, needle-shaped crystals. Cutaneous oxalosis: in this field there is dramatic vascular involvement with
destruction of the media and massive intimal thickening.

Calciphylaxis
Clinical features
Calciphylaxis was originally defined by an experimental model in rats, in
which sensitization with parathormone or dihydrotachysterol followed by
the injection of a challenging agent such as a metal salt resulted in localized
necrosis and calcification.1 The term was subsequently adopted to describe
a condition in which an abnormality of calcium/phosphate metabolism is
­followed by calcification of the vasculature of the subcutaneous fat with
­subsequent thrombosis accompanied by extensive skin necrosis.2–7
Calciphylaxis presents clinically as an often bilateral and symmetrical,
­pruritic, and frequently painful/tender eruption most often affecting the
lower limbs (Fig. 10.65). Less often, lesions may affect the breasts, but-
tocks, ­abdomen, and penis.8–24 Lesions are often well-delineated, livedoid,
­violaceous plaques and nodules associated with ischemic necrosis of the under-
lying ­tissues, sometimes extending down to the fascia. Ulceration is ­typically
­present and sometimes bullae are a feature. Gangrene and ­autoamputation
may accompany acral involvement.6 Intestinal involvement with massive
Fig. 10.63 hemorrhage has exceptionally been documented.16
Cutaneous oxalosis: note the radial crystals viewed under polarized light.

of ­calciphylaxis have also been documented.13–15 Less often, crystals are

­deposited in the skin of the face and the fingers as miliary deposits, as dermal/
subcutaneous nodules or as painful subungual nodules.16–21 Exceptionally,
generalized cutaneous nodules have been documented.22 Vascular involve-
ment is said to be more common in patients with primary disease whereas
cutaneous extravascular lesions are predominantly seen in patients with sec-
ondary disease.21

Histological features
Calcium oxalate crystals are yellow to brown, radially arranged, needle-
shaped or rectangular in shape (Figs 10.62, 10.63). In the skin they may
be found in the reticular dermis or within the subcutaneous fat. Vascular
involvement may also be seen where the media of arteries is predomi-
nantly affected (Fig. 10.64). Less commonly, crystals may be seen within
the lumina of smaller arteries or arterioles.1,11,12 The crystals show striking
yellow or blue birefringence when examined in polarized light. They are
sometimes accompanied by a foreign body giant cell reaction, particularly Fig. 10.65
when present as dermal or subcutaneous deposits.8,18,22–24 In those cases Calciphylaxis: ulcerated gangrenous lesion with surrounding erythema. By courtesy
associated with gangrene or livedo reticularis, fibrin thrombi may also be of A. Qureshi, MD, Department of Dermatology, Brigham and Women’s Hospital,
detected.8 Boston, USA.
 Calciphylaxis 345

Calciphylaxis is associated with considerable morbidity and a high mortal-

ity of up to 60%.4,14 The majority of patients succumb to secondary infection.
Calciphylaxis due to the end-stage kidney disease can exceptionally develop
in children, with four patients reported to date.25

Pathogenesis and histological features

The precise mechanism by which the subcutaneous vasculature undergoes
calcification is uncertain but is probably multifactorial. In the majority of
patients, however, sensitization occurs as a consequence of abnormal cal-
cium/phosphorus metabolism in a setting of chronic renal failure and second-
ary or tertiary hyperparathyroidism. Frequently, the patients are undergoing
dialysis. Less often, there is a background of primary hyperparathyroidism
or hypervitaminosis D.4,12,14,17 Although in many patients calcium deposition
occurs in association with an increased calcium-phosphorus product, in a
significant proportion of patients calcium and phosphorus levels are nor-
mal.4 It has been suggested that in such patients the calcification develops as
a direct response to excess parathormone or vitamin D. Challenging agents
resulting in the vascular precipitation of calcium salts are unknown but a
number of substances (including albumin, corticosteroids, and immunosup-
Fig. 10.67
pressives) have been incriminated.12 Calciphylaxis has also been described in Calciphylaxis: calcification of the small vessels and capillaries within the subcutaneous
association with decreased functional protein C.13 Very rarely, the ­condition fat is evident.
has presented in a patient with no evidence of a renal disorder or increase
in parathormone level.17 Malignant tumors, rheumatoid arthritis, giant cell
arteritis, as well as alcoholic liver disease have been implicated in these
patients.26
Histologically, the characteristic feature is calcification of the small- to
medium-sized arteries and arterioles (Figs 10.66, 10.67). Calcified debris
may sometimes be present within the lumina and occasionally the vessels
are thrombosed (Fig. 10.68). Intimal fibroblastic proliferation with ­luminal
narrowing has also been described (Fig.10.69).9 Hemorrhage within the
­subcutaneous fat may be seen and fat necrosis accompanied by a lobu-
lar lymphohistiocytic infiltrate has been documented in a number of cases
(Fig. 10.70). Interstitial calcification is only rarely a feature.9 Exceptionally,
pseudoxanthoma elasticum-like changes have been documented.27 In a related
phenomenon, epidermal and follicular calcification have been described in
the absence of vascular lesions in a patient with toxic epidermal necrolysis in
a background of hyperparathyroidism.28

Differential diagnosis
Calcification involving small arteries and arterioles not accompanied by
thrombosis has been described in patients with nephrogenic systemic fibro-
sis.29 Furthermore, incidental vascular calcifications can also be found in
patients with peripheral vascular disease, renal insufficiency, and diabetes Fig. 10.68
mellitus.30 Calciphylaxis: note the thrombosed vessel in the center of the field.

Fig. 10.66 Fig. 10.69

Calciphylaxis: there is focal fat necrosis and widespread calcification affecting the Calciphylaxis: in addition to mural calcification, there is marked intimal fibroblastic
small vessels. Note the thickened and fibrosed septa. proliferation.
346 Inflammatory diseases of the subcutaneous fat

Fig. 10.70 Fig. 10.72

Calciphylaxis: fat necrosis with conspicuous lipophages. In addition there is widespread Crystal-storing histiocytosis: within the dermis are large histiocytes with abundant
calcification. eosinophilic cytoplasm.

Crystal-storing histiocytosis
Clinical features
Crystal-storing histiocytosis is an extremely rare condition which has been
described in patients with lymphoplasmacytic neoplasms associated with kappa
light chain monoclonal gammopathy including lymphoplasmacytic lymphoma
(immunocytoma), monoclonal gammopathy of uncertain significance, multiple
myeloma, extramedullary plasmacytoma, maltoma, and large cell B-cell lym-
phoma.1–5 Primary cutaneous involvement is exceptional and the literature on
this aspect is limited to only three case reports.6–8 These patients presented with
erythematous asymptomatic subcutaneous nodules and tumors (Fig. 10.71).

Histological features
The condition is characterized by the presence of histiocytes containing eosino-
philic crystals which have been likened to Gaucher cells (pseudo-Gaucher
cells) admixed with lymphoma cells (Fig. 10.72).3 The crystals are variably

Fig. 10.73
Crystal-storing histiocytosis: the cytoplasm contains large eosinophilic crystals.

­ olygonal to rhomboid or needle-shaped and stain positively with PAS and

p
phosphotungstic acid hematoxylin (Fig. 10.73).6,7 Erythrophagocytosis may
also be evident.3
The histiocytes express CD68, and sometimes immunoglobulin heavy and
light chains may be stained weakly.3
Ultrastructurally, the crystals are sometimes membrane bound (of lysosomal
derivation) and display platelike, rectangular, trapezoid, and rhomboid
shapes with a distinct hexagonal lattice structure.3,6,7 The tumor cells may
also ­contain intracytoplasmic crystals.3

Gouty panniculitis
There are very occasional reports of gout presenting as a crystalline lobular
panniculitis.1–5

Nodular vasculitis
Fig. 10.71
Crystal-storing
histiocytosis: this
Clinical features
patient presented with Nodular vasculitis (erythema induratum) is a rare condition which usually
marked swelling of the presents in young or middle-aged women, often in those with an eryth-
face and the eyelids. rocyanotic circulation.1 Males are only rarely affected.2 Patients present

Fig. 10.74
Nodular vasculitis: early
lesion presenting as an
erythematous nodule
on the calf of a middle-
aged female. By courtesy
of M.M. Black, MD,
St Thomas’ Hospital,
London, UK.
Fig. 10.75
Nodular vasculitis: typical bilateral involvement of the calves. By courtesy of the
Institute of Dermatology, London, UK.
with painful, tender, violaceous, indurated nodules particularly affecting
the calves although the shins, feet, ankles, thighs, and upper limbs may
sometimes be involved (Figs 10.74, 10.75). Lesions are often bilateral and
the overweight with fat calves are most often affected. Seasonal variation
has been noted with an increased incidence being recorded in the cold win-
ter months. Skin lesions often recur over many years. Ulceration is com-
mon and scarring with hyperpigmentation frequently accompanies healing
(Figs 10.76–10.78).
In those cases that represent a manifestation of underlying tuberculo-
sis, the term erythema induratum (Bazin's disease) is frequently applied. In
this condition, there is invariable hypersensitivity to intradermal injection
of purified protein derivative (PPD) at a dilution of 1:10 000 and a com-
plete clearing of all skin lesions following treatment with antituberculous
chemotherapy.3–6
Nodular vasculitis 347
Fig. 10.76
Nodular vasculitis: the nodules frequently ulcerate. By courtesy of R.A. Marsden,
MD, St George’s Hospital, London, UK.
Fig. 10.77
Nodular vasculitis: in this severely affected patient ulcerated lesions are present on
the shins in addition to the calves. By courtesy of R.A. Marsden, MD, St George’s
Hospital, London, UK.
Pathogenesis and histological features
The relationship between erythema induratum and nodular vasculitis has for
many decades been the subject of controversy. Similarly, the association of
the former condition with an underlying tuberculous infection has been the
subject of prolonged debate.
As outlined above, the more recent literature gives considerable support to
the notion that occult tuberculosis is present in many patients with erythema
induratum and that the two terms are, therefore, synonymous in a substan-
tial proportion of cases. Thus, erythema induratum may be associated with
evidence of active tuberculosis.7–11 Although cultures of lesions are invari-
ably negative, the more recent demonstration of Mycobacterium tuberculosis
DNA by PCR in lesional tissue adds strong additional support to the proposal
of an underlying tuberculous etiology.12–21
Nodular vasculitis can, therefore, be regarded as a hypersensitivity reaction
in which mycobacterial antigens are one important cause. Immune complex
and delayed hypersensitivity mechanisms have both been proposed.13 Other
predisposing factors for this condition have not yet generally been identi-
fied although nodular vasculitis has been described in association with acute
348 Inflammatory diseases of the subcutaneous fat

Fig. 10.78 Fig. 10.80

Nodular vasculitis: Nodular vasculitis: well-formed epithelioid granulomata and multinucleate giant cells
multiple scarred lesions. are present.
Note the marked
hyperpigmentation.
By courtesy of the
Institute of Dermatology,
London, UK.

myeloid leukemia, chronic hepatitis C infection, and as an adverse drug reac-

tion associated with propylthiouracil.20,22–25 Nodular vasculitis has recently
been reported in a patient with ulcerative colitis.26 Bacille Calmette-Guerin
(BCG) vaccination, distal painful peripheral neuropathy, and granulomatous
aortic valve stenosis may on occasion be associated with erythema induratum
of Bazin.27–29
The histological features combine septal and lobular changes (Fig.
10.79). The presence of vasculitis has traditionally been regarded as a
sine qua non for the diagnosis of nodular vasculitis (erythema indura-
tum). Nevertheless, a recent study analyzing 101 biopsy specimens from
86 patients with clinical features of erythema induratum failed to detect
the presence of vasculitis in 9.9% of specimens, even after examination of
multiple serial sections.30
In a biopsy from an established lesion, the septa are widened and chron-
ically inflamed (Fig. 10.80). Acute vasculitis (affecting septal and ­lobular
veins and venules) with a heavy inflammatory cell infiltrate consisting of Fig. 10.81
Nodular vasculitis: vascular involvement as seen in this field is a characteristic
feature.

­ eutrophils, lymphocytes, and histiocytes is typically present, sometimes

n
accompanied by vessel wall necrosis and thrombosis (Fig. 10.81). The most
frequently affected are small lobular veins, followed by both septal veins and
lobular venules.30 In addition, septal arteries may also be involved by the vas-
culitic process.30
Occasionally, septal granulomatous inflammation can also be evident.
Lobular inflammation may occasionally be limited to a focal ele-
ment adjacent to an acutely inflamed vessel.31 More frequently, how-
ever, it presents as nodular lesions scattered throughout the whole lobule
or affecting multiple lobules. Fat necrosis is invariably present and is
often florid. The features are varied and range from typical lipophagic
fat necrosis to coagulative or more rarely caseation-like necrosis ( Figs
10.82, 10.83 ).32 Neutrophils, lymphocytes, and histiocytes with xan-
thomatized forms are typically seen. Granulomata are often present and
giant cells of both foreign body and Langerhans type are frequently a
feature ( Fig. 10.84 ).
Fig. 10.79 In biopsies from chronic or resolving lesions, fibrosis of both the septa
Nodular vasculitis: note the distinct nodules of granulomatous inflammation at the and lobules is often present. Giant cells and granulomata may still be
periphery of the lobule. present.
 Neutrophilic lobular panniculitis associated with rheumatoid arthritis 349

Differential diagnosis
Due to the frankly granulomatous nature of the histology, it is mandatory to
exclude infective causes of panniculitis, particularly mycobacterial and fungal
infections, including cryptococcosis, mycetoma, chromomycosis, sporotricho-
sis, and aspergillosis. Subcutaneous sarcoidosis should also be considered,
although in this condition granulomata are also seen in the dermis. Asteroid
inclusions and Schaumann bodies, which are both features of sarcoidosis (see
below), are not characteristic of erythema induratum.

Subcutaneous sarcoidosis
Clinical features
Involvement of subcutaneous fat in patients with sarcoidosis is rarely encoun-
tered by histopathologists even though it may occur in as many as 1.4% to
6% of all patients with this disease.1–3 Most often it presents as asymptomatic
or tender, flesh-colored to erythematous, subcutaneous nodules with frequent
clustering, principally affecting the extremities although a more general-
Fig. 10.82 ized distribution has also been documented.2–10 Exceptionally, ­subcutaneous
Nodular vasculitis: note the presence of numerous lipophages. involvement may be the initial or even the only feature of sarcoidosis.6,11
Isolated subcutaneous sarcoidosis has also been reported following inter-
feron treatment for melanoma.12,13 More commonly, however, subcutane-
ous lesions are associated with visceral disease, particularly bilateral hilar
lymphadenopathy.
Subcutaneous sarcoidosis shows a predilection for females and the major-
ity of patients are in the fifth and sixth decades.6

Histological features
The changes, which predominantly involve the lobule, consist of well-formed,
noncaseating granulomata, sometimes associated with fibrosis, which may
extend into the septa. Typically, the granulomata are of the ‘naked’ type, i.e.,
devoid of a peripheral rim of lymphocytes, and giant cells of both foreign
body and Langerhans types are usually present. Exceptionally, caseation and
calcification have been described.14,15

Differential diagnosis
Subcutaneous sarcoidosis is a diagnosis of exclusion; other causes of gran-
ulomatous inflammation – including mycobacterial and fungal infections,
foreign body reactions, and so-called ‘metastatic Crohn's disease’ – must be
Fig. 10.83 considered in the differential diagnosis.16,17
Nodular vasculitis: the eosinophilic necrotic debris reminiscent of caseation is a
typical feature.
Neutrophilic lobular panniculitis associated
with rheumatoid arthritis
Clinical features
Also known as pustular panniculitis, this rarely described entity has been
documented in middle-aged females who presented with painful nodules
predominantly affecting the lower legs.1–5 Similar changes have also been
reported on the back, upper arms, forearms, and nasal bridge in an infant
with juvenile rheumatoid arthritis.6 Blister formation, pustulation, ulceration,
and discharge of oily, necrotic debris may occur.3–5

Pathogenesis and histological features

Fig. 10.84
Nodular vasculitis: granulomata may be seen within the lobule and also in the septa.
The pathogenesis may be related to circulating immune complexes since high
levels have been identified in patients with this condition.3,4
The lobules and septa are infiltrated by neutrophils with central lobu-
lar necrosis accompanied by a histiocytic and giant cell response.2–5 Small
numbers of eosinophils are sometimes present.4 Nuclear dust can be con-
spicuous and cyst formation with membranous change has been described.4,5
Leukocytoclastic vasculitis affecting the dermal arterioles and venules may
be seen.4 Endothelial swelling, hemorrhage, and fibrin deposition may also
be present.7
350 Inflammatory diseases of the subcutaneous fat

Neutrophilic lobular panniculitis has also been reported in a patient with

nonrheumatoid arthritis.8

Differential diagnosis
Factitial disease and infections must always be excluded in neutrophil-rich
panniculitides. Similarly, pancreatic disease-associated panniculitis and α1-
antitrypsin deficiency-associated panniculitis are typically linked with a lobu-
lar neutrophil-rich infiltrate. The lobular panniculitis associated with bowel
bypass is also typically neutrophil rich.9,10

Eosinophilic panniculitis
Clinical features
Eosinophilic panniculitis is not a disease in its own right, but represents a
reaction pattern that may be found under a variety of circumstances.1 It is
seen more often in females than males (3:1). Although a wide age range is
affected, there are two peaks: one in the third decade and the other in the
sixth decade and above. Patients present predominantly with nodules and Fig. 10.86
plaques, although papules and pustules are sometimes seen.2–5 Lesions, which Eosinophilic panniculitis: note the massive eosinophilic infiltrate.
may be single or multiple, affect the legs, arms, trunk, and face in decreasing
order of frequency.
Eosinophilic panniculitis may be found in association with erythema
nodosum, immune complex-mediated vasculitis, atopic dermatitis, refractory
anemia, chronic recurrent parotitis, artifact, leukocytoclastic vasculitis, drug
reactions, eosinophilic cellulitis, insect bites, toxocariasis, gnathostomiasis,
Fasciola infection, human immunodeficiency virus (HIV), specific immuno-
therapy with aqueous lyophilized bee venom, injection site reactions, trauma,
and in patients with lymphoma.5–19 On rare occasions, no obvious underlying
condition can be detected.19 Other than in those patients with an associated
neoplasm, eosinophilic panniculitis appears to be a self-limiting and benign
condition.7

Histological features
The histological features affect the lobules and the septa and are character-
ized by an intense infiltrate of eosinophils, which may be accompanied by
variable numbers of other inflammatory cells including neutrophils, lym-
phocytes, and monocytes (Figs 10.85, 10.86). Vasculitis is usually not seen.

Fig. 10.87
Eosinophilic panniculitis: note the flame figure in the center of the field.

Fat necrosis is sometimes present. On occasions, typical ‘flame figures’, as

seen in eosinophilic cellulitis, may be noted (Fig. 10.87). The changes some-
times extend into the reticular dermis and occasionally the underlying fascia
is involved.

Fig. 10.85
Eosinophilic panniculitis:
there is a heavy,
predominantly lobular
inflammatory cell infiltrate.
Infective panniculitis
Clinical features
The clinical features in patients with infective panniculitis are not spe-
cific and include nodules, ulcerated lesions, abscesses, and erythema
nodosum-like lesions.1 Patients are usually, but not invariably, immuno-
suppressed. The legs and feet are the sites most often affected. Specific
infections, which have presented with panniculitis, include Histoplasma
capsulatum, Pseudomonas aeruginosa, Candida albicans, Aspergillus spp.,
Zygomycetes, Cryptococcus neoformans, Fusarium spp., Mycobacterium
avium intracellulare, Mycobacterium ulcerans, Mycobacterium mari-
num, Mycobacterium tuberculosis, Mycobacterium chelonei, Brucella
ssp, Neisseria meningitidis, Streptococcus pyogenes, Staphylococcus
aureus, Actinobacillus, Actinomyces spp., Coxiella burnetii and cytome­
galovirus.2–28
 Infective panniculitis 351

Histological features
Epidermal changes may include parakeratosis, acanthosis and spongio-
sis.1 The dermis is edematous and often shows a perivascular and intersti-
tial inflammatory cell infiltrate containing many neutrophils. Hemorrhage is
sometimes present.
Most commonly, the subcutaneous fat shows features of a mixed septal/
lobular panniculitis (Figs 10.88–10.92).1 Erythema nodosum-like features
may be evident.1 Changes suggestive of an infective etiology include a promi-
nent neutrophilic infiltrate, hemorrhage, basophilic necrosis and necrosis of
sweat glands, vascular proliferation, and discrete abscess formation.1,29
Granulomata are sometimes conspicuous in atypical mycobacterial infec-
tions. On other occasions acute inflammatory changes with abscess forma-
tion are seen (e.g., Mycobacterium chelonei infection). In the latter condition,
organisms may be identified in microcysts lined by neutrophil polymorphs.1
Mycobacterial infection may also occasionally manifest as phlebitis.30 Deep
fungal infections commonly involve the subcutaneous fat, presenting as granu-
lomatous or mixed suppurative and granulomatous inflammatory processes.
From the above description, it is obvious that special stains for bacteria
and fungi should be performed in all cases of panniculitis where the etiology Fig. 10.90
is uncertain. Culture may also be necessary in some instances. Infective panniculitis: in this example, there is a granulomatous infiltrate.

Fig. 10.88 Fig. 10.91

Infective panniculitis: there is intense acute inflammation with abscess formation. Infective panniculitis: a twisted hypha typical of zygomycosis is present.

Fig. 10.89 Fig. 10.92

Infective panniculitis: this example is due to cryptococcal infection. Note the typical Infective panniculitis: numerous cocci are present in this section from a patient with
yeast forms (arrowed). necrotizing fasciitis.
352 Inflammatory diseases of the subcutaneous fat

Acute infectious id panniculitis –

panniculitic bacterid
This is a recently described variant of lobular neutrophilic panniculitis, which
likely represents an id reaction to infections other than Mycobacterium
tuberculosis.1

Clinical features
Following primary infection elsewhere (sinusitis, breast and dental abscess,
impetigo, cellulitis, viral pharyngitis, Pseudomonas pneumonia, and ulcer-
ative colitis) all 10 patients (4 males, 6 females) presented with sudden
­development of tender nodules on the lower extremities, with additional
­involvement of the upper extremities in three patients. The lesions resolved
completely after adequate therapy of the primary focus. Hyperviscosity con-
ditions were ­present in three patients.
A

Histological features
Fat lobules and septa were infiltrated by a prominent inflammatory cell
infiltrate composed predominantly of neutrophils forming small microab-
scesses, accompanied by fat necrosis. Lymphocytes and histiocytes were also
present in the infiltrate, with occasional granuloma formation. Spilling of
the inflammation into the dermis was seen. Vascular changes consisted of
necrotizing vasculitis involving arterioles and venules in the fat lobules and
lower dermis, but also of thrombotic microangiopathy of the capillaries in
the ­subcutaneous fat.
Special stains for microorganisms were negative in all cases. Infection with Fig. 10.93
Sclerosing panniculitis
Mycobacterium tuberculosis was excluded in all patients.
(A & B): (A) the skin
shows features of stasis.
Dense fibrosis has
Differential diagnosis resulted in this inverted
Infection should be excluded with appropriate stains. Neutrophilic ­lobular bottle appearance.
panniculitis associated with rheumatoid arthritis can have a similar morpho­ Note the characteristic
logy, and clinicopathological correlation is vital. symmetry; (B) close-up
view of an early lesion
showing an indurated,
markedly erythematous
plaque. (A) By courtesy
Sclerosing panniculitis of the Institute of
Dermatology, London, UK;
Clinical features (B) By courtesy of J.C.
Sclerosing panniculitis (stasis-associated sclerosing panniculitis, hypo- B Pascual, MD, Alicante,
Spain.
dermatitis sclerodermaformis, lipodermatosclerosis, lipomembranous
change in chronic panniculitis) is a relatively common condition which
most often develops in middle-aged or elderly, overweight females with
a history of peripheral venous disease including varicose veins, throm-
bophlebitis, and deep venous thrombosis.1–7 Less often, the condition
follows arterial ischemia. Patients present with indurated, wood-like, The histological features are variable depending upon whether the biopsy
sclerodermiform plaques affecting the lower legs in a stocking distri- represents an early stage in the development of this disorder or an established
bution and characteristically resembling an inverted bottle appearance lesion.5,11
(Fig. 10.93).1,3 Often the changes are bilateral and symmetrical.2 The Within the subcutaneous fat, early lesions are characterized by cen-
overlying skin may show additional changes of venous stasis including trilobular ischemia with infarction of fat cells and vascular congestion/­
atrophy, ulceration, hyperpigmentation and telangiectasia. Patients with hemorrhage.5 Vascular thrombosis may also be seen but there is no evidence
sclerosing panniculitis and systemic sclerosis frequently have associated of vasculitis. A lymphocytic infiltrate is present in the septa and this may spill
­pulmonary hypertension.8 over to affect the edge of the lobule. Hemosiderin deposition is ­commonly
present.
In established lesions, ischemic changes may still be evident but more
Pathogenesis and histological features often there is microcystic change with hyalinization within the fat lob-
The pathogenesis of sclerosing panniculitis is venous stasis within the centri- ule (Figs 10.94–10.96). Membranous fat necrosis is often present and
lobular capillaries leading to ischemia and eventual infarction of the subcu- lipophagic changes may be evident. Septal scarring is present, which in
taneous fat. Increased interstitial fibrinogen as a result of excessive capillary advanced lesions can be marked with resultant atrophy of the subcutane-
permeability due to venous hypertension is thought to be of importance.4 ous fat.
Fibrin deposition around the dermal capillaries results in hypoxia. In addi- The dermis typically shows the features of stasis including chronic inflam-
tion, there is some evidence to suggest that increased matrix metalloprotei- mation, fibrosis, vessel-wall thickening, lobular capillary proliferation, and
nases and urokinase-type plasminogen activator may be of importance in the hemosiderin deposition. Acanthosis, spongiosis, and lichenification may be
pathogenesis.9,10 evident.
 Membranous fat necrosis 353

Differential diagnosis
The absence of sclerodermiform dermal changes and the presence of features
of venous stasis distinguish end-stage sclerosing panniculitis from morphea
profunda, scleroderma and acrodermatitis chronica atrophicans (a late mani-
festation of Lyme disease).

Membranous fat necrosis

Fig. 10.94
Sclerosing panniculitis:
there is typical microcystic
change.
Clinical features
Membranous fat necrosis is a non-specific change found predominantly in the
subcutaneous fat. It was first described, however, in patients with progressive
sudanophilic leukoencephalopathy (Nasu-Halola's disease).1–3 This is a rare
condition in which cystic lesions develop in subcutaneous fat and bone mar-
row associated with pathological fractures and cerebral lesions resulting in
seizures and presenile dementia.
Subsequently membranous change has been recognized as a common
manifestation of venous stasis-associated disease.4–7 It has, however, also
been observed in association with numerous other conditions includ-
ing arterial insufficiency, diabetes mellitus, erythema nodosum, nodular
­vasculitis, infective panniculitis, pancreatic disease-associated panniculitis,
subcutaneous sarcoidosis, morphea, morphea profunda, cytophagic histio-
cytic panniculitis, dermatomyositis, systemic sclerosis, lupus panniculitis,
necrobiosis lipoidica, and nodular cystic fat necrosis.6–16 It has also been
described in the breast, in appendices epiploicae, within an ovarian cys-
tic teratoma and following subcutaneous elemental mercury injections.17–21
Membranocystic change accompanied by myospherulosis has also been
documented.22

Pathogenesis and histological features

Although in the majority of cases an ischemic pathogenesis is likely, its pres-
ence following trauma and in a background of infection suggests that other
mechanisms are sometimes responsible. The membrane change likely repre-
sents altered adipocyte cell membranes although recently a contribution by
histiocytes has been postulated.5–7
Histologically, it presents as amorphous, autofluorescent, eosinophilic,
PAS-positive membranes outlining cysts within the lobules of the subcutane-
ous fat (Fig. 10.97). Pseudopapillary and arabesque patterns are commonly
present (Figs 10.98, 10.99). The membrane also stains for lipid using Sudan
black and is luxol fast blue positive.5 This is thought to represent ceroid, at
least in part.23
Ultrastructurally, the membrane is composed of perpendicularly orien-
tated microvilli alternating with dilated tubular crypts reminiscent of smooth
endoplasmic reticulum with adjacent electron-dense material.5
Fig. 10.95
Sclerosing panniculitis: close-up view of microcysts.

Fig. 10.96 Fig. 10.97

Sclerosing panniculitis: membranous fat necrosis is evident. Membranous fat necrosis: note the delicate membranes lying within small cystic spaces.
354 Inflammatory diseases of the subcutaneous fat
Fig. 10.98
Membranous fat necrosis: close-up view.
Lipodystrophy
Classification and clinical features
The lipodystrophies are a complex group of disorders characterized by a
familial or acquired, complete or partial loss of subcutaneous fat.1–5 They
have been classified as follows:1
• Familial lipodystrophy including:
– generalized lipodystrophy (Berardinelli-Seip syndrome)
– partial lipodystrophy (Dunnigan and Köbberling variants)
• Acquired lipodystrophy including:
– generalized lipodystrophy (Lawrence syndrome)
– partial lipodystrophy (Barraquer-Simons syndrome)
– HIV-associated lipodystrophy
• Localized lipoatrophy (localized lipodystrophy) including:
– drug-induced lipoatrophy
– pressure-induced lipoatrophy
– panniculitis-associated lipoatrophy
– centrifugal variant lipoatrophy
– idiopathic lipoatrophy.
Familial lipodystrophy
Congenital generalized lipodystrophy
(Berardinelli-Seip syndrome)
This exceedingly rare variant of lipodystrophy is inherited in an autosomal
recessive mode and is usually recognizable at birth.1–4 Its prevalence has been
estimated as 1:12 000 000.1 The sex incidence is equal.
It is characterized by a complete absence of metabolically active subcutane-
ous fat in association with insulin resistance, hyperinsulinemia, hypertriglyc-
eridemia with normal or slightly raised cholesterol, and nonketotic diabetes
mellitus.4 Mechanical fat such as is found in the orbits, on the palms and
soles, and around the external genitalia is unaffected.1 Patients also have a
voracious appetite associated with a hypermetabolic state and marked hyper-
hidrosis. Additional features include an anabolic syndrome with increased
height velocity, advanced bone age, muscular hypertrophy, masculine body
build, acromegaloid stigmata, hepatomegaly, enlarged external genitalia in
childhood, abundant curly hair on the scalp, hypertrichosis, umbilical ­hernia,
acanthosis nigricans, mild mental retardation with hydrocephalus, and
­hypothalamic–pituitary dysfunction.4,5
Diabetes is thought to develop as a consequence of extensive pancreatic
amyloid deposition with loss of β-cells.6 Postmortem studies have demon-
strated fatty liver with cirrhosis.7
Fig. 10.99
Membranous fat necrosis: the features are highlighted with a Masson’s trichrome
stain.
The genes for congenital generalized lipodystrophy have been mapped
to human chromosome 9q34 and 11q13, and are designated AGPAT2 and
BSCL2 (seipin gene), respectively.8–10 Not all patients have mutations in these
genes, suggesting the presence of additional yet unidentified genetic loci.11
Diagnostic criteria as outlined in Table 10.3 have recently been
recommended.1
Familial partial lipodystrophy (Dunnigan
variant)
This is another exceedingly rare condition with an estimated prevalence
of less than 1 in 15 000 000 of the population.1 The original cases were all
females and therefore a sex-linked dominant mechanism, lethal in hemizy-
gous males, was postulated.12,13 The more recent publication of families with
affected male members suggests, however, that an autosomal dominant mech-
anism is at play.14
Patients are normal at birth but at puberty they lose subcutaneous fat from
the extremities and to a lesser extent from the trunk.15 The face is spared and,
indeed, in some patients, excessive fat deposition on the face and neck has
been documented. Diabetes mellitus, hypertriglyceridemia, and low serum
high density lipoprotein (HDL) cholesterol levels become manifest in early
adulthood.1,16,17 Patients may develop chylomicronemia and pancreatitis.1
Acanthosis nigricans, hirsutism, menstrual abnormalities, and polycystic ova-
ries are also sometimes evident.1
The gene responsible for familial partial lipodystrophy has been mapped
to chromosome region 1q21-22.18–20 It has been identified as the lamin A/C
gene, which codes for a nuclear envelope protein lamin.21–23
Diagnostic criteria as outlined in Table 10.3 have recently been
recommended.1
Familial partial lipodystrophy (Köbberling
variant)
This is an exceedingly rare variant in which only a small number of affected
pedigrees have been documented.1,24–26 Sporadic variants have also been
described.1,26,27 In these patients, loss of fat is limited to the extremities. There
may be increased truncal fat.1,26 Hypertriglyceridemia, arterial hypertension,
insulin resistance or diabetes mellitus are usually present, and the patients
have increased risk for premature cardiovascular disease and pancreati-
tis.1,26 Acanthosis nigricans has been described in a single patient.26 To date,
­documented affected patients have been female.
 Acquired lipodystrophy 355

Table 10.3
Lipodystrophies: diagnostic criteria

Disorder Essential criteria Confirmatory criteria

Congenital generalized Generalized lack of body fat Acanthosis nigricans
lipodystrophy Extreme muscularity from birth Acromegaloid features
Umbilical hernia
Clitoromegaly and mild hirsutism
Severe fasting or postprandial hyperinsulinemia
Onset of diabetes or impaired glucose tolerance test in teenage years
Hypertriglyceridemia with low HDL cholesterol concentration
Characteristic body fat distribution on MRI
Familial partial Normal physical appearance at birth Normal or excessive facial adipose tissue
lipodystrophy Loss of subcutaneous fat of the extremities Acanthosis nigricans
(Dunnigan variant) commencing at puberty Mild to moderate fasting or postprandial hyperinsulinemia
Muscular-appearing extremities Onset of diabetes or impaired glucose tolerance after age 20 years
commencing at puberty Hypertriglyceridemia with low serum HDL cholesterol concentrations
Characteristic body fat distribution on MRI
Acquired generalized Generalized loss of subcutaneous fat Loss of fat from palms and soles
lipodystrophy developing in childhood or later Severe fasting or postprandial hyperinsulinemia
Extreme muscularity appearing in childhood Impaired glucose tolerance or diabetes
or later Hypertriglyceridemia with low serum HDL cholesterol concentrations
Nodular panniculitis preceding onset of lipodystrophy
Coexistence of autoimmune diseases
Acquired partial Gradual loss of subcutaneous fat of the Normal or excess fat on hips and lower extremities
lipodystrophy face, neck, trunk, and upper extremities Proteinuria
developing in childhood or adolescence Biopsy proven mesangiocapillary glomerulonephritis
Low serum C3 levels
Presence of C3 nephritic factor
Absence of insulin resistance
Presence of other autoimmune diseases
Characteristic body fat on MRI
HDL, high density lipoprotein; MRI, magnetic resonance imaging. Derived from Garg, A. (2000) American Journal of Medicine, 108, 143–152.

Familial partial lipodystrophy associated
with mandibuloacral dysplasia
This autosomal recessive variant of lipodystrophy is characterized by the
presence of a variety of bony defects including mandibular and clavicular
hypoplasia, acroosteolysis, delayed closure of cranial sutures, and joint
contractures associated with cutaneous hyperpigmentation.28,29 Genetically,
it is a heterogeneous disorder. Mutations in genes encoding nuclear lamina
proteins and zinc metalloproteinase have been detected.30–33 Lipodystrophy
varies from loss limited to the extremities (type A) through to general-
ized loss (type B). Patients also have insulin-resistant hyperinsulinemia and
hypertriglyceridemia and diminished serum HDL cholesterol levels.29
Acquired lipodystrophy
Acquired generalized lipodystrophy
Acquired generalized lipodystrophy (Lawrence syndrome, lipoatrophic dia-
betes, lipoatrophic panniculitis, lipodystrophic diabetes) can be subclassified
into three variants:
• Type 1: the panniculitis variant,
Acquired partial lipodystrophy
• Type 2: the autoimmune disease variant,
• Type 3: the idiopathic variant,
and affect 25%, 25%, and 50% of the patients, respectively.34
Acquired generalized lipodystrophy is similar to the congenital form
although there is a predilection for females (3:1).1,34–37 Patients present in
childhood or adolescence with fat loss, which progresses over a period of
months or years.1 The entire body is affected, particularly face, arms, and
legs. The muscles of the extremities appear unduly prominent. Children with
this disorder may have a voracious appetite.
Features of an inflammatory nodular panniculitis appear to have pre-
ceded the onset of lipodystrophy in a number of cases (lipoatrophic
­panniculitis).34,38,39 These patients appear to have less severe fat loss and lower
prevalence of hypertriglyceridemia and diabetes in comparison with patients
having the autoimmune or idiopathic variant of the disease.34
Autoimmune diseases associated with acquired generalized lipodystrophy
include juvenile dermatomyositis in particular, followed by Hashimoto's thy-
roiditis, juvenile rheumatoid arthritis, adult-onset dermatomyositis, ­systemic
lupus erythematosus, systemic sclerosis, Sjögren's syndrome, and vitiligo.1,40–42
Liver involvement may be marked with steatosis, autoimmune hepatitis,
and cirrhosis supervening in a substantial number of cases.4,43 Additional
features include severe insulin resistance, diabetes, hyperinsulinemia, and
hypertriglyceridemia accompanied by low serum HDL cholesterol con-
centrations.1,34 Acquired generalized lipodystrophy can also be associ-
ated with cerebellar degeneration, unicameral bone cysts, and proteinuric
nephropathy.44–46
A preceding viral illness has frequently antedated the development of acquired
generalized lipodystrophy although whether this is causal or not is unclear.1,4
A case of panniculitis of the acquired generalized lipodystrophy variant was
reported recently, presumably triggered by pulmonary tuberculosis.47
Diagnostic criteria as outlined in Table 10.3 has been recommended.1
Acquired partial lipodystrophy (Barraquer-Simon syndrome, progressive lip-
odystrophy, cephalothoracic progressive lipodystrophy) is one of the more
common variants of lipodystrophy. Females are affected three times more
often than males.1 Patients present in late childhood or adolescence with grad-
ual loss of the subcutaneous fat of the face followed by the neck, ­shoulders,
arms, thorax, and upper abdomen (Fig. 10.100).1,48–50 The distal subcutane-
ous fat is typically spared and sometimes, in contrast, there is even excessive
fat deposition around the pelvis and on the legs.
Mesangiocapillary (membranoproliferative) glomerulonephritis (MCGN II)
and hypocomplementemia often accompany this variant.51–53 C3 levels are usu-
ally low in contrast to C1q, C4, C5, C6, factor B, and properdin, which are
356 Inflammatory diseases of the subcutaneous fat
A B
normal.54,55 The glomerulonephritis and low C3 have been shown to be due
to an IgG autoantibody, the C3 nephritic factor (C3NeF).56 It has been shown
that the latter has the capacity to induce adipocyte lysis.57 Three patients have
recently been described that presented with low C4 complement levels, wide-
spread acquired lipodystrophy, and chronic autoimmune hepatitis.58
An association with a number of other autoimmune diseases including
Sjögren's syndrome, dermatomyositis, hypothyroidism, and SLE has also been
documented.59–62 Patients may in addition develop hyperlipidemia, ­nonketotic
diabetes mellitus, acanthosis nigricans, and hirsutism.1 Hepatomegaly due to
fat accumulation is occasionally present. Extrinsic allergic alveolitis has been
reported in a single patient.63
Expression gene analysis in a single patient with acquired partial
­lipodystrophy demonstrated down-regulation of the PPARγ gene, which is nor-
mally associated with adipocyte differentiation, as well as reduced ­expression
of mitochondrial genes.64 In addition, heterozygous mutations of the LMNB2
gene have been detected in three out of four analyzed patients.65
Diagnostic criteria as outlined in Table 10.3 have recently been
recommended.1
Localized lipoatrophy
Clinical features
Localized disease (lipoatrophy) is a much more common phenomenon. The
subject has, however, been made extremely complicated by virtue of the large
number of synonyms that have been used to describe the same disease process
over the years (e.g., lipodystrophy, annular lipoatrophy, annular lipodystrophy,
semicircular lipoatrophy, postinjection lipoatrophy, involutional lipoatrophy,
lipodystrophia centrifugalis abdominalis infantilis, centrifugal lipodystrophy).
Essentially, localized lipodystrophy may result from a range of injurious stim-
uli and present at a wide variety of sites but essentially all of the subtypes listed
above are variations of the same disease process which may therefore follow
localized panniculitis, connective tissue diseases, injections, trauma, etcetera.
Lesions affecting the proximal extremities or buttocks should raise the possi-
bility of infection or trauma. Localized lipoatrophy has been described follow-
ing subcutaneous injections of insulin, triamcinolone acetate and iron dextran,
and following vaccinations.66–69 It has also been described as a ­complication of
idiopathic connective tissue diseases including systemic lupus erythematosus
Fig. 10.100
(A, B) Partial lipodystrophy:
note the striking loss of
symmetry due to diminished
fatty tissue of the left side
of the face. By courtesy of
the Institute of Dermatology,
London, UK.
(profundus), dermatomyositis, polymyositis, linear morphea, facial hemiatro-
phy, lichen sclerosus et atrophicus and progressive systemic sclerosis.70–72
Other types of localized lipodystrophy include annular lipodystrophy and
a variant that affects only half the circumference of an extremity (lipoatro-
phia semicircularis). These distinctive annular lesions are likely to result from
a localized pressure effect such as that which may occur with tight cloth-
ing or persistent localized trauma.73–76 Idiopathic variants are also recognized
including lipoatrophy associated with Becker's nevus and lipodystrophia
­centrifugalis abdominalis infantilis.77–80
Pathogenesis and histological features
The exact pathogenesis of lipodystrophy is unknown. A variety of theories has
been proposed, including hypothalamic–pituitary dysfunction (overproduc-
tion of fat-mobilizing peptides and amines), disordered fat metabolism, infec-
tion, and heredity. A currently favored area of research is directed towards
the role of abnormal insulin receptors on fat cells. It has been postulated that
abnormal insulin receptors are associated with diminished uptake of lipid by
fat cells with resultant lipodystrophy, hyperlipidemia, and hyperinsulinemia.
In general, the histopathology of lipodystrophy is noninflammatory in
nature.81–83 There is a progressive diminution of adipocyte lipid accompanied
by a decrease in cell size so that the cells become separated from one another
(Fig. 10.101). The stroma becomes hyalinized or myxomatous and contains
clusters of tortuous capillaries. As the end result resembles embryonic fat, this
process of atrophy is sometimes called ‘reversal of embryogenesis’.
Patients with multiple areas of localized lipoatrophy may show mild
inflammatory changes comprising perivascular and periseptal lymphocytic
infiltration accompanied by minor septal fibrosis.
Lipoatrophic panniculitis
Clinical features
Lipoatrophic panniculitis (atrophic connective tissue panniculitis) represents a
very rarely documented inflammatory form of localized lipoatrophy.1–7 In the
original report, three children developed centrifugally enlarging erythematous
nodules and plaques with atrophic centers on the lower extremities. Healing
of the lesions resulted in the clinical appearances of localized lipoatrophy.
The areas of lipoatrophy coalesced to give an appearance resembling partial
 Localized lipoatrophy 357

A B

Fig. 10.101
Lipodystrophy: (A) there is only a very small residual amount of subcutaneous fat in the center of the field; (B) these tiny adipocytes are reminiscent of embryonic fat. By courtesy
of W.P. D. Su, MD, Mayo Clinic, Rochester, USA.

or total lipodystrophy.1 All three patients had elevated ESRs. Two patients
had associated diabetes mellitus (one with coexistent Hashimoto's thyroidi-
tis) and one developed juvenile rheumatoid arthritis. Peters and Winkelmann
described a similar condition under the rubric ‘atrophic connective tissue dis-
ease panniculitis’.2 Nowadays, this entity would probably be best included in
the spectrum of acquired total or partial lipodystrophy.
have a raised ESR, thrombocytosis, and microcytic anemia. Antinuclear fac-
tor may be present.1 A similar disorder has rarely been described in adults
(adult lipophagic atrophic panniculitis).2 Winkelmann postulates that many
cases of Weber-Christian disease documented in the earlier literature belong
to this disorder (literature summarized in ­reference 1).

Histological features Histological features

In atrophic connective tissue panniculitis the histological features are those
of a lobular panniculitis.1,7 The deep dermis may manifest a ­perivascular
­lymphocytic and histiocytic infiltrate. Lymphocytes and mononuclear
­phagocytes extensively infiltrate the fatty lobules. Eosinophils and multi-
nucleate giant cells are uncommon. In more advanced lesions, there is fatty
­atrophy accompanied by an infiltrate composed mainly of foamy mac-
rophages.3 Vasculitis is not a feature of this disorder.1
Lipophagic panniculitis of childhood
Clinical features
Lipophagic panniculitis of childhood (lipophagic-granulomatous lipoatro-
phy) is exceedingly rare and presents in children as erythematous asymp-
tomatic or tender plaques and nodules affecting the arms or legs, which are
later associated with lipoatrophy.1 Fever is common and the children ­usually
Histologically, lipophagic panniculitis is characterized by panlobular inflam-
mation with histological features of lipoatrophy.1 The inflammatory cell
infiltrate consists of histiocytes and Touton-like lipophages. Occasional
­lymphocytes, neutrophils, and plasma cells may be evident. Eosinophils are
sometimes numerous. There is no evidence of vasculitis.1
Connective tissue panniculitis
Clinical features
This extremely rare chronic condition, originally described in two female
patients by Winkelmann and Padilha-Goncalves, comprises recurrent ­tender
subcutaneous nodules mainly on the shoulders and upper arms, but the cheek,
breast, trunk, neck or leg may also be affected.1 Healing is sometimes asso-
ciated with lipoatrophy and hyperpigmentation, which can be particularly
­disfiguring (Fig. 10.102).2

A B

Fig. 10.102
(A, B) Connective tissue panniculitis: this patient shows diffuse hyperpigmentation associated with generalized scarring and deformity. By courtesy of M.M. Black, MD, London, UK.
358 Inflammatory diseases of the subcutaneous fat

Laboratory findings include leukopenia, anemia, a raised ESR, positive anti-

nuclear antibody, and an unclassifiable antibody to extractable nuclear antigen.3

Histological features
A lymphohistiocytic panniculitis associated with both acute and caseation
necrosis characterizes the lesions. Lipophagic histiocytes and giant cells may
be present, but granulomata are not a feature and there is no evidence of sep-
tal involvement or vasculitis.1,2
At present, this variant of chronic panniculitis has defied further
classification.

Lupus erythematosus profundus

Clinical features
Lupus erythematosus profundus (lupus panniculitis) is an uncommon variant of
panniculitis, which may develop in association with either discoid lupus erythe-
matosus (DLE) or systemic lupus erythematosus (SLE).1–8 The incidence of lupus
panniculitis in SLE ranges from 2% to 10%;4,9–11 DLE is present in from 33%
to 70% of cases.4,5 Lupus panniculitis may, however, also present in the absence
of any other manifestations of lupus erythematosus.9 In a recent series from the
Mayo Clinic, 50% of patients had no evidence of any autoimmune-associated
disease.4 Lupus panniculitis shows a predilection for females (4:1) and most
patients are middle aged.4 Rarely, however, children (including infants) may be
affected.7,12 Rarely, lupus panniculitis may signify recurrence of SLE.13
Patients develop discrete, firm, asymptomatic or painful nodules, one to
several centimeters across, in the subcutaneous fat; the nodules are often
associated with trauma.9 Linear distribution of lupus panniculitis has rarely
been reported and is likely associated with a more aggressive clinical behav-
iour.14 The overlying skin may appear clinically normal or show discoid lupus
plaques, poikiloderma, erythema, atrophy or ulceration (Fig. 10.103).10,15
Anetodermic lupus panniculitis has been associated with antiphospholipid
antibodies.16 Lupus erythematosus profundus is characteristically chronic,
patients developing recurrent crops of lesions. Spontaneous resolution may
occur and leave depressed atrophic disfiguring scars (lipoatrophy) (Fig.
10.104). Sites of predilection include the face, upper and outer parts of
the arm, the breasts, back, and buttocks. Breast involvement with scarring
and calcification may be clinically mistaken for carcinoma (so-called ‘lupus
­mastitis’).17,18 Salivary gland and primary periorbital lesions have also been
documented.19–23 Rarely, the disease may present with generalized lesions.8
Fig. 10.103
Lupus erythematosus
profundus:
erythematoviolaceous
plaques showing
focal ulceration at the
characteristic site. By
courtesy of the Institute of
Dermatology, London, UK.
Fig. 10.104
Lupus erythematosus
profundus: a depressed
scarred area due to end-
stage lipoatrophy.
By courtesy of the
Institute of Dermatology,
London, UK.
In cases with associated SLE, patients frequently manifest arthralgia and
Raynaud's phenomenon; there appears to be a relatively low incidence of
renal and neurological involvement.10 Positive serology may include antinu-
clear antibody, anti-DNA antibody, anti-extractable nuclear antigen (ENA)
antibodies, and rheumatoid factor.9,15 In those patients in whom there is no
evidence elsewhere of lupus erythematosus, a raised antinuclear factor may be
the only serological abnormality.4 Although in these latter patients the prog-
nosis is generally thought to be good, in some patients there is ­considerable
mortality and the disfigurement a source of considerable distress.24,25 Partial
C4 deficiency has been described in a patient with lupus erythematosus
profundus.26
Histological features
In an established lesion the histological features of lupus erythematosus
profundus are virtually diagnostic. The overlying epithelium and super-
ficial dermis may show features of DLE, poikiloderma or be unaffected
(Figs 10.105–10.108).27,28 Within the deep dermis, and extending into the
widened septa of the subcutaneous fat, is a dense chronic inflammatory
cell infiltrate consisting predominantly of nodules of lymphocytes with
lesser numbers of plasma cells (Figs 10.109–10.111).11,13,28 Lymphocytic
nuclear debris or dust within a lymphoplasmocytic infiltrate is frequently
seen.13 Occasionally, lymphoid follicles with germinal centers are evident
(Fig. 10.112). The infiltrate may surround and permeate the walls of
blood vessels and sweat glands; involvement of the perineural sheath is
occasionally a feature (Fig. 10.113).27,29 Less often, frank lymphocytic
vasculitis with mural fibrinoid necrosis and luminal thrombosis is seen
(Fig. 10.114).
The infiltrate often extends into the periphery of the fat lobules and when
associated with fat necrosis there may also be moderate numbers of neutro-
phil polymorphs. The collagen of the deep dermis and the fibrous septa of the
subcutaneous fat show striking fibrinoid degenerative changes. Fibers may be
markedly swollen and intensely eosinophilic, or fragmented into amorphous
granular debris. Similar changes are seen surrounding individual adipocytes.
In more advanced examples, glassy eosinophilic necrosis gives a diffusely
hyalinized appearance to the subcutaneous fat (Fig. 10.115). The foci of col-
lagenous degeneration are sometimes associated with mucin deposition, and
foci of calcification which may on occasion be very prominent.10,13,15,27,28,30
Extensive endarteritis obliterans has been reported in a ­single case of lupus
panniculitis, which was associated with membranocystic changes and
­dystrophic calcification.31
 Localized lipoatrophy 359

Fig. 10.105 Fig. 10.108

Lupus erythematosus profundus: low-power view showing epidermal atrophy Lupus erythematosus profundus: the epidermis appears normal.
with hyperkeratosis and a dense dermal lymphocytic infiltrate with extension into
subcutaneous fat.

Fig. 10.106 Fig. 10.109

Lupus erythematosus profundus: in this example, there are typical features of Lupus erythematosus profundus: the septa are thickened and there is a dense
discoid lupus erythematosus. infiltrate.

Fig. 10.107
Lupus erythematosus profundus: in contrast, this patient showed disease limited to Fig. 10.110
the subcutaneous fat. Lupus erythematosus profundus: the infiltrate is largely lymphocytic.
360 Inflammatory diseases of the subcutaneous fat

Fig. 10.111 Fig. 10.114

Lupus erythematosus profundus: plasma cells, as shown in this field, are sometimes Lupus erythematosus profundus: lymphocytic vasculitis, as noted in this field, is
conspicuous. not uncommon.

Fig. 10.115
Fig. 10.112 Lupus erythematosus profundus: hyalinization of the fat is a characteristic feature.
Lupus erythematosus profundus: lymphoid follicles, as shown in this field, may be
a prominent feature.
By immunohistochemistry, the predominant cells are α/β T-helper lymphocytes,
intermingled with B lymphocytes.13 Molecular analysis by polymerase chain
reaction generally reveals a polyclonal phenotype.13
Immunofluorescence commonly reveals immunoglobulin and complement
at the dermoepidermal junction and sometimes around the superficial blood
vessels.15,27

Differential diagnosis
Similar histological features may be seen in other connective tissue diseases
including linear morphea, morphea profunda, systemic sclerosis, dermatomyo-
sitis, mixed connective tissue disease, and polymyositis.32–35 Recently, Sjögren's
syndrome has been added to the causes of so-called plasma cell panniculitis.36
Lobular panniculitis with sclerosis reminiscent of lupus panniculitis has also
been described in a patient with Degos' disease (malignant atrophic ­papulosis).37
Distinction between lupus profundus and subcutaneous ­panniculitis-like T-cell
lymphoma can, on occasion, be extremely difficult on clinical as well as on
histological grounds.38–41 The presence of atypical lymphocytes with immuno-
histochemical features of cytotoxic T cells (CD3+,CD8+) accompanied by high
proliferation rate and monoclonal TCR-γ gene rearrangement is ­suggestive
of lymphoma.38 Nevertheless, lupus profundus and panniculitis-like T-cell
Fig. 10.113 ­lymphoma may coexist in the same patient.38 Overlapping ­histological ­features
Lupus erythematosus profundus: blood vessel walls are commonly thickened and with characteristics of both lupus profundus and ­subcutaneous ­panniculitis-like -
hyalinized. cell lymphoma are seen in these patients.38,42,43
 Localized lipoatrophy 361

Scleroderma panniculitis
Clinical features
Sclerosis and chronic panniculitis have been recorded as main features in
both generalized morphea and progressive systemic sclerosis.1–3 In addition,
morphea profunda has been described as a sclerosing variant of ­morphea,
which primarily affects the subcutaneous fat analogous to lupus erythemato-
sus ­profundus.4,5 This condition, which shows a female predominance (3:1),
affects a wide age range (9–62 years) and presents primarily as ­subcutaneous
sclerosis.6 The sclerosis may be generalized and extend to the ­digits, or present
as solitary or multiple, localized, inflamed, hyperpigmented or ­erythematous,
asymmetrical and ill-defined plaques with a predilection for the ­shoulders,
upper arms, and trunk.6–8 A variant localized to the paraspinal region in
children has also been described.9,10 Patients with systemic sclerosis can
also develop sclerosing panniculitis. These patients have systemic ­sclerosis
­associated with pulmonary hypertension.11
Histological features
The significant features include thickening and hyalinization of the con-
nective tissue of the deep dermis, subcutaneous fat, and muscular fascia.3
Lipomembranous fat necrosis can also be a feature.12 A perivascular and focal
interstitial lymphocytic and plasma cell infiltrate is present in the subcutane-
ous fat. Exceptionally, plasma cells may be very numerous – so-called plasma
cell panniculitis.13–15 Lymphoid nodules (usually without germinal center for-
mation) are evident and mast cells may be increased in number.6 Scattered
eosinophils are occasionally seen. Mucin deposition is sometimes a feature
and diminished elastic tissue is a frequent finding, although in some cases it
appears increased in quantity.8 Localized osseous metaplasia with transepi-
dermal elimination has been documented.16 The changes in the fascia are
­similar to those described in the subcutaneous fat.
The overlying epidermis may show interface change with basal cell
­vacuolation and lymphocytic exocytosis.1,7
Immunofluorescent findings are variable. In the majority of cases it is neg-
ative, but C3 was found at the dermoepidermal junction in one case and,
in another, C3 and IgM were identified within the blood vessel walls in the
superficial dermal vasculature.6,7
Differential diagnosis
An association of childhood dermatomyositis with subcutaneous panniculitic
T-cell lymphoma has been described in a single case report.15
Postirradiation pseudosclerodermatous
panniculitis
Clinical features
This is a rare complication of high-dose radiotherapy. Thus far, it has only been
described in female patients who have received this treatment modality for breast
carcinoma following radical mastectomy.1–4 Patients present with deep-seated
and progressive induration of the subcutis in the area of previous ­irradiation
(Fig. 10.116), usually within the first year after radiation therapy.1–3
Histological features
The main histological features are localized to the subcutaneous fat where
there is a lobular panniculitis characterized by fat necrosis with foreign body
(lipophagic) granulomata and a lymphocyte and plasma cell infiltrate.1,2 The
septa are grossly thickened by hyalinized collagen. Dermal changes may be
absent or there can be a perivascular and interstitial lymphocyte and plasma
cell infiltrate with atypical myofibroblasts.1 Dilated lymphatics may occasion-
ally be found in the dermis.3 Epidermal changes of radiotherapy are absent.2

Differential diagnosis Differential diagnosis

In patients with this condition, sections should be very carefully scrutinized
Morphea profunda differs from conventional generalized morphea by the
for evidence of recurrent/metastatic breast carcinoma. Immunohistochemistry
deeper involvement of the sclerotic process and the more intense chronic
may prove invaluable.
inflammatory cell infiltrate.6 Some authors regard eosinophilic fasciitis as
Postirradiation pseudosclerodermatous panniculitis can be histologically
part of the spectrum of morphea profunda.6
confused with both morphea profunda and lupus erythematosus profundus.2
Clinicopathological correlation should readily establish the correct diagnosis.
Dermatomyositis panniculitis
Clinical features
Panniculitis has been described as a non-specific incidental finding in biopsy
specimens of skin or muscle from patients with dermatomyositis.1–3 Rarely,
however, it presents as a symptomatic disorder, patients complaining of indu-
rated, erythematous, tender, painful plaques and nodules, located about
the arms, thighs, abdomen, and buttocks.3–11 In some cases, the panniculi-
tis ­precedes the onset of the myositis.3 With chronicity, patients can develop
lipoatrophy.12 Both children and adults may be affected.

Histological features
Dermatomyositis panniculitis is characterized by a predominantly ­lobular
infiltrate of lymphocytes and plasma cells, sometimes accompanied by lym-
phoid follicles with germinal centers.4,5 Focal fat necrosis may be present
and lymphocytic vasculitis has occasionally been documented.6 The septa
of the subcutaneous fat become progressively thickened and hyalinized.
Membranocystic changes have been described in a number of cases,
­particularly in the Japanese.1,12,13 Calcification is a late change, but can be
very prominent.1,14
Mild inflammatory changes may be seen in the subcutaneous fat in Fig. 10.116
patients with dermatomyositis in the absence of panniculitis including focal Postirradiation pseudosclerodermatous panniculitis: erythematous irregular plaque.
­lymphocytic infiltration, fibrosis, and calcification.5 By courtesy of the Institute of Dermatology, London, UK.