Download The Scar - American Osteopathic College of Dermatology - Site-Ym

JAOCD
Journal Of The American Osteopathic College Of Dermatology
The Scar
Osteopathic Principles Incarnate
Also in this issue:
Proteus Syndrome in a 14-year-old Male
Painful, Pruritic Blisters Exacerbated by Heat and Sweating
Marijuana: An Unusual Cause of Fixed Drug Eruption
last modified on April 27, 2015 8:12 AM
JOURNAL OF THE AMERICAN OSTEOPATHIC COLLEGE OF DERMATOLOGY
Page 1
Journal of the
American Osteopathic
College of Dermatology
2014-2015 AOCD OFFICERS
PRESIDENT
Rick Lin, DO, FAOCD
PRESIDENT-ELECT
Alpesh Desai, DO, FAOCD
FIRST VICE-PRESIDENT
Karthik Krishnamurthy, DO, FAOCD
SECOND VICE-PRESIDENT
Daniel Ladd, DO, FAOCD
THIRD VICE-PRESIDENT
John P. Minni, DO, FAOC
Editor-in-Chief
Karthik Krishnamurthy, DO
Sponsors:
AuroraDx
Ranbaxy
Valeant
SECRETARY-TREASURER
Jere J. Mammino, DO, FAOCD
TRUSTEES
Danica Alexander, DO, FAOCD (2012-2015)
Reagan Anderson, DO, FAOCD (2012-2015)
Michael Whitworth, DO, FAOCD (2013-2016)
Tracy Favreau, DO, FAOCD (2013-2016)
David Cleaver, DO, FAOCD (2014-2017)
Amy Spizuoco, DO, FAOCD (2014-2017)
Immediate Past-President
Suzanne Sirota Rozenberg, DO, FAOCD EEC Representatives
James Bernard, DO, FAOCD
Michael Scott, DO, FAOCD
Finance Committee Representative
Steven K. Grekin, DO, FAOCD
AOBD Representative
Stephen Purcell, DO, FAOCD
Executive Director
Marsha A. Wise, BS
AOCD • 2902 N. Baltimore St. • Kirksville, MO 63501
800-449-2623 • FAX: 660-627-2623 • www.aocd.org
COPYRIGHT AND PERMISSION: Written permission must be obtained from the Journal of the American Osteopathic College of Dermatology
for copying or reprinting text of more than half a page, tables or figures. Permissions are normally granted contingent upon similar permission from the
author(s), inclusion of acknowledgment of the original source, and a payment of $15 per page, table or figure of reproduced material. Permission fees are
waived for authors wishing to reproduce their own articles. Request for permission should be directed to JAOCD c/o AOCD, PO Box 7525, Kirksville,
MO 63501.
Copyright © 2003 by the Journal of the American Osteopathic College of Dermatology
Print and layout by: S&S Printing and Graphics LLC, 701 N. Marion St., Kirksville, MO 63501
Copy editing by: Julia Layton, Freelance Writing and Editing
Page 2
JOURNAL OF THE AMERICAN OSTEOPATHIC COLLEGE OF DERMATOLOGY
Journal of the
American Osteopathic
College of Dermatology
Table of Contents
Volume 32
JAOCD Editors............................................................................................................................................................................................. 4
Letter from the President............................................................................................................................................................................... 5
Letter from the Executive Director................................................................................................................................................................ 6
Letter form the Editor-in-Chief.................................................................................................................................................................... 7
FEATURE ARTICLE:
The scar as a representation of the osteopathic principles.............................................................................................................................11
Sarah Belden, DO, Jenifer Lloyd, DO, Michael Rowane, DO
EDITOR’S PICKS:
Marijuana: An Unusual Cause of Fixed Drug Eruption............................................................................................................................. 16
Christina Steinmetz-Rodriguez, DO, Brent Schillinger, MD
Painful, Pruritic Blisters Exacerbated by Heat and Sweating.......................................................................................................................19
Collin M. Blattner, BS, Dustin V. Wilkes, DO, Dongkun Chang, MD
Proteus Syndrome: Case Report and Review...............................................................................................................................................21
Holly Kanavy, DO, Cindy Hoffman, DO
ORIGINAL ARTICLES AND CASE REPORTS:
Reactive Keratoacanthoma Responding to Excision and Healing by Secondary Intention..........................................................................24
G. Trey Haunson, DO, Mariana A. Phillips, MD, FAAD, FACMS, Douglas J. Grider, MD, FCAP, Daniel S. Hurd, DO, FAOCD
A Case of Cutaneous Rosai-Dorfman Disease............................................................................................................................................27
Donna Tran, DO, Gabriel Guerrero, DO, Paul Shitabata, MD, Navid Nami, DO
Pathogenesis of Pruritic Disorders and Mechanisms of Phototherapy.........................................................................................................29
Soham Chaudhari, BA, Argentina Leon, MD, Ethan Levin, MD, Om Chaudhari, John Koo, MD
The Cutaneous Manifestations of Metastatic Lung Cancer: Case Report and Review................................................................................34
Sarah Ferrer-Bruker, DO
Loose Anagen Syndrome in a 2-year-old Female: A Case Report and Review of the Literature.................................................................37
Mathew Koehler, DO, Anne Nguyen, MS, Navid Nami, DO
Anetoderma Secondary to Mid-dermal Elastolysis......................................................................................................................................40
Gabriela A. Maloney, BS, Jane James, MD, PhD, Michael Welsch, MD, Marylee Braniecki, MD
Generalized Linear Porokeratosis: A Case Report and Discussion..............................................................................................................42
Stephanie Blackburn, DO, Zaina Rashid, DO, John Moad, MD, Michelle Duff, DO, Jason Barr, DO
Permanent Imiquimod-induced Depigmentation........................................................................................................................................45
Anne Donato, MD, J. Kate Jackson, PA-C, Laura Sandoval, DO, Jonathan S. Crane, DO, FAOCD
Telangiectasia Macularis Eruptiva Perstans: A Case Presentation and Discussion.......................................................................................47
Sergey Petrosian, BS, Shane Meehan, MD, Anna Slobodskya, DO, Peter Saitta, DO
Hypomelanosis of Ito in Two Infants: A Case Series with Literature Review.............................................................................................49
Mathew Koehler, DO, Nicole Rouse, BS, Tarin Molly Koehler, DO, Navid Nami, DO
Phacomatosis Cesioflammea: A Case Report of a Newborn with an Unusual Mongolian Spot and Port Wine Stain................................ 52
Joy Ishii Zarandy, DO, Sara Clark, MD, Katherine Shew, MD
PERSPECTIVES:
While Serving Abroad, Remembering the “Why” Behind Dermatology.....................................................................................................56
Leela Athalye, DO
Letter to the Editor: Wegener’s Granulomatosis Eponym...........................................................................................................................58
David Thomas, MD, JD, EdD, Jacqueline Thomas, DO
JOURNAL OF THE AMERICAN OSTEOPATHIC COLLEGE OF DERMATOLOGY
Page 3
Editor-In-Chief
Karthik Krishnamurthy, DO
Founding Editor
Jay Gottleib, DO
Assistant Editor
Julia Layton, MFA
Associate Editors
Derrick Adams, DO
Red Bluff, CA
Editorial Board
Aaron Bruce, DO
Bozeman, MT
Jonathan Crane, DO
Wilmington, NC
Michael Scott, DO
Seattle, WA
Scott Wickless, DO
Dallas, Texas
Sami Abbasi, DO
Brownstown, MI
Mohamad Goldust, MD
Tabriz, Eastern
Azerbaijan, Iran
Angela Leo, DO
New York, NY
John Perrotto, DO
West Palm Beach, FL
Brett Bender, DO
Farmington Hills, MI
Marcus Goodman, DO
Roswell, GA
Scott Lim, DO
Erie, PA
Andrew Racette, DO
Phoenix, AZ
Ryan Carlson, DO
Hilliard, OH
Melinda Greenfield, DO
Albany. GA
Chava Lustig, DO
Weston, FL
Richard Rudnicki, DO
Mesquite, TX
Igor Chaplik, DO
Aventura, FL
Denise Guevara, DO
Weston, FL
Jere Mammino, DO
Winter Springs, FL
Amara Sayed, DO
San Marcos, TX
Michael P. Conroy, MD
Columbus, OH
Andrew Hanly, MD
Miami, FL
John Minni, DO
Port St. Lucie, FL
Joseph Brant Schneider, DO
Shawnee Mission, KS
John Coppola
Ormond Beach, FL
Joel Harris, DO
Madison Heights, MI
Tony Nakhla, DO
Orange County, CA
Gregg Severs, DO
Scranton, PA
David Dorton, DO
Spring Hill, FL
Heather Higgins, DO
Troy, MI
Navid Nami, DO
Newport Beach, CA
Sean Stephenson, DO
Troy, MI
Matthew Elias, DO
Lighthouse Point, FL
David Horowitz, DO
Torrence, CA
Jon Keeling, DO
Lexington, KY
Jacqueline Thomas, DO
Fort Lauderdale, FL
Merrick Elias, DO
Delray Beach, FL
Mark Lebwohl, MD
New York, NY
Dimitria Papadopoulos, DO
Bellmore, NY
Jim Towry, DO
Ocala, FL
Michelle Foley, DO
Ormond Beach, FL
Page 4
JAOCD EDITORS
Letter
from the
President
Rick Lin, DO, MPH, FAOCD
President, AOCD
Dear Members of the AOCD,
Welcome to another issue of our journal! Under the leadership of Dr. Karthik Krishnamurthy and his dedicated board of
editors, we are seeing another issue of the Journal of the American Osteopathic College of Dermatology come to fruition.
Speaking of issues coming together, this past February, I was invited to represent the AOCD at a meeting hosted by AAD
President Dr. Brett Coldiron. The topic of discussion was the proposition to create Board certification for “micrographic surgery
and dermatologic oncology.” This proposal was favored by many of the organizations represented there. The discussion focused
on the potential outcome of mending the division between “fellowship trained” and “society trained” Mohs surgeons with a new
category of “Board certified” Mohs surgeons. It was noted that the new Board certification would bring recognized expertise
in cutaneous “surgery” and “oncology” to the house of dermatology. This recognition by other medical specialties within the
ABMS would further elevate the status of dermatology within the broader house of medicine. However, this effort to define surgical subspecialization is not without its drawbacks. The further division of dermatology into
“medical” and “surgical” dermatology is a potential outcome. This point was emphasized by some of the attendees. Concerns
about the increased potential legal risks when a general dermatologist decides to perform an excision or electrodessication and
curettage also were raised. In the case of a bad outcome, the decision is more difficult for a general dermatologist to defend
legally if a micrographic surgeon/dermatologic oncologist was available.
It was proposed that there be a five-year grandfather period during which any provider who practices Mohs surgery at least
20 percent of the time may take the examination. The candidate also will need to be board-certified by the American Board
of Dermatology. However, ABD certification will not apply to our members who are board-certified by the AOBD. We will
continue to monitor this effort to create a subspecialty board certification and how it will impact osteopathic dermatologists
and the field of dermatology as a whole.
In the meantime, I look forward to seeing many of you at our spring meeting in Charlotte, North Carolina. Dr. Dan Ladd, the
program chair, has put together a highly educational program. The latest dermatological concepts and practice-management
pearls will be presented. In addition, we are privileged to have Dr. Nicole Owens, chair of ACGME’s Residency Review
Committee for Dermatology, address our membership.
On a final note, I would like to say that the future of our College, as with any College, is dependent on its members. To face
the challenges ahead, I encourage you to reach out to the AOCD Board of Trustees to share your thoughts and volunteer your
time. We are looking for members who would like to play significant roles in the leadership of the AOCD. In the years to come,
the survival of our College will impact our future recertification process. With the ACGME merger, our future is in a state of
flux. Only through the dedication of our members will we be able to chart our future, rather than have it decided for us.
Rick Lin, DO, MPH, FAOCD
President, American Osteopathic College of Dermatology
LETTER FROM THE PRESIDENT
Page 5
Letter
from the
Executive Director
Marsha Wise
Executive Director, AOCD
Hello, Everyone,
It seems as though winter has lasted forever, but spring is finally here!
We’ve had a busy start to the year. Drs. Suzanne Sirota Rozenberg, Lloyd Cleaver, Rick Lin and I attended the AOA Osteopathic
Medical Education Leadership Conference in January. In February, Dr. Lloyd Cleaver and I attended the ACGME’s Annual
Educational Conference. Both of these meetings provided valuable updates on the Single Accreditation System, or SAS.
The information regarding SAS can be found on the AOA and ACGME websites. We encourage everyone to log on and
familiarize themselves with the single accreditation system:
http://www.osteopathic.org/inside-aoa/single-gme-accreditation-system/Pages/default.aspx
http://www.acgme-i.org/Requirements-and-Process-Overview/What-is-Accreditation
Programs may begin to apply for pre-accreditation status in April 2015.
In February, the ACGME announced that Dr. Stephen Purcell was appointed to the Dermatology Residency Review
Committee. We’re excited to have Dr. Purcell represent the AOCD and the osteopathic profession. Dr. Purcell’s leadership in
the AOCD has been invaluable, and he is a true advocate for osteopathic dermatologists.
During the General Membership Meeting recently held in Seattle, the membership voted to accept the changes to the bylaws
that had been presented last summer. On March 2, we received word that the AOA approved our proposed changes. These
changes are now in effect and can be found on our website at: https://aocd.site-ym.com/?page=ByLaws.
March and April have been busy with the AAD meeting and our Spring Conference in Charlotte, NC. A panel discussion on
“Unified U.S. Dermatology Training Accreditation and the Unification of the Specialty of Dermatology” took place at the AAD
Annual Meeting on Sunday, March 22. Be sure to look for highlights of these meetings in upcoming Dermline publications.
Exciting changes are in store for our Fall Conference. Our meeting is scheduled for October 16th through 19th, 2015, in
Orlando at the Loews Royal Pacific Resort. An information packet with further details will be mailed to our members about
the changes happening with this meeting.
Please call or email the AOCD office (660-665-2184, [email protected]) if you have questions or need assistance.
Sincerely,
Marsha Wise
Executive Director, American Osteopathic College of Dermatology
Page 6
LETTER FROM THE EXECUTIVE DIRECTOR
Letter
from the
Editor-in-Chief
Karthik Krishnamurthy, DO, FAOCD
Editor-in-Chief
Dear Readers,
Many of you are familiar with the “Blurred Lines” controversy in which the Marvin Gaye estate won judgment for
copyright infringement. Many artists are outraged, fearing this will set a dangerous precedent, claiming that all
music is derivative in some way. What is considered “original” versus “copied” can be ill-defined -- which side does
“was-influenced-by” sit on? This has made me ponder how we authors face this same issue every time we prepare a
manuscript. We all gasp at the word “plagiarism,” look over our shoulders as we whisper the word, almost as if we
would with “murder.” And yet almost everyone reading this column has infringed on someone else’s work, almost certainly without realizing
it. It’s not something we would ever consciously do.
It is exceptionally difficult to find ways to incorporate relevant information in an original way when citing a resource,
especially since there is a limited and acceptable way in which we are trained to communicate certain data in the
medical field. The online resource iThenticate is a service we can use to check for verbatim overlap when preparing
our manuscripts, but this only gets us so far.
According to our Assistant Editor:
Copying another author’s words verbatim is only the most obvious type of plagiarism. Let’s say you change a
couple of words in a sentence -- that’s still plagiarism, even if you attribute it to the source. The new sentence is too
close to the original. In addition to attribution, it needs quotation marks around all of the words not changed. (If
you ask me, it’s easier to just use the original and put quotes around the whole thing.) If you significantly change
both sentence structure and words, a.k.a. paraphrase, it’s also plagiarism -- unless you attribute it. Paraphrasing is
fine as long as you give credit to the source. Plagiarism isn’t only about another author’s words, though. You can
plagiarize yourself. And regardless of the words you use, restating another author’s idea or interpretation without
attribution is plagiarism (and a much more complicated subject).
I guess imitation is not always the highest form of flattery.
If you’d like to explore this more, try “Avoiding plagiarism, self-plagiarism, and other questionable writing practices,”
by Miguel Roig, PhD (https://ori.hhs.gov/avoiding-plagiarism-self-plagiarism-and-other-questionable-writingpractices-guide-ethical-writing). It speaks specifically to science writing.
Fraternally,
Karthik Krishnamurthy, DO, FAOCD
Editor-in-Chief, Journal of the American Osteopathic College of Dermatology
LETTER FROM THE EDITOR -IN-CHIEF
Page 7
DISCOVER
A NEW LEVEL OF
D E R M A T O P A T H O L O G Y
S E R V I C E S
E X P E RT S I N D E R M ATO PAT H O LO GY
Aurora Diagnostics’
dermatopathology laboratories
are focused on providing
unsurpassed dermatopathology
services to our referring
physicians. Our network
of expertise consists of
over forty board-certified
dermatopathologists that are
based locally throughout the
country providing advanced
technology and unparalleled
customer support.
We believe that the practice
of medicine and the delivery
of healthcare are both personal
and best served locally.
LABORATORY LOCATIONS:
BIRMINGHAM, AL
Cunningham Pathology
TAMPA, FL
DermDX Tampa
ACCESS TO ADVANCED DIAGNOSTICS
MIAMI, FL
DermDX Miami
Global Pathology Laboratory
JACKSONVILLE, FL
DermDX Jacksonville
BOSTON, MA
DermDX New England
MONROE, MI
Pinkus Dermatopathology Laboratory
CONVENIENT LOCAL SERVICE
PLYMOUTH, MN
Aurora Diagnostics
Twin Cities Dermatopathology
EATONTOWN, NJ
Aurora Diagnostics
Pathology Solutions
LAS VEGAS, NV
LMC Pathology Services
WOODBURY, NY
Aurora Diagnostics
Laboratory of Dermatopathology
A PA RT N E R F O R YO U R P R ACT I C E
GREENSBORO, NC
Aurora Diagnostics
GPA Laboratories
RIDGELAND, SC
Aurora Diagnostics
Biopsy Diagnostics
DISCOVER, C A LL 866.420.5512
W W W . A U R O R A D X . C O M
SAN ANTONIO, TX
Aurora Diagnostics
South Texas
Dermatopathology Laboratory
RETIN-A MICRO
®
(tretinoin) Gel microsphere,
Exclusively available in a 50g pump
Except as otherwise indicated, all product names, slogans, and other marks are trademarks of the Valeant family of companies.
© 2015 Valeant Pharmaceuticals North America LLC. DM/RAM/14/0003(1)a 3 /15 Printed in USA.
The Scar as a Representation of the Osteopathic Principles
Sarah Belden, DO,* Jenifer Lloyd, DO,** Michael Rowane, DO***
*Traditional Rotating Intern, University Hospitals Regional Hospitals, Richmond Heights, OH
**Program Director, Dermatology Residency Program, University Hospitals Regional Hospitals, Richmond Heights, OH
***Director of Medical Education, University Hospitals Regional Hospitals, Richmond Heights, OH
Abstract
A scar is the manifestation of the skin’s healing process following an injury. It can be a cosmetic concern to some individuals while dismissed and disregarded by
others. New treatment options continue to be investigated, but no solution currently exists for erasing a problematic scar. By viewing the scar as a source of somatic
dysfunction using the four osteopathic principles, the dermatologist is able to employ the use of osteopathic manipulative treatment techniques as an adjunctive tool in
scar management. Here we explore the scar through an osteopathic lens and describe treatment strategies that have been shown to be effective in improving the somatic
dysfunction caused by the presence of a scar.
Introduction
A scar, or cicatrix, is the end result of the
wound repair mechanism in adults and children
following an injury, either traumatic or surgical,
beyond the epidermis. It is the consequence of
a surgical incision and is inevitable despite the
surgeon’s best efforts to hide it within the skin’s
natural contour lines.
It is a common lesion encountered in dermatology,
and it is the source of much cosmetic concern.
More than 230 million surgical procedures are
performed around the world each year, all of
which result in cutaneous wounds that heal
with scars.1 A recent survey indicated that 91%
of patients who underwent a routine surgical
procedure would value any improvement in
scarring.2 Scars also affect other body systems
including the musculoskeletal system or deep
viscera in the form of adhesions.3,4 They are also
linked to pain and depression.5,6
The cosmetic outcome of a scar and its subsequent
implications on a patient’s overall wellbeing is of
primary importance in dermatology. Patients are
often left desperate for treatment options after
first-line treatments—such as silicone sheeting,
pressure dressings and intralesional steroids—
fail.
Osteopathic manipulative treatment
(OMT) is a non-invasive, cost-effective therapy
for scar management that may be employed
by considering the scar as an application of
osteopathic principles and practices. Here, we
apply A.T Still’s four osteopathic principles
to the scar and describe the mechanisms
responsible for the interaction between the scar
and its surrounding skin as a source of somatic
dysfunction. The OMT techniques applicable
to scar management are reviewed and their
effectiveness explored, revealing the growing
opportunity for further osteopathic research.
Discussion
Osteopathy and scars
Principle 1. The body is a unit; the person is a unit of
body, mind, and spirit.
This osteopathic principle represents how a scar
can affect a person’s entire wellbeing. Much like
BELDEN, LLOYD, ROWANE
the saying “a scar is more than skin deep,” a scar
may have a deeper value to one person but not to
another. It can serve as a permanent reminder of
the past, whether it is pleasant or unpleasant, that
extends to the body, mind and spirit.
It is known that the connection between the skin
and the mind is a powerful one. For example,
stress can exacerbate psoriasis and cause acne
breakouts.7 Stress can also play a role in scar
formation. Furtado et al. found that psychological
stress influences the rate of recurrence of keloids
when stress is experienced the day before
keloid excision, increasing the chances of keloid
recurrence by 34%.8 The location of the scar
and the patient’s age or gender are factors that
influence its impact. A scar on the chest of a
young female, for example, may cause increased
self-consciousness and impact the clothing she
chooses to wear.
There is a variety of psychosocial comorbidities
associated with scarring. Depression is the
predominant finding in patients suffering
from burn scars5. A combination of anxiety,
depression and PTSD-related disorders were
seen in 64% of the patients who developed scars
following ICU admission for severe soft-tissue
infections in one study.6 Other psychosocial
characteristics of patients with scars, particularly
within the burn population, include avoidance
of social interaction,9 loneliness10 and living a
solitary lifestyle.11
Thus, the first step in scar management is to
consider the whole patient. The stressors and
history behind the scar are important to address
prior to subsequent treatment. Approaches such
as suggesting stress-management techniques
perioperatively may help improve the chances of
a better scar outcome. Counseling or referring
to psychiatry is important for patients displaying
psychological symptoms. Education plays a
helpful role, such as teaching the patient the
importance of keeping the scar covered from the
sun and applying sunscreen after the surgery. It
is important to consider the whole patient when
performing a procedure; the patient’s age, incision
length and location should be respected in order
to ensure the best possible scar outcome.
Principle 2. The body is capable of self-regulation,
self-healing, and health maintenance.
Upon any introduction of trauma to the skin, the
body elicits an instant repair mechanism that is
designed to restore the natural homeostasis of the
tissue. This repair mechanism is divided into a
series of stages, each having unique characteristics.
The first stage of wound healing is known as
the inflammatory phase, where cytokines and
inflammatory cells are recruited and infiltrate the
site to destroy potential pathogens, remove debris,
and initiate coagulation through the formation of
an initial thrombus.12 The inflammatory pathway
of wound healing, a large determinant of the
outcome of a scar, has long been the focus of
attack for anti-scarring research, but strategies
that block inflammation alone have so far proved
suboptimal with significant side effects.13
The second stage, called proliferation, is
characterized by the fibroblast cell. Fibroblasts
are responsible for producing collagen, which
provides the structure to the wound and creates a
new matrix—the groundwork of a scar.
Remodeling, the final stage of wound repair,
begins at about two to three weeks following
trauma and can last for years depending on the
size of the wound.12 During this stage, fibroblasts
are responsible for organizing and cross-linking
the collagen, increasing the strength of the new
site, and causing contraction of the wound edges
in the process.
The appearance of a scar is influenced by many
factors: the depth of trauma (injury limited to the
epidermis can heal without scarring), the location
(the chest is an area more susceptible to scar
formation), whether the patient is at risk of keloid
or hypertrophic scarring (genetics, ethnicity, etc.),
age, and nutritional and vitamin deficiencies.3,12
It is important to appreciate that the dynamics
between the wound repair process and the scar
do not end immediately. Rather, an interplay
between the traumatized tissue, the scar, and
the surrounding non-traumatized tissue results
in altered tissue arrangement that manifests as
tissue texture changes contributing to the scar’s
appearance.3,14,15
Page 11
This mechanism can best be explained through
the osteopathic bioelectric model of fascia as
described by Judith O’Connell, DO, FAAO, which
illustrates the important relationship between the
dermis and its underlying fascia.15,16 Fascia is
found between the deep and superficial adipose
layers and is connected to the dermis through
perpendicular septa of fibrous extensions.17 It
communicates with the dermis via bioelectric
currents through the extracellular fluid, which is
considered a homeostatic relationship within the
skin.15,18
The presence of a scar applies extra mechanical
tension to the tissue, causing a disruption of the
normal homeostatic signaling between the fascia
and dermis. The collagen within the scar itself
also releases microelectrical-potential changes
into the extracellular fluid.15,18 This aberrant
bioelectric current not only alters the local
architecture of the dermis and fascia but also
the arrangement of surrounding tissue (neural,
muscular, vascular, and lymphatic), resulting in
changes such as stiffness, altered motion, pain, and
edema that can be restored using OMT.3,15,16,19
Thus, it is important to acknowledge that the
wound repair process and its end product, the
scar, is not a static process. Rather, there are many
dynamic homeostatic elements that are ongoing
following scar formation that contribute to the
overall somatic dysfunction and scar appearance.
Principle 3. Structure and function are reciprocally
interrelated.
This principle stems from Dr. Still’s belief that
abnormal tissue structure is likely to result in
disruptions in tissue function and vice versa. A
scar disrupts the normal architecture and function
of surrounding skin. The clinical result is an area
of skin tissue whose biomechanical function and
normal viscoelastic behavior is compromised; it is
an area of somatic dysfunction.
The skin’s basic protective functions are altered
in the presence of a scar. The fibrotic infiltration
of a scar alters the complex arrangement
of desmosomes and elastin that is used to
provide protection and support, leaving the site
susceptible to mechanical damage. Similarly,
protection against UV radiation is compromised
as a scar alters the arrangement of melanin
pigments.12 The processes of hyperkeratinization
and DNA repair are also compromised by
the altered vascularization created by a scar.20
Sensation becomes impaired when the anatomy
of the skin’s free nerve endings that normally
extend to the epidermis is altered even by the
most superficial of scars. Adnexal structures (e.g.
hair follicles, sweat and sebaceous glands) as well
as components of the dermal extracellular matrix
may fail to regenerate following the formation of
a scar, resulting in a loss of normal skin function
and impaired morphology.12
Scars, in the form of adhesions, have the potential
to disrupt normal visceral function. Intraabdominal adhesions are cited to occur after
50% to 100% of the surgical interventions of the
abdomen.4 They can lead to bowel obstruction,
irregular bowel movements, meteorism, digestive
Page 12
disorders, female infertility, and chronic lower
abdominal pain.3,21
Scars can also cause dysfunction of major muscles
and joints. Frozen shoulder, for example, is a
well-known complication of the shoulder joint
following rotator cuff injury where the shoulder
exhibits pain and neurological symptoms from
scar accumulation.
Muscular dysfunction may be observed in the
dermatological arena following the formation
of facial scars. The SMAS is a structure that
ensheaths the facial muscles and neurovasculature
and plays an intricate role in coordinating and
exaggerating facial expressions.22 If a scar extends
to the level of the SMAS, the thickened fibrosis
may cause stiffness of the fascia, which may lead
to altered range of motion of the facial muscles,
affecting normal facial expression.18
Principle 4. Rational treatment is based on an
understanding of the basic principles of body unity,
self-regulation, and the interrelationship of structure
and function.
Treatment relies on a full understanding of
how a scar can affect the entire body while
acknowledging the first-line evidence-based
treatment strategies and knowing alternatives
for more refractory cases. First-line treatment
for scars includes a variety of options such as
silicone sheeting, pressure dressings, intralesional
steroids, 5-FU, bleomycin, and verapamil, as
well as laser therapy, localized radiotherapy,
micro-needling, and intralesional cryotherapy
for the more refractory cases.23 Osteopathic
manipulative therapy is a cost-effective and noninvasive treatment option that may be employed
as an adjunct and for those scars resistant to
the standard therapy. Several techniques may
be utilized and have been shown to be effective
in improving the appearance of a scar and its
surrounding tissue.
It is important for the osteopathic dermatologist
to gain an understanding of which scar
characteristics are clinically relevant for OMT
and the rationales for treatment based on the
models of osteopathic care.
Identifying a scar to be treated
The first step in effective OMT is to properly
identify whether a scar and its surrounding
tissue would benefit from treatment. Its level of
acuity must be assessed. It is important to not
manipulate acute scars, i.e., hot, boggy, tender or
erythematous scars, or those exhibiting venous
congestion/edema. Manipulation of an acute
scar would delay the wound healing process,
which would worsen the structure and function
dynamics of the scar.24
The scar should exhibit chronic somatic
dysfunction. By its standard definition, chronic
somatic dysfunction is “impairment or altered
function of related components of the somatic
(body framework) system characterized by
tenderness, itching, fibrosis, paresthesia and tissue
contraction; identified by TART”.25 The forces
exerted by the scar to the surrounding tissue, as
described above, may manifest as tissue texture
changes listed in Table 1. The extent of the tissue
texture changes and the restriction and resistance
(pathological barriers) of the deeper tissue may be
determined by palpation.24
Table 1. Tissue texture changes associated with
chronic somatic dysfunction of a scar*
Ropiness: cord-like, fibrotic feeling
(in the scar itself )
Stringiness: fine or string-like
myofascial structures
Firmness, hardening
Temperature changes
Increased/decreased moisture
Lymphedema
*Adapted from: American Association of Colleges
of Osteopathic Medicine - Educational Council
on Osteopathic Principles. Glossary of osteopathic
terminology. Chevy Chase, MD: American Association
of Colleges of Osteopathic Medicine; rev. Nov 2011.
Lymphedema is a common finding associated
with the chronic somatic dysfunction of a scar.
The term “scar lymphedema” is used to describe
the localization of lymphatic fluid around the scar
site due to the damage of the lymphatic channels
and pathways caused by the surgical incision.25
The difference between edema and lymphedema
surrounding a scar is based upon location of the
swelling. With lymphedema, swelling affects
only the “upstream” side of a healed incision (such
as the circumscribed central area of a U-shaped
scar), whereas nonspecific edema will surround
the entire scar.26
“Active scar” is another term used to describe a
scar that would benefit from OMT; it is “active”
if it exhibits soft-tissue changes characterized by
increased skin drag, owing to increased moisture
(sweating), impaired skin stretch, and a thickened
skin fold.24
The exact timeline of when it is appropriate to
treat scars using OMT has not been formally
established.27 The use of pressure therapy on scars
after burn injury showed that earlier treatment
(scars treated <6 months after burn injury)
resulted in better outcome than those treated
later.28 It has been proposed that noninvasive
scar management, such as manipulation, typically
occur within the early maturation phase of the
wound healing process in order to improve scar
outcome and accelerate time of scar maturity.29
More studies are needed to investigate the most
appropriate time to implement OMT.
Treatments
The biomechanical model and the respiratorycirculatory model of osteopathy help guide the
dermatologist to select the most appropriate
OMT therapies. Based on these models, softtissue techniques, myofascial release and a
lymphatic approach to the scar are considered.
The therapeutic principles of the models in
THE SCAR AS A REPRESENTATION OF THE OSTEOPATHIC PRINCIPLES
respect to the scar are explained below.
Biomechanical Model: Soft Tissue
Techniques and Myofascial Release
The goal of the biomechanical model seeks to
address problems with the soft tissue, muscle and
fascia by removing the restrictive forces of the
tissue.30 As previously mentioned, there are many
restrictive forces or tissue texture abnormalities
that may be palpated surrounding the scar. Soft
tissue OMT and scar (myofascial) release are two
techniques that address these forces and have been
shown to improve scar outcome.
Both techniques utilize the concept of pressure
restoring balance to the scar. Physical pressure
at the site of a scar causes local hypoxia, which
induces the regeneration of fibroblasts, suppresses
collagen production, and activates collagenase,
which overall expedites collagen dismantling.33
The fibroblasts, which play a role in contracting
Figure 2:
Diaphragm release of
the palmar fascia to
induce motion patterns
in multiple planes of an
elbow scar.
collagen lattices, are relaxed through the pressure of
manipulation.34,35 This relaxation results in increased
microcirculation to the site owing to the restoration of
tissue texture abnormalities.36 It has been shown that
manipulation encourages collagen fibrils of the dermis to
realign.37 The immediate result of these changes can be
palpated through the form of a release.30
There is a variety of soft-tissue techniques that may
be used for treating scars. The treatment goals include
increasing tissue elasticity, enhancing circulation to
local fascial structures, improving local tissue nutrition
and oxygenation, improving local immune response,
and providing a general state of relaxation.38 Scar softtissue manipulation is distinguished from scar massage
therapy in that it makes use of the barrier-and-release
phenomenon; scar massage does not.24
Soft-tissue
techniques used for scars include effleurage, skin rolling,
stretching, and petrissage.24,38,39,40
Figure 1:
Indirect myofascial scar
release of an elbow scar.
BELDEN, LLOYD, ROWANE
Effleurage is a light stroking soft-tissue technique that is
used on more superficial scar tissue. McKay performed
a five-week treatment of soft-tissue techniques including
effleurage to improve the appearance and function of
cleft-lip scars.39 Based upon patient subjective results, she
found soft-tissue manipulation to be an effective means
for increased patient satisfaction and improvement of the
appearance of the scar.
Skin rolling is another soft-tissue technique. It involves
lifting the skin away from the deeper structures and
“rolling” the skin fold along the body.38 Pohl examined
the changes in the structure of collagen in scars following
Page 13
manual treatment using skin rolling with
ultrasound.36 Prior to therapy, the tension of
the scar was appreciated using ultrasound echoes
that detected higher densities within the collagen
fibers. Following the skin-rolling technique, she
found a reduction in the densifications of collagen
within the dermis as well as an overall increase
of thickness in the dermis. These changes were
attributed to the relaxation of fibroblasts.32,34,35
Soft-tissue stretching along the site of a scar
has also been shown to be effective in scar
management. Soft-tissue stretch engages the
barrier palpated along the distal ends of the
scar while slowly stretching and releasing the
surrounding tissue in multiple planes.24 Lewit et
al. used soft-tissue skin stretching in combination
with heat on “active” scar sites following a variety
of operations including appendectomy, breast
surgery and gynecologic surgery and found
marked immediate results with general softtissue stretch. 24 The treatment led to decreased
pain and increased tissue mobility in the majority
of cases. The scar ends were found to be the most
active sections of the scar, and treatment was
aimed predominately at these sites.
Petrissage, which is a deeper kneading and
squeezing pressure, is considered to be an
excellent soft-tissue technique for scars.41,42
Morien et al. investigated a combination of
effleurage, petrissage, stretching and rolling in
a group of post-burn patients, which showed
improvement in range of motion at the scar
site and overall patient satisfaction.40 Field
et al. compared a group of post-burn patients
who received a combination of skin rolling,
stretching and stroking to a group who received
no manipulation.43 It was found that those in
the manipulation group experienced a relief of
pruritus, pain, anxiety and improvement in mood
associated with their scarring.
“Scar release” is an indirect form of a myofascialrelease technique that may be used to reduce
asymmetric tension and restore functional balance
to the stresses transmitted through a scar.­ It is
utilized to engage deeper tissue such as muscle
and fascia. Successfully releasing the deep fascial
restriction and correcting the restrictive forces in
turn activates surrounding bioenergetic tissue.16
It has been reported to be an effective technique
in improving post-mastectomy axillary cord
anchoring secondary to scar formation, leading
to improvement of axillary-scar appearance and
surrounding lymphedema.44
Respiratory-Circulatory Model:
Diaphragm Release and Lymphatic Pump
Based upon the respiratory-circulatory model,
lymphatic techniques are designed to remove
impediments to lymphatic circulation and
promote and augment the flow of lymph.42
As previously noted, lymphedema can be a
prominent feature of the chronic scar; it may
even be measured using lymphoscintography.26
Mobilizing the tissue surrounding the scar can
help improve circulation and the exchange of
lymphatic fluids and metabolites, which can
ultimately encourage the normal distribution of
Page 14
Table 2. Diaphragms to treat based on scar location*
Scar
Location
Scalp, face,
neck
Upper
extremity
Chest, upper
back
Abdomen,
lower back,
buttocks,
pelvis
Lower
extremity
Suggested
Diaphragm
Tentorium
thoracic inlet
Palmar fascia
Respiratory
diaphragm
Pelvic
diaphragm
Plantar fascia
*Adapted from: O’Connell J. Chapter 47. Myofascial release approach. In: Chila AG, Carreiro JE, Dowling DJ,
Gamber RG, Glover JC, Habenicht AL, Jerome JA, Patterson MM, Rogers FJ, Seffinger MA, Willard FH.
Foundations of Osteopathic Medicine. 3rd ed. Philadelphia, Baltimore: Lippincott Williams & Wilkins. 2001.
fibrin and collagen.42
The proposed application of lymphatic treatments
to scars involves first opening the myofascial
pathways to increase microcirculation to the site
(via the soft-tissue techniques and myofascial
release), and then treating the diaphragms.42
By definition, diaphragms occur at important
anatomical crossroads in the body where curves
and cavities change and where passage points
for major circulatory and lymphatic vessels
occur.16 Maximizing the motion of diaphragms
helps to improve circulatory and lymphatic
flow, which would be beneficial in the setting of
a scar exhibiting lymphedema in the setting of
chronic somatic dysfunction.30 In dermatology,
the relevant diaphragms are both peripheral and
central, based on the location of the scar as listed
in Table 2. Clinical studies are needed in order
to explore the outcome of diaphragm release and
other lymphatic treatments for scars.
Examples of Osteopathic Manipulative
Treatment Techniques
Indirect myofascial scar release (Figure 1)14
1. Place fingers parallel to either side of the scar.
2. Approximate your fingers gently to reduce
tension on the scar.
3. Move the tissues on either side gently in
different directions (cephalic, caudal, left, right) to
determine the tension pattern in the surrounding
tissues.
4. Gently move your fingers on either side of the
scar in the direction that most reduces tension
until you perceive a sense of balance.
5. Hold in the balanced position until you perceive
a release, that is, a further relaxation of tension.
6. Have the patient exhale and hold the breath in
step 5 to enhance the balance of tension.
7. Reassess tension of the soft tissue surrounding
the wound or scar.
Direct myofascial release skin stretch with heat24
1. Lightly stroke the whole area of the scar and
area around it for relaxation.
2. Undergo skin stretching in all directions.
3. Apply a hot pack to the site for a short duration
along with pressure and shifting the soft tissue in
multiple planes.
4. Following the application of the hot pack,
resume tissue stretch in all directions.
5. Upon resistance, apply simple pressure in the
direction of the pathological barrier until release
is felt.
6. Achieve relaxation of the tissue by lightly
stroking the scar and surroundings.
Diaphragm release (Figure 2)16
Based on the location of the scar and patient
history, choose the most appropriate diaphragm
to treat, as noted in Table 2.
1. Using compression, distraction or the full
deep respiration cycle, induce motion and note
the different patterns of interaction between the
normal and dysfunctional tissue response.
2. The dysfunctional pattern, whether a barrier
or point of ease, should become apparent at the
diaphragm, making the primary dysfunction at
the scar evident, and a release should begin.
3. If treating using respirations, motion in the
tissue should begin as a release occurs, with a new
end point of motion manifesting.
Conclusion
By viewing the scar through an osteopathic lens,
the dermatologist is able to gain an understanding
of how the scar is more than just a fibrosis on
the skin; it represents how one dermatological
lesion can affect the entire person. It is an active
participant within the homeostatic environment
of the skin that can affect both structure and
function of the human body. Based on available
clinical data, osteopathic manipulative treatment
should be considered in the dermatological arena
as a therapeutic strategy for scar management.
Further clinical studies are needed to establish
the most effective OMT modalities and the most
appropriate time to initiate and continue therapy.
References
1. Weiser TG, Regenbogen SE, Thompson KD,
Haynes AB, Lipsitz SR, Berry WR, Gawande AA.
An estimation of the global volume of surgery: a
modeling strategy based on available data. Lancet.
2008 Jul;372(9633):139-44.
2. Young VL, Hutchison J. Insights into patient
and clinician concerns about scar appearance:
semiquantitative structured surveys. Plast Reconstr
Surg. 2009 Jul;124(1):256-265.
3. Bordoni B, Zanier E. Skin, fascias and scars:
THE SCAR AS A REPRESENTATION OF THE OSTEOPATHIC PRINCIPLES
symptoms and systemic connections. J Multidiscip
Healthc. 2013 Dec;28(7):11-24.
4. DiZerega GS. Contemporary adhesion
prevention. Fertil Steril. 1994;61:219–235.
5. Roh YS, Chung HS, Kwon B, Kim G. Association
between depression, patient scar assessment and
burn-specific health in hospitalized burn patients.
Burns. 2012 Jun;38(4):506-12.
6. Hellgren EM, Lagergren P, Larsson AC, Schandl
AR, Sackey PV. Body image and psychological
outcome after severe skin and soft tissue infection
requiring intensive care. Acta Anaesthesiologica
Scandinavica. 2013 Feb;57(2):220-8.
7. Bolognia JL, Schaffer JV, Duncan KO, Ko CJ.
Dermatology Essentials. Oxford: Elsevier; 2014.
Chapter 7, Psychocutaneous disorders; p. 50-55.
8. Furtado F, Hochman G, Farber PL, Muller MC,
Hayashi LF, Ferreira LM. Psychological stress as
a risk factor for postoperative keloid recurrence. J
Psychosom Res. 2012 Apr;72(4):282-7.
9. Ye EM. Psychological morbidity in patients with
facial and neck burns. Burns. 1998 Nov;24:646-8.
10. Taal L, Faber AW. Posttraumatic stress and
maladjustment among adult burn survivors 1 to 2
years postburn: Part II: the interview data. Burns.
1998 Aug;24(5):399-405.
11. Fauerbach JA, Heinberg LJ, Lawrence JW,
Munster AM, Palombo DA, Richter D, Spence
RJ, Stevens SS, Ware L, Muehlberger T. Effect
of early body image dissatisfaction on subsequent
psychological and physical adjustment after
disfiguring injury. Psychosom Med 2000 JulAug;62(4):576-82.
12. Eming SA. Chapter 141. Biology of wound
healing. In: Bolognia JL, Jorizzo JL, Schaffer
JV, editors. Dermatology. 3rd ed. Philadelphia:
Elsevier Limited; 2012. p. 2313-2325.
13. Wong VW, Beasley B, Zepeda J, Dauskardt
RH, Yock PG, Longaker MT, Gurtner GC.
A Mechanomodulatory Device to Minimize
Incisional Scar Formation. Adv Wound Care
(New Rochelle). May 2013;2(4):185–194.
14. Krettek JM. Chapter 14. Surgical patient.
In: Somatic Dysfunction in Osteopathic Family
Medicine. 1st ed. Nelson KE, Glonek T, editors.
Philadelphia, Baltimore: Lippincott Williams &
Wilkins. 2007. p 137.
15. O’Connell J. Bioelectric responsiveness of
fascia: a model for understanding the effects
of manipulation. Techniques in Orthopaedics.
2003;18(1):67-73.
16. O’Connell J. Chapter 47. Myofascial release
approach. In: Chila AG, Carreiro JE, Dowling DJ,
Gamber RG, Glover JC, Habenicht AL, Jerome JA,
Patterson MM, Rogers FJ, Seffinger MA, Willard
FH. Foundations of Osteopathic Medicine. 3rd
ed. Philadelphia, Baltimore: Lippincott Williams
& Wilkins. 2001.
17. Fang RC, Mustoe TA. Chapter 11. Structure
and function of the skin. In: Guyuron B, Eriksson
E, Persing JA, Chung KC, Disa JJ, Gosain AK,
Kinney BM, Rubin JP. Plastic Surgery: Indications
BELDEN, LLOYD, ROWANE
and Practice. 1st ed. 2009. Saunders Elsevier. p
105-112.
18. Becker RO, Selden G. The Body Electric:
Electromagnetism and the foundation of life. New
York: William Morrow and Company. 1985.
19. Kottke FJ, Stillwell GK, Lehman JF.
Krusen’s Handbook of Physical Medicine and
Rehabilitation. 3rd ed. Philadelphia: W.B.
Saunders Company. 1982.
20. Scheithauer MO, Rettinger G. Operative
treatment of functional facial skin disorders. GMS
Curr Top Otorhinolaryngol Head Neck Surg.
2005;4:18.
21. Brüggmann D, Tchartchian G, Wallwiener
M, Münstedt K, Tinneberg HR, Hackethal A.
Intra-abdominal adhesions: definition, origin,
significance in surgical practice, and treatment
options. Dtsch Arztebl Int. 2010;107(44):769–
775.
22. Flowers FP, Breza TS. Chapter 142. Surgical
anatomy of the head and neck. In: Bolognia JL,
Jorizzo JL, Schaffer JV, editors. Dermatology. 3rd
ed. Philadelphia: Elsevier Limited; 2012: 23272341.
23. Monstrey S, Middelkoop E, Vranckx JJ, Bassetto
F, Ziegler UE, Meaume S, Teot L. Updated scar
management practical guidelines: non-invasive
and invasive measures. J Plast Reconstr Aesthet
Surg. Aug 2014;67(8) 1017-1025.
24. Lewit K, Olsanka S. Clinical importance of
active scars: abnormal scars as a cause of myofascial
pain. J Manipulative Physiol Ther. 2004. 27(6);
399-402.
25. Van Duyn J. Lymphedema in face scars. South
Med J. 1969;62:1149.
26. Warren AG, Slavin SA. Scar lymphedema: fact
or fiction? Ann Plast Surg. 2007 Jul;59(1):41-5.
27. Shin TM, Bordeaux JS. The role of massage
in scar management: a literature review. Dermatol
Surg. 2012 Mar;38(3):414-23.
28. Leung PC, Ng M. Pressure treatment for
hypertrophic scars resulting from burns. Burns.
1908;6:244-50.
29. Parry I, Sen S, Palmieri T, Greenhalgh D.
Nonsurgical scar management of the face: does
early versus late intervention affect outcome?
Journal of Burn Care and research. 2013;34(5):569575 2013.
30. American Association of Colleges of
Osteopathic Medicine - Educational Council on
Osteopathic Principles. Glossary of osteopathic
terminology. Chevy Chase, MD: American
Association of Colleges of Osteopathic Medicine;
rev. Nov 2011.
31. DiGiovanna EL. Chapter 4. Somatic
dysfunction. In: DiGiovanna EL, Schiowitz S,
Dowling DJ, editors. An Osteopathic Approach
to Diagnosis and Treatment. 3rd ed. Philadelphia,
Baltimore: Lippincott Williams & Wilkins. 2005.
33. Son D, Harijan A. Overview of surgical scar
prevention and management. J Korean Med Sci.
2014 Jun;29(6):751-7.
34. Adams LW, Priestley GC. Contraction of
collagen lattices by skin fibroblasts: drug induced
changes. Archives of Dermatological Research.
1988;280:114-118.
35. Coulomb B, Dubertret L, Bell E, Touraine R.
The contractility of fibroblasts in a collagen lattice
is reduced by corticosteroids. J Invest Dermatol.
1984;82:341-344.
36. Pohl H. Changes in the structure of collagen
distribution of the skin caused by a manual
technique. J Bodyw Mov Ther. 2010;14: 27-34.
37. Stearns ML. Studies of the development of
connective tissue in transparent chambers in the
rabbit ear. Am J Anat. 1940; 67:55-57.
38. Ehrenfeuchter WC. Chapter 50. Soft Tissue/
Articulatory Approach. In: Chila AG, Carreiro
JE, Dowling DJ, Gamber RG, Glover JC,
Habenicht AL, Jerome JA, Patterson MM, Rogers
FJ, Seffinger MA, Willard FH. Foundations
of Osteopathic Medicine. 3rd ed. Philadelphia,
Baltimore: Lippincott Williams & Wilkins. 2001.
39. McKay E. Assessing the effectiveness of
massage therapy for bilateral cleft lip reconstruction
scars. Int J Ther Massage Bodywork. Jun 2014;
7(2).
40. Morien A, Garrison D, Smith NK. Range
of motion improves after massage in children
with burns: a pilot study. J Bodyw Mov Ther.
2008;12:67–71.
41. Steele KM, Li TS, Lemley WW, Kribs JW,
Essing-Beatty DR, Garlitz JM, Comeaux ZJ.
Chapter 1. Introduction to osteopathic diagnosis
and treatment. In: The Pocket Manual of OMT.
2nd ed. Philadelphia: Lippincott Williams &
Wilkins. 2011.
42. Kuchera ML. Chapter 51. Lymphatics
approach. In: Chila AG, Carreiro JE, Dowling
DJ, Gamber RG, Glover JC, Habenicht AL,
Jerome JA, Patterson MM, Rogers FJ, Seffinger
MA, Willard FH. Foundations of Osteopathic
Medicine. 3rd ed. Philadelphia, Baltimore:
Lippincott Williams & Wilkins. 2001.
43. Field T, Peck M, Hernandez-Reif M, Krugman
S, et al. Post-burn itching, pain, and psychological
symptoms are reduced with massage therapy. J
Burn Care Rehabil 2000;21:189–93.
44. Josenhans E. Physiotherapeutic treatment for
axillary cord formation following breast cancer
surgery.
Zeitschrift fur Physiotherapeuten.
2007;59(9):868-78.
Correspondence: Sarah Belden, DO; sebelden@
gmail.com
32. Randolph RK, Simon M. Dermal fibroblasts
actively metabolize retinoic acid but not retinol. J
Invest Dermatol. 1998 Sep;111(3):478-484.
Page 15
Marijuana: An Unusual Cause of Fixed Drug Eruption
Christina Steinmetz-Rodriguez, DO,* Brent Schillinger, MD**
*First-year dermatology resident, Palm Beach Consortium for Graduate Medical Education, West Palm Hospital, West Palm Beach, FL
**Clinical assistant professor of medicine, Nova Southeastern College of Osteopathic Medicine, Ft. Lauderdale, FL; Dermatology Associates PA of the Palm Beaches, Delray
Beach, FL
Abstract
Fixed drug eruptions (FDE) are a frequently reported mucocutaneous drug eruption. We present a case of multiple mucocutaneous lesions due to marijuana use
presenting as FDE. Marijuana use continues to increase worldwide with the growing legalization for both medicinal and recreational use. As a consequence, it is
crucial that clinicians be aware of any possible adverse reactions. The most common systemic and cutaneous signs of marijuana use are reviewed here. Dermatologists
may be the first provider to encounter such clues, and as such we may be the first to recognize substance abuse and dependence, allowing earlier intervention for treatment.
Introduction
First described by Burns in 1889, subsequently
named “eruption erythemato-pigmentee fixe” by
Brocq, the “fixed drug eruption” is one of the most
common types of drug eruptions, and its incidence
continues to increase over the years relative to
other drug eruptions.1-3 The most characteristic
findings of FDE are “lesions that recur at the
same anatomic sites upon repeated exposure to
an offending agent,” according to Pai et al.3 A
large number of drugs, including barbiturates,
penicillin, sulfonamides, tetracycline, bismuth and
iodides, have been linked to FDE.4 Marijuana
use, however, remains an underreported cause of
FDE. As legalization of marijuana in the United
Figure 1
States becomes more widespread, it is important
for clinicians to recognize the cutaneous
manifestations of marijuana use. Because drug
abuse carries a negative stigma, patients are not
always immediately forthright in reporting their
history of illicit drug use. By both recognizing
cutaneous signs and routinely inquiring about
illicit drug use, dermatologists can be the first
to recognize signs of illicit drug use in patients,
resulting in earlier treatment.
Case Presentation
A 32-year-old man presented to the
dermatology clinic with complaints of recurring
hyperpigmented patches on his face over the
past year that were transient. He denied any
pain, pruritis or discomfort. He noticed that the
lesions would erupt in the same location on his
face each time, on a monthly basis, and resolve in
six to seven days. He denied any prior medical
history and reported no medication use including
over-the-counter medications.
Physical examination revealed a well-defined,
2 cm, circular hyperpigmented patch over
his right zygoma with mild scaling at the
periphery (Figure 1). Additionally, two 0.5 cm
hyperpigmented macules bilaterally on the lower
lip, and a 1 cm macule in the philtral ridge, were
seen on examination (Figure 2).
Figure 2
Shave biopsy of the zygomatic lesion revealed
interface vacuolar changes with dermal
melanophages and some eosinophils, as well as
near-full-thickness epidermal necrosis (Figures
3 and 4). The PAS stain failed to reveal any
dermatophytes. However, the PAS did reveal
normal thickness of the epidermal basement
membrane, consistent with fixed drug eruption.
Discussion
Fixed Drug Eruptions
Drug eruptions are one of the most
common cutaneous disorders encountered
by dermatologists, representing 2% to 3% of
all dermatological issues.3 FDE is a form of
drug allergy that presents as single or multiple
round, sharply demarcated, dusky red lesions
several centimeters in diameter that occur at
the same sites after each administration of
the inciting drug.5 Pruritis and burning are
often associated symptoms. The average age
of onset is approximately 30 years old, and
the most commonly implicated medication is
trimethoprim-sulfamethoxazole.5,6 Between the
time when the individual is first exposed to the
medication and development of the first lesion,
a variable refractory period can exist, ranging
from a week to months or even years.5 With
subsequent exposure, lesions appear within 30
minutes to eight hours. Typically, the lesions
heal with residual hyperpigmentation. However,
other types of FDE have been reported (Table 1).
Figure 3
After the biopsy results returned, a careful review
of the patient’s medical history revealed that
each episode was produced by the same event
-- recreational use of marijuana. A short course
of topical corticosteroid therapy resulted in
complete resolution of the lesions, and the patient
was advised to abstain from marijuana use.
Figure 4
Page 16
MARIJUANA: AN UNUSUAL CAUSE OF FIXED DRUG ERUPTION
Table 1. Types of Fixed Drug Eruptions (FDE) and Examples of Causes3,5
FDE Type
Presentation
Known Causes
Erythema multiforme-like
Lesion with three zones:
central, dusky purpura;
elevated, edematous, pale ring;
and surrounding erythema
Mefenamic acid20
Pigmenting
Lesions that heal with residual
hyperpigmentation
Toxic epidermal necrolysis-like
Linear
Wandering
Nonpigmenting
Widespread, bullous lesions
NSAIDs21
Involved sites that don’t flare
with each exposure and activity
that does not always appear at
the same location with each
recurrence
Acetaminophen
Subepidermal blisters that heal
without scarring
Aminophenazone,
antipyrine, barbiturates,
cotrimoxazole, trimethoprim,
sulfamethoxazole,
diazepam, mefenamic
acid, acetaminophen,
phenylbutazone, piroxicam,
sulfadiazine, sulfathiazole
Multiple lesions that are
Trimethoprim
distributed linearly; may follow
Blaschko’s lines or nerve-root
distribution
Lesions that do not leave any
residual hyperpigmentation
and appear uniformly red
Bullous
Barbiturates, penicillin,
NSAIDs sulfonamides,
tetracyclines, bismuth, iodides
Our patient presented with the classic pigmented
FDE, with lesions appearing within six hours of
marijuana use.
While generally only a solitary lesion appears
on first exposure, repeated administration of the
medication can lead to new lesions or an increase
in size of the original lesions.5 Although they
can occur anywhere on the skin, FDE’s most
Pseudoephedrine
hydrochloride,
tetrahydrozoline, contrast
media, betahistine, etodolac
commonly occur on the glans penis, lips, palms,
soles and groin area.5 Overall, the legs are most
commonly affected in women and the genitalia
are most commonly affected in men.1
As explained by Pai et al., the reaction “is believed
to be a lymphocyte CD8-mediated reaction,
wherein the offending drug may induce local
reactivation of memory T cell lymphocytes …
Table 2: Cutaneous manifestations of illicit drug use8,10
Illicit Drug
Percent of Americans Using
(12+ Years Old)
Cutaneous Manifestations
Cocaine/Crack
0.6%
Nasal septal perforation, “snorter warts,”
madarosis, bullous erythema multiforme,
“crack hands,” scleroderma, HenochSchonlein purpura, vasculitis due to
levamisole
Ecstasy
0.4% hallucinogen use
(including LSD and ecstasy)
“Ecstasy pimples,” guttate psoriasis
0.1%
Track marks, cellulitis, candida folliculitis,
transcutaneous botulism, granuloma
formation, pruritis, fixed drug eruption,
“puffy hand syndrome,” tourniquet
hyperpigmentation
Cannabis
Methamphetamine
Heroin
7.5%
0.2%
STEINMETZ-RODRIGUEZ, SCHILLINGER
Contact urticaria, cannabis arteritis, skin
aging
“Meth mites,” “meth mouth,” xerosis,
premature aging
targeted initially by the viral infection.”1
Histological examination displays two possible
scenarios depending on when the biopsy is
done. In lesions that are only one to two days
old, examination reveals hydropic degeneration
of basal keratinocytes with dyskeratotic cells in
the epidermis and exocytosis of mononuclear
cells.3 Healed hyperpigmented lesions often
demonstrate pigmentary incontinence revealing
dermal melanophages with little perivascular
infiltration of inflammatory cells, as seen in our
patient.3 To identify the culprit of the FDE,
provocation tests can be done, with the patch
test being the most commonly used method. The
patch test is effective as long as it is placed over a
previously involved site and the patient is not in
the refractory period.3 Challenging a patient with
an oral provocation test has been associated with
generalized bullous lesions in some cases.5 In our
case, we did not re-challenge the patient with the
suspected drug due to legal concerns. Treatment
consists of cessation of the suspected drug along
with the use of topical steroids and systemic
antihistamines.3 Extensive lesions, or those with
bullae, may require systemic corticosteroids.3
Post-inflammatory hyperpigmentation can be
treated with hydroquinone bleaching creams.5
Cutaneous manifestations of illicit drug use
According to the Substance Abuse and Mental
Health Administration, in 2013 “an estimated
24.6 million individuals aged 12 or older were
current illicit drug users,” representing over
9% of the population in the United States.8
Dermatologists may be the first to recognize
drug abuse in select patients, allowing for earlier
intervention and treatment (Table 2). As often
the vascular and cardiac manifestations are
internal, they cannot be readily seen by clinicians
outside of dermatology.
Cannabis
Cannabis remains the most commonly used illicit
drug, with an estimated 7% of the population in
the United States using this substance regularly.9
Since the Neolithic times, cannabis, which is the
Latin name for hemp, has been widely used, with
the first account of marijuana in the Western
medical literature reported in 1840 by the British
physician O’Shaughnessy.9,10 Today, Cannabis
sativa has a wide variety of uses ranging from
recreational use for its psychoactive properties
or medicinal properties, to biofuel, insulation,
animal litter, paper, cosmetics, rope and fabric
manufacturing.10 The stem provides the fibers,
while the resin produced from the flowering
tops is often used recreationally. The seeds are
commonly used for birdseed or fishing bait.11
There are four subspecies of Cannabis sativa,
varying in geographic location and in application
(Table 3). “Hashish” refers to the unadulterated
resin that is collected and dried, while marijuana
refers to the cut flowers, leaves and stems, which
generally possess a fifth of the potency of hashish.9
Cannabis can be smoked or consumed in
foods, infusions or vapor form.
Delta9-tetrahydrocannibol
(THC), the
main
Page 17
References
Table 3: Subspecies of Cannabis sativa10
Cannabis sativa Subspecies
Use
Region
Indica (Indian hemp)
Recreational use (high THC
content), seldom used for its
fiber
Himalayas, Middle East, India
Sativa (cultivated hemp)
Spontanea (wild hemp)
Kafiristanica (Afghan hemp)
Recreational (high
tetrahydrocannabinol [THC]
content), industrial uses
Industrial use (low THC
content, not commonly used for
recreation)
Eastern Europe, China, Russia
2. Brocq L. Eruption erythemato-pigmentee
fixe due a l’antipyrine. Ann Dermatol Venereol.
1894;5:308–313.
3. Lee AY. Fixed drug eruptions. Incidence,
recognition and avoidance. Am J Clin Dermatol.
2000;1(5):277-285.
Recreational use (high THC
Afghanistan, Pakistan
content), unfit for manufacturing
of fibers
4. Stritzler C, Kopf AW. Fixed drug eruption
caused by 8-chlorotheophylline in Dramamine
with clinical and histologic studies. J Invest
Dermatol. 1960;34:319-330.
Conclusion
5. Gendernalik SB, Galeckas KJ. Fixed drug
eruptions: a case report and review of literature.
Cutis. 2009;84(4):215-219.
psychoactive substance in cannabis, which is
found in the plant’s resin, is responsible for its
perception- and mood-altering properties. The
concentration of THC can vary from 0.1 to 12%,
depending upon the subspecies and method of
preparation.12 Onset of activity after smoking
marijuana is within 10 to 20 minutes, and the
effects usually resolve within three hours.9
Cutaneous manifestations of marijuana present as
conjunctival injection, contact urticaria, and type
1 hypersensitivity, which can include anaphylaxis
or cannabis arteritis. Cannabis arteritis, a subtype
of thromboangiitis obliterans, is seen mainly in
long-term users.12 Cannabis arteritis is believed
to be caused by the vasoconstrictive side effects
of THC and contaminants such as arsenic
(known to cause thromboangitis obliterans
in cigarette smokers) and is one of the major
causes of peripheral arterial disease in patients
under the age of 50.10,12 Manifestations of this
atherogenesis include Raynaud’s phenomenon;
digital necrosis with small, dry necrotic patches
on the extremities; and decreased tibial and
pedal pulses. Diagnosis is based upon duplex
ultrasound in order to differentiate it from
atherosclerosis.12 Treatment includes cessation of
marijuana, aspirin (81 mg to 200 mg daily) or, in
severe cases, iloprost.12 Smoking marijuana is also
associated with premature skin aging, resulting
in prominent wrinkles.7 A case of erythema
multiforme-like recurrent drug eruption was also
reported with marijuana use.13 No reported cases
of fixed drug eruption secondary to marijuana use
were found in a literature search.
In the 1980s, an epidemic of fixed drug eruptions
occurred in Holland due to heroin being smoked,
and presented as hyperpigmented lesions of the
tongue.14 Despite denial by our patient, one
possibility is that heroin may have been mixed
in the marijuana cigarette, and thus the FDE
may have been due to adulterants and not the
marijuana.
Page 18
Worldwide, primarily
equatorial regions
1. Pai VV, Bhandari P, Kikkeri NN, Athanikar
SB, Sori T. Fixed drug eruption to fluconazole: a
case report and mini-review of literature. Indian J
Pharmacol. 2012;44(5):643-645.
To our knowledge, this is the first case report
describing fixed drug eruption elicited by
recreational marijuana use. With 19.8 million
current users in the United States and the growing
rate of use associated with legislature changes,
questions regarding a patient’s recreational drug
use should be included in the patient’s history.8
By recognizing the cutaneous findings of illicit
drug use, dermatologist can stand on the forefront
of early recognition.
6. Ozkaya-Bayazit E, Bayazit H, Ozarmagan
G. Drug related clinical pattern in fixed drug
eruption. Eur J Dermatol. 2000;10(4):288-291.
7. Liu SW, Lien MH, Fenske NA. The effects
of alcohol and drug abuse on the skin. Clin
Dermatol. 2010;28(4):391-399.
8. Substance Abuse and Mental Health Services
Administration, Center for Behavioral Health
Statistics and Quality. The NSDUH Report:
Substance Use and Mental Health Estimates
from the 2013 National Survey on Drug Use
and Health: Overview of Findings. SAMHSA:
Rockville (MD); 2014.
9. Lieberman CM, Lieberman BW. Current
concepts: marihuana—a medical review. N Engl J
Med. 1971;284(2):88-91.
10. Tennstedt D, Saint-Remy A. Cannabis and
skin diseases. Eur J Dermatol. 2011;21(1):5-11.
11. Williams C, Thompstone J, Wilkinson M.
Work-related contact urticaria to Cannabis
Sativa. Contac Dermatitis. 2008;58(1):62-63.
12. Hennings C, Miller J. Illicit drugs: what
dermatologists need to know. J Am Acad
Dermatol. 2013;69(1):135-142.
13. Ozyurt S, Muderrisoglu F, Ermete M, Afsar
F. Cannabis-induced erythema multiformelike recurrent drug eruption. Int J Dermatol.
2014;53(1):e22-23.
14. Westerhof W, Wolters EC, Brookbakker JT,
Boelen RE, Schipper ME. Pigmented lesions of
the tongue in heroin addicts-fixed drug eruption.
Br J Dermatol. 1983;109(5):605-610.
Correspondence:
Christina
SteinmetzRodriguez, DO; [email protected]
MARIJUANA: AN UNUSUAL CAUSE OF FIXED DRUG ERUPTION
Painful, Pruritic Blisters Exacerbated by Heat and Sweating
Collin M. Blattner, BS,* Dustin V. Wilkes, DO,** Dongkun Chang, MD***
*Medical Student, 4th year, Des Moines University, Des Moines, IA
**Attending Dermatologist, Department of Dermatology, JPS Health Network, Fort Worth, TX
***Attending Pathologist, Department of Pathology, JPS Health Network, Fort Worth, TX
Abstract
Bullous congenital ichthyosiform erythroderma is a rare genodermatosis that affects 1 in 200,000 people. Management for adults entails symptomatic relief, but infants
may require intensive care if substantial blistering is present. We present a case of bullous congenital ichthyosiform erythroderma in a 48-year-old male and provide a
discussion about the disease and treatment options.
Introduction
Bullous congenital ichthyosiform erythroderma
(BCIE) is a rare genodermatosis that was
formerly known as epidermolytic hyperkeratosis
(EHK) or epidermolytic ichthyosis (EI). About
50% of cases arise from spontaneous mutation,
but autosomal-dominant (AD) and rare
autosomal-recessive forms also exist.1-3 BCIE
clinically manifests with erythema, blistering,
and erythroderma in infancy, but the severity of
disease may decrease over time.1
and soles with fissures and cracks (Figure 1).
Brown, cardboard-like scale with desquamation on
the neck, back, abdomen, and extremities was also
present. The lesions extended to the volar aspect of
the wrists, the dorsa of the feet, and the Achilles
tendon. Dark-brown hyperkeratosis with mild
scaling, arrayed in a linear fashion, was present in his
axillae, antecubital fossa (Figure 2), and popliteal
There were also few coarse, irregularly shaped,
keratohyalin granules and intracytoplasmic
vacuolization, along with involvement of the
entire suprabasal layer. This was consistent with
the diagnosis of BCIE.
Case Report
A 48-year-old African American male presented
for evaluation of blisters and scaling over the
entirety of his body since birth. The blisters were
painful, pruritic, and made worse by heat and
sweating. He had previously used Eucerin lotion
without relief. The patient had an otherwise
unremarkable 12-point review of symptoms
except for mild joint pain, 15 pack-year smoking
history, and moderate alcohol intake.
Fig 3. Orthokeratotic hyperkeratosis,
hypergranulosis, church-spire-like
papillomatosis, and marked vacuolar changes
in the keratinocytes of the upper spinous and
granular layers (H&E, 40x)
Dermatological
examination
revealed
marked hyperkeratosis, thickened palms with
palmoplantar keratoderma, hyperlinear creases,
Discussion
Fig 2. Antecubital fossa with dark-brown
hyperkeratosis and scaling
fossa. The hair, teeth, nails, mucosa, and other body
surfaces were spared. The patient’s mother, maternal
aunt, and two cousins had a similar skin condition
with pronounced scaling. Differential diagnosis
included BCIE, epidermolysis bullosa, lamellar
ichthyosis, X-linked ichthyosis, staphylococcal
scalded skin syndrome, Stevens-Johnson syndrome,
and toxic epidermal necrolysis.
Fig 1. Thickened palm with palmoplantar
keratoderma and hyperlinear creases
BLATTNER, WILKES, CHANG
Two 4mm punch biopsies were taken from
representative lesions on the abdomen and
left knee. Histopathological findings revealed
orthokeratotic hyperkeratosis, hypergranulosis,
church-spire-like papillomatosis, and marked
vacuolar changes in the keratinocytes of the
upper spinous and granular layers (Figure 3).
BCIE is a rare AD genodermatosis that was
first described by Brocq in 1902.4 It is caused
by mutations in keratin 1 and keratin 10 that
impair intermediate filament formation in the
suprabasal keratinocytes, although a case with a
novel mutation in the 1A helix initiation motif
of keratin 1 has been reported.4 Confirmation of
disease can be established by mutation-specific
testing for keratin defects using buccal swabs
or blood.5 Cost constraints prohibited genetic
testing and genetic counseling for our patient,
but these services should be offered to affected
individuals and families. Patients should also
be made aware of the possibility of passing the
chromosomal defect on to their children.
Clinically, BCIE presents in neonates with
erythema, widespread superficial blistering, and
erythroderma. If the blisters rupture, they may
leave raw, denuded areas that can cause secondary
infections, sepsis, dehydration, electrolyte
imbalances, and hypothermia. In light of these
concerns, affected newborns should be handled
gently and transferred to the intensive care unit
(ICU) immediately after birth. Although a
Page 19
delicate scale may be present following delivery,
hyperkeratosis is seldom noticeable until the
third month of life. Clinical data from 28
patients with BCIE in Japan found that 96.4%
had rash, 67.9% had erythroderma, and 75% of
patients younger than 20 years had generalized
blistering.6 As a person ages, the symptoms
may wane or even disappear, but the classically
described “corrugated cardboard” scale persists.6
Proliferation of scale allows for the overgrowth
of bacteria, particularly Staphylococcus aureus, that
causes malodor.6
In 1994, DiGiovanna and Bale separated the
various clinical presentations of BCIE into two
primary types based on the presence or absence
of palm and sole hyperkeratosis.5 The two
primary types were further subdivided into three
subtypes each that described the various clinical
presentations. Some subtypes have generalized
involvement; others are more localized.5 EHK
is still being used as a synonym for BCIE even
though multiple unusual subtypes of BCIE
(annular, linear, cyclic) have been described.7-11
The histopathological hallmark of BCIE is
“epidermolytic hyperkeratosis” (EHK) despite
the identical finding being present in several
conditions including acanthoma, epidermoid cyst,
infundibular cyst, epidermal nevus, hidradenoma,
nevus comedonicus, seborrheic keratosis, actinic
keratosis, leukoplakia, basal cell carcinoma,
squamous cell carcinoma, and melanoma.12
Although no cure exists for BCIE, oral retinoids
such as isotretinoin, acitretin, and etretinate are
the mainstay of therapy.13 Studies of etretinate
for children with BCIE demonstrated a good
safety profile and remission rates of 70% to
80%.14 Dosing is started at 1 mg/kg/d to 2 mg/
kg/d, and once remission is achieved, the dose
can be adjusted to the minimal amount necessary
to keep the skin free of lesions.14 Children who
underwent treatment with oral retinoids had
improved quality of life and enhanced social and
psychological development, and a subset showed
improved physical growth.15 Adjunctive therapies
that provide symptomatic relief include high-dose
beta-carotene, topical retinoids, 10% glycerin,
lactic acid, alpha-hydroxy acid, calcipotriol,
antibacterial soap, and urea.16-18 Proper use of
emollients and other barrier ointments that
retain moisture are recommended. Gene therapy
is a promising new treatment option that is being
studied at the University of Colorado. Researchers
hope to generate induced pluripotent stem cells
that allow for genetic correction of the defect in
keratin 1 or keratin 10.
Conclusion
In conclusion, accurate diagnosis of BCIE is
important so that genetic counseling and prenatal
diagnosis may be offered to affected families.19
Management includes oral retinoids for children
and symptomatic care with proper use of
emollients and mild antibacterial cleansers for
adults.14 Infants should be treated in the ICU to
prevent secondary infections, sepsis, dehydration,
electrolyte imbalances, or death.14
Page 20
References
Review.
2. Terheyden P, Grimberg G, Hausser I, Rose
C, Korge BP, Krieg T, Arin MJ. Recessive
epidermolytic hyperkeratosis caused by a
previously unreported termination codon
mutation in the keratin 10 gene. J Invest
Dermatol. 2009 Nov;129(11):2721-3.
14. Brecher AR, Orlow SJ. Oral retinoid
therapy for dermatologic conditions in children
and adolescents. J Am Acad Dermatol. 2003
Aug;49(2):171-82; quiz 183-6. Review.
1. Frost P, Van Scott EJ. Ichthyosiform
dermatoses. Classification based on anatomic and
biometric observations. Arch Dermatol. 1966
Aug;94(2):113-26.
3. Tsubota A, Akiyama M, Kanitakis J, Sakai K,
Nomura T, Claudy A, Shimizu H. Mild recessive
bullous congenital ichthyosiform erythroderma
due to a previously unidentified homozygous
keratin 10 nonsense mutation. J Invest Dermatol.
2008 Jul;128(7):1648-52.
4. Uezato H, Yamamoto Y, Kuwae C, Nonaka
K, Oshiro M, Kariya K, Nonaka S. A case of
bullous congenital ichthyosiform erythroderma
(BCIE) caused by a mutation in the 1A helix
initiation motif of keratin 1. J Dermatol. 2005
Oct;32(10):801-8.
5. DiGiovanna JJ, Bale SJ. Clinical heterogeneity
in epidermolytic hyperkeratosis. Arch Dermatol.
1994 Aug;130(8):1026-35.
6. Kurosawa M, Takagi A, Tamakoshi A,
Kawamura T, Inaba Y, Yokoyama K, Kitajima Y,
Aoyama Y, Iwatsuki K, Ikeda S. Epidemiology
and clinical characteristics of bullous congenital
ichthyosiform
erythroderma
(keratinolytic
ichthyosis) in Japan: results from a nationwide
survey. J Am Acad Dermatol. 2013 Feb;68(2):27883.
7. Lacz NL, Schwartz RA, Kihiczak G.
Epidermolytic hyperkeratosis: a keratin 1 or 10
mutational event. Int J Dermatol. 2005;44(1):1-6.
13. Li H, Törmä H. Retinoids reduce formation of
keratin aggregates in heat-stressed immortalized
keratinocytes from an epidermolytic ichthyosis
patient with a KRT10 mutation. Acta Derm
Venereol. 2013 Jan;93(1):44-9.
15. Ruiz-Maldonado R, Tamayo L. Retinoids in
disorders of keratinization: their use in children.
Dermatologica. 1987;175 Suppl 1:125-32.
16. Kragballe K, Steijlen PM, Ibsen HH, van de
Kerkhof PC, Esmann J, Sorensen LH, Axelsen
MB. Efficacy, tolerability, and safety of calcipotriol
ointment in disorders of keratinization. Results of
a randomized, double-blind, vehicle-controlled,
right/left comparative study. Arch Dermatol.
1995 May;131(5):556-60.
17. Kwak J, Maverakis E. Epidermolytic
hyperkeratosis. Dermatol Online J. 2006 Sep
8;12(5):6.
18. Achar A, Naskar B, Laha R, Ray S.
Epidcermolytic hyperkeratosis: a case report. J
Indian Med Assoc. 2009 Mar;107(3):171-2.
19. Rothnagel JA, Lin MT, Longley MA, Holder
RA, Hazen PG, Levy ML, Roop DR. Prenatal
diagnosis for keratin mutations to exclude
transmission of epidermolytic hyperkeratosis.
Prenat Diagn. 1998 Aug;18(8):826-30.
Correspondence: Dustin V. Wilkes, DO;
[email protected]
8. Sheth N, Greenblatt D, McGrath JA. New
KRT10 gene mutation underlying the annular
variant of bullous congenital ichthyosiform
erythroderma with clinical worsening during
pregnancy. Br J Dermatol. 2007;157:602–4.
9. Kocaturk E, Zemheri E, Kavala M, Aktas
S, Sarigul S, Sudogan S. Two cases of linear
epidermolytic
hyperkeratosis:
therapeutic
challenge with acitretin. Eur J Dermatol.
2010;20(3):404-5.
10. Chassaing N, Kanitakis J, Sportich S, CordierAlex MP, Titeux M, Calvas P, Claudy A, Berbis
P, Hovnanian A. Generalized epidermolytic
hyperkeratosis in two unrelated children from
parents with localized linear form, and prenatal
diagnosis. J Invest Dermatol. 2006;126(12):27157.
11. Sybert VP, Francis JS, Corden LD, Smith LT,
Weaver M, Stephens K, McLean WH. Cyclic
Ichthyosis with Epidermolytic Hyperkeratosis:
A Phenotype Conferred by Mutations in the
2B Domain of Keratin K1. Am J Hum Genet.
1999;64:732–8.
12. Kumar P, Kumar R, Mandal RK, Hassan S.
Systematized linear epidermolytic hyperkeratosis.
Dermatol Online J. 2014 Jan15;20(1):21248.
PAINFUL, PRURITIC BLISTERS EXACERBATED BY HEAT AND SWEATING
Proteus Syndrome: Case Report and Review
Holly Kanavy, DO,* Cindy Hoffman, DO**
*PGY-4, St. Barnabas Hospital, Bronx, NY
**Program Director, Dermatology Residency Program, St. Barnabas Hospital, Bronx, NY
Abstract
Proteus syndrome (PS) is a rare, progressive hamartomatous disorder characterized by overgrowth and hyperplasia of diverse tissues including connective tissue, bone,
skin, adipose, and central nervous system. Mosaic expression of a post-zygotic somatic mutation in the AKT1 gene results in random distribution of affected tissues and
creates significant phenotypic variability among patients. Herein, we describe a case of PS presenting with a cerebriform connective-tissue nevus in a 14-year-old male
and review the pathogenesis, clinical presentation and differential diagnosis, management, and prognosis of patients with the disorder.
Introduction
Proteus syndrome was first described in 1979
by Cohen and Hayden, and it was named by
Weidmann et al. in 1983 for the Greek god
Proteus, who was capable of assuming many
forms.1,2 With fewer than 100 confirmed cases
reported, Proteus syndrome is extremely rare;
its estimated incidence is less than 1:1,000,000
persons.3 It is seen twice as frequently in males,
and there is no ethnic predilection.4 The variable
presentation and rarity of the disease led to
frequent misdiagnosis of the disorder until 1999,
when Biesecker et al. proposed detailed and
specific diagnostic criteria.3
of the lesion was performed. Histology revealed
dense connective tissue beneath an acanthotic,
acantholytic epidermis.
Stellate cells and
entrapped adipose tissue were present in the
dermis (Figures 2a [2x], 2b [10x]). The patient
was assigned a diagnosis of Proteus syndrome
and referred for genetic testing.
Case Presentation
A 14-year-old Caucasian male presented with
a slowly enlarging growth on the bottom of his
left foot that was present for about three years.
The patient reported some discomfort with
ambulation due to the increasing size of the
lesion. His medical history included chronic
macrocytosis and reticulocytopenia, which
prompted a bone marrow biopsy at the age of
10. No evidence of hematologic malignancy
was found; however, a non-clonal chromosome
15 deletion: 45 XY del(15)(q11.2) was revealed.
(Chromosome 15 deletions have been described
in association with myelodysplastic syndrome.)
The patient also had a history of developmental
abnormalities and was diagnosed with autism/
Asperger’s disease. An MRI of the brain from
five years prior revealed encephalomalacia and
periventricular leukomalacia (localized areas of
necrosis attributed to infarction or ischemia).
One of the patient’s two brothers had spina bifida.
A full skin examination revealed one café au lait
macule on the back. The plantar aspect of the left
foot contained several flesh-colored cerebriform
papules and nodules (Figure 1). Partial biopsy
Figure 1
KANAVY, HOFFMAN
Figure 2a
mutation results in a greater number of disease
manifestations than a late mutation, because the
early somatic cell carrying a mutation would give
rise to more affected cell lineages.
Due to the clinical overlap with other
hamartomatous disorders, a mutation in the
tumor suppressor gene PTEN was initially
thought to be pathogenic in PS. However, it
is now believed that individuals with PTEN
gene mutations and asymmetric overgrowth
do not meet the diagnostic criteria for Proteus
syndrome.
Instead, these individuals are
considered part of a larger group of disorders
called PTEN hamartoma tumor syndromes.
Other entities in this group include Cowden
syndrome, Bannayan-Riley-Ruvalcaba syndrome,
and Proteus-like syndrome.7 AKT1 is activated
by loss-of-function mutations in PTEN, which
explains why patients with such mutations and
those with activating mutations in AKT1 display
overlapping clinical features.
Clinical Manifestations
Figure 2b
Pathogenesis
Proteus syndrome is a progressive, hamartomatous
disorder that may involve any germ layer. The
hypothesized pathogenesis involves a postzygotic somatic mutation in the AKT1 gene
(chromosome 14q32.33), which is lethal in the
non-mosaic state.5 This gene belongs to the AKT
family of serine/threonine kinases and is involved
in regulation of multiple cellular processes,
including proliferation and survival, cell size and
response to nutrient availability, tissue invasion
and angiogenesis.6 Constitutive activation of
the protein underlies the overgrowth and tumor
susceptibility in patients carrying this mutation.
Mosaic expression of the mutation is what results
in the random distribution of affected tissue and
creates significant phenotypic variability among
patients. Accordingly, an early post-zygotic
The clinical features of PS arise postnatally with
irregular, asymmetric, progressive overgrowth
that can involve many tissues, most commonly
bone, connective tissue and fat. Skeletal changes
include gigantism of the hands and/or feet and
partial or complete hemihypertrophy. Localized
overgrowths may exert asymmetric forces on the
spine and result in scoliosis. Connective-tissue
abnormalities, such as cerebriform connectivetissue nevi (CCTN), typically present in the
first or second year of life and tend to evolve
slowly, in some patients continuing to develop
throughout adolescence.8 The lesion is virtually
pathognomonic for PS and appears as gyriform
gross thickenings of cutaneous and subcutaneous
tissues, most commonly on the soles and
occasionally on the hands, abdomen, and nose.
Other dermatological manifestations include
linear verrucous epidermal nevi, which tend
to develop in the first year of life, and vascular
malformations that can be either venous,
capillary, lymphatic-type, or mixed.8 Four types
of abnormalities of fat may occur in Proteus
syndrome: (1) lipomas, (2) lipohypoplasia, (3)
fatty overgrowth, and (4) localized fat deposits or
partial lipohyperplasia. Lipomas may be single or
multiple and occur subcutaneously or internally.
Lipomas of the abdomen and thorax can be very
aggressive despite their benign histology.8
Specific facial features have been described in
Page 21
Table 1. Proteus Syndrome Diagnostic Criteria
Criteria Category
(Diagnosis requires either A,
two from B, or three from C)
Clinical Characteristics
Category A
Cerebriform connective tissue nevus
Category B
1. Linear epidermal nevus
PS is not inherited, so prenatal testing is not
indicated.
Differential Diagnosis
2. Asymmetric, disproportionate overgrowth with at least one of
the following:
·
Affected limbs
·
Hyperostosis of the skull
·
Hyperostosis of the external auditory canal
·
Megaspondylodysplasia
·
Viscera: spleen or thymus
3. Specific tumors before the second decade:
·
Bilateral ovarian cystadenoma
·
Parotid monomorphic adenoma
Category C
1. Dysregulated adipose tissue with either of the following
(either of the following):
·
Lipomatous overgrowth
·
Regional lipohypoplasia
2. Vascular malformations (one of the following):
·
Capillary malformation
·
Venous malformation
·
Lymphatic malformation
·
Lung bullae
3. Facial phenotype (all of the following):
·
Dolichocephaly
·
Long face
·
Down-slanting palpebral fissures
·
Depressed nasal bridge
·
Wide or anteverted nares
·
Open mouth at rest
patients with PS and are most commonly seen in
individuals with cognitive deficits. These include
down-slanting palpebral fissures, flattening of
the malar bones, a relative lengthening of the
face, low nasal bridge with wide nostrils, and a
persistently open mouth.3 Our patient did not
display any of these characteristics.
Central nervous system abnormalities are seen
in up to 40% of patients with PS.4 Dietrich et
al. described 12 children with PS whose CNS
abnormalities included hemimegalencephaly
(8), hypodense periventricular white matter (4),
periventricular calcification (3), corpus callosal
abnormalities (3), atrophic brains (2), and DandyWalker malformation (1).9 Mental deficiency is
seen in approximately 30% of cases.3
While no specific hematologic abnormalities have
been described in association with PS, studies
have demonstrated that AKT1 and AKT2 are
critical regulators of long-term hematopoietic
stem-cell function.10 It is feasible that an
AKT1 gene mutation may underlie the chronic
macrocytosis and reticulocytopenia observed in
our patient.
Patients with PS are prone to developing several
types of tumors, most commonly monomorphic
adenomas of the parotid gland, ovarian
cystadenomas, meningiomas, and various types of
testicular tumors.3 Cystic lung disease may cause
Page 22
pulmonary insufficiency, persistent atelectasis,
pneumonia, or even death.3
Other manifestations include ophthalmologic
findings such as strabismus, epibulbar cysts,
and epibulbar dermoids (42%); otolaryngologic
abnormalities (37%); mental deficiency (30%);
non-cystic pulmonary disease (20%); dental
abnormalities (19%); reproductive/genital nontumor abnormalities (18%); male reproductive
tumors (11%) and renal/urologic manifestations
(9%); and hair and nail abnormalities.7
Diagnosis
The diagnosis of Proteus syndrome is based on
clinical findings. Individuals must meet all of the
general criteria, including mosaic distribution
of lesions, sporadic occurrence, and progressive
course, along with certain specific criteria as
outlined in Table 1.3
Although PS is primarily a clinical diagnosis,
molecular genetic testing for the somatic
mutation in the AKT1 gene can be helpful to
confirm the diagnosis. This can be technically
challenging because blood is not an appropriate
source and tissue may show low-level mosaicism.
Skin scrapings from epidermal nevi in PS
patients have been shown to be a good source of
mutant cells and may provide an alternate source
for genetic testing.11 It is important to note that
Among the differential diagnoses for Proteus
syndrome are those entities described as part of
PTEN hamartoma tumor syndrome. BannayanRiley-Ruvalcaba syndrome is an autosomaldominant disorder characterized by macrocephaly,
angiomatosis, lipomatosis, polyposis of the colon
and rectum, and pigmented macules of the
penis. These patients lack the progressive digital
overgrowth, skull exostoses, epidermal nevi,
and palmar or plantar changes seen in Proteus
syndrome. Patients with Cowden syndrome
typically present with facial trichilemmomas,
acral keratoses, papillomatous lesions, lipomas,
hemangiomas, and epidermal nevi (Cowden
nevus), but do not develop cerebriform
connective-tissue nevi. These patients also
carry an increased risk for breast, thyroid, and
endometrial cancers. Patients with Proteus-like
syndrome have significant clinical features of PS
but do not meet the diagnostic criteria for PS.
They are distinguished by macrocephaly, marked
lipohypertrophy, and lack of progressive bony
overgrowth.7
In SOLAMEN (segmental overgrowth,
lipomatosis, AVMs, epidermal nevus) syndrome,
patients display thickening of the soles and
increased wrinkling instead of the gyri found
in CCTN. There is segmental proportionate
overgrowth with soft-tissue hypertrophy
and ballooning effect, as well as lymphatic
and shunting arteriovenous malformations.12
Proteus syndrome may be distinguished from
neurofibromatosis by the absence of multiple café
au lait macules, Lisch nodules, axillary freckling,
and multiple neurofibromas. Hemihyperplasia
and multiple lipomatosis syndrome (HHML) is
characterized by subcutaneous lipomatosis and
asymmetric overgrowth (hemihyperplasia) that is
not as progressive as in PS.3
Syndromes
characterized
by
vascular
malformations may also be considered in the
differential diagnosis of PS. In Maffucci syndrome,
enchondromatosis, most commonly of the hands
and feet, with multiple cavernous hemangiomas
are seen.3 This should not be difficult to
distinguish from Proteus syndrome owing to the
lack of enchondromatosis in Proteus syndrome.
Klippel-Trenaunay syndrome is characterized by
the three main features of nevus flammeus (portwine stain), venous and lymphatic malformations,
and soft-tissue hypertrophy of the affected limb.
There are no CCTN seen, and overgrowth is
present at birth and more severe than in PS.3
In Parkes Weber, a mutation in the RASA1
gene leads to multiple capillary malformations,
including AV fistulas that can lead to heart
failure, as well as overgrowth of one limb, most
commonly the leg.3 In the differential diagnosis
of the CCTN is isolated plantar collagenoma, a
hamartomatous lesion consisting of proliferation
of normal collagen tissue.13 Collagenomas
are commonly encountered in other genetic
disorders, such as Buschke-Ollendorff syndrome,
a rare autosomal-dominant condition, resulting
from nonsense mutation in the LEMD3 gene,
which encodes for a potent negative regulator
of bone morphogenic protein and transforming
growth factor-β signaling pathways. Recently,
PROTEUS SYNDROME: CASE REPORT AND REVIEW
a mutation in LEMD3 has been reported in
familial cutaneous collagenomas as well.14
with parents and children and refer for counseling
and peer-support groups if needed.20
Histopathologically, cerebriform connectivetissue nevi are characterized by an irregular
proliferation of highly collagenized fibrous
tissue.15 Biopsies of lipomatous overgrowths
reveal nonencapsulated lobules and mature
adipocytes.16 Vascular malformations are lined by
flat endothelium, exhibiting a normal, slow rate
of turnover. The flat, organoid type of epidermal
nevus in PS shows acanthosis, hyperkeratosis, and
papillomatosis.16,17
Regarding progression of skin lesions,
Beachkofsky et al. evaluated 36 patients with
Proteus syndrome with serial photography for an
average of 53 months. Cerebriform connectivetissue nevi showed progression in 13 children but
not in 3 adults. Lesions progressed by expansion
into previously uninvolved skin, increased
thickness, and development of new lesions.
Lipomas increased in size and/or number in 8
out of 10 children. Epidermal nevi and vascular
malformations generally did not spread or
increase in number.21
Histopathology
Management
The sporadic and unpredictable nature of
Proteus syndrome can pose a challenge for
health care providers. Since PS can affect many
different parts of the body to varying degrees,
a multidisciplinary approach is important in
the management and prevention of secondary
complications. Serial clinical photography with
an initial skeletal survey and targeted follow-up
radiographs should be performed to evaluate the
degree of obstruction or deformation based on
the patient’s medical history and physical exam.18
Other imaging recommendations include
intracranial MRI to evaluate for CNS
malformations that may be associated with
developmental delay, mental retardation or
seizures.
Findings may include multiple
meningiomas, polymicrogyria, and periventricular
heterotopias.3 Abdominal MRI is recommended
to exclude intra-abdominal lipomas, regardless of
the presence of symptoms, due to the aggressive
nature of these lesions. CT of the chest to
evaluate pulmonary cystic malformations should
be carried out if clinically warranted to evaluate
for cystic malformations.3
One of the most common causes of death for
patients with PS, including children, is deep
venous thrombosis and pulmonary embolism.
For this reason, perioperative anticoagulant
is recommended.18 Chronic anticoagulation,
however, is not recommended, particularly since
many of these patients have underlying vascular
anomalies.
Tumor surveillance is not recommended in PS
patients. These patients appear to be predisposed
to a broad range of malignancies, and it has not
been demonstrated that early detection of tumors
in PS improves prognosis.18
Cerebriform connective-tissue nevus (CCTN)
is a common dermatologic overgrowth that is
usually found at the plantar aspect of the foot.
The grooves in CCTN can be difficult to clean,
leading to the accumulation of bacteria and
fungus that may cause infection and a malodor.
CCTN can progressively increase in size, grow
on previously non-involved areas of the foot and
coalesce. This can be disfiguring, painful, and
interfere with ambulation.3 Surgical removal of
CCTN can lead to disappointing results since
recurrence and painful scarring is possible.19
Dermatological follow-ups and the use of custom
orthotics to manage pain, pressure ulcerations,
and/or skin breakdown are preferred treatments.1,3
Because patients and their families can undergo a
great deal of stress from this disease, clinicians are
encouraged to assess psychosocial issues routinely
KANAVY, HOFFMAN
Prognosis
Long-term prognosis varies across patients.
Approximately 20% of PS patients suffer
premature death, most commonly due to venous
or pulmonary thromboembolism, pneumonia, or
surgical complications.8,22
Conclusion
Proteus syndrome is a complex disease that can
involve many areas of the body, especially the
skeletal system, connective tissue, fat, and central
nervous system. The variable clinical presentation,
rarity of the disorder, and clinical overlap with
several other diseases has led to significant
confusion and misdiagnosis. Molecular genetic
testing can be performed, with the highest yield
from epidermal nevi or tissue specimens. Patients
should be managed with a multidisciplinary
approach.
References
1. Cohen Jr MM, Hayden PW. A newly
recognized hamartomatous syndrome. Birth
Defects Orig Artic Ser. 1979;15:291-296.
2. Wiedemann HR, Burgio GR, Aldenhoff P,
Kunze J, Kaufmann HJ, Schirg E. The proteus
syndrome. Partial gigantism of the hands and/
or feet, nevi, hemihypertrophy, subcutaneous
tumors, macrocephaly or other skull anomalies
and possible accelerated growth and visceral
affections. Eur J Pediatr. 1983;140:5-12.
3. Biesecker LG, Happle R, Mulliken JB,
Weksberg R, Graham JM Jr, Viljoen DL, Cohen
MM Jr. Proteus syndrome: Diagnostic criteria,
differential diagnosis, and patient evaluation. Am
J Med Genet.1999;84:389–395.
4. Turner JT, Cohen MM Jr, Biesecker LG.
Reassessment of the Proteus syndrome
literature: application of diagnostic criteria to
published cases. Am J Med Genet A. 2004 Oct
1;130A(2):111-22.
5. Lindhurst MJ, et al. A mosaic activating
mutation in AKT1 associated with the proteus
syndrome. N Engl J Med. 2011;365:611–19.
6. Altomare DA, Testa JR. Perturbations of
the AKT signaling pathway in human cancer.
Oncogene. 2005;24:7455–7464.
7. Blumenthal G. PTEN hamartoma
tumor syndromes. Eur J Hum Genet. 2008
Nov;16(11):1289-300.
Manifestations. Am J Neuroradiol. 1998;19:987–
990.
10. Juntilla MM, Patil VD, Calamito M, Joshi
RP, Birnbaum MJ, Koretzky GA. AKT1 and
AKT2 maintain hematopoietic stem cell function
by regulating reactive oxygen species. Blood. 2010
May 20;115(20):4030–4038.
11. Wieland I, Tinschert S, Zenker M. Highlevel somatic mosaicism of AKT1 c.49G>A,
mutation in skin scrapings from epidermal
nevi enables non-invasive molecular diagnosis
in patients with Proteus syndrome. Am J Med
Genet. 2013;161A:889–891.
12. Caux F. Segmental overgrowth, lipomatosis,
arteriovenous malformation and epidermal
nevus (SOLAMEN) syndrome is related to
mosaic PTEN nullizygosity. Eur J Hum Genet.
2007;15:767-73.
13. Nelson A. Isolated plantar collagenoma not
associated with Proteus syndrome. J Am Acad
Dermatol. 2008 Mar;58(3):497-9.
14. McCuaig C. Connective tissue nevi in
children: institutional experience and review. J
Am Acad of Dermatol. 2012 Nov;67(5):890-7.
15. Cohen MM Jr. Putting a foot in one’s mouth or
putting a foot down: nonspecificity v. specificity of
the connective tissue nevus in Proteus syndrome.
Proc Greenwood Cent. 1995;14:11-13.
16. Nguyen D, Turner JT, Olsen C, Biesecker LG,
Darling TN. Cutaneous manifestations of Proteus
syndrome. Arch Dermatol. 2004;140:947-953.
17. Nazzaro V, Cambiaghi S, Montagnani
A, Brusasco A, Cerri A, Caputo R. Proteus
syndrome: ultrastructural study of linear
verrucous and depigmented nevi. J Am Acad
Dermatol. 1991 Aug;25:377–383.
18. Biesecker LG. The challenges of Proteus
syndrome: diagnosis and management. Eur J
Hum Genet. 2006 Nov;14(11):1151–1157.
19. Guidera KJ, Brinker MR, Kousseff BG, Helal
AA, Pugh LI, Ganey TM, Ogden JA. Overgrowth
management in Klippel-Trenaunay-Weber and
Proteus syndromes. J Pediatr Orthop.1993 JulAug;13:459–466.
20. Turner J, Biesecker B, Leib J, Biesecker L,
Peters KF. Parenting children with Proteus
syndrome: Experiences with and adaptation
to courtesy stigma. Am J Med Genet.
2007;143A:2089–2097.
21. Beachkofsky TM, Sapp JC, Biesecker LG,
Darling TN. Progressive overgrowth of the
cerebriform connective tissue nevus in patients
with proteus syndrome. J Am Acad Dermatol.
2010;63:799–804.
22. Slavotinek AM, Vacha SJ, Peters KF, Biesecker
LG. Sudden death caused by pulmonary
thromboembolism in Proteus syndrome. Clin
Genet. 2000;58:386–9.
Correspondence:
Holly
[email protected]
Kanavy,
DO;
8. Cohen, MM. Proteus Syndrome: An Update.
Am J Med Genet C Semin Med Genet. 2005
Aug 15;137C(1):38-52.
9. Dietrich, et al. The Proteus Syndrome: CNS
Page 23
Reactive Keratoacanthoma Responding to Excision
and Healing by Secondary Intention
G. Trey Haunson, DO,* Mariana A. Phillips, MD, FAAD, FACMS,** Douglas J. Grider, MD, FCAP,*** Daniel S. Hurd, DO, FAOCD****
*Private Practice Dermatology, MetroDerm, Hiram, GA
**Dermatology and Mohs Surgery, Carilion Clinic, Roanoke, VA
***Dermatopathology, Solstas Lab Partners, Roanoke, VA
****Program Director, Dermatology Residency, LewisGale Hospital Montgomery, Blacksburg, VA
Abstract
Keratoacanthomas (KA) are rapidly-growing tumors of uncertain etiology. KAs mimic squamous-cell carcinoma (SCC) histologically but have the capacity to regress
spontaneously or, rarely, progress to metastatic SCC. KA recurrence has been noted following complete excision and destructive treatment modalities. The term “reactive
KA” has been used in this setting. We report three cases of reactive KAs that responded to excision and healing with secondary intention.
Introduction
While the pathogenesis of keratoacanthoma
(KA) development is debated and likely
multifactorial, KA formation at sites of cutaneous
trauma are well-documented in the literature.1
The term “reactive KA” has been used in this
setting. In reviewing the literature, the time from
treatment to appearance of reactive KA ranges
from two weeks to six months, with a mean of
two months.1-5 Most patients are elderly, with
a mean age of 80, and most reactive KAs occur
on exposed areas of the extremities.1-5 We report
three cases of reactive KA effectively treated with
surgical excision utilizing minimal cutaneous
trauma.
Case 1
A 57-year-old woman with a history of numerous
SCCs on the bilateral dorsal forearms presented
for evaluation of two hyperkeratotic nodules
on the right forearm (Figure 1A). Biopsies
confirmed well-differentiated SCCs (Figure 1B).
Both were completely excised, and the defects
closed primarily. She returned five weeks later
for evaluation of hyperkeratotic plaques involving
both previous excision scars and a new nodule
on the mid forearm. Biopsy of all three lesions
Figure 1. (A) Two hyperkeratotic nodules, right forearm. (B) Exo-endophytic crateriform atypical
squamous proliferation with central keratin debris and features suggestive of arising from
infundibular portion of hair follicle. Interpreted as SCC extending to biopsy base (H&E, 2x
magnification). (C) Reactive KA within excision scar. (D) Re-excision with crateriform atypical
squamous proliferation with central keratin debris appearing to arise from infundibular portion of
hair follicle. Features typical of classic keratoacanthoma toward periphery (H&E, 2x).
Figure 2. (A) Shave with excoriation and features of lichen simplex chronicus with tongues and lobules of atypical keratinocytes extending to biopsy base
(H&E, 4x). (B) Lesions treated with IL bleomycin or triamcinolone. (C) No recurrence at follow-up.
Page 24
REACTIVE KERATOACANTHOMA RESPONDING TO EXCISION AND HEALING BY SECONDARY INTENTION
Figure 3. (A) Recurrent SCC on left elbow. (B) Reactive KAs within excision scar. (C) Re-excision of squamous proliferation with histologic features
suggestive of KA arising in infundibular portion of pilosebaceous unit (H&E, 2x).
showed well-differentiated SCC. The largest
lesion was re-excised and closed primarily.
She returned five weeks later for treatment of the
remaining SCCs, and a new nodule was noted in
the recent re-excision scar (Figure 1C). Reactive
KAs were suspected, and all three lesions on
the right forearm were excised and left to heal
by secondary intention. Histology confirmed
well-differentiated SCC with clear surgical
margins (Figure 1D). The patient returned
four weeks later with three new hyperkeratotic
nodules involving the remainder of the scar on
the right lower forearm. Histology revealed
excoriated atypical squamous proliferations
(Figure 2A). All three nodules were treated
with 0.2 cc intralesional bleomycin (1 unit/
cc). Additional nodules developing in previous
saucerization scars were biopsied and found to
represent hypertrophic scars, which were injected
with IL triamcinolone (Figure 2B). The patient
has shown no evidence of recurrence after four
months of follow-up (Figure 2C).
Case 2
An 81-year-old man presented for re-excision
of a recurrent SCC on the left elbow (Figure
3A). The lesion had been previously excised
three times over an eight-month period. The
SCC was removed with two stages of Mohs
micrographic surgery (MMS), and the defect
was closed primarily. The patient returned four
weeks later with two hyperkeratotic nodules
within the excision scar (Figure 3B). Biopsy
revealed a squamous proliferation with features
of KA (Figure 3C). Reactive KA was suspected,
and the nodules were excised utilizing minimal
electrocautery and the defect left to heal by
secondary intention. There has been no evidence
of recurrence after 18 months of follow-up.
that leg without complication. Biopsy revealed
SCC. The lesion was excised with one stage
of MMS and repaired with primary closure.
Four months later she returned with a nodule
developing in the center of the scar (Figure 4A).
Biopsy showed an invasive, well-differentiated
SCC (Figure 4B). Reactive KA was suspected,
and the lesion was excised with the defect allowed
to heal by secondary intention. One vein was
ligated with 4-0 polyglactin 910 suture, and no
electrodessication was used. There has been no
evidence of recurrence after six months of followup.
Discussion
The pathogenesis of KA development is
likely multifactorial. Genetic predisposition,
immunosuppression, ultraviolet (UV) radiation,
chemical carcinogens, and viral infections have
all been implicated.1 KA formation at sites
of thermal burns, laser resurfacing, chemical
peels, skin graft donor sites, and other forms of
cutaneous trauma has been documented.1 KA
recurrence following routine surgical excision
occurs at a rate of 4% to 8%, though this does not
appear to denote increased malignant behavior.2,3
Brisk KA recurrence has been documented
following histologically confirmed complete
excision and MMS.4 The term “reactive KA”
has been used in this setting. In reviewing the
literature, the time from treatment to appearance
of reactive KA ranges from two weeks to six
months, with a mean of two months.1-5 Most
patients are elderly, with a mean age of 80, and
most reactive KAs occur on exposed areas of the
extremities.1-5
Distinguishing between a recurrent, incompletely
excised SCC and a reactive KA is a subject of
debate. A true recurrence would be expected
to develop in the most central aspect of a scar.
Some of the lesions we encountered occurred on
the lateral aspect of excision scars, which suggests
the lesions were instead reactive in nature.
Additionally, the rapid timing of recurrence
supports this etiology.
The dilemma is further compounded by
indistinct histologic features.2,5 It is not possible
to distinguish reactive KAs histologically. A
well-differentiated SCC with endophytic
or crateriform features mimics KA both in
architecture and sometimes in cytology with
the classic description of keratinocytes at
the periphery exhibiting glassy eosinophilic
cytoplasm.2 However, most reactive KAs seem
to have the helpful feature of being associated
with the infundibular portion of one or more
hair follicles.2 KAs are thought to arise from
Case 3
A 76-year-old woman presented with a rapidlyenlarging nodule on the left upper pre-tibia. She
had a history of two previous SCCs excised from
HAUNSON, PHILLIPS, GRIDER, HURD
Figure 4. (A) Reactive KA within excision scar. (B) Re-excision with shallow ulcer overlying invasive
SCC associated with fibrosing granulation tissue consistent with prior biopsy site (H&E, 4x).
Page 25
follicular infundibula in hair-bearing (most often
exposed) skin.2 It is also possible that although
the natural history of a KA results in spontaneous
involution, a bona fide SCC might arise within a
lesion of KA.3
Correspondence: G. Trey Haunson, DO;
[email protected]
It has been proposed that surgical trauma,
including the use of electrodessication and
placement of sutures, can contribute to the
formation of reactive KAs, possibly representing
a form of Koebner phenomenon.5 Minimizing
surgical trauma led to resolution of several
recrudescent reactive KAs in our case series.
Needle puncture sites should also be minimized
during anesthesia administration.5
We report one patient who developed several
lesions that responded to IL bleomycin.
Intralesional 5-FU and methotrexate are other
non-surgical treatment modalities that have
been reported to be successful for reactive KAs.2
Systemic retinoids such as acitretin have also
been effective in maintaining lesion clearance.2,3
Destructive modalities such as electrodessication
and curettage (ED&C) and external beam
radiation have been associated with worsening of
the condition.2
Conclusion
Early recognition of the reactive KA phenomenon
is important in order to prevent disfigurement
and morbidity to the patient. In our series, the
reactive KAs were excised, and particular effort
was made to minimize electrodessication and
suture placement. This approach was effective for
all lesions treated.
References
1. Pattee SF, Silvis NG. Keratoacanthoma
developing in sites of previous trauma: a report of
two cases and review of the literature. J Am Acad
Dermatol. 2003;48:S35-8.
2. Hadley JC, Tristani-Firouzi P, Florell SF,
Bowen GM, et al. Case series of multiple recurrent
reactive keratoacanthomas developing at surgical
margins. Dermatol Surg. 2009;35:2019-24.
3. Schwartz RA. Keratoacanthoma: A clinicopathologic enigma. Dermatol Surg. 2004;30:32633.
4. Goldberg LH, Silapunt S, Beyrau KK, et al.
Keratoacanthoma as a postoperative complication
of skin cancer excision. J Am Acad Dermatol.
2004;50:753-8.
5. Chesnut GT, Maggio KL, Turiansky GW.
RE: Case series of multiple recurrent reactive
keratoacanthomas developing at surgical margins.
Dermatol Surg. 2011;37:884-5.
Page 26
A CASE OF CUTANEOUS ROSAI-DORFMAN DISEASE
A Case of Cutaneous Rosai-Dorfman Disease
Donna Tran, DO,* Gabriel Guerrero, DO,** Paul Shitabata, MD,*** Navid Nami, DO****
*Dermatology Resident, PGY3, Western University of Health Sciences, College Medical Center, Long Beach, CA
**Intern, College Medical Center, Long Beach, CA
***Director of Dermatopathology, Western University of Health Sciences, Torrance, CA
****Program Director, Dermatology Residency Program, Western University of Health Sciences, College Medical Center, Long Beach, CA
Abstract
Rosai-Dorfman disease (RDD), also known as sinus histiocytosis with massive lymphadenopathy (SHML), is a benign, self-limiting disease of histiocytes with
unknown etiology. RDD typically presents in the first or second decade of life with massive, painless cervical lymphadenopathy. Cutaneous RDD is a rare, extra-nodal
variant that is strictly limited to the skin. In both forms, the histiocytes stain positive for S-100 protein and negative for CD1a. Herein, we describe a rare case of
cutaneous RDD presenting on the face and trunk of a 79-year-old man and review the literature on systemic RDD and its rare cutaneous variant.
Introduction
Systemic Rosai-Dorfman disease (S-RDD),
also known as sinus histiocytosis with massive
lymphadenopathy (SHML), is a non-Langerhans
cell histiocytosis first recognized as a distinct
clinicopathologic entity by Rosai and Dorfman in
1969.1 It commonly presents as bilateral, painless
cervical lymphadenopathy with fever, leukocytosis,
anemia, elevated erythrocyte sedimentation rate,
and polyclonal hypergammaglobulinemia.1,2
Although less common, other lymph nodes may
be involved.2 Lymphadenopathy with extranodal
disease may occur in up to 43% of patients and
includes sites on the skin, soft tissues, eyes,
respiratory tract, liver, spleen, testes, skeleton and
nervous system.2,3 Purely extranodal cutaneous
disease without lymph node involvement is rare.
Herein, we describe a rare case of cutaneous
RDD without lymph node involvement in a
79-year-old man.
Case Report
A 79-year-old male with no significant past
medical history presented to our dermatology
clinic with multiple, asymptomatic lesions on his
face and trunk of two years’ duration. Physical
examination revealed violaceous papules and
nodules on his cheek, chest and upper back
(Figures 1a - 1c). No other lesions were noted,
and no lymphadenopathy was appreciated. He
denied any history of fever, weight loss, night
sweats, or malaise. His complete blood cell count,
complete metabolic panel, antinuclear antibody,
serum protein electrophoresis, and urine protein
electrophoresis were all within normal limits.
Erythrocyte sedimentation rate was slightly
elevated at 21 mm/hr.
A skin biopsy of two lesions was performed, and
histopathological examination revealed a diffuse,
predominantly histiocytic dermal infiltrate with
a background of small lymphocytes, neutrophils,
and scattered plasma cells (Figure 2). A number
of histiocytes showed emperipolesis (Figure 3).
Immunohistochemical staining was positive for
S-100 protein (Figure 4) and CD68, and negative
for CD1a. Based upon clinicopathological
correlation, a diagnosis of cutaneous RosaiDorfman disease was made, and the patient
was referred to oncology for workup of systemic
involvement.
Discussion
S-RDD, or sinus histiocytosis with massive
lymphadenopathy, is a rare disorder characterized
by a proliferation of non-Langerhans cell
histiocytes in the lymph node. It may have
extranodal involvement, the skin being the most
common site. RDD limited to the skin without
nodal involvement, or cutaneous Rosai-Dorfman
disease (C-RDD), is even rarer, with only 85
cases having been described.4,5 Contrary to the
systemic form, C-RDD generally has no systemic
involvement or laboratory abnormalities.4,5
Clinically, the cutaneous lesions are similar in
both S-RDD and C-RDD. The lesions are often
slow-growing, asymptomatic papules and nodules
with yellow to red, brown, or violaceous color,
varying in size from less than 1 cm to 30 cm.4-6,8
The lesions may be localized or disseminated.4,5
C-RDD tends to occur in slightly older age
1a
1b
groups, in women, and in non-black ethnic
groups, in contrast to the systemic form, which
affects children and young adults in the first or
second decade of life.1,2,4-6
The etiology of S-RDD and C-RDD remains
unclear, and a debate between infection, immune
dysregulation, and neoplasia remains.2,4,9 To date,
many infectious agents, including Epstein-Barr
virus, human herpesvirus 6, Brucella, Klebsiella
rhinoscleroma and many others, have been
reported in association with RDD.2 In addition,
autoimmune diseases such as systemic lupus
erythematosus, rheumatoid arthritis, and thyroid
disease have been associated with RDD.4,5
Histopathologically, systemic and cutaneous
RDD are indistinguishable. The main microscopic
findings include proliferation of large polygonal
and palely eosinophilic histiocytes with variable
amounts of a mixed, but predominantly chronic,
inflammatory infiltrate. Emperipolesis is often
present, which is the intracytoplasmic inclusion
of inflammatory cells including lymphocytes,
plasma cells, and neutrophils within vacuoles.2,4,6-8
The cells are also characterized by round or oval
vesicular nuclei.2,4,6-8 The pattern of the infiltrate
in cutaneous layers is usually nodular and diffuse
but may be patchy or interstitial and correlates
with the clinical presentation.6-8 The infiltrate is
mostly confined to the dermis but may have some
subcutis involvement or be confined to only the
subcutis.4,6-8 Epidermal changes are usually absent
or mild.4,6,8 The histiocytes stain positive for
S-100 protein and negative for CD1a, unlike the
Langerhans cells, which statin positive for both
markers.4,6,8
1c
Figures 1a - 1c: Violaceous papulonodular lesions on the left cheek, chest, and back.
TRAN, GUERRERO, SHITABATA, NAMI
Page 27
or indirectly from the disease. Due to S-RDD
having lesions in any organ system, complications
are more common with S-RDD than C-RDD.
Treatment of RDD is based on anecdotal reports,
and several therapies have been utilized with
variable rates of success, including glucocorticoids
and chemotherapy for S-RDD.
RF. The cutaneous manifestations of sinus
histiocytosis with massive lymphadenopathy.
Arch of Dermatol. 1978;114:191-97.
Correspondence:
Donna
[email protected]
Tran,
DO;
C-RDD is benign and usually self-limited.
Documented treatments of C-RDD include
surgical excision, glucocorticoids, antibiotics,
cryotherapy,
radiotherapy,
thalidomide,
isotretinoin, acitretin, interferon-alpha, dapsone,
methotrexate, and pulsed dye laser, with surgery
yielding the highest success rates.4,5
Conclusion
Figure 2. Diffuse dermal infiltrate with
histiocytic predominance; background of small
lymphocytes, neutrophils, and scattered plasma
cells (H&E, 20x).
Due to the rarity of C-RDD, insufficient data and
studies of small sample sizes fail to clarify whether
C-RDD is a specific subset of S-RDD, a separate
entity, or if the two are part of a spectrum. The
pathogenesis of RDD remains largely unknown.
Although studies do not support progression
of C-RDD to S-RDD, long-term follow-up is
nonetheless recommended to rule out systemic
involvement and associated autoimmune and
neoplastic diseases 4-7 Our patient had only skin
involvement with no adenopathy or systemic
involvement. His lesions were controlled with
topical mid-potency glucocorticoid.
References
1. Rosai J, Dorfman RF. Sinus histiocytosis with
massive lymphadenopathy: a newly recognized
benign clinicopathologic entity. Arch Pathol.
1969;87:63-70.
2. Foucar E, Rosai J, Dorfman R. Sinus
histiocytosis with massive lymphadenopathy
(Rosai-Dorfman disease): review of the entity.
Semin Diagn Pathol. 1990;7:19-73.
Figure 3. Histiocytes with large cytoplasm
presenting emperipolesis (H&E, 60x).
3. Thawerani H, Sanchez RL, Rosai J, Dorfman
RF. The cutaneous manifestations of sinus
histiocytosis with massive lymphadenopathy.
Arch of Dermatol. 1978;114:191-97.
4. Brenn T, Calonje E, Granter S, et al. Cutaneous
Rosai-Dorfman disease if a distinct clinical entity.
Am J Dermatopathol. 2002;24(5):385-391.
5. Frater JL, Maddox JS, Obadiah JM, Hurley
MY. Cutaneous Rosai-Dorfman disease:
comprehensive review of cases reported in the
medical literature since 1990 and presentation
of an illustrative case. J Cutan Med Surg.
2006;10(6):281-90.
6. Wang KH, Chen WY, Liu HN, Huang CC,
Lee WR, Hu CH. Cutaneous Rosai-Dorfman
disease: clinicopathological profiles, spectrum
and evolution of 21 lesions in six patients. Br J
Dermatol. 2006 Feb;154(2):277-86.
Figure 4. Immunohistochemistry staining
positive for S100 protein in the histiocytic cell
(60x).
7. Chu P, LeBoit P. Histologic features of cutaneous
sinus histiocytosis (Rosai-Dorfman disease):
study of cases both with and without systemic
involvement. J Cutan Pathol. 1992;19:201-06.
Both S-RDD and C-RDD generally have a benign
course with spontaneous regression over a period
of months to years, although a small number of
patients may have significant morbidity, directly
9. Thawerani H, Sanchez RL, Rosai J, Dorfman
Page 28
8. Lu C, Kuo T, Wong W, Hong H. Clinical and
histopathologic spectrum of cutaneous RosaiDorfman disease in Taiwan. J Am Acad Dermatol.
2004;51(6):931-9.
A CASE OF CUTANEOUS ROSAI-DORFMAN DISEASE
Pathogenesis of Pruritic Disorders and Mechanisms of Phototherapy
Soham Chaudhari, BA,* Argentina Leon, MD,** Ethan Levin, MD,** Om Chaudhari,*** John Koo, MD****
*Osteopathic Medical Student, 4th year, Touro University Nevada, Osteopathic College of Medicine, Henderson, NV
**Research Fellow, Department of Dermatology, University of California, San Francisco, CA
***University of Nevada Las Vegas, College of Sciences, Honors College, Las Vegas, NV
****Professor and Vice Chairman, Department of Dermatology; Director, Psoriasis Treatment Center, University of California, San Francisco, CA
Abstract
Phototherapy is an efficacious method for managing many cutaneous conditions. Although psoriasis is the most commonly treated condition, phototherapy also has a role
in the management of pruritic disorders, including atopic dermatitis (AD), prurigo nodularis (PN), and uremic pruritus (UP). We have reviewed the pathogenesis
of pruritus and the mechanism of action of phototherapy in treating pruritic disorders. AD is an inflammatory skin condition with an induction of pruritus due to
cytokines released by CD4-positive-T helper (Th) 2 cells. Langerhans cells, T cells, proinflammatory cytokines, and keratinocytes are decreased in AD patients treated
with phototherapy. PN has an increase in mast cells and neuropeptides that mediate pruritus. UV light decreases the release of these neuropeptides and alleviates
pruritus in PN. Finally, UP causes a microinflammatory state with changes in cutaneous nociceptive endings. A circulating substance responsible for pruritus in UP is
annihilated through the apoptotic actions of phototherapy.
Introduction
Pruritus is the number one symptom presented
to any dermatology practice.1 The physical
and psychological distress caused by chronic
pruritus has a significant impact on quality
of life for patients. Because topical therapy is
often inadequate in controlling pruritus, other
treatments are needed. Phototherapy can alleviate
the constant sensation of itch without many of
the adverse effects of systemic medications. In
addition, it is safe and can be utilized in all age
categories.2 UVB (290-320 nm) and UVA (320400 nm) are implemented in UV-based therapy.
Broadband UVB (BB-UVB) and broadband
UVA (BB-UVA) use a light source covering
their entire spectrum. Narrowband UVB (NBUVB) uses 311-313 nm, and UVA1 uses 340400 nm with a peak at 365 nm. UVA1 can be
administered at high dose (HD-UVA1) (130 J/
cm2), medium dose (MD-UVA1) (50 J/cm2), and
low dose (LD-UVA1) (20 J/cm2). Monochromic
excimer laser (MEL) (308nm) is a more targeted
phototherapy device that delivers 308 nm UVB to
a localized area and can expand treatment options
by sparing unaffected areas. Both cutaneous and
systemic diseases can present with pruritus as
the primary symptom. This article summarizes
the pathogenesis of pruritic disorders including
AD, PN, and UP and the mechanism of action of
phototherapy in each of these (Table 1).
Discussion
Pathogenesis of Itch: Localized itch involves
alpha-delta fibers, whereas diffuse, generalized
itch is transmitted through dermal unmyelinated
c-fibers. Both of these nociceptive fibers travel
to the dorsal horn of the spinal cord, which is
then processed by the cerebral cortex through
the spinothalamic tract.3 They have a slow
conduction velocity and innervate large areas
of the skin.4 Dry skin and disruption of the
skin barrier can induce keratinocytes to release
pruritogenic substances.5 Nerve fibers typically
end at the dermal-epidermal junction, although
some project into the epidermis.6 Itch receptors,
formed mostly by keratinocytes, respond to
Figure 1. Pruritus
CHAUDHARI, LEON, LEVIN, CHAUDHARI, KOO
Page 29
pruritogens such as histamine, proteases, growth
factors, neuropeptides, cytokines, and opioids
(Figure 1).7,8 They are found only in skin, mucus
membranes, and cornea.9 Substance P (SubP)
and calcitonin gene-related peptide (CGRP) are
the most studied neurotransmitters and have both
central and peripheral activity.10,11 Allokinesis,
the perception of non-pruritic stimuli as pruritic,
is due to central sensitization. This explains the
intense pruritus AD patients experience in
response to sweat or sudden changes in ambient
temperature.
Mast cells produce two proteinases, tryptase and
chymase. Tryptase activates C fibers and thus
stimulates the sensation of itch. It also triggers the
release of SubP, which not only causes pruritus
but also evokes further mast-cell activation.
Increased levels of tryptase have been observed in
patients with UP.12
of eczematous lesions is a Th2-driven response,
chronic lesions demonstrate a greater level of Th1
activity.18 Acute and chronic AD lesions contain
more mRNA expression for IL-4, IL-5, and
IL-13 than normal skin. The mRNA expression
of IFN-gamma, however, is similar to that of
normal skin.20,30 Chronic lesions express more
IL-5, IL-12 and anti-eosinophil cationic protein
(ECP) antibody eosinophils than acute lesions.
Thus, IL-12 may be important in the transition
from acute to chronic lesions. The predominance
of Th2 cytokines in the acute phase, such as
IL-4 and IL-5, stimulates eosinophils, which
produce IL-12, thereby activating Th1 cells and
undifferentiated T cells to produce IFN-gamma,
causing a negative feedback on Th2 responses
and maintaining the AD lesion over an extended
period (Figure 2).19
interfere with ceramide metabolism, as cytolytic
alpha toxin causes keratinocyte damage and
superantigenic toxin causes release of TNFalpha and Beta-hemolysin, which interfere with
ceramide metabolism.34 These toxins also prevent
keratinocytes from producing antimicrobial
peptides to kill S. aureus.35
Mechanism of Action for Phototherapy in AD:
Many studies have demonstrated the beneficial
effects of phototherapy in treating AD.36 The
intralesional mRNA expression of IFN-gamma
was successfully downregulated during the course
of UVA1 therapy, whereas IL-4 mRNA expression
remained relatively unchanged even after those
with chronic AD improved under treatment.37,38
The high efficacy of UVA1 phototherapy in
the treatment of AD can be attributed to the
The sensations of pain and itch are carried by
different C-fibers. Frequency of the stimulus can
modulate the magnitude of itch but does not
change the quality of itch into pain. Histamineinduced itch activates some motor areas,
suggesting a neuronal association between itch
and scratching.13 Scratching and vibration are
transmitted by larger A-beta fibers that inhibit
itch signals on the slower C-fibers.14 While
pain causes one to avoid a motor response, itch
causes a stimulatory motor response. Painful
stimuli can inhibit itch, as observed in pruritic
patients who only stop scratching once skin
lesions begin bleeding and become painful. Itch
and pain share the same cortical brain areas but
have different patterns of activation: Itch has a
weaker activation of somatosensory cortices and
a stronger activation of ipsilateral motor areas as
compared with pain processing.15,16
ATOPIC DERMATITIS (AD)
Pathogenesis of AD: The pathogenesis of
AD is a complex interplay between several
different cell types and factors. CD-4 positive
Th2 cells have been found to play a major role
in pruritus induction by producing and releasing
cytokines and chemokines.17
Localization
to the skin in AD is due to the presence of a
skin-homing receptor on memory effector T
lymphocytes, called “cutaneous lymphocyteassociated antigen,” which interacts with the
vascular endothelial cell-surface antigens to direct
circulating T lymphocytes to the reactive skin
site.18 Th1 cells initiated by IL-12 predominantly
secrete IL-2 and interferon-gamma (IFNgamma), whereas Th2 cells are activated by IL10 to produce mainly IL-4, IL-5, and IL-13.1924
Atopic disorders such as eczema have been
associated with a hyper Th2 response, as they
signal B lymphocytes to produce IgE, stimulate
eosinophils and mast cells, and cause type 1
hypersensitivity reactions.25-27 Environmental
factors may enhance Th2 allergic response.28 AD
patients commonly have a higher Staphylococcus
aureus burden than the general population, and
the Th2 cytokines of AD augment the toxicity
of the lytic staphylococcal protein alpha toxin.29
It has been shown that, although the initiation
Page 30
Figure 2. Atopic dermatitis
The stratum corneum is the permeability barrier
between the body and the external environment,
and thus when it is impaired, increased
transepidermal water loss causes xerosis and
intense pruritus.31 The barrier is compromised
due to an overexpression of an enzyme that
hydrolyzes sphingomyelin, producing free fatty
acid and sphingosylphosphorylcholine, an
inducer of keratinocyte proliferation and upregulator of plasminogen activator, resulting in
decreased ceramides.32 Additionally, scratching
from pruritus induces trauma and further
insult to an already compromised stratum
corneum, which triggers keratinocytes to release
proinflammatory cytokines. It is also because
of this defective barrier that microorganisms
such as S. aureus enter and colonize eczematous
skin.33 Toxins released by microbes further
combination of UV-light induced apoptosis
of T lymphocytes as well as the reduction of
Langerhans cells and mast cells in the dermis.39
Preventing Langerhans cells and mast cells
from exiting the epidermis results in a decreased
number of Ig-E binding cells in the dermis.40
Phototherapy induces the immunosuppressive
mechanisms of the body, such as suppressing the
antigen-presenting function of Langerhans cells,
inducing apoptosis in infiltrating T cells, causing
DNA damage, and halting the rapid accumulation
of epidermal keratinocytes.41-43 Colonization by
Staphylococcus aureus and Pityrosporum orbiculare
is decreased through the use of UV radiation.44,45
UV light also increases the thickness of the
stratum corneum and therefore results in
smaller eczematous reactions due to a decreased
penetration of antigens.46 Thus, UV light exerts
PATHOGENESIS OF PRURITIC DISORDERS AND MECHANISMS OF PHOTOTHERAPY
Figure 4. Uremic pruritus
UREMIC PRURITUS (UP)
Figure 3. Prurigo nodularis
its beneficial effects through a multitude of
mechanisms. Although AD is the primary disease
explained above, a similar mechanism of action
for UV-based therapy can be applied to PN and
LSC owing to their similar inflammatory nature.
PRURIGO NODULARIS (PN)
Pathogenesis of PN: A background of atopic
diathesis has been suggested for PN after
examining the history of AD, allergic rhinitis,
and bronchial asthma.47,48 Tanaka et al. found
PN patients with an atopic background to
develop the disease at a younger age and display
a hypersensitivity reaction pattern similar to that
observed in AD, suggesting a close pathological
link between the two disorders.49 The typical
PN nodule is secondary to traumatization.
Histopathologically, PN has an increased
downward projection of the epidermis, suggesting
pseudoepitheliomatous hyperplasia. Skin biopsies
of PN reveal an increase in the number of mast
cells in both the epidermis and the dermis, with
some invasion into the cutaneous nerve-fiber
bundles.50,51 Mast cells are known to release
nerve growth factor (NGF) and are seen in
proximity to nerves expressing increased levels
of NGF receptor (NGFr) (Figure 3).52,53 Thus,
the overexpression of NGF in PN explains the
neurohyperplasia, which subsequently explains the
strong itch secondary to increased axon firing.54
The mast cells in PN lesions also demonstrate
morphological changes, such as enlarged cell
bodies with a dendritic shape as compared to
the round shape seen in normal skin.52,55,56 Thus,
neuropeptides and histamine from mast cells
cooperatively generate neurogenic inflammation
to induce and transmit itch. Eosinophils can also
CHAUDHARI, LEON, LEVIN, CHAUDHARI, KOO
release NGF and contribute to neurohyperplasia
of PN.53 Dermal Langerhans cells are increased
in PN, suggesting their involvement in the
development or persistence of PN.57 In addition,
the numbers of Merkel cells are increased in PN
at the basal cell layer, explaining the abnormal
sensitivity to touch from these slowly adapting
sensory touch receptors.58
Mechanism of Action for Phototherapy in
PN: UV light hinders rapid epidermal cell
turnover and thereby leads to a reduction in
pseudoepitheliomatous hyperplasia of the
epidermis.59 PN patients have an increase in the
number of nerve fibers in the papillary dermis.60
These nerve fibers demonstrate immunoreactivity
for SubP and CGRP and thus mediate the
cutaneous neurogenic inflammation and pruritus
in PN. It is postulated that MEL modulates
the release of these neuropeptides.61-63 The
long remission noted for MEL could be due
to inhibition of neuropeptide releases, which
cause pruritus and can consequently perpetuate
the rubbing, scratching, and picking cycle.
MEL treatment causes a depletion of T cells
and alterations of apoptosis-related molecules,
along with a decreased proliferation index of
keratinocytes.64 PUVA downregulates CGRP
and Th2 cytokines and depletes epidermal
dendritic cells.65-67 The longer wavelengths used
in PUVA penetrate the acanthotic thick epidermis
more fully than classical NB-UVB.63,67-69 UVB
irradiation inhibits mast-cell granule release.70
Thus, phototherapy is successful in combating
itch in PN because it reduces the number of
epidermal nerve fibers.66
Pathogenesis of UP and Mechanism of
Action for Phototherapy in UP: Although the
pathogenesis of UP is not completely understood,
it is known to present with dystrophic
neurotrophic changes in cutaneous nociceptor
nerve endings, with a “microinflammatory” state
of increased Th1 markers, chemokines, and
interleukin-6 (IL-6).71,72 It also causes calciumphosphate imbalance, hyperparathyroidism,
anemia, increased serum histamine levels, and
peripheral neuropathy.73,74
UVB therapy is beneficial for patients with
UP. Possible mechanisms include reduction in
skin divalent-ion content, reduction in Vitamin
A and retinol content, stabilization of or
reduction in number of mast cells, detoxification
of undetermined pruritogenic substances,
photoactivation of antipruritogenic substances,
and changes in the excitability of epidermal nerve
endings. Mast-cell proliferation, degranulation,
and subsequent histamine release plays a role in
uremic pruritus (Figure 4). Histamine secretion
is evoked by an increased release of SubP.76 NBUVB induces apoptosis of dermal mast cells
and reduces the release of neuropeptides such as
SubP by decreasing epidermal nerve fibers.66,77
Nitric oxide and IL-2 have also been implicated
in the pathogenesis of uremic pruritus, both of
which are decreased by NB-UVB.76,78-80 Schultz
et al. suggest the response to UVB indicates a
deposition of some substance in the skin that
is degraded or inactivated by the light. Because
uremic patients respond to cholestyramine, and
phototherapy serves to clear bilirubin in jaundiced
premature infants, bile salts were considered to be
involved in UP pathogenesis.81 Individuals with
advanced CRF had higher levels of serum total
bile acids when compared to controls, and those
with pruritus had higher levels of bile acids than
those without pruritus. Thus, the intensity of
pruritus correlated with bile acid concentration.82
Certain bile acids also cause cytotoxicity to
mastocytes, thereby releasing histamine.83
Page 31
Table 1: Comparison of Mechanism of Action of Phototherapy in Pruritic Disorders
Disease
Atopic Dermatitis
Type of Phototherapy
UVA1
Mechanism of Action
↓IFN – gamma
↓T cells
↓Langerhans cells
↓Mast cells
↓IgE binding
↓colonization by Staphylococcus aureus
and Pityrosporum orbiculare
↑Stratum corneum thickness
Prurigo Nodularis
MEL
↓epidermal cell turnover
↓neuropeptide release
↓T cells
PUVA
↓CGRP
↓Th2 cytokines
↓Dendritic cells
Uremic Pruritus
UVB
UVB
↓Mast-cell granule release
↓Skin-divalent ions
↓Vitamin A and Retinols
↓Mast cells
↓SubP
↓Nitric oxide
↓IL-2
↑Antipruritogenic substances
Conclusion
The mechanisms of action for phototherapy
in each of the discussed pruritic disorders are
unique and dependent on the pathophysiology
of the disease. Phototherapy decreases pruritus in
AD, PN, and UP through its apoptotic and antiinflammatory actions and is therefore a useful
therapeutic modality for these disorders. Due to
the similarity in mechanisms of these diseases,
there is sufficient evidence to support the use of
various forms of UV-based treatment for reducing
pruritus and its associated manifestations.
References
1. Charlesworth EN, Beltrani VS. Pruritic
dermatoses: overview of etiology and therapy. Am J
Med. 2002;113 Suppl 9A:25S-33S.
2. Veith W, Deleo V, Silverberg N. Medical
phototherapy in childhood skin diseases. Minerva
Pediatr. 2011;63(4):327-33.
in pruritus research: scratching the brain for more
effective itch therapy. J Clin Invest. 2006;116(5):117486.
7. Inoue K, Koizumi S, Fuziwara S, Denda S, Inoue K,
Denda M. Functional vanilloid receptors in cultured
normal human epidermal keratinocytes. Biochem
Biophys Res Commun. 2002;291(1):124-9.
8. Heymann WR. Itch. J Am Acad Dermatol.
2006;54(4):705-6.
9. Denman ST. A review of pruritus. J Am Acad
Dermatol. 1986;14(3):375-92.
10. Steinhoff M, Stander S, Seeliger S, Ansel JC,
Schmelz M, Luger T. Modern aspects of cutaneous
neurogenic
inflammation.
Arch
Dermatol.
2003;139(11):1479-88.
11. Steinhoff M, Vergnolle N, Young SH, Tognetto M,
Amadesi S, Ennes HS, et al. Agonists of proteinaseactivated receptor 2 induce inflammation by a
neurogenic mechanism. Nat Med. 2000;6(2):151-8.
3. Andrew D, Craig AD. Spinothalamic lamina I
neurons selectively sensitive to histamine: a central
neural pathway for itch. Nat Neurosci. 2001;4(1):727.
12. Dugas-Breit S, Schopf P, Dugas M, Schiffl H,
Rueff F, Przybilla B. Baseline serum levels of mast
cell tryptase are raised in hemodialysis patients and
associated with severity of pruritus. J Dtsch Dermatol
Ges. 2005;3(5):343-7.
5. Denda M, Nakatani M, Ikeyama K, Tsutsumi M,
Denda S. Epidermal keratinocytes as the forefront of
the sensory system. Exp Dermatol. 2007;16(3):15761.
14. Melzack R, Schecter B. Itch and Vibration.
Science. 1965;147(3661):1047-8.
4. Schmelz M, Schmidt R, Bickel A, Handwerker
HO, Torebjork HE. Specific C-receptors for itch in
human skin. J Neurosci. 1997;17(20):8003-8.
6. Paus R, Schmelz M, Biro T, Steinhoff M. Frontiers
Page 32
13. Valet M, Pfab F, Sprenger T, Woller A, Zimmer
C, Behrendt H, et al. Cerebral processing of
histamine-induced itch using short-term alternating
temperature modulation--an FMRI study. J Invest
Dermatol. 2008;128(2):426-33.
15. Stander S, Schmelz M. Chronic itch and
pain--similarities and differences. Eur J Pain.
2006;10(5):473-8.
16. Drzezga A, Darsow U, Treede RD, Siebner
H, Frisch M, Munz F, et al. Central activation by
histamine-induced itch: analogies to pain processing:
a correlational analysis of O-15 H2O positron
emission tomography studies. Pain. 2001;92(12):295-305.
17. Homey B, Steinhoff M, Ruzicka T, Leung DY.
Cytokines and chemokines orchestrate atopic
skin inflammation. J Allergy Clin Immunol.
2006;118(1):178-89.
18. Leung DY. Atopic dermatitis: new insights and
opportunities for therapeutic intervention. J Allergy
Clin Immunol. 2000;105(5):860-76.
19. Grewe M, Bruijnzeel-Koomen CA, Schopf
E, Thepen T, Langeveld-Wildschut AG, Ruzicka
T, et al. A role for Th1 and Th2 cells in the
immunopathogenesis of atopic dermatitis. Immunol
Today. 1998;19(8):359-61.
20. Hamid Q, Naseer T, Minshall EM, Song YL,
Boguniewicz M, Leung DY. In vivo expression of
IL-12 and IL-13 in atopic dermatitis. J Allergy Clin
Immunol. 1996;98(1):225-31.
21. Sonkoly E, Muller A, Lauerma AI, Pivarcsi A,
Soto H, Kemeny L, et al. IL-31: a new link between
T cells and pruritus in atopic skin inflammation. J
Allergy Clin Immunol. 2006;117(2):411-7.
22. Neis MM, Peters B, Dreuw A, Wenzel J, Bieber
T, Mauch C, et al. Enhanced expression levels of
IL-31 correlate with IL-4 and IL-13 in atopic and
allergic contact dermatitis. J Allergy Clin Immunol.
2006;118(4):930-7.
23. Nomura I, Goleva E, Howell MD, Hamid QA,
Ong PY, Hall CF, et al. Cytokine milieu of atopic
dermatitis, as compared to psoriasis, skin prevents
induction of innate immune response genes. J
Immunol. 2003;171(6):3262-9.
24. Jeong CW, Ahn KS, Rho NK, Park YD, Lee DY,
Lee JH, et al. Differential in vivo cytokine mRNA
expression in lesional skin of intrinsic vs. extrinsic
atopic dermatitis patients using semiquantitative RTPCR. Clin Exp Allergy. 2003;33(12):1717-24.
25. Knoell KA, Greer KE. Atopic dermatitis. Pediatr
Rev. 1999;20(2):46-51; quiz 2.
26. Friedmann PS. The pathogenesis of atopic eczema.
Hosp Med. 2002;63(11):653-6.
27. Jelinek DF. Regulation of B lymphocyte
differentiation. Ann Allergy Asthma Immunol.
2000;84(4):375-85; quiz 85-7.
28. Leung DY, Bieber T. Atopic dermatitis. Lancet.
2003;361(9352):151-60.
29. Travers JB. Toxic interaction between Th2
cytokines and Staphylococcus aureus in atopic
dermatitis. J Invest Dermatol. 2014;134(8):2069-71.
30. Hamid Q, Boguniewicz M, Leung DY.
Differential in situ cytokine gene expression in
acute versus chronic atopic dermatitis. J Clin Invest.
1994;94(2):870-6.
31. Werner Y. The water content of the stratum
corneum in patients with atopic dermatitis.
Measurement with the Corneometer CM 420. Acta
Derm Venereol. 1986;66(4):281-4.
32. Hara J, Higuchi K, Okamoto R, Kawashima
M, Imokawa G. High-expression of sphingomyelin
deacylase is an important determinant of ceramide
deficiency leading to barrier disruption in atopic
dermatitis. J Invest Dermatol. 2000;115(3):406-13.
PATHOGENESIS OF PRURITIC DISORDERS AND MECHANISMS OF PHOTOTHERAPY
33. Cho SH, Strickland I, Tomkinson A, Fehringer
AP, Gelfand EW, Leung DY. Preferential binding of
Staphylococcus aureus to skin sites of Th2-mediated
inflammation in a murine model. J Invest Dermatol.
2001;116(5):658-63.
invasion of peripheral nerve in skin lesions of atopic
dermatitis. Acta Derm Venereol Suppl (Stockh).
1992;176:74-6.
35. Ong PY, Ohtake T, Brandt C, Strickland
I, Boguniewicz M, Ganz T, et al. Endogenous
antimicrobial peptides and skin infections in atopic
dermatitis. N Engl J Med. 2002;347(15):1151-60.
53. Johansson O, Liang Y, Emtestam L. Increased
nerve growth factor- and tyrosine kinase A-like
immunoreactivities in prurigo nodularis skin -- an
exploration of the cause of neurohyperplasia. Arch
Dermatol Res. 2002;293(12):614-9.
34. Esche C, de Benedetto A, Beck LA. Keratinocytes
in atopic dermatitis: inflammatory signals. Curr
Allergy Asthma Rep. 2004;4(4):276-84.
36. Gambichler T. Management of atopic dermatitis
using photo(chemo)therapy. Arch Dermatol Res.
2009;301(3):197-203.
37. Grewe M, Gyufko K, Schopf E, Krutmann J.
Lesional expression of interferon-gamma in atopic
eczema. Lancet. 1994;343(8888):25-6.
38. Krutmann J. Ultraviolet A-1 irradiation as a
tool to study the pathogenesis of atopic dermatitis.
Methods Enzymol. 2000;319:296-302.
39. Dawe RS. Ultraviolet A1 phototherapy. Br J
Dermatol. 2003;148(4):626-37.
40. Grabbe J, Welker P, Humke S, Grewe M, Schopf
E, Henz BM, et al. High-dose ultraviolet A1 (UVA1),
but not UVA/UVB therapy, decreases IgE-binding
cells in lesional skin of patients with atopic eczema.
J Invest Dermatol. 1996;107(3):419-22.
41. Majoie IM, Oldhoff JM, van Weelden H,
Laaper-Ertmann M, Bousema MT, Sigurdsson V,
et al. Narrowband ultraviolet B and medium-dose
ultraviolet A1 are equally effective in the treatment
of moderate to severe atopic dermatitis. J Am Acad
Dermatol. 2009;60(1):77-84.
42. Caricchio R, Reap EA, Cohen PL. Fas/Fas
ligand interactions are involved in ultraviolet-Binduced human lymphocyte apoptosis. J Immunol.
1998;161(1):241-51.
43. Duthie MS, Kimber I, Norval M. The effects of
ultraviolet radiation on the human immune system.
Br J Dermatol. 1999;140(6):995-1009.
44. Faergemann J, Larko O. The effect of UV-light on
human skin microorganisms. Acta Derm Venereol.
1987;67(1):69-72.
45. Ring J, Alomar A, Bieber T, Deleuran M, FinkWagner A, Gelmetti C, et al. Guidelines for treatment
of atopic eczema (atopic dermatitis) Part II. J Eur
Acad Dermatol Venereol. 2012;26(9):1176-93.
46. Jekler J, Larko O. Combined UVA-UVB
versus UVB phototherapy for atopic dermatitis: a
paired-comparison study. J Am Acad Dermatol.
1990;22(1):49-53.
47. Rowland Payne CM, Wilkinson JD, McKee
PH, Jurecka W, Black MM. Nodular prurigo-a clinicopathological study of 46 patients. Br J
Dermatol. 1985;113(4):431-9.
48. Miyachi Y, Okamoto H, Furukawa F, Imamura S.
Prurigo nodularis. A possible relationship to atopy. J
Dermatol. 1980;7(4):281-3.
49. Tanaka M, Aiba S, Matsumura N, Aoyama H,
Tagami H. Prurigo nodularis consists of two distinct
forms: early-onset atopic and late-onset non-atopic.
Dermatology. 1995;190(4):269-76.
50. Green R, Cordero A, Winkelmann RK. Epidermal
mast cells. Arch Dermatol. 1977;113(2):166-9.
51. Sugiura H, Maeda T, Uehara M. Mast cell
CHAUDHARI, LEON, LEVIN, CHAUDHARI, KOO
52. Liang Y, Marcusson JA, Jacobi HH, HaakFrendscho M, Johansson O. Histamine-containing
mast cells and their relationship to NGFrimmunoreactive nerves in prurigo nodularis: a
reappraisal. J Cutan Pathol. 1998;25(4):189-98.
54. Liang Y, Marcusson JA, Johansson O. Light
and electron microscopic immunohistochemical
observations of p75 nerve growth factor receptorimmunoreactive dermal nerves in prurigo nodularis.
Arch Dermatol Res. 1999;291(1):14-21.
55. Perez GL, Peters MS, Reda AM, Butterfield JH,
Peterson EA, Leiferman KM. Mast cells, neutrophils,
and eosinophils in prurigo nodularis. Arch Dermatol.
1993;129(7):861-5.
56. Liang Y, Jacobi HH, Marcusson JA, HaakFrendscho M, Johansson O. Dendritic mast
cells in prurigo nodularis skin. Eur J Dermatol.
1999;9(4):297-9.
57. Johansson O, Liang Y, Heilborn JD, Marcusson
JA. Langerhans cells in prurigo nodularis investigated
by HLA-DR and S-100 immunofluorescence double
staining. J Dermatol Sci. 1998;17(1):24-32.
58. Nahass GT, Penneys NS. Merkel cells and prurigo
nodularis. J Am Acad Dermatol. 1994;31(1):86-8.
59. Vaatainen N, Hannuksela M, Karvonen J. Local
photochemotherapy in nodular prurigo. Acta Derm
Venereol. 1979;59(6):544-7.
60. Weedon D. Tumors of the epidermis. 2nd ed.
London: Churchill Livingstone; 2002.
61. Vaalasti A, Suomalainen H, Rechardt L. Calcitonin
gene-related peptide immunoreactivity in prurigo
nodularis: a comparative study with neurodermatitis
circumscripta. Br J Dermatol. 1989;120(5):619-23.
62. Abadia Molina F, Burrows NP, Jones RR, Terenghi
G, Polak JM. Increased sensory neuropeptides in
nodular prurigo: a quantitative immunohistochemical
analysis. Br J Dermatol. 1992;127(4):344-51.
63. Lee MR, Shumack S. Prurigo nodularis: a review.
Australas J Dermatol. 2005;46(4):211-18; quiz 9-20.
64. Bianchi B, Campolmi P, Mavilia L, Danesi A, Rossi
R, Cappugi P. Monochromatic excimer light (308
nm): an immunohistochemical study of cutaneous
T cells and apoptosis-related molecules in psoriasis.
J Eur Acad Dermatol Venereol. 2003;17(4):408-13.
65. Rombold S, Lobisch K, Katzer K, Grazziotin TC,
Ring J, Eberlein B. Efficacy of UVA1 phototherapy in
230 patients with various skin diseases. Photodermatol
Photoimmunol Photomed. 2008;24(1):19-23.
66. Wallengren J, Sundler F. Phototherapy reduces
the number of epidermal and CGRP-positive dermal
nerve fibres. Acta Derm Venereol. 2004;84(2):111-5.
67. Gambichler T, Hyun J, Sommer A, Stucker M,
Altmeyer P, Kreuter A. A randomised controlled trial
on photo(chemo)therapy of subacute prurigo. Clin
Exp Dermatol. 2006;31(3):348-53.
69. Tamagawa-Mineoka R, Katoh N, Ueda
E, Kishimoto S. Narrow-band ultraviolet B
phototherapy in patients with recalcitrant nodular
prurigo. J Dermatol. 2007;34(10):691-5.
70. Danno K, Toda K, Horio T. Ultraviolet-B
radiation suppresses mast cell degranulation
induced by compound 48/80. J Invest Dermatol.
1986;87(6):775-8.
71. Fantini F, Baraldi A, Sevignani C, Spattini
A, Pincelli C, Giannetti A. Cutaneous
innervation in chronic renal failure patients. An
immunohistochemical study. Acta Derm Venereol.
1992;72(2):102-5.
72. Kimmel M, Alscher DM, Dunst R, Braun
N, Machleidt C, Kiefer T, et al. The role of microinflammation in the pathogenesis of uraemic pruritus
in haemodialysis patients. Nephrol Dial Transplant.
2006;21(3):749-55.
73. Narita I, Iguchi S, Omori K, Gejyo F. Uremic
pruritus in chronic hemodialysis patients. J Nephrol.
2008;21(2):161-5.
74. Patel TS, Freedman BI, Yosipovitch G. An update
on pruritus associated with CKD. Am J Kidney Dis.
2007;50(1):11-20.
75. Szepietowski JC, Schwartz RA. Uremic pruritus.
Int J Dermatol. 1998;37(4):247-53.
76. Urbonas A, Schwartz RA, Szepietowski JC.
Uremic pruritus--an update. Am J Nephrol.
2001;21(5):343-50.
77. Szepietowski JC, Morita A, Tsuji T. Ultraviolet B
induces mast cell apoptosis: a hypothetical mechanism
of ultraviolet B treatment for uraemic pruritus. Med
Hypotheses. 2002;58(2):167-70.
78. Mettang T, Pauli-Magnus C. The
pathophysiological puzzle of uremic pruritus-insights and speculations from therapeutic
and epidemiological studies. Perit Dial Int.
2000;20(5):493-4.
79. Yamaoka J, Sasaki M, Miyachi Y. Ultraviolet
B radiation downregulates inducible nitric oxide
synthase expression induced by interferon-gamma or
tumor necrosis factor-alpha in murine keratinocyte
Pam 212 cells. Arch Dermatol Res. 2000;292(6):3129.
80. Walters IB, Ozawa M, Cardinale I, Gilleaudeau P,
Trepicchio WL, Bliss J, et al. Narrowband (312-nm)
UV-B suppresses interferon gamma and interleukin
(IL) 12 and increases IL-4 transcripts: differential
regulation of cytokines at the single-cell level. Arch
Dermatol. 2003;139(2):155-61.
81. Silverberg DS, Iaina A, Reisin E, Rotzak R,
Eliahou HE. Cholestyramine in uraemic pruritus. Br
Med J. 1977;1(6063):752-3.
82. Borgeat A, Stirnemann HR. Ondansetron is
effective to treat spinal or epidural morphine-induced
pruritus. Anesthesiology. 1999;90(2):432-6.
83. Quist RG, Ton-Nu HT, Lillienau J, Hofmann
AF, Barrett KE. Activation of mast cells by bile acids.
Gastroenterology. 1991;101(2):446-56.
Correspondence: Soham Chaudhari, BA;
[email protected]
68. Clark AR, Jorizzo JL, Fleischer AB. Papular
dermatitis (subacute prurigo, “itchy red bump”
disease): pilot study of phototherapy. J Am Acad
Dermatol. 1998;38(6 Pt 1):929-33.
Page 33
The Cutaneous Manifestations of Metastatic Lung Cancer:
Case Report and Review
Sarah Ferrer-Bruker, DO*
*Third-year Dermatology Resident PGY-6, Palm Beach Consortium for Graduate Medical Education, West Palm Hospital, West Palm Beach, FL; West Palm Beach VA
Medical Center, West Palm Beach, FL
Abstract
Cutaneous metastasis comprises a tiny minority of skin tumors, estimated at 2%, and its timely diagnosis is extremely important to the clinical course of patients.
Cutaneous metastasis of all primary systemic cancers usually indicates a poor prognosis with only a few months of survival time. Lung cancer remains the leading cause
of cancer-related death among men and women in the United States. This article highlights an atypical presentation of lung metastasis to the skin and provides an
overview of other uncommon and common cutaneous effects of lung cancer in general.
Introduction
Although uncommon in clinical practice,
cutaneous metastasis is important to keep on a
clinical provider’s list of differential diagnoses.
Lung cancer continues to earn listings as the
“most common cause of cancer-related deaths
in both men and women,” “cancer most likely
to metastasize in general,” and, affecting
dermatologists particularly, “most common tumor
to metastasize to the skin in males,” particularly in
men over 40.1-3 The data reinforce the importance
of having a low threshold for biopsy, especially if
patient history directs.
Case Presentation
An 83-year-old male presented to our
dermatology clinic with a complaint of a rash
on his lower abdomen for approximately two
months. The patient’s rash was asymptomatic.
He had cataract surgery planned, which was put
on hold due to this rash, which he attributed to
a reaction from EKG leads placed in the area of
the rash upon his pre-op clearance studies. He
was sent to the ER for a suspected cellulitis-type
infection, and subsequently we were consulted.
His past medical history was notable for
intestinal resection for colon cancer resulting in
the use of an ostomy bag for more than 18 years.
He also had a history of lung cancer for which
he underwent partial lobectomy of the right
lower lobe along with radiation two years prior
for a T2aN0M0 lung tumor non-small-cell type
(adenocarcinoma). He had regular follow-ups
with all of his subspecialists and primary care
providers, and review of systems was negative.
On exam, his left lower abdomen was significant
for an intact ostomy bag, with superior
and bilateral lower abdominal quadrants
demonstrating large, indurated, erythematous
and violaceous blanchable plaques oriented
horizontally, not extending below his pannus fold.
The left aspect of the rash had a “peau d’orange,”
palpable nodularity (Figure 1).
Figure 2
Figure 3
Two 4.0 mm punch biopsies were performed at
initial consultation, with an initial differential
diagnosis inclusive of infection; panniculitis;
erysipeloid and/or carcinoma en cuirasse-like
presentation of underlying carcinoma; atypical
angiosarcoma, due to patient history of radiation
to the area; and interstitial granulomatous
dermatitis.
Figure 4
Figure 1
Figure 5
Page 34
THE CUTANEOUS MANIFESTATIONS OF METASTATIC LUNG CANCER: CASE REPORT AND REVIEW
Pathology revealed findings consistent with
metastatic carcinoma, lymphangitic-type spread
(Figure 2, H&E). The immunostain pattern
of CK-7 positive (Figure 3), TTF-1 positive
(Figure 4), and CK-20 negative (Figure 5)
favored primary lung carcinoma.
The patient was then referred to hematology/
oncology. On close review of past records
and considering findings on new imaging
demonstrating two new masses at an area adjacent
to his previous partial lobectomy, this was
thought to be a recurrence of a previous diagnosis
of non-small-cell cancer. He was quickly started
on a chemotherapy regimen of gemcitabine and
followed regularly in dermatology clinic to track
his metastatic lesions. Although initially given an
ominous prognosis, the patient is doing very well.
His abdominal lesions are fading, which correlate
to his overall response to treatment (Figure 6,
almost one year after initial biopsy).
Discussion
Although usually detected in a patient with known
and widespread disease, on occasion cutaneous
metastasis may be the presenting sign of clinically
silent lung cancer. Early detection of cutaneous
metastasis, then, affects how fast a patient may be
diagnosed and placed on appropriate therapy by
hematology/oncology. Further, depending on the
morphologic presentation, cutaneous metastasis
may not only help with diagnosis of otherwise
asymptomatic disease, as with the case presented
in this article, but may also serve as a marker in
monitoring response to chemotherapy.
Reviewing statistics involving cancers most likely
to metastasize to the skin may be confusing. The
proportion of patients with metastatic disease
with cutaneous involvement depends upon the
particular malignancy. When looking at the
percentage of all patients with metastatic disease
who have developed metastasis particularly to
the skin, melanoma dominates.6 Differences also
occur when factoring in age and sex of patients.
When approached broadly, one retrospective
study of 4,020 patients showed that breast,
melanoma, and lung, in that order, top the list for
most common cancers to spread to the skin.6 For
older men who present with skin metastases, lung
cancer is the most common primary, at about
24%, followed by colorectal cancer, melanoma,
and carcinoma of the oral cavity. In women, lung
cancer ranks fourth after primary breast cancer,
colon cancer, and melanoma.5-6 Overall, if a
patient has lung cancer, their chance of cutaneous
metastasis varies, ranging 1% to 12%. Although
the skin is not the first organ it usually spreads to,
when it does it does so quickly, with mean time of
less than six months.6
Clinical Presentation
In most cases, skin metastases present after the
diagnosis of a known primary. Occasionally, these
lesions may be the inciting event that eventually
leads to diagnosis of underlying disease. In one
study, 11 out of 21 patients with metastatic lung
cancer had their metastatic skin lesions present as
the first sign of extranodal disease.6
Skin metastasis from lung cancer does not have
a typical presentation. Anatomically, the chest,
abdomen, and head and neck are common sites.
Morphologically, lesions are usually nodular,
painless, and may be either single or multiple. The
scalp, head and neck are the most common sites,
along with anterior chest and abdomen.3,6 Several
atypical presentations of metastatic lung cancer
have been described including spread to both
upper and lower limbs, gingiva, genitalia, and
incision sites.7-8 Although nodules are the most
common presentation, different patterns have
been reported including zosteriform, ulcerative,
fungating, and erysipeloid-like presentations.6-9
Diagnosis
Diagnosis is made on biopsy. Patterns on H&E
are generally either nodules of tumor cells within
the dermis or cords of atypical tumor cells mixed
Figure 6
within a fibrotic stroma.
The most common type of lung cancers reported
to metastasize to the skin are adenocarcinoma
and large-cell carcinoma, followed by squamouscell.10 A couple of studies from Japan have
demonstrated that large-cell carcinoma has the
highest incidence of metastasis to the skin.4
On histology, metastatic adenocarcinoma of the
lung may display glandular, well-differentiated
structures with mucin, in which case GI, ovarian,
breast and kidney metastases must be ruled
out. CK 20 paranuclear dot positivity helps
differentiate from Merkel-cell carcinoma. Other
types of lung cancer that rarely metastasize to
the skin include mesothelioma and bronchial
carcinoid, which usually show more of a
trabecular pattern and sometimes present with
carcinoid syndrome.10,11
Immunohistochemistry (IHC) has evolved into
a reliable tool in diagnosis. An IHC battery of
an unknown cutaneous metastasis helps narrow
down the differential diagnosis. Although not
originally studied in the skin, useful markers
include CK 7 and CK 20 and anti-thyroid
transcription factor (TTF). CK 7 is very
sensitive and is positive in virtually all cases of
primary lung adenocarcinoma; however, it has
lower specificity since it is also positive in may
other types of lung carcinoma (70% of largecell neuroendocrine, 40% of large-cell, and 23%
of squamous-cell).12 Anti-TTF is a sensitive
and specific marker that identifies pulmonary
origin of an adenocarcinoma, bronchoalveolar
carcinoma, and small-cell carcinoma if a thyroid
origin is excluded.12
Overall, IHC panels are not substitutes for the
big-picture approach to diagnosis, incorporating
a thorough review of systems and history, exam,
and screening tools such as appropriate bloodwork
and radiologic studies. Communication of the
above to pathology and consulting specialists may
prove to be invaluable.
Treatment and Prognosis
Treatment approach for any cutaneous metastasis
is multidisciplinary. If the cutaneous metastases
are localized and discrete, surgery alone or
combined with chemotherapy and/or radiation
may be possible for functional or even cosmetic
reasons. Some studies have shown that treatment
of localized disease with surgery or combination
modalities may increase survival.13 If disease is
more disseminated, chemotherapy remains the
best option. Sometimes during chemotherapy,
cutaneous lesions may be thought of as a
marker for response to therapy. Patients without
cutaneous metastasis tend to live longer than
those who present with them. Mean survival is
short, usually five to six months after diagnosis of
cutaneous metastasis. Living past a year, as with
our patient, is unusual but has been reported.4-5
Conclusion
Although uncommon, cutaneous metastasis may
occasionally be the presenting sign of an internal
FERRER-BRUKER
Page 35
malignancy. Since lung cancer is so prevalent,
it is an important differential diagnosis of any
unexplained, fresh lesion in someone with risk
factors. These lesions are usually on the trunk,
head and neck, but could present practically
anywhere and with many morphologies, like the
erysipeloid and peau d’orange presentation in
this case. Despite an ominous prognosis, early
recognition and timely diagnosis usually confers
a better survival time, as with our patient. Biopsy
is essential, with immunohistochemical panels
proving to be helpful and guiding tools. Likely
these panels will become more sophisticated
and expand their utility in terms of determining
prognosis and targets for therapy.
13. Garrido M, Ponce C, Martinez J, Martinez
C, Sevilla J. Cutaneous metastases of lung cancer.
Clin Transl Oncol. 2005 May;8:330-3.
Correspondence: Sarah Ferrer-Bruker, DO;
[email protected]
References
1. Helm T, Lee T, Elston D. Dermatologic
Manifestations of Metastatic Carcinomas.
Medscape. [Internet]. 2014 Aug 11 [Cited
Jan 2015 1]. Available from: http://emedicine.
medscape.com/article/1101058-overview
2. Alcaraz I, Cerroni L, Rutten A, Kutzner
H, Requena L. Cutaneous metastasis from
internal malignancies: a clinicopathologic
and immunohistochemical review. Am J
Dermatopathol. 2012 Jun;34(4):347-93.
3. Rammurti Kamble, Lalit Kumar, Vinod
Kochupillai, Atul Sharma, MS Sanhoo, BK
Mohanti. Cutaneous metastasis of lung cancer.
Postgrad Med J. 1995;71 741-743.
4. Terashima T, Kanazawa M. Lung Cancer with
Skin Metastasis. Chest. 1994 Nov; 106(5): 14481450.
5. Mollet, TW, Garcia CA, Koester, G. Skin
metastases from lung cancer. Dermatol Online
J. [Internet]. 2009;15(5). [Cited 2015 Jan 1].
Available from: http://escholarship.org/uc/
item/9r83m6wj
6. Lookingbill DP, Spangler N, Helm KF.
Cutaneous metastases in patients with metastatic
carcinoma: a retrospective study of 4020 patients.
J Am Acad Dermatol. 1993 Aug;29:228-36.
7. Marcoval J, Moreno A, Peyrí J. Cutaneous
infiltration by cancer. J Am Acad Dermatol. 2007
Oct;57:577-80. Epub 2007 Mar 26.
8. Rosen T. Cutaneous Metastasis. Med Clin
North Am. 1980 Sep; 65:885-900.
9. Wen-Hao L, Chih-Yen T, Te-Chun H, PoYuan W. Zosteriform Skin Metastasis of Lung
Cancer. Chest. 2012;142(6);1652-1654.
10. Dreizen S, Dhingra H, Chiuten DF,
Umawasdt T, Valdivieso M. Cutaneous and
subcutaneous metastasis of lung cancer. Postgrad
Med. 1986;80:111-116.
11. Brownstein MH, Helwig EB. Metastatic
tumors of skin. Cancer. 1972 May;29:1298-1307.
12. Jerome Marson V, Mazieres J, Gourssard O,
Garcia O, Berjaud J, Dahan M, Carles P, Daste
G. Expression of TTF-1 and cytokeratins in
primary and secondary epithelial lung tumours:
correlation with histological type and grade.
Histopathology. 2004 Aug;45:125-34.
Page 36
THE CUTANEOUS MANIFESTATIONS OF METASTATIC LUNG CANCER: CASE REPORT AND REVIEW
Loose Anagen Syndrome in a 2-year-old Female:
A Case Report and Review of the Literature
Mathew Koehler, DO,* Anne Nguyen, MS,** Navid Nami, DO***
* Dermatology Resident, 2nd year, Opti-West/College Medical Center, Long Beach, CA
** Medical Student, 4th Year, Western University of Health Sciences, College of Osteopathic Medicine, Pomona, CA
*** Dermatology Residency Program Director, Opti-West/College Medical Center, Long Beach, CA
Abstract
Loose anagen syndrome is a rare condition of abnormal hair cornification leading to excessive and painless loss of anagen hairs from the scalp. The condition most
commonly affects young females with blonde hair, but males and those with darker hair colors can be affected. Patients are known to have short, sparse hair that does
not need cutting, and hairs are easily and painlessly plucked from the scalp. No known treatment exists for this rare disorder, but many patients improve with age.
Case Report
We present the case of a 27-month-old female
presenting to the clinic with a chief complaint
of diffuse hair loss for the last five months. The
mother stated that she began finding large clumps
of hair throughout the house, most notably in the
child’s play area. She stated that the condition
had progressed to where she is afraid to wash
or comb her hair and is exceptionally careful
changing her clothes, as even minor pulling on
the hair will result in additional loss. The mother
reports that her once long, curly locks are now
short and straight, and no hair will grow past her
Figure 1
neck line. The patient had no notable medical
history and took no daily medicines. An older
brother and sister had no similar findings. She
was growing well and meeting all developmental
milestones. The mother denied any major
traumas, psychologically stressful periods or any
major illnesses that the patient or the family
experienced in the last year. The mother denied
any hair manipulation or hair-pulling behaviors
and stated that the daughter is so concerned about
her hair being pulled out she is now refusing to
play in close proximity to her siblings or friends.
On physical examination, we found a shy white
female with sparse blond hair. Her hair reached
only to the neck, and the mother stated that she
does not need haircuts (Figures 1 and 2). She
appeared generally healthy and eventually began
playing in the examination room. She had no
other skin, dental or nail findings. Her eyebrows,
body hair and eye lashes were unaffected.
Laboratory evaluation done by her pediatrician,
including complete blood count, renal panels,
liver panel, anti-nuclear antibody and thyroid
studies, were all within normal limits.
A hair-pull test was done, with more than 10 hairs
being pulled without pain. The mom and patient
were very upset when this test was done, as it was
not fully explained, and refused further hair pulls.
They did allow me to pull lightly on individual
hairs, which repeatedly were easily pulled from
the child’s head without pain. A trichogram was
done, which showed a distorted anagen bulb with
a “rumpled sock” appearance (Figure 3).
Based on the history and physical examination, a
diagnosis of loose anagen syndrome (LAS) was
made. The mother and child were advised on the
natural history of this condition and were offered
a trial of minoxidil 5% hair solution to be applied
to her scalp daily. We encouraged her to continue
being mindful of and avoid activities that would
result in further hair loss such as combing,
shampooing and pulling narrow-necked clothing
over her head. The patient will continue to
follow with us, and although not happy with her
condition, they were relieved to have received a
diagnosis.
Discussion
Loose anagen syndrome is an uncommon
condition characterized by loosely attached hairs
of the scalp leading to diffuse thinning with poor
growth, thus requiring few haircuts. It was first
described in 1984 by Zaun, who called it “syndrome
of loosely attached hair in childhood.”1 A few
years later, Price and Gummer along with Hamm
and Traupe began describing similar cases in the
American literature and coined the current term
“loose anagen hair syndrome,” or LAHS.2,3 The
annual incidence has been estimated at 2.5 cases
per million, with 6:37 cases in boys as compared
to girls.4 However, it has been suggested that the
condition may be underestimated in boys due to
differences in hairstyle.5 Cases described within
families occurring in an autosomal-dominant
pattern further suggest a ratio that is probably
closer to 1.6-8
The classical clinical picture is that of a young girl
with blonde hair that can be easily and painlessly
plucked. Even so, cases do occur frequently in
boys and adults, as well as in individuals with
dark hair. Recent formal reports document cases
from Egypt and India.8,9 Three phenotypes, types
A, B, and C, have been described. In Type A, hair
is sparse and does not grow long. In Type B, the
individual has unruly hair that is either diffuse or
patchy. In Type C, the hair appears normal but
has excessive shedding and loose anagen hairs.10
The eyebrows and eyelashes are not affected.7,11
A diagnosis relies on the presence of loose anagen
Figure 3
Figure 2
KOEHLER, NGUYEN, NAMI
Page 37
Table 1. Differential Diagnosis of Pediatric Alopecia
Condition
Loose Anagen
Syndrome
Lupus
Alopecia Areata
Trichotillomania
Tinea Capitis
Clinical Findings
Hair-pull Test
>10 hairs painlessly
pulled. Individual
hairs easily pulled.
Erythematous papules and
plaques with scale. Lesions
expand centrifugally.
Follicular plugging with
atrophy, scarring, and
telangiectasia. Darkskinned individuals
may have peripheral
hyperpigmentation with
central hypopigmentation.
Normal
Follicular red dots
on trichoscopy. On
histology, vacuolar
interface change with
chronic inflammation of
eccrine sweat glands and
arrector pili. Increased
dermal mucin. IgG and
C3 deposition at D-E
junction.
Patchy or full alopecia of
hair-bearing areas, most
commonly the scalp. Patches
have bizarre and irregularly
shaped borders with hairs
of varying lengths. Occiput
sparing.
On histology,
incomplete, disrupted
follicular anatomy,
trichomalacia, pigment
casts.
Normal
Comma hair on
trichoscopy. Infection
with T. tonsurans (>90%
of cases in the U.S.)
results in the classic
black dot appearance.
Normal
Non-scarring, round-tooval patch of hair loss.
Totalis, universalis, ophiasis
and reticular variants. Nail
changes may be present.
May be chronic and
relapsing.
Most commonly presents
as alopecia with or without
scale. Presentation can range
from a non-inflammatory
scaling resembling
seborrheic dermatitis to
severe pustulosis also known
as a kerion.
Telogen Effluvium Thinning involving the
entire scalp and other hairbearing regions.
hairs that when examined under the microscope
display derangements involving the inner and
possibly the outer root sheaths.12 A hair-pull
test or trichogram can be performed in order to
support the diagnosis, although there are several
drawbacks. Few controlled studies have been
done in order to properly define the parameters
for a positive test. Authors have suggested using
greater than 10 loose anagen hairs, compared to
the usual one or two hairs in normal subjects,
as the cutoff for constituting a positive pull
test.10 On trichogram, greater than 70% loose
anagen hairs compared to the normal 10% is
considered positive. To avoid overdiagnosis, one
must keep in mind that anagen hairs can be
found on normal scalp; their presence is neither
pathognomonic nor specific.13 The differential for
LAS should include alopecia areata, tinea capitis,
trichotillomania, traction alopecia, and secondary
syphilis.14 See Table 1 for differential.
Much research has been done, although the
Page 38
Pathology
Diffusely thin hair that
“Rumpled sock” look
tends to not grow beyond
to anagen bulb on
the shoulders. Bald patches trichogram.
may be present. Hair may be
dull, unruly, or matted.
Yellow dots, exclamation May be positive in
mark appearance, and
the diffuse variant.
dystrophic hairs on
trichoscopy.
Mixture of normal
Positive for two
anagen and telogen hairs or more normal
with >20% telogen hairs. telogen hairs.
precise pathogenesis of this syndrome has yet
to be elucidated. The reigning theory is that of
inner-root-sheath derangement leading to poor
adhesion between the cuticle of the inner root
sheath and that of the hair shaft, causing poor
anchoring. Normal anagen hair is a complex
structure requiring orderly development and
maturation in order to achieve the proper hair
follicle. Deranged anagen follicles of LAS exhibit
characteristic features under both light and
electron microscopy.7,12,13 The keratinized cell
sheath portion of the Henle layer is abnormally
thickened and tortuous. Cells are irregularly
shaped and contain nuclear debris. In addition,
there is premature keratinization and dyskeratosis
with pyknotic nuclei, sparse filaments, and
trichohyalin granules, in an edematous cytoplasm.
The Huxley layer also exhibits premature
keratinization with edema. Lastly, the cuticle cells
of the hair shaft and Henle layer contain vacuoles
with irregularly arranged cells.12 On gross
examination, the hair bulb is long, tapered, and
twisted along the long axis. The cuticle appears as
a “rumpled sock.”2,12,15
Abnormalities in keratinization have prompted
molecular analysis studies. Particular attention
has been devoted to identifying the keratins
within the inner root sheath, outer root sheath,
and companion layer. Of significance, Chaplain
et al. identified a G-to-A substitution mutation
in the cytokeratin K6hf of the companion layer
leading to replacement of glutamic acid by lysine.
It is hypothesized that this mutation may lead to
instability of the intermediate filament network
and thus poor anchoring of the hair shaft to the
sheath.7 It was not until recently that keratins of
the inner root sheath, K25-28, were described.16,17
Molecular analysis for possible mutation in these
genes has yet to be done.
Although the majority of cases have been sporadic,
as previously mentioned, there is some evidence
of autosomal-dominant inheritance with variable
penetrance.6,7 There have been associations with
certain conditions such as Noonan’s syndrome,13,18
coloboma,19 hypohidrotic ectodermal dysplasia,20
and woolly hair.21
There is no agreed upon or universally effective
treatment for LAS. In some individuals, the
condition improves with age, most notably
around puberty. However, in some individuals the
condition persists into adulthood. A recent case
report showed good results using daily therapy
with minoxidil without any side effects in a 2-yearold patient.22 While minoxidil is generally safe
and inexpensive, there are some considerations
when prescribing to pediatric patients. Rare cases
of reversible generalized hypertrichosis have been
reported in children using excessive amounts of
minoxidil for alopecia areata, so caution should
be used.23 Another consideration in pediatric
patients is excessive systemic absorption, which
could potentially cause cardiovascular symptoms
such as tachycardia, palpitations and dizziness, so
patients and their caregivers should be advised to
monitor for side effects.24
Loose anagen syndrome is an uncommon
condition that can cause a significant psychosocial
impact in patients and families. More research
is needed to fully understand the cause of this
condition and to improve the limited treatment
options available. Patients should be advised that
this condition is thought to be benign in nature,
and many patients’ hair normalizes with age. We
have chosen to recommend minoxidil to our
patient while warning the mother of the potential
of cardiovascular side effects and hypertrichosis.
We will continue to follow her progress.
References
1. Zaun H Differential diagnosis of alopecia
in children. In: Happle R, Grosshans E, eds.
Pediatric dermatology. Berlin: Springer; 1987.
157-166 p.
2. Price VH, Gummer CL. Loose anagen
syndrome. J Am Acad Dermatol. 1989;20(2 Pt
1):249-56.
LOOSE ANAGEN SYNDROME IN A 2-YEAR-OLD FEMALE: A CASE REPORT AND REVIEW OF THE LITERATURE.
3. Hamm H, Traupe H. Loose anagen hair of
childhood: the phenomenon of easily pluckable
hair. J Am Acad Dermatol. 1989;20(2 Pt 1):2428.
4. Sinclair R, Cargnello J, Chow CW. Loose
anagen syndrome. Exp Dermatol. 1999;8(4):2978.
5. Pham CM, Krejci-manwaring J. Loose anagen
hair syndrome: an underdiagnosed condition in
males. Pediatr Dermatol. 2010;27(4):408-9.
6. Baden HP, Kvedar JC, Magro CM. Loose
anagen hair as a cause of hereditary hair loss in
children. Arch Dermatol. 1992;128(10):1349-53.
7. Chapalain V, Winter H, Langbein L, et al.
Is the loose anagen hair syndrome a keratin
disorder? A clinical and molecular study. Arch
Dermatol. 2002;138(4):501-6.
8. Dey V, Thawani M. Loose anagen hair
syndrome in black-haired Indian children.
Pediatr Dermatol. 2013;30(5):579-83.
9. Abdel-raouf H, El-din WH, Awad SS, et al.
Loose anagen hair syndrome in children of Upper
Egypt. J Cosmet Dermatol. 2009;8(2):103-7.
familial association between ocular coloboma
and loose anagen syndrome. Clin Genet.
1995;47(4):214-6.
20. Azon-masoliver A, Ferrando J. Loose anagen
hair in hypohidrotic ectodermal dysplasia. Pediatr
Dermatol. 1996;13(1):29-32.
21. García-hernández MJ, Price VH, Camacho
FM. Woolly hair associated with loose anagen
hair. Acta Derm Venereol. 2000;80(5):388-9.
22. Chandran NS, Oranje AP. Minoxidil 5%
solution for topical treatment of loose anagen hair
syndrome. Pediatr Dermatol. 2014;31(3):389-90.
23. Herskovitz I, Freedman J, Tosti A. Minoxidil
induced hypertrichosis in a 2 year-old child.
F1000Res. 2013;2:226.
24. Georgala S, Befon A, Maniatopoulou
E, Georgala C. Topical use of minoxidil in
children and systemic side effects. Dermatology.
2007;214(1):101-2.
Correspondence: Matthew Michael Koehler,
DO; [email protected]
10. Olsen EA, Bettencourt MS, Coté NL. The
presence of loose anagen hairs obtained by
hair pull in the normal population. J Investig
Dermatol Symp Proc. 1999;4(3):258-60.
11. Chapman DM, Miller RA. An objective
measurement of the anchoring strength of
anagen hair in an adult with the loose anagen hair
syndrome. J Cutan Pathol. 1996;23(3):288-92.
12. Mirmirani P, Uno H, Price VH. Abnormal
inner root sheath of the hair follicle in the loose
anagen hair syndrome: an ultrastructural study. J
Am Acad Dermatol. 2011;64(1):129-34.
13. Tosti A, Piraccini BM. Loose anagen hair
syndrome and loose anagen hair. Arch Dermatol.
2002;138(4):521-2.
14. Bolognia J, Jorizzo JL, Schaffer JV.
Dermatology. 3rd edition. Philadelphia (PA):
Saunders; 2012. 1093p.
15. Dicle O, Velipasaoglu S, Ozenci CC,
Akkoyunlu G, Demir N. Report of a new case
with loose anagen hair syndrome and scanning
electron microscopy findings. Int J Dermatol.
2008;47(9):936-8.
16. Porter RM, Corden LD, Lunny DP, Smith FJ,
Lane EB, Mclean WH. Keratin K6irs is specific
to the inner root sheath of hair follicles in mice
and humans. Br J Dermatol. 2001;145(4):558-68.
17. Langbein L, Rogers MA, Praetzel S, Winter
H, Schweizer J. K6irs1, K6irs2, K6irs3, and
K6irs4 represent the inner-root-sheath-specific
type II epithelial keratins of the human hair
follicle. J Invest Dermatol. 2003;120(4):512-22.
18. Mazzanti L, Cacciari E, Cicognani A,
Bergamaschi R, Scarano E, Forabosco A.
Noonan-like syndrome with loose anagen
hair: a new syndrome?. Am J Med Genet A.
2003;118A(3):279-86.
19. Murphy MF, Mcginnity FG, Allen GE. New
KOEHLER, NGUYEN, NAMI
Page 39
Anetoderma Secondary to Mid-dermal Elastolysis
Gabriela A. Maloney, BS,* Jane James, MD, PhD,** Michael Welsch, MD,** Marylee Braniecki, MD**
*Midwestern University, Downers Grove, IL
**Pathology Department, University of Illinois Hospital & Health Sciences System, Chicago, IL
Abstract
Anetoderma usually presents as circumscribed, 1 cm to 2 cm patches and plaques of flaccid skin secondary to loss of dermal elastic tissue. Lesions often occur in the neck,
upper extremities, chest, and back. On histopathology, one sees complete loss of dermal elastin involving the papillary and reticular dermis, with infiltration of plasma
cells and histiocytes. A 40-year-old female with no significant medical history presented with multiple round, 1 cm to 2 cm lesions scattered on her upper back and chest.
Skin biopsy demonstrated elastic-fiber loss localized to the mid-dermis along with a lymphohistiocytic infiltrate with elastophagocytosis and active inflammatory phase
in the papillary and mid-reticular dermis. The histopathological findings were consistent with mid-dermal elastolysis with advancing inflammation, and the clinical
features were consistent with anetoderma. The microscopic examination revealed an active inflammatory phase of mid-dermal elastolysis, supporting the postulated
theory that MDE may be part of a continuous spectrum with anetoderma.
Case Report
A 40-year-old female with no significant medical
history presented with multiple round, 1 cm to
2 cm lesions scattered throughout the upper
back and chest. The lesions were characterized
by lax, wrinkled skin with underlying palpable
depression (Figure 1). They were often preceded
by two to six months of local erythema and had
increased in number over the past two years. No
response was seen after topical steroids. Skin
Figure 1: Multiple round-to-ovoid, wrinkled skin lesions with overlying palpable depressions and
surrounding erythema.
biopsy and elastic-fiber staining demonstrated
elastic-fiber loss in the mid-dermis along with
a lymphohistiocytic infiltrate with evidence
of elastic-fiber phagocytosis and an active
inflammatory background in the papillary and
reticular dermis (Figures 2, 3 and 4). This is a case
demonstrating the development of anetoderma
as seen by the progressive inflammation and
elastophagocytosis in the papillary and reticular
dermis that developed in the setting of middermal elastolysis (MDE).
Figure 2: H&E (10x): Active inflammatory
phase with mid-dermal stromal histiocytes
with scattered plasma cells.
Discussion
Figure 3: H&E (20x): Multinucleated
histiocytes with elastophagocytosis.
Page 40
Figure 4: Elastic stain (20x): Elastic fibers
engulfed by histiocytes.
Mid-dermal elastolysis (MDE) is a rare acquired
disorder of elastic-tissue degradation limited
to the mid-dermis. It consists of a clear band
of mid-dermal elastic-tissue loss as a result of
inflammatory destruction of dermal elastotic
fibers.1 The elastic-tissue loss occurs as a result
of inflammatory destruction of dermal elastic
fibers. Remnants of abnormal elastic tissue and
granuloma formation may be present, along with
evidence of elastophagocytosis.2 Elastic tissue is
usually preserved around hair follicles, resulting
in perifollicular papules on the affected skin.
ANETODERMA SECONDARY TO MID-DERMAL ELASTOLYSIS
The condition was first described in 1977 by
Shelley and Wood, and since then, there have
been approximately 80 cases reported in the
literature.3 It has a female predominance and
presents clinically as diffuse, fine wrinkling on
the neck, arms, and trunk in patients between the
ages of 30 and 50 years.2
It is classified into three types: type I, or classic
type, with well-demarcated patches with
wrinkling; type II, with perifollicular papular
protrusions; and type III, with reticular/annular
patches with wrinkling.
Mid-dermal elastolysis has been reported to
originate from involuting sites of granuloma
annulare that started as a patchy, slightly indurated
and violaceous eruption involving the neck and
trunk and eventually became atrophic, pale and
wrinkled. Urticaria, atopic dermatitis, Sweet’s
syndrome, phototoxic dermatitis, and pityriasis
rosea have also been described to precede MDE.4
Mid-dermal elastolysis can also occur in areas of
preceding erythema, which is consistent with our
patient’s clinical presentation.5
Anetoderma, also known as dermatitis maculosa
atrophicans, is an elastic-tissue disorder that
shows focal loss of elastic fibers in the dermis.
The term “anetoderma” is derived from the
Greek words “anetos,” meaning slack, and
“derma,” meaning skin.1 Sac-like tumors that
herniate upon palpation were first described
by Schweninger and Buzzi in 1891, but
anetoderma was first officially described in 1892
by Jadassohn.7,8 It usually presents as multiple,
circumscribed, 5 mm to 25 mm areas of flaccid
skin with fine wrinkling that can occur in the
neck, upper extremities, chest, and back. The
lesions are skin color but can present with a bluewhite discoloration.6 Affected areas of skin can
herniate after palpation (“buttonhole” sign) and
can show central depressions.1
Anetoderma is classified as either primary
(idiopathic) or secondary. Primary anetoderma
is divided in two types: Jadassohn-Pellizzari type,
which has preceding inflammatory lesions, and
Schweninger-Buzzi type, which has no preceding
inflammation. It is seen more commonly in
women than men and mostly occurs in individuals
between 15 and 25 years of age.9 Secondary
anetoderma may be associated with tumors,
depositions, autoimmune disorders, infections,
drugs and inflammatory cutaneous disorders.
The loss of elastic tissue is usually localized to
those sites of previous skin lesions caused by the
primary disease.1
On histopathology, there is focal loss of elastic
fibers in the dermis with infiltration of plasma
cells and histiocytes. The elastic fibers can have
an irregular shape and may be fragmented or
engulfed by macrophages. Remnants of abnormal
elastic tissue and granuloma formation may be
present.1
Activated macrophages and fibroblasts from
existing inflammatory processes can destroy
dermal stromal elements by releasing proteolytic
enzymes. UV light exposure and autoimmunity
against elastic fibers are thought to contribute to
the condition. Defects in the synthesis of elastin
and dysregulation of elastic-fiber digestion by
metalloproteinases (MMPs) also seem to play
a role.5 Giant cells and elastophagocytosis may
be present in both mid-dermal elastolysis and
MALONEY, JAMES, WELSCH, BRANIECKI
anetoderma. Emer et al. described a case of
anetoderma that was instigated by penicillin G to
treat syphilis in an HIV-positive patient without
any previous skin complaints.9
Mid-dermal elastolysis and anetoderma, both
disease entities resulting from elastic-fiber
degradation, are differentiated histopathologically
by the extent and location of elastic-fiber loss. The
former consists of elastic-tissue loss localized to
the mid-dermis, and the latter is characterized by
elastic-fiber loss in the entire dermis.1
It has been speculated that MDE and anetoderma
are within the same spectrum of disorders, as they
present similar histopathological configurations
to different extents, suggesting MDE may evolve
into anetoderma secondary to long-standing
inflammation.4,10,11 Our patient demonstrated a
classic histopathology of MDE with secondary
anetoderma resulting from an active inflammation
and elastophagocytosis, lymphocytes, plasma cells
and histiocytes extending to the papillary and
reticular dermis.
Mid-dermal elastolysis and anetoderma need to
be differentiated from other connective-tissue
diseases affecting elastic fibers, including cutis
laxa, pseudoxanthoma elasticum (PXE), and
PXE-like papillary dermal elastolysis. Posttraumatic scars, perifollicular elastolysis, papular
elastorrhexis, pseudoxanthoma elasticum, focal
dermal hypoplasia (Goltz syndrome), and nevus
lipomatosus are other entities that may be included
in the differential diagnosis of anetoderma.1
Cutis laxa is an entity with redundant and loose
skin seen on the eyelids, cheeks, shoulder girdle,
abdomen and neck. It presents clinically with
premature aging secondary to loose skin folds
with or without internal organ involvement. In
this condition, the whole dermis is affected with
diminished and fragmented elastic fibers, and it
can occur in an acquired or hereditary form.1
Pseudoxanthoma elasticum (PXE) and PXElike papillary dermal elastolysis present as
cobblestoning yellow papules and redundant folds
in flexor areas. The former can be associated with
ocular and cardiovascular involvement.1 It occurs
in sites of previous scars, axilla, groin, and lateral
neck and consists of clumped and calcified elastic
fibers in the mid-dermis. The latter is seen in
inframammary folds, lower abdomen, axilla, and
neck, and has a band-like pattern of clumping
and fragmentation of elastic tissue in the papillary
dermis.9
Intralesional triamcinolone injections and
systemic administrations of dapsone, aspirin,
penicillin G, vitamin E, and inositol niacinate
have been used to treat existing anetodermal
lesions without success.1 Administration of
hydroxychloroquine, colchicine, and aminocaproic
acid, as well as surgical excision, have resulted
in some improvement. Cho et al. reported
anetoderma presenting after Stevens-Johnson
syndrome successfully treated with ablative
carbon dioxide fractional laser.12 Lasers destroy
the hydrogen bonds in the collagen triple helix,
instigating an inflammatory cascade that is
believed to be responsible for rebuilding stable
and more native-like collagen and elastic fibers,
thereby reverting the pathological process.9
Conclusion
We report a case demonstrating the development
of anetoderma as seen by progressive
inflammation and elastophagocytosis in the
papillary and reticular dermis that developed in
the setting of mid-dermal elastolysis (MDE). The
histopathological findings were consistent with
mid-dermal elastolysis with active inflammation,
and the clinical features were consistent with
anetoderma. The microscopic examination
revealed elastic fiber loss localized to the middermis along with a lymphohistiocytic infiltrate
with elastophagocytosis and active inflammatory
phase in the papillary and mid-reticular dermis.
Such areas of active inflammation indicate the
development of anetoderma in the pre-existing
MDE background as elastic-fiber degradation
spread beyond the mid-dermis to involve the
papillary and reticular dermis.
Anetoderma often occurs from existing
inflammatory processes that lead to elastic-fiber
destruction, thus the overall findings in this case
may support the theory that MDE is part of a
continuous spectrum with anetoderma.
References
1. Bolognia JL, Jorizzo JL, Schaffer JV, eds.
Dermatology. 3rd ed. Philadelphia: Elsevier
Saunders; 2012. 1631-35 p.
2. Gambichler T. Mid-dermal elastolysis revisited.
Arch Dermatol Res. 2010;302:85-93.
3. Shelley WB, Wood MD. Wrinkles due to
idiopathic loss of mid-dermal elastic tissue. Br J
Dermatol. 1977;97:441-5.
4. Lai JHC, Murray SJ, Walsh NM. Evolution of
granuloma annulare to mid-dermal elastolysis:
report of a case and review of the literature. J
Cutan Pathol. 2014;41:462-8.
5. Gambichler T. Mid-dermal elastolysis revisited.
Arch Dermatol Res. 2010;302:85-93.
6. Venecie PY, Winkelmann RK, Moore BA.
Anetoderma: clinical findings, associations, and
long-term follow-up evaluations. Arch Dermatol.
1984;120:1032-9.
7. Schweninger E, Buzzi F. Multiple benign
tumor-like new growths of the skin. International
Atlas Seltener Hautkrankheiten, plate 15.
Leipzig: L Voss, 1891.
8. Jadassohn J. Uber eine eigenartige form
von’atrophica maculosa cutis. Arch Dermatol
Syphilol. 1892;24:342-58.
9. Emer J, Roberts D, Sidhu H, et al. Generalized
Anetoderma after Intravenous Penicillin Therapy
for Secondary Syphilis in an HIV patient. J Clin
Aesthet Dermatol. 2013;6(8):23-28.
10. Gambichler T, Breuckmann F, Kreuter A,
et al. Immunohistochemical investigation of
mid-dermal elastolysis. Clin Exp Dermatol.
2004;29:192-5.
11. Verhagen AR, Woederman MJ. Postinflammatory elastolysis and cutis laxa. Br J
Dermatol. 1975;92:183-90.
12. Cho S, Jung JY, Lee JI. Treatment of
anetoderma occurring after resolution of StevensJohnson Syndrome using ablative 10,600nm
carbon dioxide fractional laser. Dermatol Surg.
2012;38(4):677-79.
Correspondence: Gabriela Maloney
[email protected]
BS;
Page 41
Generalized Linear Porokeratosis: A Case Report and Discussion
Stephanie Blackburn, DO,* Zaina Rashid, DO,** John Moad, MD,*** Michelle Duff, DO,**** Jason Barr, DO*****
*Dermatology Resident, 1st year, Affiliated Dermatology/MWU, Scottsdale, AZ
**Assistant Professor, Midwestern University, Phoenix, AZ
*** Medical Director, Dermatopathologist Laboratory, Dayton, OH
****Dermatology Resident, 2nd year, Affiliated Dermatology/MWU, Scottsdale, AZ
*****Program Director, Affiliated Dermatology/MWU Residency Program, Scottsdale, AZ
Abstract
Linear porokeratosis is a clinical variant of porokeratosis that usually arises in infancy or childhood, but may present in adulthood. There are two presentations, the first
being more common and localized. It is unilateral and confined to one extremity. In the rarer version, the lesions affect multiple extremities and the trunk, appearing in
a zosteriform pattern.1 Of all the variants of porokeratosis, linear porokeratosis has the greatest chance of malignant transformation, with squamous cell carcinoma and
basal cell carcinoma being the most common. We present a case of a 57-year-old man with reddish-brown skin lesions showing central atrophy with surrounding scale,
hyperpigmentation and erythema present on the right posterior back, right arm, right lateral leg and right buttock. Within the lesion on his leg there was noted actinic
damage. There are numerous treatment options for porokeratosis, with varying benefits and risks. It is important to take into consideration the age of the patient and
the morphology of the lesions being treated in order to leave the patient with the most cosmetically pleasing outcome. For our patient, we elected to treat with topical
imiquimod 5% and fluorouracil 5% because of the large areas of involvement.
Introduction
The porokeratoses are a group of acquired or
genetic disorders of epidermal keratinization
characterized by singular or multiple, annular,
atrophic lesions surrounded by a keratotic
border.16 The peripheral keratinization of the
demarcated lesions corresponds to a typical
histopathologic feature, namely, the cornoid
lamella. Various forms of porokeratosis have
been established based on the clinical course of
the disease, the morphology and the distribution
of the lesions.1 Linear porokeratosis is a clinical
variant of porokeratosis. It consists of one or
more plaques that are similar in appearance to
classic porokeratosis; however, the plaques follow
the lines of Blaschko and are most commonly
on the extremities. When linear porokeratotic
lesions have a typical clinical appearance, it is
easy to diagnose. However, in lesions that are
smaller and have less elevation of borders, it may
be confused with other linearly arranged lesions.
Differential diagnosis includes inflammatory
linear verrucous epidermal nevus, linear lichen
planus, incontinentia pigmenti (stage II), linear
psoriasis, linear Darier’s disease, and lichen
striatus. We present a case of linear porokeratosis
with arising SCC in situ in a 57-year-old male.
Figure 1
Figure 2
Figure 3
Figure 4
Case Report
A 57-year-old Caucasian male presented for
evaluation of a lesion on the left lateral arm
and was found to have extensive skin lesions
showing central atrophy with surrounding scale,
hyperpigmentation and erythema. The lesions
were confined to the right side of his body and
followed the lines of Blaschko. They were present
on the right posterior back in a curved/whorled
fashion, the right arm, and the right lateral leg
and buttock (Figures 1-4). Extending down
the lateral leg, it was evident that the inferior
portion had actinic activity present (Figure 5).
A shave biopsy was taken during his first visit,
showing SCC in situ. Two punch biopsies taken
Page 42
GENERALIZED LINEAR POROKERATOSIS: A CASE REPORT AND DISCUSSION
Figure 5
Figure 6
of the lower extremity showed definitive cornoid
lamellae with thin and flattened epidermis. Subtle
interface change with few necrotic keratinocytes
was also noted. There was mild superficial
perivascular lymphocytic inflammation with
melanophages. Focal parakeratosis with few
superficial epidermal dyskeratotic keratinocytes
was noted. (Figure 6) Past medical history,
medications, allergies, social history, and family
history were noncontributory.
The patient reported that he developed the
lesions in 1967 when he was 12 years old. At
this time he suffered from an episode of severe
sun exposure with peeling and blistering on his
chest, arms and back. Shortly after, he noticed
the development of vesicles that started on his
right arm, no bigger than the size of a pustule.
The vesicles then spread to his right leg and back.
He reported that his lower extremities were not
exposed and did not get sunburned. After a few
years, he presented to his primary care physician,
who referred him to a skin specialist who thought
the lesions were due to “shooting up” drugs. No
biopsy was performed at that visit.
At 18 years of age, the patient entered the
Navy. The lesions had remained constant
since appearing years before. He noticed that
they would bleed and become erythematous
during hot weather. Due to these symptoms,
in approximately 1976 he saw a dermatologist
in Hawaii at an Army hospital. A biopsy was
taken; however, the diagnosis was never relayed
to him and no treatment was performed. Again
BLACKBURN, RASHID, MOAD, DUFF, BARR
during the 1980s, he visited a dermatologist with
the Navy in Hawaii. He had a second biopsy
performed and remembers being treated with a
5% “fading” cream that was applied to his right
arm only and wrapped with cellophane. In
approximately 2005, he was evaluated at an Air
Force Base, where he saw a dermatologist. A
biopsy was performed. He was told that it was
not cancerous, and no further action was taken.
of the underlying dermis shows mild perivascular
mononuclear cell infiltrate.1 Fibroblasts also taken
from the underling dermis of a lesion have shown
instability of the short arm of chromosome 3.5
The nuclei of keratinocytes beneath the cornoid
lamella in the epidermal basal layer have shown
over-expression of p53.6 It has been noted that
this may explain the malignant potential of
porokeratosis.3
Pathogenesis
Treatment
Porokeratosis is a premalignant disease of
epidermal keratinization characterized by
atrophic macules and patches with a surrounding
border of hyperkeratinization. The cornoid
lamella is the hyperkeratotic border of vertical
mounds of parakeratotic corneocytes that lies
in the periphery around the lesions.16 Clonal
proliferation of atypical keratinocytes from
the stratum corneum and superior epidermis,
demonstrating abnormal terminal keratinocyte
differentiation, leads to the formation of the
cornoid lamella. The pathway that leads to the
clonal proliferation of abnormal keratinocytes
is not known; it has been thought that genetic
susceptibility, UV-radiation exposure, viral
infection, and immune status may be contributing
factors.4 Immunodeficiency may be due to organ
transplant, chemotherapy, chronic kidney disease,
HIV, hepatitis C, or repeated trauma as well as
other pathological processes.13 Mosaicism is
a proposed genetic mechanism for two types
of porokeratosis, porokeratosis of Mibelli and
linear porokeratosis. Mosaicism occurs when
cells within an individual have different genetic
makeup.8 There is conflicting evidence as to
the association between ultraviolet radiation
and porokeratosis. Support for the relationship
is due to the observation that disseminated
superficial actinic porokeratosis (DSAP) occurs
in individuals with extensive sun exposure,
occurs on areas of sun-exposed skin, and occurs
in experimental settings with the use of artificial
ultraviolet radiation. However, the relative
sparing of the face weakens the relationship
between UV radiation and the development of
porokeratosis. Also, treatment of DSAP with
psoralen plus ultraviolet A (PUVA) has shown
to improve lesions.9 Immunosuppression or
immunodeficiency has been shown to increase
the risk of porokeratosis. The evidence is due
to reports of remission of porokeratosis after
cessation of immunosuppressive therapy.10,11
Also, porokeratosis has developed in areas of
long-term topical corticosteroid use.12
Biopsy
Biopsy of porokeratosis shows stacked, tightly
packed parakeratotic cells that are welldifferentiated from the rest of the corneocytes.1
The stratum granulosum is either absent or
decreased, and the stratum spinosum may possess
vacuolated or dyskeratotic cells.3 The defective
desquamation of the corneocytes may be due to a
decrease in the keratohyalin granules and lamellar
bodies underneath the cornoid lamella.1 Biopsy
There are numerous modalities used for
the treatment of porokeratosis. In general,
treatment of linear porokeratosis is disappointing
and contradictory.21 Treatment modalities
include topical creams such as fluorouracil
5%, corticosteroids, retinoids, keratolytics, and
calcipotriol; surgical treatments such as curettage,
excision, cryotherapy, and electrodessication;
laser treatment with carbon dioxide laser; and
dermabrasion. Systemic retinoids can also be
utilized as a method of clearance and prophylaxis.
For our patient, fluorouracil 5% and imiquimod
5% were selected as treatment options due to the
large areas of the lesions and extensive actinic
damage within each lesion. Fluorouracil 5% is
a topical antineoplastic, anti-metabolite cream
containing pyrimidine fluorouracil, used in the
treatment of actinic keratosis and superficial
basal cell carcinoma. It works by inhibiting DNA
and RNA synthesis. Anti-metabolites block the
replication of DNA by preventing the building
blocks of DNA (the purines and pyrimidines)
from being incorporated into DNA, which halts
normal development and division. Imiquimod is
an immune-response modifier that acts as a tolllike receptor 7 agonist. Like fluorouracil 5%, it is
used to treat actinic keratoses and superficial basal
cell carcinoma. Field therapy with imiquimod
5% is a treatment of choice on areas where
surgery or other treatments may be complicated,
difficult or otherwise undesirable. This is why it
was selected for our patient, who had very large
areas of skin involvement that would not have
been surgically operable without skin grafts or
other measures. Imiquimod’s mechanism of
action is via stimulation of innate and acquired
immune responses, leading to inflammatory-cell
infiltration within the field of drug application
followed by apoptosis of diseased tissue. Our
patient, after being treated with fluorouracil 5%
and imiquimod 5%, was clear of actinic keratosis
within the plaques. He did not follow up, so
definitive clearance is unable to be determined.
Discussion
Since its first description by Mibelli and Respighi
in 1893, many new variants of porokeratosis have
been described. A patient may develop more
than one type of porokeratosis simultaneously
or consecutively. Each variant consists of its own
properties regarding morphology, distribution
and clinical course.1 The initial lesions present
in a centrifugal manner as keratotic papules.1
These lesions then progress, showing central
Page 43
atrophy with a collar of keratin. A biopsy of the
lesion’s border shows parakeratotic cells stacked
tightly, sticking out from the rest of the stratum
corneum. This cornoid lamella is the hallmark
of porokeratosis. Further manifestations include
thinning of the stratum granulosum, dyskeratotic
cells in the stratum spinosum and subsequent
thinning of the epithelium. Abnormalities in
the maturation of keratinocyte clones has been
implicated in the pathogenesis of porokeratosis.
The most common forms of porokeratosis are:
• Classic porokeratosis of Mibelli (PM)
• Disseminated superficial actinic
porokeratosis (DSAP) and its nonactinic variant, disseminated superficial
porokeratosis (DSP)
• Linear porokeratosis
• Porokeratosis palmaris et plantaris
disseminata (PPPD)
• Punctate porokeratosis, which might
represent a variant of PPPD
Besides these, there are a few rare, atypical
morphological forms such as facial porokeratosis,
giant porokeratosis, punched-out porokeratosis,
hypertrophic verrucous porokeratosis and
reticulate
porokeratosis.7
Porokeratosis
ptychotropica is a recently described subtype
of inflammatory perianal disease showing
symmetrically
distributed,
reddish-brown
papules and plaques involving the gluteal cleft
and genital areas.13-15 Porokeratoma, otherwise
known as porokeratotic acanthoma, is a tumorlike acanthoma showing cornoid lamellation
characteristic of porokeratosis.16 These lesions
have a keratotic or verrucous appearance and are
commonly found on the limbs. Histologically,
they have multiple and confluent cornoid
lamellae.
A rare congenital disorder of
keratinization characterized by eccrine and hairfollicle involvement is known as porokeratotic
adnexal ostial nevus (POAN). This name was
proposed to incorporate porokeratotic eccrine
ostial and dermal duct nevus (PEODDN) and
porokeratotic eccrine and hair-follicle nevus
(PEHFN).17 Pruritic popular porokeratosis is
a variant described in only about 10 previous
reports in the English literature.18,19 This form
of porokeratosis represents lesions that arise fairly
abruptly in a patient with or without preexisting
disseminated superficial porokeratosis and tend
to resolve over months.19
Less-commonly reported clinical entities that
share the histopathologic characteristic of cornoid
lamellation include viral warts, some ichthyoses,
naevoid hyperkeratosis, seborrheic keratosis,
squamous cell carcinoma, basal cell carcinoma,
verruca vulgaris, scars, milia, and solar keratosis.3
A differential diagnosis includes psoriasis, actinic
keratoses, Darier’s disease, and lichen striatus,
along with others.
Malignant transformation occurs in all of the
five major forms of porokeratosis, with variable
rates of transformation depending on the clinical
variant. Lesions of linear porokeratosis have an
increased risk of malignant transformation into
Page 44
squamous cell carcinoma, including Bowen’s
disease, and basal cell carcinoma.21 A few
risk factors have been established, including
excessive sun exposure, radiation therapy,
internal malignancies, and a family history of
porokeratosis.2 It has been hypothesized that
the increased malignant potential for linear
porokeratosis may be due to allelic loss in addition
to overexpression of the tumor suppressor
gene p53 within linear porokeratosis lesions.22
Monitoring for suspicious lesions is key in the
care of patients with porokeratosis.
Conclusion
Linear porokeratosis is a rare variant of
porokeratosis that has an increased risk of
malignant transformation. Individuals with this
type should have regular follow-up visits and
yearly skin exams. There are multiple treatment
options, and each patient case is different.
References
1. Sertznig P, von Felbert V, Megahed M.
Porokeratosis: present concepts. J Eur Acad
Dermatol Venereol. 2012;26:404-412.
2. Maubec E, Duvillard P, Margulis A, Bachollet
B, Degois G, Avril MF. Common skin cancers
in porokeratosis. Br J Dermatol. 2005;152:13601398.
3. Chow KY. Linear Porokeratosis. Hong Kong
Dermatol Venereol Bull. 2000;8:21-23.
4. Murase J, Gilliam AC. Disseminated superficial
actinic porokeratosis co-existing with linear and
verrucous porokeratosis in an elderly woman:
Update on the genetics and clinical expression of
porokeratosis. J Am Acad Dermatol. 2010;63:886.
5. Imakado S, Ostuka F, Ishibashi Y, et al.
Abnormal DNA ploidy in cells of the epidermis
a case of porokeratosis.
Arch Dermatol.
1988;124:331-2
6. Magee, JW, McCalmont, TH, LeBoit PE.
Over-expression of p53 tumor suppressor protein
in porokeratosis. Arch Dermatol 1988;124:331-2
7. Palleschi GM, Torchia D. Porokeratosis
of Mibelli and Superficial disseminated
porokeratosis. J Cutan Pathol. 2008;35:253-5
8. Stankiewicz P, Lupski JR. Gene, Genomic,
and Chromosomal Disorders. IN: Goldman
L, Schaffer AL, eds. Cecil Medicine. 24th ed.
Philadelphia, PA: Saunders Elsevier; 2011: chap
40.
9. Schwarz T, Seiser A, Gschnait F. Disseminated
superficial “actinic” porokeratosis. J Am Acad
Dermatol. 1984;11:724.
10. Gilead L, Guberman D, Zlotogorski A, et
al. Immunosuppression-induced porokeratosis
of Mibelli: Complete regression of lesions upon
cessation of immunosuppressive therapy. J Eur
Acad Dermatol Venereol. 1995;5:170.
1993;28:651.
12. Yazkan F, Turk BG, Dereli T, Kazandi AC.
Porokeratosis of Mibelli induced by topical
corticosteroid. J Cutan Pathol 2006;33:516.
13. Taking urchin RH, White KP, White CR
Jr., Simpson EL. Verrucous porokeratosis of the
gluteal cleft (porokeratosis ptychotropica): a rare
disorder easily misdiagnosed. J Cutan Pathol.
2010 July;37(7):802-7.
14. McGuigan K, Shurman D, Campanelli C,
Lee JB. Porokeratosis ptychotropica: a clinically
distinct variant of porokeratosis. J Am Acad
Dermatol 2009;60:501-3.
15. Corradin MT, Giulioni E, Forcione M,
Fiorentino R, Faggion D, Alaibac M, BelloniFortina A. Porokeratosis ptychotropica. Eur J
Dermatol. 2011 May-Jun;21(3):416-7.
16. Kanitakis J, Rival-Tringali AL, Chouvet B,
Vignot E, Claudy A, Faure M. Porokeratoma
(porokeratotic acanthoma): immunohistological
study of a new case. J Cutan Pathol. 2009
Jul;36(7):804-7.
17. Goddard DS, Rogers M, Frieden IJ, Krol
AL, White CR Jr, Jayaraman AG, RobinsonBostom L, Bruckner AL, Ruben BS. Widespread
porokeratotic adnexal ostial nevus: clinical
features and proposal of a new name unifying
porokeratotic eccrine ostial and dermal duct nevus
and porokeratotic eccrine and hair follicle nevus.
J Am Acad Dermatol. 2009 Dec;61(6):1060.
18. Choi KH, Kim TY. A case of inflammatory
disseminated superficial porokeratosis in a colon
cancer patient. Ann Dermatol 2009;21:150-3.
19. Tee SI, Chong WS. Eruptive pruritic papular
porokeratosis. Indian J Dermatol Venereol
Leprol. 2012 Nov-Dec;78(6):758-60.
20. Levitt JO, Keeley BR, Phelps RG. Treatment
of porokeratosis of Mibelli with cantharidin. J
Am Acad Dermatol. 2013 Nov;69(5):e254-5.
21. Curkova AK, Hegyi J, Kozub P, Szep Z,
D’Erme AM, Simaljakova M. A case of linear
porokeratosis treated with photodynamic therapy
with confocal microscopy surveillance Dermatol
Ther. 2014 May-Jun;27(3):144-7.
22. Dervis E, Demirkesen C. Generalized
linear porokeratosis. Int J Dermatol. 2006
Sep;45(9):1077-9.
23. Malhotra SK, Puri KJ, Goyal T, Chahal KS.
Linear porokeratosis. Dermatol Online J. 2007
Oct 13;13(4):15.
24. Garg T, Ramchander, Varghese B, Barara M,
Nangia A. Generalized linear porokeratosis: a
rare entity with excellent response to acitretin.
Dermatol Online J. 2011 May 15;17(5):3.
Correspondence: Stephanie Blackburn, DO;
[email protected]
11. Tsambaos D, Spiliopoulos T. Disseminated
superficial
porokeratosis:
complete
remission subsequent to discontinuation of
immunosuppression. J Am Acad Dermatol.
GENERALIZED LINEAR POROKERATOSIS: A CASE REPORT AND DISCUSSION
Permanent Imiquimod-induced Depigmentation
Anne Donato, MD,* J. Kate Jackson, PA-C,** Laura Sandoval, DO,*** Jonathan S. Crane, DO, FAOCD****
*Internal Medicine Resident, 1st year, New Hanover Regional Medical Center, Wilmington, NC
**Dermatology Physician Assistant, Dermone, Wilmington, NC
***Dermatology Resident, 1st year, Campbell University School of Osteopathic Medicine, Buies Creek, NC; Sampson Regional Medical Center, Clinton, NC
****Dermatologist, Dermone, Wilmington, NC; Campbell University School of Osteopathic Medicine, Buies Creek, NC; Dermatology Residency Program Director, Sampson
Regional Medical Center, Clinton, NC
Abstract
Imiquimod may be used as a topical therapy for actinic keratosis.1 We report on a patient treated with imiquimod for actinic keratoses who developed an inflammatory
reaction, which subsequently resulted in depigmentation of the skin at the sites of imiquimod application. At nine-year follow-up, the patient still had skin
depigmentation. We hope to increase awareness amongst dermatologists of this rare but potentially permanent adverse effect of imiquimod and discuss the possible
mechanisms by which depigmentation may occur.
Introduction
Imiquimod is a topical immune-response modifier
commonly used in dermatology. It is approved by
the U.S. Food and Drug Administration (FDA)
for the treatment of condyloma acuminata;
non-hyperkeratotic, non-hypertrophic actinic
keratosis; and superficial basal-cell carcinomas
less than 2 cm in diameter located on the trunk
(excluding anogenital area), neck, or extremities
(excluding hands and feet).1 The most frequently reported dermatologic
adverse reactions include localized erythema,
xeroderma, and crusted skin.1 Pigmentary
changes secondary to imiquimod use have been
previously reported and are therefore mentioned
as a possible side effect on the package.2 However,
there are relatively few clinical cases available
in the literature, and there is a lack of multiyear follow-up to determine the duration of
depigmentation. The FDA lists 68 reports of
pigmentary changes out of a total of 1,257 reports
related to imiquimod from 1997 to 2003.3 In
this case, we report an unusual presentation of
imiquimod-induced depigmentation with nine
years of follow-up, supporting the possibility that
this adverse effect may be permanent.
Case Report
A 57-year-old woman presented with multiple
actinic keratoses at various locations including
the nose, right upper lip, and chest. She was
prescribed imiquimod 5% cream to apply to
the lesions Monday, Wednesday, and Friday
nights. After one month, this was increased to
application every night for three weeks. Five days
after starting the nightly application, the patient
called complaining of swelling and blistering
around her lips, swelling around her eyes, and
erythema where she had applied the imiquimod.
She was instructed to stop the imiquimod and
return to office for evaluation. On evaluation, the
patient was noted to have erythema, edema, and
crusting on facial and chest application sites. The
patient was instructed to use petroleum jelly three
times a day and continue the discontinuation
of topical imiquimod. At the follow-up two
months later, the patient had developed areas of
DONATO, JACKSON, SANDOVAL, CRANE
depigmentation on the chest from the imiquimod.
Nine years after use of imiquimod cream, the
patient continues to have areas of depigmentation
on her chest (Figure 1).
Discussion
Imiquimod-induced depigmentation is a
rare side effect. In our case, depigmentation
continued at nine years post imiquimod therapy,
providing valuable insight suggesting that the
depigmentation can be permanent. A literature
review revealed the development of imiquimodinduced depigmentation in a limited number of
previously published case reports.3-15 The nineyear follow-up in our case supports that this effect
may be long-lasting and of cosmetic significance
to patients.
The possible mechanism of the pigmentary
changes secondary to imiquimod use relates to
its properties as an immune-response modifier.
Imiquimod stimulates cytokine production
(interferon-alpha,
interferon-gamma,
and
interleukin-12), thereby leading to cell-mediated
immunity including anti-viral and anti-tumor
activity.16,17 This creates an inflammatory
reaction, such as the erythema that our patient
initially experienced where she applied the
imiquimod cream. Thus, the depigmentation
may be analogous to post-inflammatory
hypopigmentation.
Additional mechanisms may also play a role.
Imiquimod may further cause depigmentation
via a mechanism similar to the pathogenesis of
vitiligo. Imiquimod promotes cytokine release,
which results in the activation of cytotoxic T cells
and antigen presentation by Langerhans cells.17
Depigmentation in vitiligo occurs with the
presentation of autoantigens by Langerhans cells
leading to activation of cytotoxic T cells to destroy
melanocytes. Melanocytes also have increased
sensitivity to the oxidative stress that may be
mediated by imiquimod.18 Depigmentation may
Page 45
be a result of direct effects on melanocytes. One
study demonstrated that imiquimod induces
apoptosis of melanocytes.19 Therefore, the
desirable therapeutic anti-viral and anti-tumor
effects of imiquimod, through a mechanism
involving inflammation and Langerhans cells
antigen presentation, may also lead to the
undesirable side effect of depigmentation.
Imiquimod may also lead to depigmentation via
its signaling of the innate immune system through
toll-like receptor 7 (TLR7).20 Melanocytes treated
with imiquimod led to reduced pigmentation,
suggesting TLRs in melanocytes play a role in
inflammation-related pigmentary changes.
Conclusion
Given that imiquimod is a commonly used
therapy, dermatologists should be aware of the
potential side effect of depigmentation that may
be permanent. Patients should be educated about
their treatment options and informed about
this possible side effect before deciding whether
or not to use imiquimod therapy. Alternative
treatments such as cryosurgery may also result
in depigmentation; in fact, in a small study
comparing cryotherapy to imiquimod therapy
for actinic keratosis, the cosmetic outcome was
better with imiquimod, with significantly fewer
patients experiencing hypopigmentation.21 The
mechanism leading to imiquimod-induced
depigmentation likely involves post-inflammatory
hypopigmentation as well as immune-mediated
effects on melanocytes.
References
1. Imiquimod: Drug Information [Internet].
Waltham, MA: UpToDate. [Cited 2014 Aug
24]. Available from http://www.uptodate.com/
contents/imiquimod-drug-information.
2. ALDARATM (imiquimod) cream, 5%
[Internet]. FDA. [Cited 2014 Aug 24]. Available
from http://www.accessdata.fda.gov/drugsatfda_
docs/label/2002/20723s11s12lbl.pdf.
3. Brown T, Zirvi M, Cotsarelis G, Gelfand JM.
Vitiligo-like hypopigmentation associated with
imiquimod treatment of genital warts. J Am Acad
Dermatol. 2005 Apr;52(4):715-6.
4. Al-Dujaili Z, Hsu S. Imiquimod-induced
vitiligo. Dermatol Online J. 2007;13(2):10.
5. Burnett CT, Kouba DJ. Imiquimod-induced
depigmentation: report of two cases and
review of the literature. Dermatol Surg. 2012
Nov;38(11):1872-5.
6. Gowda S, Tillman DK, Fitzpatrick JE, Gaspari
AA, Goldenberg G. Imiquimod-induced vitiligo
after treatment of nodular basal cell carcinoma. J
Cutan Pathol. 2009 Aug;36(8):878-81.
7. Jacob SE, Blyumin M. Vitiligo-like
hypopigmentation with poliosis following
treatment of superficial basal cell carcinoma with
imiquimod. Dermatol Surg. 2008 Jun;34(6):8445.
imiquimod cream. Clin Exp Dermatol. 2006
Sep;31(5):721-2.
9. Senel E, Seckin D. Imiquimod-induced
vitiligo-like depigmentation. Indian J Dermatol
Venereol Leprol. 2007 Nov-Dec;73(6):423.
10. Serrao VV, Paris FR, Feio AB. Genital
vitiligo-like depigmentation following use of
imiquimod 5% cream. Eur J Dermatol. 2008
May-Jun;18(3):342-3.
11. Stefanaki C, Nicolaidou E, Hadjivassiliou M,
Antoniou C, Katsambas A. Imiquimod-induced
vitiligo in a patient with genital warts. J Eur Acad
Dermatol. 2006 Jul;20(6):755-6.
12. Urbina F. Giant basal cell carcinoma.
Improvement and vitiligo-like hypopigmentation
after intermittent treatment with 5% imiquimod.
Acta Dermatol Croatica. 2012 Dec;20(4):275-8.
13. Sriprakah K, Godbolt A. Vitiligo-like
depigmentation induced by imiquimod treatment
of superficial basal cell carcinoma. Aust J
Dermatol. 2009 Aug;50(3):211-13.
14. Li W, Xin H, Ge L, Song H, Cao W.
Induction of vitiligo after imiquimod treatment
of condylomata acuminata. BMC Infectious
Diseases. 2014 Jun; 14: 329.
15. Kwon HH, Cho KH. Induction of VitiligoLike Hypopigmentation after Imiquimod
Treatment of Extramammary Paget’s Disease.
Ann Dermatol. 2012 Nov; 24(4):482-84.
16. Sauder DN. Immunomodulatory and
pharmacologic properties of imiquimod. J Am
Acad Dermatol. 2000 Jul;43(1 Pt 2):S6-11.
17. Suzuki H, Wang B, Shivji GM, Toto P,
Amerio P, Tomai MA, et al. Imiquimod, a topical
immune response modifier, induces migration
of Langerhans cells. J Invest Dermatol. 2000
Jan;114(1):135-41.
18. Mashiah J, Brenner S. Possible mechanisms in
the induction of vitiligo-like hypopigmentation
by topical imiquimod. Clin Exp Dermatol. 2008
Jan;33(1):74-6.
19. Kim CH, Ahn JH, Kang SU, Hwang HS,
Lee MH, Pyun JH, et al. Imiquimod induces
apoptosis of human melanocytes. Arch Dermatol
Res. 2010 May;302(4):301-6.
20. Jin SH, Kang HY. Activation of toll-like
receptors 1, 2, 4, 5, and 7 on human melanocytes
modulate pigmentation. Ann Dermatol. 2010
Nov;22(4):486-9.
21. Foley P, Merlin K, Cumming S, Campbell
J, Crouch R, Harrison S, et al. A comparison
of cryotherapy and imiquimod for treatment
of actinic keratosis: lesion clearance, safety, and
skin quality outcomes. J Drugs Dermatol. 2011
Dec;10(12):1432-8.
Correspondence: Jonathan S. Crane, DO,
FAOCD; [email protected]
8. Mendonca CO, Yates VM. Permanent facial
hypopigmentation following treatment with
Page 46
PERMANENT IMIQUIMOD-INDUCED DEPIGMENTATION
Telangiectasia Macularis Eruptiva Perstans:
A Case Presentation and Discussion
Sergey Petrosian, BS,* Shane Meehan, MD,** Anna Slobodskya, DO,*** Peter Saitta, DO****
*Medical Student, 3rd year, New York Institute of Technology College of Osteopathic Medicine, Old Westbury, NY
**Director of Dermatopathology, Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY
***Dermatology Resident, 1st year, St. John Episcopal Hospital, Far Rockaway, NY
****Dermatologist and Clinical Instructor, Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY
Abstract
Telangiectasia macularis eruptiva perstans (TMEP) is a rare subtype of cutaneous mastocytosis that tends to appear during adulthood. Cutaneous mastocytosis is a
proliferation of mast cells limited to the skin that spares other organs. Dermatoscopy of the lesions show red-to-brown, telangiectatic macules diffusely spread over the
trunk and upper extremities. We present a case of a 32-year-old male with TMEP who lacked systemic symptoms and discuss the clinical presentation, histopathology,
and treatments.
Another 3 mm punch biopsy was taken from
the patient’s lower back on the right side. The
pathology report described occasional small
lymphocytes and scattered mast cells (Figure 5).
Leder stain highlighted approximately 18 mast
cells per high power field in the papillary and
superficial dermis (Figure 6).
The patient was sent for genetic testing. No
abnormalities were reported.
The constellation of physical and histological
features pointed toward a diagnosis of
telangiectasia macularis eruptiva perstans.
Discussion
Figure 1. Multiple brown-to-red, telangiectatic macules of varying sizes, diffusely distributed on
the patient’s back.
preceding illness, dyspnea, epistaxis, abdominal
pain and diarrhea. Past medical and surgical
history was insignificant. Family history included
a first cousin on the maternal side with vitiligo
and epistaxis and a mother who died of breast
cancer. The patient had no known drug allergies.
Figure 2. Erythematous, telangiectatic macules
of varying sizes on the patient’s chest.
Case Report
A 32-year-old Caucasian male presented
complaining of new-onset skin lesions on his
chest, back and left eye. He reported that the
lesions began to appear about three months
prior and since then had increased in number.
The patient complained that the lesions felt
pruritic, burning and very uncomfortable. He also
reported that he had sudden onset of flushing
and sweating with stress. A review of systems was
negative for weight loss, constitutional symptoms,
PETROSIAN, MEEHAN, SLOBODSKYA, SAITTA
Physical examination revealed no visible oral
mucosal telangiectasias or lesions. Cutaneous
findings included multiple brown-to-red,
telangiectatic macules of varying sizes diffusely
placed on the body, with the majority of the
lesions present on the scapula (Figures 1 and
2). The remainder of the exam was essentially
normal.
A total tryptase level, CBC with differential,
CMP, BMP, and thyroid-hormone level were
obtained, and all were within normal limits.
A 6 mm biopsy was taken from the patient’s skin
overlying the right scapula. The pathology report
described dilated small blood vessels within the
superficial dermis (Figure 3). A Leder stain
highlighted a slightly increased number of mast
cells within the dermis (Figure 4).
Mastocytosis is a collection of rare disorders, all
caused by the pathologic proliferation of mast
cells. The disorders are typically categorized
into two major subtypes based on whether or
not the proliferation is localized. When limited
to the skin, the term “cutaneous mastocytosis” is
used. If the proliferation of cells is widespread
throughout the organs of the body, it is termed
“systemic mastocytosis.”1 Mast cells play a role in
inflammatory and allergic responses by releasing
cytokines, histamines, tryptases, interleukins and
other chemical mediators upon degranulation.
The downstream effects of these mediators on
their receptors cause the clinical manifestations
seen in mastocytosis.
Systemic mastocytosis is marked by syncope,
tachycardia, pruritus, dyspnea, abdominal pain,
diarrhea or flushing.1 Cutaneous mastocytosis, on
the other hand, does not manifest with systemic
symptoms. It is subdivided into four categories:
urticaria pigmentosa, mastocytoma, diffuse
and erythrodermic cutaneous mastocytosis,
and telangiectasia macularis eruptiva perstans
(TMEP).1,2 TMEP was initially described
by Parkes Weber in 1930 and is found in less
than 1% of patients diagnosed with cutaneous
mastocytosis.2,3
TMEP, unlike the other types of cutaneous
mastocytosis, often presents in adulthood.3
Clinically, it is characterized by red-to-brown,
telangiectatic macules. The lesions are usually
Page 47
between 2 mm and 4 mm in diameter and are
commonly found on the trunk and proximal
extremities, symetrically.3 The palms, soles and
face are classically spared.3 There may be variable
amounts of pruritus associated with the lesions.
Darier’s sign (urticaria after friction accompanied
with erythema, pruritus and swelling) is
commonly absent in this form of cutaneous
mastocytosis, but is found in other types.
Figure 3. Scapula lesion, H&E stain: Increased
perivascular and interstitial mast cells
surrounding dilated telangiectatic blood
vessels. Figure 4. Scapula lesion, Leder stain: Mast
cells surrounding dilated, thin-walled
blood vessels in the dermis.
Figure 5. Lower-back lesion, H&E stain:
Increased perivascular and interstitial mast
cells surrounding dilated telangiectatic blood
vessels. TMEP has been found in the setting of systemic
mastocytosis.2,3 Suspicion of systemic involvement
should arise if patients have simultaneous
symptoms of anaphylaxis, dyspnea, diarrhea,
syncope, tachycardia, pruritus, abdominal pain,
and flushing.1 Tryptase is a large component of
the granules contained within mast cells, and
therefore measuring the total serum tryptase level
is a good test to decipher if patients have systemic
involvement.
Histopathologic studies of skin biopsies are used
to confirm the diagnosis of TMEP. Histologically,
TMEP demonstrates increased perivascular and
interstitial mast-cell collections surrounding
dilated telangiectatic blood vessels.4 The mast
cells are usually located in the upper portion
of the dermis, surrounding the dilated blood
vessels.4 The number of mast cells is only slightly
increased, and there may also be associated
findings of epidermal hyperpigmentation.3
There is no gold standard therapy for TMEP, and
the goal is to alleviate symptoms. H1 antihistamine
antagonists can be used to treat the pruritus and
flushing symptoms, while H2 antagonists can be
used in treating the gastric hypersecretion.3,5,6 It is
important for patients to avoid triggers that can
stimulate mast-cell degranulation. Triggers can
include, but are not limited to: alcohol, bacterial
toxins, stress, exercise, food, sunlight, temperature
extremes, narcotics and anesthesia.3,7,8 Psoralen
(oral), UVA photochemotherapy, high-dose
UVA-1 and narrow-band UVB phototherapy
have all been shown to improve symptoms
and cosmetic appearance.3,9-11 Surgery via a
585 nm flashlamp-pumped dye laser has also
shown cosmetic improvement in the cutaneous
lesions.3,12,13 The replacement of antihistamine
therapy with montelukast therapy was shown to
be effective in the treatment of TMEP.14 Most of
the results from treatment are temporary unless
therapy is continued indefinitely. A recent study
used cabozantinib, a signal transduction inhibitor
that blocked growth of mast cells with the D816V
codon mutation.15
References
1. Izikson L, English JC, Zirwas MJ. The flushing
patient: differential diagnosis, workup, and
treatment. J Am Acad Dermatol. 2006;55:193–
208.
Figure 6. Lower-back lesion, Leder stain:
Mast cells surrounding dilated, thin-walled
blood vessels in the dermis. Page 48
2. Soter NA. Mastocytosis and the skin. Hematol
Oncol Clin North Am. 2000;14: 537-55.
3. Watkins C, Bokor W, Leicht S, Youngberg
G, Krishnaswamy G. Telangiectasia macularis
eruptiva perstans: more than skin deep.
Dermatology Reports [serial online]. January
2011;3(1):23-30.
4. Ragi J, Lazzara DR, Harvell JD, Milgraum
SS. Telangiectasia Macularis Eruptiva Persians
Presenting as Island Sparing. Journal Clin
Aesthet Dermatol. 2013;6(4):41-42.
5. Crawhall JC, Wilkinson RD. Systemic
mastocytosis: management of an unusual case
with histamine (H1 and H2) antagonists and
cyclooxygenase inhibition. Clin Invest Med.
1987;10:1-4.
6. Johnson GJ, Silvis SE, Roitman B, et al.
Long-term treatment of systemic mastocytosis
with histamine H2 receptor antagonists. Am J
Gastroenterol. 1980;74:485-9.
7. Murali MR, Castells MC, Song JY, et al. Case
records of the Massachusetts General Hospital.
Case 9-2011. A 37-year- old man with flushing
and hypotension. N Engl J Med; 2011;364:115565.
8. Alto WA, Clarcq L. Cutaneous and systemic
manifestations of mastocytosis. Am Fam
Physician. 1999;59:3047-60.
9. Sotiriou E, Apalla Z, Ioannides D.
Telangiectasia macularis eruptive perstans
successfully treated with PUVA therapy.
Photodermatol Photoimmunol Photomed.
2010;26:46-7.
10. Prignano F, Troiano M, Lotti T. Cutaneous
mastocytosis:
successful
treatment
with
narrowband ultraviolet B phototherapy. Clin Exp
Dermatol. 2010;35:914-5.
11. Czarnetzki BM, Rosenbach T, Kolde G, et
al. Phototherapy of urticaria pigmentosa: clinical
response and changes of cutaneous reactivity,
histamine and chemotactic leukotrienes. Arch
Dermatol Res. 1985;277:105-13.
12. Monahan TP, Petropolis AA. Treatment
of telangiectasia macularis eruptiva perstans
with total skin electron beam radiation. Cutis.
2003;71:357-9.
13. Ellis DL. Treatment of telangiectasia
macularis eruptiva perstans with the 585-nm
flashlamp-pumped dye laser. Dermatol Surg.
1996;22:33.
14. Cengizlier R, et al. Treatment of telangiectasia
macularis eruptive perstans with montelukast.
Allergol Immunopathol (Madr). 2009;37:334
15. Shah K, Dunn A, Amato C, et al.
Carbozantinib may be an effective treatment
of TMEP with D816V mutation in KIT. J Am
Acad Dermatol. 2014;70(5)(suppl1):AB132
Correspondence:
[email protected]
Sergey
Petrosian,
BS;
TELANGIECTASIA MACULARIS ERUPTIVA PERSTANS: A CASE PRESENTATION AND DISCUSSION
Hypomelanosis of Ito in Two Infants:
A Case Series with Literature Review
Mathew Koehler, DO,* Nicole Rouse, BS,** Tarin Molly Koehler, DO,*** Navid Nami, DO****
*Dermatology Resident, 2nd year, Opti-West/College Medical Center, Long Beach, CA
**Medical Student, 4th Year, Western University of Health Sciences, College of Osteopathic Medicine, Pomona, CA
***Family Medicine Physician, Venice Family Clinic, Venice, CA
****Dermatology Residency Program Director, Opti-West/College Medical Center, Long Beach, CA
Abstract
Hypomelanosis of Ito is an uncommon condition representing pigmentary and chromosomal mosaicism. Characteristic findings include whorls and streaks of
hypopigmentation involving some or all of the skin surface and generally following the lines of Blaschko. Associated systemic findings include orthopedic, neurologic,
ocular and dental anomalies, but the severity of extracutaneous involvement varies greatly from cases to case. We report two cases of hypomelanosis of Ito: a 4-month-old
male infant with extensive cutaneous involvement, associated joint contractures and presumed neurologic developmental delay; and a 3-month-old male with limited
skin involvement and no apparent systemic involvement.
Introduction
Pigmentary disorders are common in infants
and children, often causing emotional distress
to parents and providers. Hypomelanosis of
Ito is an uncommon condition representing
somatic mosaicism, with hypopigmented patches
and streaks following the lines of Blaschko.
Associated systemic findings range from none to
severe systemic effects. The diagnosis is clinical,
based on history and physical examination,
and subsequent workup is based on associated
findings. Currently, there is no treatment for
cutaneous manifestations.
Case Reports
Case 1
A 4-month-old male Hispanic infant presented
to our clinic with a primary concern of unusual
pigmentation covering the child’s entire body.
The mother stated that when the infant was
born, she noticed mild pigmentation changes,
but by two weeks of age the pigmentation was
very noticeable. The child had been diagnosed
with bilateral sensorineural hearing loss, plantar
flexion contractures of the feet bilaterally, ankle
contractures and flexion contractures of the
fingers. His pediatrician was concerned for
developmental delay based on poor head control
and delayed motor skills. The gestational period
was uneventful, with the patient being born
at term with a normal vaginal delivery. Family
history was reviewed and not contributory.
On examination, the patient had whorls and
streaks of hypopigmented patches involving the
majority of his skin surface in a blaschkolinear
pattern (Figures 1 and 2). The patient had no
teeth at the time of examination. Examination
of the eyes revealed matching eye color and no
strabismus. Head control was indeed poor, and he
had stiff joints of the hands and feet bilaterally.
No laboratory work or biopsies were done. Based
on the child’s history and physical examination, a
diagnosis of hypomelanosis of Ito was made. No
specific treatments were rendered, but referrals
were made to a geneticist, neurologist and
orthopedic surgeon for evaluation and possible
treatment. Since initial evaluation, the patient has
been lost to follow-up.
KOEHLER, ROUSE, KOEHLER, NAMI
Case 2
A 3-month-old male Indian infant presented
to our clinic for concerns of pigmentation
changes. The parents stated that at birth it was
undetectable, but the pigmentation became
pronounced by about six weeks of age. They had
tried hydrocortisone lotion as well as emollients
without improvement. Beyond his skin findings,
the child has been eating well and meeting all
milestones. Family history was reviewed and
found to be non-contributory.
Physical examination showed the ventral aspect
of the child’s trunk, the proximal legs and the
left forearm to have hypopigmented patches
following a blaschkolinear pattern (Figure 3).
The remaining body surfaces had no noticeable
pigmentation changes. The child did not
have teeth at the time of exam. There were no
noticeable musculoskeletal abnormalities, and eye
examination showed matching irises. The child’s
case was discussed with the pediatrician and the
parents, and no referrals were made. Instead,
we decided to continue to monitor the child’s
development and make further evaluations based
on potential findings as they arise.
Figure 2
Figure 3
Discussion
Figure 1
Hypomelanosis of Ito (HI) is an uncommon
syndrome presenting as hypopigmented
whorls or streaks that generally follow the
lines of Blaschko. This striking physical
Page 49
Table 1. Diagnostic Criteria Proposed by Ruiz-Maldonado, et al.1
Criteria 1
(must have)
Congenital or acquired nonhereditary cutaneous hypopigmentation in
linear streaks or patches involving more than two body segments
Minor
2+ congenital malformations other than neuro or MSK
Chromosomal anomalies
Major
Definitive dx
Presumptive dx
1+ nervous system anomalies
1+ MSK anomalies
Criteria 1 and 1+ Majors, or
Criteria 1 and 2+ Minors
Criteria 1 alone, or
Criteria 1 with 1 minor
pattern represents chromosomal mosaicism in
pigment production of the skin.1 The majority
of cases follow the blaschkolinear pattern, but
occasionally checkerboard, dermatomal, phylloid
and plaque-like patterns can be found.2-4 The
extent of involvement varies from segmental to
total cutaneous involvement.5 It presents within
the first year of life in 75% of patients, with
lighter-skinned children sometimes presenting
as late as childhood. There is a slight female
predominance.6 Historically, HI had been
described as incontinentia pigmenti achromians,
as it appeared to be a negative image of
incontinentia pigmenti, but this term has fallen
out of favor because the two conditions are not
related.
Associated systemic abnormalities are common,
but hypopigmentation is the only constant feature
and has wide phenotypic variability based on
when gene defects occurred during embryologic
migration.5 As this condition is uncommon,
Table 2. Differential Diagnosis of Blaschkolinear Pigment Alteration
Condition
Hypomelanosis
of Ito
Incontinentia
Pigmenti
Lichen Striatus
Linear and
Whorled Nevoid
Hypermelanosis
(LWNH)
McCune-Albright
Syndrome
Focal Dermal
Hypoplasia (Goltz
Syndrome)
Page 50
and many mild cases likely go unreported, it is
difficult to know the true number of HI cases that
have associated systemic anomalies. Nehal et al.
found that extracutaneous manifestations were
only present in 33% of cases, and that the severity
of these symptoms was directly correlated with
the level of mosaicism, as with our two patients.7
Associated
findings
include
neurologic,
musculoskeletal (MSK), dental and ocular
abnormalities.5 Neurologic symptoms are most
common, ranging from seizures to severe mental
retardation. Musculoskeletal symptoms are
also common and include abnormalities of the
phalanges, limbs, spine, skull and sternum.2,8-10
Dental abnormalities include anodontia and
dysplasia. Strabismus and hypertelorism have
been reported. Recently, an infant was diagnosed
with HI and associated pulmonary hypoplasia.11
Diagnosis is clinical, based on the cutaneous
findings, but associated symptoms may help
identify HI. Some authors, however, only apply the
term HI when there are extracutaneous symptoms
associated with the hypopigmentation.12
Alternative terms to use for patients with only
cutaneous findings could be “linear nevoid
Presentation
Associated Findings
- X-linked dominant, and deadly in males
- NEMO gene mutation
- Four stages:
Newborns: linear papules and vesicles; eosinophilia
Lesions progress to verrucous streaks that usually
resolve
3-6 months: hyperpigmented whorls and swirls along
Blaschko lines
2nd-3rd decade: hyperpigmented whorls become
hypopigmented
- Scarring alopecia
- Dystrophic nail changes
- Anodontia or conical deformities of the teeth
- Ophthalmologic problems
- Central nervous system manifestations
- Also represents somatic mosaicism
- Hyperpigmented and hypopigmented macules that
follow lines of Blaschko
- Present at birth or in infancy and continues to grow
for 1-2 years, then stabilizes
- Variable, may have no findings
- Central nervous system involvement
- Musculoskeletal abnormalities
- Heart abnormalities
- Numerous genetic defects associated
- Somatic mosaicism
- Hypopigmented macules and papules that follow the
lines of Blaschko
- Covers more than two dermatomes
- Often bilateral, but not symmetrical
- Sudden eruption of erythematous or skin-toned linear
papules
- Usually asymptomatic, but can be pruritic
- Active eruption lasts approximately 6-12 months
- Post-inflammatory pigment alteration common for
years
- Unilateral
- GNAS1 mutation
- Café-au-lait macules that follow the lines of Blaschko
and present in infancy
- Often unilateral
- “Coast of Maine” border of café-au-lait macule
- X-linked dominant
- Mutation in PORCN gene
- Hypopigmented or hyperpigmented blaschkolinear
lesions with associated dermal atrophy and
telangiectasias
- Central nervous system involvement (seizures, mental retardation)
- Dental anomalies
- Musculoskeletal abnormalities
- Abnormal neural migration1
- Nail involvement possible.
- No known associated systemic findings
- Multiple endocrine abnormalities
- Precocious puberty
- Polyostotic fibrous dysplasia
- Oral mucosal lentigines may present later in life
- Ectrodactyly (lobster-claw deformity)
- “Raspberry-like” papillomas favoring perioral and perianal area
- Ocular and dental abnormalities common
HYPOMELANOSIS OF ITO IN TWO INFANTS: A CASE SERIES WITH LITERATURE REVIEW
hypopigmentation” or “pigmentary mosaicism.”
This naming system seems ill-conceived, though,
since the true effects of subtle neurologic and
extracutaneous defects may not be evident until
years later, as developmental milestones and
speech progress, and the eventual recognition
of those defects would require a renaming of
the child’s condition. We prefer to consider this
a spectrum of disease and use HI to describe all
patients with this phenotypic pattern.
In 1992, Ruiz-Maldonado et al. proposed criteria
to diagnose HI, found in Table 1.10 They based
the criteria on clinical experience and previous
reports, though they admit the criteria may not
be accurate in diagnosing HI until its etiology
has been found. They categorized the presence of
chromosomal anomalies as a minor criterion, and
present HI as a neurocutaneous syndrome. While
significant advances have been made since this
classification was introduced, it may still provide
useful guidance for practitioners.
Mosaicism is the presence of two genetically
distinct cell lines in a single person derived from
a homogeneous zygote.13-15 In embryogenesis,
chromosomes are randomly distributed and
migrate dorsoventrally along lines of Blaschko,
resulting in two populations of epidermal skin
with different pigment-producing potential.
Phenotype varies greatly depending on the
timing of the mutation and the cell lines affected.
As would be expected, a mutation presenting
earlier in embryologic development will have
more widespread pigmentary mosaicism and be
associated with more severe systemic findings.7
Mutations occurring late in development are
likely more segmental and associated with absent
or mild systemic findings. Our two cases seem to
support this.
Multiple genetic defects have been found in
patients with HI. Thomas et al. found mosaicism
in lymphocytes and skin fibroblasts along with
autosomal or sex chromosomes.4 Moss et al.,
however, found no dermal abnormalities but did
find mosaicism within involved keratinocytes16
Pascual-Castroviejo et al. recorded autosomaldominant inheritance in some patients, but
most cases appear to be sporadic.9 Happle et al.
published a case report of sporadic inheritance in
a 26-year old male.17 Despite the variation, four
common genetic defects have been found: short
arm of X-chromosome (XP11), short arm of
chromosome 12, trisomy of chromosome 18, and
triploides.1,18 In addition, failure of X-inactivation
(lyonization) may be responsible for sporadic
cases of HI.19
Histopathologic examination could be useful if the
diagnosis is in doubt, but it is not required in the
evaluation of HI. Histology can show only subtle
changes of fewer melanocytes and fewer, smaller
melanosomes that do not produce sufficient
pigment.2,6 Cytogenetic analysis may reveal
chromosomal mosaicism in the keratinocytes, but
this test may not be available in all areas. Electron
microscopy reveals fewer dendrites.20-23 None of
the histological, genetic or electron-microscopy
findings are adequate to diagnose HI. Differentials
for hypopigmentation that follow Blaschko lines
can be found in Table 2.
Presentations of HI may vary, and it is important
to perform a thorough examination to identify
any concurrent musculoskeletal, neurologic,
KOEHLER, ROUSE, KOEHLER, NAMI
dental and ocular symptoms. Identification of
hypopigmentation can be made with histology,
genetic testing and Wood’s light. Once HI is
suspected, optional testing includes radiography
for skeletal abnormalities, electromyelography
(EMG) for muscle function, head CT or MRI,
ophthalmologic exam, and electroencephalography
(EEG) if seizures are present. Magnetic resonance
imaging appears to be the most sensitive test to
visualize neural migration abnormalities.24,25 It
is prudent to involve primary care, orthopedic or
physical medicine specialists, and neurologists (as
needed) early in the patient’s life. A referral to a
geneticist is also likely warranted.
Conclusion
There are no specific treatments for
hypomelanosis of Ito, but prompt identification
of associated findings may improve prognosis
in patients. Once identified, early involvement
of a multidisciplinary team is warranted based
on the extracutaneous findings. The striking
physical findings are a result of pigmentary and
chromosomal mosaicism, but there is still much
to be learned about the genetic mutations leading
to these findings. With improved knowledge,
more focused workups and treatments may be
available in the future.
References
1. Hamosh A. Hypomelanosis of Ito. HMI
Johns Hopkins University. 2001 [updated 2011;
cited 2014]. Available from: http://www.omim.
org/entry/300337?search=hypomelanosis
of
ito&highlight=hypomelanosi of ito.
2. Kuster W, Konig A. Hypomelanosis of Ito: no
entity, but a cutaneous sign of mosaicism. Am J Med
Genet. 1999;85(4):346-50.
3. Metzker A, Morag C, Weitz R. Segmental
pigmentation disorder. Acta Derm Venereol.
1983;63(2):167-9.
4. Thomas IT, Frias JL, Cantu ES, Lafer CZ,
Flannery DB, Graham JG, Jr. Association of
pigmentary anomalies with chromosomal and
genetic mosaicism and chimerism. Am J Hum
Genet. 1989;45(2):193-205.
5. Ponti G, Pellacani G, Tomasi A, Percesepe A,
Guarneri C, Guerra A, et al. Hypomelanosis of Ito
with a trisomy 2 mosaicism: a case report. J Med
Case Rep. 2014;8:333.
6. Sharma S, Gupt R, Saxena GN, Raghu MS,
Patodi A. Hypomelanosis of Ito. J Assoc Phys India.
2014;62(1):47-8.
7. Nehal KS, PeBenito R, Orlow SJ. Analysis of 54
cases of hypopigmentation and hyperpigmentation
along the lines of Blaschko. Arch Dermatol.
1996;132(10):1167-70.
8. Jelinek JE, Bart RS, Schiff SM. Hypomelanosis of
Ito (“incontinentia pigmenti achromians”). Report
of three cases and review of the literature. Arch
Dermatol. 1973;107(4):596-601.
9. Pascual-Castroviejo I, Lopez-Rodriguez L, de
la Cruz Medina M, Salamanca-Maesso C, Roche
Herrero C. Hypomelanosis of Ito. Neurological
complications in 34 cases. Can J Neurol Sci.
1988;15(2):124-9.
10. Ruiz-Maldonado R, Toussaint S, Tamayo L,
Laterza A, del Castillo V. Hypomelanosis of Ito:
diagnostic criteria and report of 41 cases. Pediatr
Dermatol. 1992;9(1):1-10.
11. Bhat RY, Patra S, Varma PV, Prakashini K.
Hypomelanosis of Ito with an unusual pulmonary
abnormality in an infant. Indian Dermatol Online
J. 2014;5(2):196-7.
12. Hall BD. Of mice, persons, and pigment. Am J
Hum Genet. 1989;45(2):191-2.
13. Donnai D, Read AP, McKeown C, Andrews T.
Hypomelanosis of Ito: a manifestation of mosaicism
or chimerism. Am J Med Genet. 1988;25(12):80918.
14. Ritter CL, Steele MW, Wenger SL, Cohen BA.
Chromosome mosaicism in hypomelanosis of Ito.
Am J Med Genet. 1990;35(1):14-7.
15. Sybert VP, Pagon RA, Donlan M, Bradley
CM. Pigmentary abnormalities and mosaicism for
chromosomal aberration: association with clinical
features similar to hypomelanosis of Ito. J Pediatr.
1990;116(4):581-6.
16. Moss C, Larkins S, Stacey M, Blight A, Farndon
PA, Davison EV. Epidermal mosaicism and
Blaschko’s lines. J Med Genet. 1993;30(9):752-5.
17. Happle R. Incontinentia pigmenti versus
hypomelanosis of Ito: the whys and wherefores of a
confusing issue. Am J Med Genet. 1998;79(1):64-5.
18. Koiffmann CP, de Souza DH, Diament A,
Ventura HB, Alves RS, Kihara S, et al. Incontinentia
pigmenti achromians (hypomelanosis of ITO, MIM
146150): further evidence of localization at Xp11.
Am J Med Genet. 1993;46(5):529-33.
19. Hatchwell E, Robinson D, Crolla JA, Cockwell
AE. X inactivation analysis in a female with
hypomelanosis of Ito associated with a balanced
X;17 translocation: evidence for functional disomy
of Xp. J Med Genet. 1996;33(3):216-20.
20. Grosshans EM, Stoebner P, Bergoend H,
Stoll C. [Incontinentia pigmenti achromians
(ITO). Clinical and histopathological study].
Dermatologica. 1971;142(2):65-78.
21. Happle R, Krenz J, Pfeiffer R. [Ito’s syndrome
(incontinentia pigmenti achromians)]. Hautarzt.
1976;27(6):286-90.
22. Nordlund JJ, Klaus SN, Gino J. Hypomelanosis
of Ito. Acta Derm Venereol. 1977;57(3):261-4.
23. Saxena U, Ramesh V, Iyengar B, Misra
RS. Hypomelanosis of ito: histochemical and
ultrastructural observations. Australas J Dermatol.
1989;30(1):45-7.
24. Ardinger HH, Bell WE. Hypomelanosis of Ito.
Wood’s light and magnetic resonance imaging as
diagnostic measures. Arch Neurol. 1986;43(8):84850.
25. Lungarotti MS, Martello C, Calabro A, Baldari
F, Mariotti G. Hypomelanosis of Ito associated with
chromosomal translocation involving Xp11. Am
Journal Med Genet. 1991;40(4):447-8.
Correspondence:
Mathew
[email protected]
Koehler,
DO;
Page 51
Phacomatosis Cesioflammea: A Case Report of a Newborn with
an Unusual Mongolian Spot and Port Wine Stain
Joy Ishii Zarandy, DO,* Sara Clark, MD,** Katherine Shew, MD***
* Family Medicine Resident, 2nd year, AnMed Health, Anderson, SC
**Pediatric Hospitalist, Greenville Health Hospital System, Greenville, SC
***Dermatologist, Anderson Dermatology and Skin Surgery Center, Anderson, SC
Abstract
Phacomatosis cesioflammea is a rare congenital cutaneous disorder that presents with aberrant Mongolian spot and port-wine stain in a newborn. About
half of reported cases develop extracutaneous symptoms, especially involving the central nervous system, so early diagnosis is key in managing these patients
so that appropriate referral to a specialist is promptly initiated.1 This case report documents the process of evaluating a newborn with an unusual Mongolian
spot and port-wine stain. A thorough list of differential diagnoses, including nevus simplex, arteriovenous malformations, infantile hemangioma, KlippelTrenaunay syndrome and Sturge-Weber Syndrome, was ruled out before ultimately diagnosing the patient with phacomatosis cesioflammea. After a year of
close neurodevelopmental monitoring, the patient has not manifested any systemic complications, and his prognosis remains good.
Introduction
Phacomatosis cesioflammea is the most
common subtype of a group of rare
congenital cutaneous abnormalities known
as phacomatosis pigmentovascularis (PPV).
The Latin translation of phacomatosis
cesioflammea, meaning “bluish gray” and
“flame,” appropriately describes the classic
appearance of congenital dermal melanocytosis
(Mongolian spots) and nevus flammeus (portwine stain). Cutaneous lesions alone are
largely asymptomatic, but approximately 50%
of cases have systemic involvement, which
usually presents within the first months of life.1
For this reason, a complete physical, including
a dilated ocular exam by an ophthalmologist,
and close neurodevelopmental monitoring
are imperative parts of management.1,2
Furthermore, keeping in mind a broad
differential is prudent when diagnosing any rare
disorder so as not to overlook a more common
condition with similar presentation. This case
report documents the process of diagnosing a
newborn with phacomatosis cesioflammea and
subsequent management considerations.
Case Report
A healthy term African-American male, born
vaginally after an uncomplicated pregnancy to
a 23-year-old G1P1, presented with unusual
skin findings on initial newborn exam (Figure
1). An extensive Mongolian spot covered his
right flank, buttock, and thigh (Figure 2), and
a large port-wine stain extended from his chest
to the fingertips of the right extremity (Figure
3). A 6 mm x 20 mm café-au-lait spot was
also noted on the right lower back. Limbs were
symmetric, without leg-length or limb-girth
discrepancies. History and clinical exam were
otherwise unremarkable. Family history was
significant only for eczema in his mother.
The first task at hand was to formulate a list
of differential diagnoses. Vascular birthmarks
such as port-wine stains are common findings
in a newborn, either in the absence of or
in association with congenital cutaneous
syndromes.3 Port-wine stains are low-flow
capillary malformations that present as
blanchable, red or pink patches in 0.1% to
2% of newborns.4 Nevus simplex, also known
as “salmon patch” or “stork bite,” is evident
in 80% of newborns and may be similar in
appearance to a port-wine stain.4 Unlike this
Figure 2
patient’s vascular markings, nevus-simplex
patches have indistinct borders, favor the
midline such as the nape of the neck or eyelids,
and resolve spontaneously. Arteriovenous
malformation, another vascular cutaneous
finding, may present as macular-vascular
patches that generally possess a thrill and grow
over time.5 Infantile hemangiomas, the most
frequently encountered type of vascular tumor,
often appear at birth as telangiectasia with
surrounding pallor due to vasoconstriction.4
These lesions may resemble port-wine stains in
early stages and then enlarge in the first few
years of life before spontaneously resolving.6
The prominence and unilaterality of the
patient’s port-wine stain, preferentially
distributed to the right upper extremity, raised
concern for presence of an associated syndrome
such as Klippel-Trenaunay syndrome (KTS)
or Sturge-Weber syndrome (SWS). KTS is
a congenital malformation of the capillary,
venous, and lymphatic systems in the
extremities. Cutaneous findings classically
present with unilateral extremity enlargement
from underlying musculoskeletal hypertrophy,
visceral hemangiomas, and venous varicosities.7
SWS presents with facial port-wine stain,
leptomeningeal capillary malformations, and
central nervous system (CNS) abnormalities
including seizures, mental retardation,
glaucoma or neurologic deficits. Cutaneous
manifestations are often progressive and
Figure 3
Figure1
Page 52
PHACOMATOSIS CESIOFLAMMEA: A CASE REPORT OF A NEWBORN WITH AN UNUSUAL MONGOLIAN SPOT AND PORT WINE STAIN
bilateral.8 After further evaluation, KTS and
SWS were placed low on the list of differential
diagnoses given that the patient had no note
of leg- or arm-size abnormalities and no
facial rashes, and these diagnoses would not
adequately explain the patient’s extensive
Mongolian spot.
Mongolian spots are the most common type
of hyperpigmented lesions in a newborn,
especially in Asian, African American, and
Hispanic populations.9
These lesions are
benign and present as blue-to-gray macules
due to delayed disappearance of dermal
melanocytes deep in the dermis. Pigment is
usually located near the sacral and buttock
area and fades within the first two years of
life.10 Lesions located in extrasacral areas are
known as “aberrant” and may raise concern for
underlying disorders. For example, perioral
Mongolian spots have been reported in 20% to
50% of patients with cleft lip.11 There have also
been cases of persistent ventrally and dorsally
distributed Mongolian spots associated with
certain lysosomal-storage disorders.12
The patient was eventually given a working
diagnosis of phacomatosis cesioflammea,
which was later confirmed by dermatology
consultation.
This cutaneous disorder
adequately explained the patient’s unusual
presentation of Mongolian spot and port-wine
stain. The overall anticipated prognosis for
this particular patient is good. The absence of
systemic involvement is especially encouraging.
Close contact has been maintained with the
patient’s mother and pediatrician, who report
he is happy and developing appropriately. He
had a dilated ocular exam per ophthalmology,
which was normal, and is to follow up annually
with dermatology to monitor cutaneous lesions.
Discussion
Phacomatosis pigmentovascularis, or PPV,
is a group of rare congenital cutaneous
abnormalities diagnosed clinically by the
coexistence of pigmented nevi and vascular
malformations.2
The first case of PPV
was described in 1947 by Ota et al., who
categorized the disorder into types I through
V, with subtype “a” for cutaneous involvement
only and “b” for presence of extracutaneous
findings.2 In 2005, a simpler classification
system was established by Happle involving
four main groups: phacomatosis cesioflammea,
phacomatosis
spilorosea,
phacomatosis
cesiomarmorata, and unclassifiable PPV.2
Phacomatosis cesioflammea, or PPV type
II, is diagnosed by the presence of aberrant
Mongolian spots and port-wine stain.
Additional cutaneous findings may include
nevus anemicus (hypopigmentation due to
permanent vasoconstriction), nevus of Ota
ZARANDY, CLARK, SHEW
(pigmentation along the first or second
branches of the trigeminal nerve), café-aulait macules, CNS involvement or ocular
symptoms. Prognosis of the disorder largely
depends on the presence of systemic disease.8
Roughly 250 total cases of PPV have been
reported worldwide, with phacomatosis
cesioflammea accounting for 77% of these
cases.2
Studies reveal a slight female
predominance8 as well as an increased
incidence in Argentinian, Hispanic, and
Japanese populations.13 Limited literature
of twin studies in PPV strongly suggest twin
discordance, in which monozygotic twins of
PPV patients are unaffected.14
The pathogenesis of PPV is largely unknown.
The most promising hypothesis involves “twin
spotting” or didymosis, a phenomenon wellstudied in plants and animals.15 Didymosis
represents a specific form of somatic
recombination whereby two neighboring
but genetically different mutant clonal cells
sporadically cross over to form distinctive
homozygous cell lines.1 In the case of PPV, this
process likely occurs in genes coding for vessel
and melanocyte development, thus resulting
in the mosaic appearance of both vascular and
pigmented nevi.14
Skin lesions alone are largely asymptomatic
and may lighten over time.16
However,
approximately 50% of PPV cases have
systemic involvement, usually appearing
within the first months of life.1 Research
suggests a correlation between the amount of
cutaneous involvement and an increased risk
for multi-systemic complications.8 The central
nervous system is most commonly affected,
presenting with seizures, cerebral atrophy,
neurodevelopmental
delay,
psychomotor
retardation, external hydrocephalus, stroke,
and intracerebral hemorrhage.8,13,16 Common
ocular findings include glaucoma, episcleral
vascular
malformations,
conjunctival
melanocytosis, primary acquired melanosis,
epiretinal membrane, vitreous hemorrhage,
pigmented cataracts, amblyopia, and related
choroidal melanoma.1,2 Other complications
include atrial septal defect, renal agenesis,
umbilical hernia, idiopathic facial paralysis,
diabetes insipidus, vitiligo, hyper IgE, IgA
deficiency, pyogenic granuloma, cavernous
hemangioma, scoliosis, premature tooth
eruption, macrocephaly, Arnold-Chiari type
I, syndactyly, bilateral deafness, and eczema.
Some reports note an association with KTS
and SWS.17
Initial workup should include a complete
physical exam, close neurodevelopmental
monitoring, and a thorough dilated ocular exam
by an ophthalmologist.2 No treatment may be
warranted in patients with cutaneous findings
only, but for cosmetic purposes a pulsed dye
laser can be used for nevus flammeus and a
Q-switched laser for pigmented nevi.16 These
procedures should be performed in childhood
before school age for the best results.18
Evidence of extracutaneous involvement may
require further evaluation with early referral
and prompt treatment to optimize patient
outcome.16
Conclusion
Mongolian spots and port-wine stains can be
common findings on initial newborn exams.
Special attention should be paid when dealing
with atypical presentations of these otherwisebenign pigmented and vascular birthmarks,
or if the two present simultaneously such
as in phacomatosis cesioflammea.
Upon
diagnosis, a thorough physical exam should
be performed, including a dilated eye exam by
an ophthalmologist and close monitoring for
signs of neurodevelopmental delay, to assess
for extracutaneous manifestations.2 In patients
with cutaneous findings alone, prognosis is
good, and treatments such as pulsed dye laser
or Q-switched laser are optional for cosmetic
purposes.16
Patients with extracutaneous
findings, which mainly involve the central
nervous system, may require referral to a
specialist for further management as indicated.
While phacomatosis cesioflammea is a rarely
reported disorder, physicians should keep it
in mind when evaluating any newborn with
prominent and unusual birthmarks.
Acknowledgments
Special thanks the patient’s mother for her close
communication and cooperation throughout
the writing of this article. Thanks as well to
AnMed Health Women’s and Children’s
Hospital, Dr. Lorraine Bruce, Dr. Matthew
Cline, Greenwood Genetics, Melanie LaVoie,
Dr. Theresa Knoepp, Dr. David Malpass, and
Dr. Mary K. Spraker for their contributions in
providing medical care for this patient.
References
1. Brittain P, Walsh E, Smidt A. Blotchy Baby:
A case of Phakomatosis Pigmentovascularis. J
Pediatr. 2013;162:1293.
2. Shields CL, Kligman BE, Suriano M,
et al. Phacomatosis Pigmentovascularis of
Cesioflammea Type in 7 Patients: combination
of ocular pigmentation (melanocytosis or
melanosis) and nevus flammeus with risk
for melanoma. Arch Ophthalmol. 2011
June;129(6):746-750.
3. Jacobs AH, Walton RG. The incidence of
birthmarks in the neonate. Pediatrics. 1976;
58:218.
Page 53
4. Kanada KN, Merin MR, Munden A,
Friedlander SF. A prospective study of
cutaneous findings in newborns in the United
States: correlation with race, ethnicity, and
gestational status using updated classification
and nomenclature. J Pediatr. 2012;161:240.
5. Requena L, Sangueza OP. Cutaneous
vascular anomalies. Part I. Hamartomas,
malformations, and dilation of preexisting
vessels. J Am Acad Dermatol. 1997;37:523.
J Am Acad Dermatol. 2008;58(1):88-93.
18. Segatto MM, Scmitt EU, Hagemann LN,
da Silva RC, Cattani CAS. Phacomatosis
Pigmentovascularis Type IIa - Case Report.
An Bras Dermatol. 2013;88(6 Suppl 1):S85-8.
Correspondence: Joy Zarandy, DO; joy.
[email protected]
6. Vidaurri-de la Cruz H, Tamayo-Sanchez
L, Duran-McKinster C, de la Luz OrozcoCovarrubias
M,
Ruiz-Maldonado
R.
Phakomatosis Pigmentovascularis IIA and IIB:
Clinical findings in 24 patients. J Dermatol.
2003;30:381-388.
7. Jacob AG, Driscoll DJ, Shaughnessy WJ, et
al. Klippel-Trénaunay syndrome: spectrum and
management. Mayo Clin Proc. 1998;73:28.
8. Okunola P, Ofovwe G, Abiodun M, Isah
A, Ikubor J. Phakomatosis pigmentovascularis
type IIB in association with external
hydrocephalus. BMJ Case Rep. 2012 June
25;2012.
9. Cordova A. The Mongolian spot: a study of
ethnic differences and a literature review. Clin
Pediatr (Phila). 1981;20:714.
10. Gupta A, Thappa DM. Mongolian spots-a prospective study. Pediatr Dermatol. 2013;
30:683.
11. Kurata S, Ohara Y, Itami S, et al. Mongolian
spots associated with cleft lip. Br J Plast Surg.
1989;42:625.
12. Hackbart BA, Arita JH, Pinho RS, et al.
Mongolian spots are not always a benign sign.
J Pediatr. 2013;162:1070.
13. Rasi A, Tabaie M, Hassannejad H.
Phakomatosis pigmentovascularis type IIa.
Iranian J Dermatol. 2012;15:62-65.
14. Castori M, Sarazani S, Binni F, Pezzella FR,
Cruciani G, Grammatico P. Monozygotic twin
discordance for phacomatosis cesioflammea
further supports the post-zygotic mutation
hypothesis. Am J Med Genet. 2011;155:22532256.
15. Bolognia JL, Jorizzo J, Schaffer JV.
Dermatology. 3rd Edition. China: Elsevier;
2012. Chapter 55, Twin Spotting; Vol 1,
Section 9.
16. Wobser M, Goebeler M, Hamm H.
Extensive Red and Blue Patches in a Young
Girl. Klin Padiatr. 2013;225:46-47.
17. Fernandez-Guarino M, Boixeda P, de las
Heras E, Aboin S, Garcia-Millan G, Olasolo
PJ. Phakomatosis Pigmentovascularis: Clinical
findings in 15 patients and review of literature.
Page 54
PHACOMATOSIS CESIOFLAMMEA: A CASE REPORT OF A NEWBORN WITH AN UNUSUAL MONGOLIAN SPOT AND PORT WINE STAIN
last modified on April 27, 2015 8:12 AM
Perspectives
Views from the JAOCD Readership
ATHALYE Page 55
While Serving Abroad, Remembering the “Why” Behind Dermatology
Leela Athalye, DO; Chief Resident, Western University/College Medical Center, Long Beach, CA
Addis Ababa, Ethiopia. Here, we created our
own clinic using an elementary school and saw
over 1,100 patients within a week’s time. Every
day, we would walk into a chaotic scene where
people were lined up for hours just to see us. It
was an extremely rewarding experience to end
each day knowing we had served each person who
had waited to the best of our abilities. Along the
way, we picked up some of the local language,
Amharic, which to this day we try to use with the
occasional Ethiopian patient we may encounter. Most of us started the long, often arduous journey
to become dermatologists for one reason: to help
people. However, with the various complicated
steps we take on a daily basis, like learning the
billing, dealing with insurance companies, and
memorizing the board fodder, we often forget the
simple, true motivation behind what we do. I feel
fortunate that my dermatology program through
Western University/College Medical Center
continues to instill the spirit of altruism by
providing us the opportunity to serve underserved
people in the global community. Our dermatology program is the only
osteopathic dermatology program in the state
of California. Historically it has been led by Dr.
David Horowitz, and now is being continued
by Dr. Navid Nami. From day one of our
dermatology residency, Dr. Horowitz reminded
us of why we are doing this. He gave us a list
of tips that successful people use on a daily basis
to not only be successful in our dermatology
residencies but also in every aspect of our lives so
that hopefully, we can represent our osteopathic
communities well.
One of the major lessons Dr. David taught all our
residents is the importance of caring for people,
not only in our local communities but also in our
world at large. Fifteen years ago, Dr. Horowitz
was approached by an Ethiopian pastor who
described the great need for dermatologic care
in some of the underserved and impoverished
areas of Ethiopia. Dr. Horowitz was inspired to
address this growing dilemma by bringing a team
of physicians with him to volunteer in Africa. In
addition to Ethiopia, Dr. Horowitz has dedicated
his time and money to a dozen medical missions,
including ones in Mexico, the Philippines,
Guatemala, Ecuador, Dominican Republic,
and Kenya. Through his amazing clinical
and philanthropic experiences, Dr. Horowitz
Our Dominican team working together to take
care of patients of all ages. (Residents Michael
Kassardjian, Donna Tran, Leela Athalye)
Page 56
Lines of people waiting to be seen after lunch
in Addis Ababa.
encourages his residents to partake in at least one
medical mission per year to not only better their
dermatologic knowledge of rarer conditions but
also to serve some of the most underprivileged
regions of the world. While I was applying to dermatology residency,
Dr. David took his team to the Philippines, where
they performed hundreds of surgeries. They were
also able to experience the local culture, e.g.,
trying various exotic seafood dishes. My first year
of residency, we returned to one of Dr. David’s
fondest and most well-traveled destinations of
We also spent time volunteering at an HIVdermatology clinic, as well as a leprosy
clinic. Here we saw HIV-related dermopathy
that we had only read about and were able
to learn about the various stages of leprosy
first-hand, as well as see the local approach
to diagnosis. We saw interesting pathology,
including a hemangiopericytoma on an infant’s
hand, X-linked ichthyosis and Madura foot. It
was an amazing experience for all of us because it
was the first time any of us residents had been to
Africa and we were awarded the chance to meet
so many interesting local people. My second year of residency, we went to the
Dominican Republic, where we served a small
community in San Francisco de Marcos. Here,
we traveled with the Global Health Organization
and saw mainly dermatology but also primary
care patients with the help of our multispecialty
team. We treated a range of conditions, from
mundane conditions like verruca, acne, melasma
Our team of providers and student translators in the Dominican Republic: The many people needed
to make a successful mission.
WHILE SERVING ABROAD, REMEMBERING THE “WHY” BEHIND DERMATOLOGY
and photodermatitis to less-common entities like
xeroderma pigmentosum. We also performed
house calls in the local community, where we
treated severe decubitus ulcers and performed
hospice care. One of the best parts of our experience was that
we were able to further develop our Spanishspeaking skills by talking to patients, as well
as with the help of the volunteer Dominican
students who translated. Through our interaction
with these Dominican students, we were able to
not only have a better cultural experience but also
give back further to the community as mentors,
which is a role we treasure to date.
Our international dermatology experiences are
one of the most cherished memories that I will take
away as I graduate from residency in the next few
months. We were able to not only travel to new
and exotic locations but also reach many people
and provide them with the medical aid they have
needed for years. Dr. Horowitz’s ambition to treat
patients internationally has only grown stronger
as he has retired as program director; with his
direction, we continue to be excited about serving
abroad. We are currently planning our next
medical mission to Guatemala and look forward
to again embracing the philanthropic reason why
we all joined this profession in the first place.
THOMAS, THOMAS Our dermatology team in the Dominican Republic, led by our fearless leader in altruism, Dr. David
Horowitz.
Page 57
Letter to the Editor:
Wegener’s Granulomatosis Eponym
David Thomas, MD, JD, EdD,* Jacqueline Thomas, DO**
*Professor and Chair of Surgery, Nova Southeastern University College of Osteopathic Medicine, Ft. Lauderdale, FL
**Assistant Professor of Dermatology and Mohs Surgery, Nova Southeastern University College of Osteopathic Medicine, Ft. Lauderdale, FL
To the JAOCD Editor,
Thank you very much for the latest illuminating
issue of The Journal of the American Osteopathic
College of Dermatology. While all of the articles
were truly worthwhile, there is some controversy
concerning the eponym in the title of one of
the articles, “Herpes Zoster Ophthalmicus in
a Patient with Wegener’s Granulomatosis,” in
Volume 31, page 24. In 2008, there was a move to
remove this eponym from this disease and refer to
it in a more explicative form as “granulomatosis
and polyarteritis.”
In 1936, Dr. Friedrich Wegener described
several cases of small vessel vasculitis with
granulomatous inflammation.1 In 1954, Goldman
and Churg described seven cases of their own and
reviewed another 22 previously reported cases.2
Subsequently, the disease became known as
Wegener’s granulomatosis, and that eponym has
remained a fixture of the entity.
In 1989, just prior to his death in 1990, Wegener
was awarded the Master Clinician award by the
American College of Chest Surgeons; however,
in 2007, the American College of Chest Surgeons
rescinded this award predicated on Wegener’s
known affiliation with the Nazi Party.3
Several authors specializing in diseases of the
chest, rheumatology, and nephrology have stated
that in view of that affiliation, the eponym should
no longer be used.3-5
While there is no evidence of war crimes or
criminal activity, the record clearly reflects Dr.
Friedrich Wegener’s intimate association with
and membership in the Nazi regime. As such, his
character must come into question, and therefore
it seems inappropriate to give him the honor of
attaching his name to a disease entity. The Chest
Society took the first step by removing its Master
Clinician designation.
Generally speaking, we feel the practice of
medicine would be well-served, and the teaching
of medicine to our students enhanced, if we
refrained from the use of eponyms completely
and used only scientific, descriptive terminology
for disease entities. While it might be awkward to
refer to Starling’s Law as “End Diastolic Filling
and Stroke Volume,” the descriptor, as opposed
to the eponym, would not only be a far more
understandable path but would also remove any
potential for embarrassing ethical disclosures that
might be associated with an investigator.
Yours truly,
David L. Thomas, MD, JD, EdD
Jacqueline Thomas, DO
References
1. Wegener F. Ueber generalisierte septische
Gefäßerkrankungen [About generalized septic
vascular diseases]. Verh Deut Pathol Ges.
1936;29:202-10.
2. Godman GC, Churg J. Wegener’s
granulomatosis: pathology and review of the
literature. AMA Arch Pathol. 1954;58:533-53.
3. Rosen M. Dr. Friendrich Wegener: the ACCP
and history. Chest. 2007;132:739-741.
4. Allam SR. Controversy over eponym
“Wegener’s granulomatosis.” Nephrology World
[Internet]. May 4, 2010 (Accessed January 29,
2015). Available from: http://nephrologyworld.
blogspot.com/2010/05/controversy-overeponym-wegeners.html
5. Woywodt A, Matterson L. Wegener’s
granulomatosis—probing the untold past of
the man behind the eponym. Rheumatology
[Internet]. 2006;45(10):1303-1306 (Accessed
January 29, 2015). Available from: from
http://rheumatolog y.oxfordjournals.org/
content/45/10/1303.full
Correspondence: Jacqueline A. Thomas, DO;
[email protected]
Separately, Woywodt and Matterson conducted
an extensive six-year probe into the life of Dr.
Wegener.5 They found that as early as 1933,
he joined the Nazi Party, rising to the rank of
Lieutenant Colonel and serving as the pathologist
in Lodz in 1939. His office was adjacent to
a Polish ghetto. They found no indication of
criminal conduct on the part of Wegener, but
they did uncover a letter concerning Wegener’s
reviewing an article on pulmonary air embolism.
Air embolism was seen in septic abortions and was
a notorious finding in Nazi altitude experiments
done on prisoners.
Page 58
LETTER TO THE EDITOR: WEGENER’S GRANULOMATOSIS EPONYM
Save the Dates for Upcoming AOCD Meetings
2015 Fall Meeting
Loews Royal Pacific Resort
at Universal Orlando
Orlando, FL
October 15-18
Thursday, October 15, 2015
8:00 a.m. - 12:00 p.m.
12:00 p.m. - 1:00 p.m.
1:00 p.m. - 5:00 p.m.
8:00 a.m. - 5:00 p.m.
4:00 p.m. - 8:00 p.m.
AOCD BOT Meeting
Leaders Luncheon
AOCD Program Director Meeting
Exhibitor Set Up
Resident In Training Exam
Friday, October 16, 2015
7:00 a.m. - 7:30 a.m.
7:30 a.m. - 11:30 a.m.
11:30 a.m. - 12:00 p.m.
12:00 p.m. - 1:30 p.m.
1:30 p.m. - 4:30 p.m.
4:30 p.m. - 5:30 p.m.
7:00 p.m.
CLIA Proficiency
Lectures
Break with Exhibitors
Lunch Lecture
Lectures
Business Meeting
Presidential Reception
Saturday, October 17, 2015
7:00 a.m. - 10:00 a.m.
10:00 a.m. - 10:30 a.m.
10:30 a.m. - 11:30 a.m.
11:30 a.m. - 1:00 p.m.
1:00 p.m. - 1:30 p.m.
1:30 p.m. - 5:30 p.m.
Lectures
Break with Exhibitors
Lectures
Lunch Lecture
Break with Exhibitors
Lectures
Sunday, October 18, 2015
9:30 a.m. - 12:00 p.m.
12:00 p.m. - 1:30 p.m.
1:30 p.m. - 5:00 p.m.
5:00 p.m.
Lectures
Lunch on your own
Lectures
End of Conference
*Schedule Subject to Change
2017 Spring Meeting
Ritz Carlton | Atlanta, GA
March 29 - April 2
2016 Spring Meeting
Ritz Carlton Battery Park | New York, NY
March 30 - April 3
Continuing Medical Education Division
CERTIFICATION OF HOME STUDY FORM
(Category 2-B credit)
This to certify that I, ______________________________________, have read the following journals from Jan. 1, 2013-Dec. 31, 2015
Journal Name
The D.O.
J.A.O.A
J.A.M.A.
N.E.J.M.
Cancer
Chest
Geriatrics
Lancet
Medicine
Obstetrics and Gynecology
Orthopedics
Osteopathic Medicine
Other Journals Not Listed:
Total Credits Earned for
3-Year CME Cycle
Credits Earned
18 credits
18 credits
78 credits
78 credits
18 credits
18 credits
18 credits
18 credits
18 credits
18 credits
18 credits
18 credits
_____________
_____________
_____________
_____________
_____________
_____________
_____________
_____________
_____________
_____________
_____________
_____________
_____________
J.A.O.C.D.!
!
!
6 credits!
(Journal of the American Osteopathic of Dermatology)!
_____________
_____________
_____________
Medical Text Books:
Five (5) credit hours may be granted for the reading of medical books. Please list the titles of any medical books you have
read but not yet reported.
Total Credits Earned for Journal Reading and Medical Text Books:
Total
Physician’s Signature
AOA#
Email Address
Phone No.
AOA Division of CME
142 E. Ontario St., Chicago, IL 60611
Phone: (312) 202-8262
Fax: (312) 202-8202
Email: [email protected] or