ARCHIVES
OF
DERMATOLOGY
SEPTEMBER 2007
VOLUME 143, NUMBER 9
ARCHIVES A CENTURY AGO
Some Further Observations on the Treatment
of Pigmented Hairy Naevi With Liquid Air;
Three Additional Case Reports.
1108
THE CUTTING EDGE
Infliximab as a Therapy for Idiopathic
Hypereosinophilic Syndrome
Josephine A. Taverna, MD; Adam Lerner, MD;
Lynne Goldberg, MD; Stephen Werth, MD;
Marie-France Demierre, MD, FRCPC
1110
PAGES 1093-1234
Primary Cutaneous Diffuse Large
B-Cell Lymphoma, Leg Type:
Clinicopathologic Features and Prognostic
Analysis in 60 Cases
Florent Grange, MD, PhD;
Marie Beylot-Barry, MD, PhD; Phillipe Courville, MD;
Eve Maubec, MD; Martine Bagot, MD, PhD;
Béatrice Vergier, MD, PhD; Pierre Souteyrand, MD;
Laurent Machet, MD, PhD; Sophie Dalac, MD;
Eric Esteve, MD; Isabelle Templier, MD;
Emmanuel Delaporte, MD; Marie-Françoise Avril, MD;
Caroline Robert, MD, PhD; Stephane Dalle, MD;
Liliane Laroche, MD, PhD; Michele Delaunay, MD;
Pascal Joly, MD, PhD; Janine Wechsler, MD;
Tony Petrella, MD
1144
STUDIES
OBSERVATIONS
Clinical Severity of Psoriasis in Last
20 Years of PUVA Study
Tamar Nijsten, MD, PhD;
Caspar W. N. Looman, PhD;
Robert S. Stern, MD
1113
Clinical, Biochemical, and Genetic Study of
11 Patients With Erythropoietic Protoporphyria
Including One With Homozygous Disease
Carmen Herrero, MD, PhD; Jordi To-Figueras, PhD;
Celia Badenas, PhD; Manuel Méndez, PhD;
Patricia Serrano, MD;
Rafael Enrı́quez-Salamanca, MD, PhD;
Mario Lecha, MD, PhD
1125
Five-Year Follow-up of a Randomized,
1131
Prospective Trial of Topical Methyl
Aminolevulinate Photodynamic Therapy vs
Surgery for Nodular Basal Cell Carcinoma
Lesley E. Rhodes, MD, FRCP; Menno A. de Rie, MD;
Ragna Leifsdottir, MD; Raymond C. Yu, MD, FRCP;
Ingeborg Bachmann, MD; Victoria Goulden, MD, FRCP;
Gavin A. E. Wong, MRCP; Marie-Aleth Richard, MD;
Alex Anstey, MD, FRCP; Peter Wolf, MD
Effect of Cold Air Cooling on the Incidence
of Postinflammatory Hyperpigmentation After
Q-Switched Nd:YAG Laser Treatment of Acquired
Bilateral Nevus of Ota–like Macules
Woraphong Manuskiatti, MD; Sasima Eimpunth, MD;
Rungsima Wanitphakdeedecha, MD
1139
Familial Acanthosis Nigricans Due
to K650T FGFR3 Mutation
David R. Berk, MD; Elaine B. Spector, PhD;
Susan J. Bayliss, MD
1153
Eczematoid Graft-vs-Host Disease:
A Novel Form of Chronic Cutaneous
Graft-vs-Host Disease and Its Response
to Psoralen–UV-A Therapy
Daniel Creamer, MD;
Claire L. Martyn-Simmons, MRCP(England);
Genevieve Osborne, MRCP(England);
Michelle Kenyon, MSc; Jon R. Salisbury, MD;
Stephen Devereux, MD; Antonio Pagliuca, MD;
Aloysius Y. Ho, MD; Ghulam J. Mufti, MD;
Anthony W. P. du Vivier, MD
1157
Epidermolysis Bullosa Nevus:
An Exception to the Clinical and Dermoscopic
Criteria for Melanoma
Sarah H. Cash, MD; Tara T. Dever, MD;
Patrice Hyde, MD; Jason B. Lee, MD
1164
Herpes Gestationis in a Mother and Newborn:
1168
Immunoclinical Perspectives Based on a Weekly
Follow-up of the Enzyme-Linked Immunosorbent
Assay Index of a Bullous Pemphigoid Antigen
Noncollagenous Domain
Yumi Aoyama, MD; Kanako Asai, MD; Kana Hioki, MD;
Michinori Funato, MD; Naomi Kondo, MD;
Yasuo Kitajima, MD
(REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007
1097
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ARCHIVES
OF
DERMATOLOGY
EVIDENCE-BASED DERMATOLOGY: STUDY
Balancing the Benefits and Risks
of Drug Treatment: A Stated-Preference, Discrete
Choice Experiment With Patients With Psoriasis
Elizabeth M. Seston, PhD; Darren M. Ashcroft, PhD;
Christopher E. M. Griffiths, MD, FRCP
1175
Diffuse Nodules in a Woman With Renal Failure
Erin B. Lesesky, MD; Michelle T. Pelle, MD;
Terence C. O’Grady, MD
1201
Tender Nodules on the Palms and Soles
Lisa Esler-Brauer, MD; Ilene Rothman, MD
1201
CORRESPONDENCE: RESEARCH LETTERS
EVIDENCE-BASED DERMATOLOGY:
RESEARCH COMMENTARY
Use of Antibiotic Ointment After Clean
Cutaneous Surgery
Michael Bigby, MD
1209
1180
A Novel Missense Mutation in the CYLD Gene
in a Spanish Family With Multiple
Familial Trichoepithelioma
Agustı́n España, MD; Fermin Garcı́a-Amigot, PhD;
Leyre Aguado, MD; Jesús Garcı́a-Foncillas, MD
1210
1185
A Novel PTPN11 Gene Mutation in a Patient
With LEOPARD Syndrome
Aurélie Du-Thanh, MD; Hélène Cave, PharmD, PhD;
Didier Bessis, MD; Carine Puso, MD;
Jean-Jacques Guilhou, MD;
Olivier Dereure, MD, PhD
EDITORIAL
Evidence-Based Dermatology Section Welcomes
a New Feature: Critically Appraised Topic
Michael Bigby, MD
EVIDENCE-BASED DERMATOLOGY:
CRITICALLY APPRAISED TOPIC
What Is the Chance of a Normal Pregnancy
in a Woman Whose Fetus Has Been
Exposed to Isotretinoin?
Michael J. Sladden, MAE, MRCP(UK);
Karen E. Harman, MD, MRCP
CORRESPONDENCE: COMMENTS AND OPINIONS
1187
ON THE HORIZON
Accessible Evidence-Based Medicine:
Critically Appraised Topics
David A. Barzilai, MD, PhD;
Martin A. Weinstock, MD, PhD
1189
EDITORIALS
Long-term Treatment for Severe Psoriasis:
We’re Halfway There, With a Long Way to Go
Joel M. Gelfand, MD, MSCE
1191
Dermatology and the Human Genome:
An Epidemiologic Approach
Marta Gwinn, MD, MPH; Muin J. Khoury, MD, PhD
1194
OFF-CENTER FOLD
Hyperpigmented Keratotic Nodules
Ser Ling Chua, MRCP; Kusum Kulkarni, MRCPath;
Eric Saihan, FRCP
1201
Verrucous Papules and Plaques
in a Pediatric Patient
Mercedes E. Gonzalez, MD; Fiona P. Blanco, MD;
Maria C. Garzon, MD
1201
Sponsorship of Graduate Medical Education:
One Successful Model
William D. James, MD
1211
Narrowband UV-B Phototherapy
for Extragenital Lichen Sclerosus
Alexander Kreuter, MD; Thilo Gambichler, MD
1213
Exclusively Benign Dermoscopic Pattern
in a Patient With Acral Melanoma
Ralph P. Braun, MD; Olivier Gaide, MD;
Andreas M. Skaria, MD; Alfred W. Kopf, MD;
Jean-Hilaire Saurat, MD; Ashfaq A. Marghoob, MD
1213
In Reply
Toshiaki Saida, MD, PhD
1215
Evidence Insufficient to Recommend
Melanoma Surveillance Following
Phototherapy for Jaundice
Thomas B. Newman, MD, MPH;
M. Jeffrey Maisels, MB BCh
1216
In Reply
Vincent Descamps, MD, PhD
1216
Allergic Contact Dermatitis:
Another Adverse Effect of Over-the-counter
Topical Hydrocortisone
Kalman L. Watsky, MD;
Erin M. Warshaw, MD, MS
1217
In Reply
William H. Eaglstein, MD;
Scott M. Ravis
1217
(REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007
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ARCHIVES
OF
DERMATOLOGY
CORRESPONDENCE: VIGNETTES
SKINSIGHT
Successful Treatment of Pityriasis Versicolor
With 5-Aminolevulinic Acid
Photodynamic Therapy
Young Jin Kim, MD;
You Chan Kim, MD, PhD
1218
Leukemia Cutis: A Presenting Sign
in Acute Promyelocytic Leukemia
Tania R. Markowski, BA; Donna Bilu Martin, MD;
Grace F. Kao, MD; Linda Lutz, MD;
April Deng, MD, PhD; Anthony A. Gaspari, MD
1220
Necrolytic Migratory Erythema: The Outermost
Marker for Glucagonoma Syndrome
Mary L. Gantcheva, MD, PhD;
Valentina K. Broshtilova, MD;
Adriana I. Lalova, MD, PhD
1221
Lymphomatoid Granulomatosis Induced
by Imatinib-Treatment
Amir S. Yazdi, MD; Gisela Metzler, MD;
Susanne Weyrauch, MD; Mark Berneburg, MD;
Michael Bitzer, MD;
Hans-Konrad Müller-Hermelink, MD;
Martin Röcken, MD
1222
Focal Acne During Topical Tacrolimus
Therapy for Vitiligo
Lucio Bakos, MD, PhD;
Renato Marchiori Bakos, MD, MSc
1223
Pneumocystis carinii Pneumonia in Infant
Treated With Oral Steroids for Hemangioma
Mandi L. Maronn, MD; Timothy Corden, MD;
Beth A. Drolet, MD
1224
Clinical and Dermoscopic Features
of Agminated Blue Nevus
Maria A. Pizzichetta, MD; H. Peter Soyer, MD;
Cesare Massone, MD; Lorenzo Cerroni, MD
1225
Subungual Exostosis
Marı́a Elena Sánchez-Castellanos, MD;
Cecilia Sandoval-Tress, MD;
Patricia Ramı́rez-Bárcena, MD
1234
CORRECTION
Error in Byline in: Breaking Strength
of Barbed Polypropylene Sutures: Rater-Blinded,
Controlled Comparison With Nonbarbed
Sutures of Various Calibers
Rashid [M.] Rashid, MD, PhD; Mark Sartori, BS;
Lucile E. White, MD; Mark T. Villa, MD;
Simon S. Yoo, MD; Murad Alam, MD, MSCI
1186
REGULAR DEPARTMENTS
This Month in Archives of Dermatology
1107
Online CME Article
1113
Archives Feature
1121
Call for Papers
1136
Announcement
1162
Archives Web Quiz Winner
1182
Classified Advertising
1229
Journal Advertiser Index
1232
Contact Information
1233
Information for authors and readers and the subject and
author indexes are available on our Web site:
http://www.archdermatol.com.
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OF
DERMATOLOGY
Mission Statement: The Archives of Dermatology publishes information concerning the skin, its diseases, and their treatment. Its mission is to explicate the structure
and function of the skin and its diseases and the art of using this information to deliver optimal medical and surgical care to the patient. We attempt to enhance the
understanding of cutaneous pathophysiology and improve the clinician’s ability to diagnose and treat skin disorders. This journal has a particular interest in publishing clinical and laboratory studies that reveal new information pertinent to the interests and needs of the medical dermatologist, dermatologic surgeon, and all those
concerned with state-of-the-art care of cutaneous disease. We believe that knowledge derived from well-designed clinical trials and studies of cost-effectiveness are
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THIS MONTH IN ARCHIVES OF DERMATOLOGY
SECTION EDITOR: ROBIN L. TRAVERS, MD
Effect of Cold Air Cooling
on the Incidence
of PIH After Q-Switched
Nd:YAG Laser Treatment
of Acquired Bilateral Nevus
of Ota–like Macules
P
ostinflammatory hyperpigmentation (PIH) is very likely the
most common adverse effect of laser
treatment in dark-skinned individuals. Treatment of PIH is difficult, thus
emphasizing the need for prevention
strategies. Acquired bilateral nevus of
Ota–like macules (ABNOMs) are
clinically characterized by bluebrown macules on periocular and nasal skin, and Q-switched lasers represent an excellent therapeutic
modality. In this randomized, controlled, split-face study, Manuskiatti
et al sought to evaluate the benefit of
epidermal cooling on reducing the occurrence of PIH after Q-switched
Nd:YAG laser treatment of ABNOMs.
Unexpectedly, cold air cooling was associated with an increased risk of PIH
after laser treatment, through an unknown mechanism.
See page 1139
Herpes Gestationis in a
Mother and Newborn
H
erpes gestationis (HG) is a rare,
autoimmune, bullous disease
that affects women in the second or
third trimester of pregnancy. Immunologically, HG is characterized by linear deposition of C3 with or without
associated IgG at the basement membrane zone on direct immunofluorescence and by the presence of serum antibodies directed against the
180-kDa bullous pemphigoid antigen (BP180). In this case report,
Aoyama et al describe a mother and
neonate with cutaneous manifestations of HG. The BP180 enzymelinked immunosorbent assay indexes were observed in both patients
and clearly demonstrated that the vesicular lesions in the neonate were
caused by transplacental passage of
pathogenic BP180 antibodies.
See page 1168
Eczematoid Graft-vs-Host Disease
G
raft-vs-host disease (GVHD) is a multisystem disease initiated by allogeneic T lymphocytes that recognize foreign tissue antigens in the host.
In the chronic form, GVHD demonstrates cutaneous manifestations that may
be classified as lichenoid or sclerodermatous in nature. In this case series of
patients who developed cutaneous GVHD after hematopoietic stem cell transplantation, Creamer et al
identified a novel, distinct
B
A
group of 10 who were characterizedbypersistent,widespread, chronic eczematous
dermatitis. Histopathologically, these eczematous features strikingly coexisted
with changes of GVHD. The
factors provoking the expression of an eczematous
phenotype in these patients
remain unclear.
See page 1157
Clinical, Biochemical, and Genetic Study of 11 Patients
With Erythropoietic Protoporphyria Including One
With Homozygous Disease
E
rythropoietic protoporphyria (EPP) is an inherited disorder of porphyrin metabolism caused by a partial deficiency of the ferrochelatase gene
(FECH). Clinical expression of the disease commonly results from the coinheritance of a null FECH mutation plus a wild-type low-expressed allele, which
further reduces ferrochelatase activity to below a critical threshold of about 35%.
The low-expression allele IVS3-48C is relatively common among European populations, such that overt EPP is typically inherited in such a way that it resembles an autosomal dominant disease with low clinical penetrance. In this
case series, Herrero et al confirm the common view that clinically overt EPP is
most typically associated with inheritance of the low-expression IVS3-48C allele in trans to a severe FECH mutation. One rare homozygous mutation was
identified in a patient showing early signs of liver involvement.
See page 1125
Balancing the Benefits and Risks of Drug Treatment
P
soriasis is a common, chronic, inflammatory, hyperproliferative skin disease. Therapeutic options for psoriasis vary widely in terms of efficacy and
toxic effects. In this discrete choice experiment, Seston et al explore the extent
to which different attributes of a treatment affect a patient’s choice of therapy
and the hierarchical importance of these attributes. Most respondents were willing to trade among different attributes of a treatment to achieve an improvement in their psoriasis with minimal adverse effects. For example, patients indicated that they would wait longer for therapy to work if the chance of a severe
adverse effect could be reduced. Long-term risks (such as skin cancer or liver
damage) were prioritized over short-term risks (such as skin irritation). Only
one-quarter of the sample patients were unwilling to trade among attributes and
always chose the therapy with a particular level of their chosen attribute, most
often no risk of skin cancer.
See page 1175
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ARCHIVES A CENTURY AGO
SECTION EDITOR: MARK BERNHARDT, MD
THE JOURNAL OF
CUTANEOUS DISEASES
VOL. XXV.
SEPTEMBER, 1907.
NO. 9.
SOME FURTHER OBSERVATIONS ON THE TREATMENT
OF PIGMENTED HAIRY NAEVI WITH LIQUID AIR;
THREE ADDITIONAL CASE REPORTS.
By WILLIAM B. TRIMBLE, M. D.
Everyone is more or less familiar with this new remedial agent, yet it may be well to quote here
some of its physical characteristics. Liquid air is the common air we breathe, very much reduced in
temperature. It liquefies at 312º F. below zero. We can readily understand how cold it must be when
we are told that it is about 400º colder than the ordinary atmospheric air.
J Cutan Dis.
September 1907;25(9);409-413.
The bridge at midnight trembles,
The country doctor rambles,
Bankers’ nieces seek perfection,
Expecting all the gifts that wise men bring.
The wind howls like a hammer,
The night blows cold . . .
Love Minus Zero/No Limit
Bob Dylan, 1965
Temperature, °C
⫹116
0
Occurrence
At this temperature, Hell’s lakes of sulfuric brimstone freeze over
Temperature of water when Dr John Gorrie created the first artificial ice
(Apalachicola, Florida, July 14, 1850) a
−2
Coldest temperature recorded in West Palm Beach, Florida (January 19, 1977)
−4 to −20
Temperature of ethyl chloride spray, depending on delivery system
−20 to −30
Your tongue sticks to a metal pole, stupid!
−39
Temperature at which the bulb of mercury in a thermometer (aka, the witch’s tit)
freezes
−57
Temperature of over-the-counter wart treatment
−70
Coldest temperature recorded in contiguous 48 states (Rogers Pass, Montana,
January 20, 1954)
−75
Exposed skin freezes within 30 seconds
−78
Surface temperature of a block of dry ice
−89
Coldest air temperature recorded on earth (Vostok, Antarctica, July 21, 1983)
−196
Temperature of liquid nitrogen in which Ted Williams’ head is preserved
−230
Average surface temperature on the dark side of the moon
−235
Lowest temperature in our solar system (Neptune’s moon Triton)
−271
Temperature of intergalactic deep space
−272.000000083
Bose-Einstein condensate first formed (Boulder, Colorado, June 5, 1995)
−273
Absolute zero (Sorry, Bob. That is the limit.)
a
Bernhardt M. Selections: Morbus Maculosus Werlhofu. Arch Dermatol. 1992;128(9):1298.
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THE CUTTING EDGE
SECTION EDITOR: GEORGE J. HRUZA, MD; ASSISTANT SECTION EDITORS: MICHAEL P. HEFFERNAN, MD; CHRISTIE AMMIRATI, MD
Infliximab as a Therapy for Idiopathic
Hypereosinophilic Syndrome
Josephine A. Taverna, MD; Adam Lerner, MD; Lynne Goldberg, MD; Stephen Werth, MD; Marie-France Demierre, MD, FRCPC;
Boston University School of Medicine (Drs Taverna, Lerner, Goldberg, and Demierre) and Tufts University School
of Medicine (Dr Werth), Boston, Massachusetts
The Cutting Edge: Challenges in Medical and Surgical Therapeutics
REPORT OF A CASE
A 77-year-old woman from Guyana presented with a
3-year history of a generalized, pruritic eruption associated with chronic chills, fatigue, generalized malaise, and
a 14-kg weight loss over a 9-month period (Figure 1).
Her medical history was significant for hypertension and
diabetes, and her medications included glucophage, atenolol, and lisinopril. She had no personal or family history of atopy. Her physical examination findings were remarkable for exfoliative erythroderma and keratoderma
associated with generalized lymphadenopathy (Figure 1).
Complete blood cell counts were normal except for a persistently elevated absolute eosinophil count (1500-3000/
µL) for more than 8 months. Positron emission tomographic scans detected enhanced fludeoxyglucose F 18
uptake bilaterally in the supraclavicular, axillary (largest node measuring 2.5 cm), and inguinal nodes (largest node measuring 2 cm). A left inguinal lymph node
biopsy specimen revealed dermatopathic lymphadenitis
and no evidence of a lymphoproliferative disorder. Histopathologic examination of a skin sample revealed parakeratosis, hypogranulosis, psoriasiform epidermal hyperplasia, mild spongiosis, a mild superficial perivascular
lymphocytic infiltrate with occasional plasma cells and
A
rare eosinophils, and numerous melanophages. Flow cytometry and skin and bone marrow biopsy specimens revealed no evidence of a clonal T- or B-cell population on
immunophenotyping or molecular genetic analysis, and
FIP1L1-PDGFRA gene fusion was not detected. Extensive studies were performed to rule out infectious, allergic, vasculitic, rheumatic, and malignant causes of eosinophilia. A transthoracic echocardiogram, which was
obtained to rule out heart failure or mural thrombus in
the setting of chronic hypereosinophilia, demonstrated
no abnormalities.
THERAPEUTIC CHALLENGE
The pruritic eruption was initially thought to be caused
by the use of a newly prescribed medication (lisinopril).
Unfortunately, erythroderma and keratoderma persisted long after therapy with the angiotensinconverting enzyme inhibitor was discontinued. In the following 3 years, the patient was treated unsuccessfully with
a variety of therapeutic modalities, including systemic corticosteroids, psoralen–UV-A, isotretinoin, bexarotene, and
extracorporeal photopheresis. Two years after her initial presentation, the patient required inpatient hospitalization for intense pruritus and failure to thrive, and
B
Figure 1. Exfoliative erythroderma (A) and keratoderma (B) before treatment with infliximab.
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the decision was made to initiate treatment targeting Tcell activation. After 3 monthly cycles of denileukin diftitox infusions (18 µg/kg/d) in combination with oral bexarotene, there was no improvement in erythroderma or
pruritus. A 1-month course of oral imatinib mesylate
therapy (400 mg/d) was not helpful. A trial of chemotherapy with 2 cycles of fludarabine–mitoxantrone–
dexamethasone (fludarabine phosphate, 25 mg/m2 days
1-3; mitoxantrone, 10 mg/m2 day 1; and dexamethasone, 20 mg/d days 1-5), resulted in a transient decrease
in the patient’s absolute eosinophil count but no clinical improvement. An effective treatment was needed to
ameliorate her skin lesions and severe pruritus.
SOLUTION
Intravenous infusions of infliximab (5 mg/kg) were followed by a sharp decrease in the peripheral blood eosinophil count to 700/µL (Figure 2), with complete resolution of erythroderma, keratoderma, and pruritus after
3 monthly cycles of therapy (Figure 3). For maintenance, the patient received 5 additional monthly cycles
of infliximab that were well tolerated, without reported
adverse effects or evidence of recurrent disease. Infliximab therapy was subsequently discontinued, and the pa3500
Series 1
Eosinophils, µL
3000
2500
2000
1500
1000
500
0
Feb
2005
Apr
2005
Jun
2005
Aug
2005
Oct
2005
Dec
2005
Feb
2006
Apr
2006
Jun
2006
Month
Figure 2. Eosinophil count in a patient with idiopathic hypereosinophilic
syndrome. Infliximab therapy was initiated in late November 2005, with a
sharp decrease in absolute eosinophil counts. Normalization of eosinophil
count was achieved after 3 monthly doses of infliximab, and the effect was
maintained after 7 monthly doses.
A
tient’s skin remained clear at the 1-month follow-up visit.
Her debilitating skin condition, which was associated with
hypereosinophilia, had responded quickly and dramatically to infliximab therapy alone, resulting in improved
sleep and functional status.
COMMENT
Hypereosinophilic syndrome (HES) is a heterogeneous
group of conditions that are characterized by blood hypereosinophilia and end-organ dysfunction due to eosinophilic infiltration and toxic mediator release.1-3 Endorgan damage commonly affects the skin, heart, lungs,
and nervous system. Idiopathic HES (IHES), which is a
diagnosis of exclusion, is defined as blood eosinophilia
exceeding an eosinophil count of 1500/µL for more than
6 consecutive months, of unknown etiology, with evidence of end-organ damage.1-3 The distinctions between
myeloid and lymphoid lineages of IHES are based on differences in molecular pathogenesis, clinical presentation, complications, and prognosis and are necessary to
guide patient treatment.4 Lymphocytic HES (l-IHES) is
characterized by a nonmalignant expansion of a T-cell
population that produces eosinophilopoetic cytokines (ie,
interleukin 5). It carries a good prognosis, with prolonged survival, and may respond to glucocorticoid
therapy or to treatment with human monoclonal anti–
interleukin 5 antibody.4,5 Cutaneous lesions are common in l-HES and vary from pruritic erythematous macules, papules, plaques, or nodules to urticaria and
angioedema.4 Myeloproliferative HES (m-IHES) is characterized by clonally derived eosinophils, carries a poor
prognosis, and may respond to imatinib mesylate (a tyrosine kinase inhibitor) therapy, particularly in the presence of FIP1L1-PDGFRA gene fusion.4,6 If left untreated,
patients with m-IHES can undergo a rapidly fatal course
owing to congestive heart failure or to the development
of acute leukemic disease.4 Other therapies for m-IHES
reported in the literature include hydroxyurea, interferon alfa,7 cyclosporine, and allogenic stem cell transplantation.8 Based on the results of clinical and molecular analysis, our patient had l-IHES: she presented with
cutaneous end-organ damage in the absence of heart inB
Figure 3. Full response to infliximab following 7 monthly infusions, with complete resolution of erythroderma (A) and keratoderma (B).
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volvement, failed to improve with imatinib mesylate
therapy, and did not harbor the FIP1L1-PDGFRA fusion
gene. We report the first case (to our knowledge) of l-IHES
that was responsive to infliximab therapy.
Infliximab is a chimeric, human-mouse antibody for tumor necrosis factor (TNF) ␣ that has been shown to be effective in the treatment of Crohn disease, rheumatoid arthritis, severe psoriasis (ie, recalcitrant erythrodermic
psoriasis),9-11 and pityriasis rubra pilaris.12 Tumor necrosis factor ␣ is a proinflammatory cytokine that contributes to lymphocyte and eosinophil recruitment by upregulating vascular cell adhesion molecule 1 (VCAM-1),
endothelial leukocyte adhesion molecule 1 (ELAM-1), and
intercellular adhesion molecule 1 (ICAM-1) on activated
endothelial cells.13-15 The precise mechanism by which infliximab therapy could induce remission in an erythrodermic patient with HES is not fully understood but could be
the result of inhibition of TNF-␣–induced eosinophildependent recruitment, toxic effects, and leukocyte infiltration. It has been proposed that through a positive feedback loop of TNF interacting with TNF receptors on
keratinocytes, “secondary” keratinocyte cytokines are released, including ICAM-1.16 Also, Costa et al17 have shown
that blood eosinophils isolated from hypereosinophilic patients can also represent a potential source of TNF-␣. By
blocking TNF-␣ expression from primary sources in the
skin, TNF-␣ inhibitors could break the cycle of cytokine
feedback by down-regulating VCAM-1, ICAM-1, and
ELAM-1 expressions on dermal endothelial cells, thereby
preventing eosinophils from homing to skin and subsequent toxic mediator release.
Several adverse effects of infliximab therapy have been
reported. In a recent meta-analysis, Bongartz et al18 showed
an increased risk of serious infection and a dosedependent increased risk of malignancy in patients with
rheumatoid arthritis treated with anti–TNF antibody
therapy. For this reason, the decision to initiate TNF-␣
therapy requires careful thought, and patients must be monitored closely during treatment. In our patient, the clinical
response resulted in significantly improved functioning and
symptom relief. The efficacy of a treatment suggested by a
single report may serve to provide clues about the pathogenesis of the disease but will need to be subjected to further study before the treatment is widely used.
Accepted for Publication: September 28, 2006.
Correspondence: Marie-France Demierre, MD, FRCPC,
Boston University School of Medicine, Skin Oncology Program, Boston Medical Center, 720 Harrison Ave,
DOB801A, Boston, MA 02118 (mariefrance.demierre
@bmc.org).
Author Contributions: Dr Demierre had full access to
all the data in the study and takes responsibility for the
integrity of the data and the accuracy of the data analysis. Study Concept and Design: Taverna, Lerner, and
Demierre. Acquisition of Data: Taverna, Lerner, Werth,
and Demierre. Analysis and Interpretation of Data: Taverna,
Lerner, Goldberg, and Demierre. Drafting of the Manuscript: Taverna. Critical Revision of the Manuscript for Important Intellectual Content: Taverna, Lerner, Goldberg,
Werth, and Demierre. Obtained funding: Demierre. Administrative, Technical, and Material Support: Taverna,
Goldberg, and Demierre. Study Supervision: Taverna,
Goldberg, Werth, and Demierre.
Financial Disclosure: Dr Demierre has acted as a speaker
for Schering, Ligand, Therakos, Merck, and Gloucester;
has received research support from Ligand, Therakos,
Merck, Gloucester, Genmab, Curagen, and Novartis; has
been a consultant for Ligand and Novartis; and has served
on the advisory board of Gloucester.
Previous Presentation: This work was presented as a case
series at the Annual Fall meeting of the Massachusetts
Academy of Dermatology; September 17, 2006; Newport, Rhode Island.
Additional Contributions: We thank Robert E. Tigelaar,
MD, for thoughtful discussions and Swarne Adikari for
technical photographic assistance.
REFERENCES
1. Chusid MJ, Dale DC, West BC, Wolff SM. The hypereosinophilic syndrome: analysis of fourteen cases with review of the literature. Medicine (Baltimore). 1975;
54(1):1-27.
2. Brito-Babapulle F. The eosinophilias, including the idiopathic hypereosinophilic
syndrome. Br J Haematol. 2003;121(2):203-223.
3. Tefferi A. Blood eosinophilias: a new paradigm in disease classification, diagnosis, and treatment. Mayo Clin Proc. 2005;80(1):75-83.
4. Roufosse F, Cogan E, Goldman M. Recent advances in pathogenesis and management of hypereosinophilic syndromes. Allergy. 2004;59(7):673-689.
5. Sutton SA, Ass’ad AH, Rothenberg ME. Anti–IL-5 and hypereosinophilic syndromes.
Clin Immunol. 2005;115(1):51-60.
6. Cools J, DeAngelo DJ, Gotlib J, et al. A tyrosine kinase created by fusion of the
PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med. 2003;348(13):1201-1214.
7. Yoon TY, Ahn GB, Chang SH. Complete remission of hypereosinophilic syndrome after interferon-alpha therapy: report of a case and literature review.
J Dermatol. 2000;27(2):110-115.
8. Ueno NT, Anagnostopoulos A, Rondon G, et al. Successful non-myeloablative
allogeneic transplantation for treatment of idiopathic hypereosinophilic syndrome.
Br J Haematol. 2002;119(1):131-134.
9. Fiehn C, Andrassy K. Case number 29: hitting three with one strike: rapid improvement of psoriatic arthritis, psoriatic erythroderma, and secondary renal amyloidosis by treatment with infliximab (Remicade). Ann Rheum Dis. 2004;63
(3):232.
10. O’Quinn RP, Miller JL. The effectiveness of tumor necrosis factor alpha antibody (infliximab) in treating recalcitrant psoriasis: a report of two cases. Arch
Dermatol. 2002;138(5):644-648.
11. Winterfield LS, Menter A, Gordon K, Gottlieb A. Psoriasis treatment: current and
emerging directed therapies. Ann Rheum Dis. 2005;64(suppl 2):ii87-ii92.
12. Liao WC, Mutasim DF. Infliximab for the treatment of adult-onset pityriasis rubra pilaris. Arch Dermatol. 2005;141(4):423-425.
13. Bochner BS, Luscinskas FW, Gimbrone MA, Newman W. Adhesion of human
basophils, eosinophils and neutrophils to interleukin 1–activated human vascular endothelial cells: contributions of endothelial cell adhesion molecules. J Exp
Med. 1991;173(6):1553-1557.
14. Kyan-Aung U, Haskard DO, Poston RN, Thornhill MH, Lee TH. Endothelial leukocyte adhesion molecule-1 and intercellular adhesion molecule-1 mediate the
adhesion of eosinophils to endothelial cells in vitro and are expressed by endothelium in allergic cutaneous inflammation in vivo. J Immunol. 1991;146(2):
521-528.
15. Weller PF, Rand TH, Goelz SE, Chi-Rosso G, Lobb RR. Human eosinophil adherence to vascular endothelium mediated by binding to vascular cell adhesion
molecule 1 and endothelial leukocyte adhesion molecule 1. Proc Natl Acad Sci
U S A. 1991;88(16):7430-7433.
16. Williams IR, Kupper TS. Immunity at the surface: homeostatic mechanisms of
the skin immune system. Life Sci. 1996;58(18):1485-1507.
17. Costa JJ, Matossian K, Resnick MB, et al. Human eosinophils can express the
cytokines tumor necrosis factor alpha and macrophage inflammatory protein-1
alpha. J Clin Invest. 1993;91(6):2673-2684.
18. Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V. AntiTNF antibody therapy in rheumatoid arthritis and the risk of serious infections
and malignancies: systematic review and meta-analysis of rare harmful effects
in randomized controlled trials. JAMA. 2006;295(19):2275-2285.
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STUDY
Clinical Severity of Psoriasis
in Last 20 Years of PUVA Study
Tamar Nijsten, MD, PhD; Caspar W. N. Looman, PhD; Robert S. Stern, MD
Objective: To assess the severity of psoriasis over time.
Design: We analyzed the results of structured dermatologic examinations administered over a 20-year period beginning 10 years after study enrollment.
Setting: The PUVA [psoralen–UV-A] Follow-up Study,
which is a prospective cohort study.
Patients: The analyses were restricted to 815 patients
(83.2% of those eligible) who underwent at least 2 of 4
possible examinations between 1985 and 2005.
Main Outcome Measure: A 4-point physician global
assessment (PGA).
Results: The distribution of the PGA levels in the study
group did not change significantly over time, except that
in 2005 more patients had no psoriasis compared with
P
patients who underwent examinations in the previous
study years (9.6% vs ⬍ 5.1%, P ⬍ .03). The PGA level
changed more than 1 level between examinations in only
14% of patients. Multistate Markov models estimated that
patients had a likelihood of about 80% to remain at the
same PGA level 1 year later. After 10 years, this likelihood varied between 19% and 53%, depending on the
PGA level. Except for patients who were clear of disease
at baseline, on average patients had about 1 year without psoriasis over 20 years. On average, individuals with
moderate to severe disease remained at these levels for
11 or more years.
Conclusion: Three decades after a large and diverse group
of patients sought a cure for their psoriasis, consistent
control of their psoriasis often had not been achieved.
Arch Dermatol. 2007;143(9):1113-1121
SORIASIS IS A COMMON
chronic skin condition that
affects about 2% of the people
in the United States. 1 Although it is widely accepted
that psoriasis waxes and wanes and varies substantially in severity among patients, the severity of psoriasis over a long
CME available online at
www.archdermatol.com
Author Affiliations:
Departments of Dermatology
(Dr Nijsten) and Public Health
(Dr Looman), Erasmus Medical
Center, Rotterdam,
the Netherlands; and
Department of Dermatology,
Beth Israel Deaconess Medical
Center, Harvard Medical
School, Boston, Massachusetts
(Dr Stern).
period in a single person or group has not
been well documented. In the 1960s and
1970s, several cross-sectional studies based
on self-reports and without clearly defined outcomes estimated that 40% of patients with psoriasis had experienced a
“complete remission” at least once in their
lifetime.2-4 In clinical trials with a maximum of 16 weeks of follow-up, the mean
relative change of the psoriasis area and
severity index ranged from −20% to 50%
among almost 500 placebo-treated patients.5 A recent study using the General
Practice Research Database found that the
prevalence of psoriasis, as reported as an
independent diagnosis, declined in pa-
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tients older than 70 years, suggesting that
psoriasis may go into remission in elderly patients.6
The severity of psoriasis in a given individual at any point reflects both endogenous (underlying disease activity) and exogenous factors, including treatment. The
short- to intermediate-term effects of therapies on disease severity have been examined in hundreds of clinical trials, but they
are unlikely to be representative of the psoriasis severity over a long period among
individuals who have this disease for an
average of 40 or more years. Also, persons entering clinical trials are likely to
have worse psoriasis than their usual state.
Patients who are receiving active treatment are likely to have less disease, and
there is a discrepancy between the efficacy of treatments observed in clinical trials
and their effectiveness in daily life.
For editorial comment
see page 1191
The PUVA [psoralen–UV-A] Follow-up Study is a long-term prospective
cohort safety study, which has included
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Annual clinical
examinations likely
to be related to
seeking care
Patients receiving
PUVA therapy, %∗
89
1975
Start
92
64 51 42 37
1977-1982
Periodical clinical examinations likely not to be related to seeking care
15
19
5
1986
1991
2001
3
2005
Start
PUVA
approval
Figure 1. Time line of the clinical examinations for the entire PUVA [psoralen–UV-A] Follow-up Study and for the study period. Asterisk indicates the percentage of
patients who received 10 or more PUVA treatments for that year.
study-sponsored structured dermatologic examinations, including an assessment of psoriasis severity using
a physician global assessment (PGA) scale administered
over nearly 30 years.7 In contrast to earlier examinations in the first study decade, by 1985 the timing of these
examinations was not coordinated with therapeutic decisions and/or disease status. Therefore, the results of the
last 4 examinations were used in this study. The primary objective of the present study was to analyze change
of psoriasis severity among participants in a prospective
cohort study over the last 2 decades.
METHODS
THE PUVA FOLLOW-UP STUDY
The PUVA Follow-up Study is a long-term safety and efficacy
study that has prospectively studied 1380 patients with moderate to severe psoriasis who were first treated with PUVA in
1975 and 1976 at 16 university centers in the United States. In
1977, a total of 1380 of 1450 patients who participated in the
original trial enrolled in the PUVA Follow-up Study. By 2005,
22 cycles of follow-up interviews and 9 cycles of physical examinations had been completed. The Declaration of Helsinki
protocols were followed, and at time of enrollment all patients
provided written informed consent. A more detailed description of this cohort study has been published previously.8,9
GLOBAL PSORIASIS SEVERITY
During 5 periods of the cohort study, from entry (1975-1976)
to 1983, members were invited to come to a participating center for an in-person follow-up interview (which assessed treatment exposures and health-related outcomes since last interview) and a structured dermatologic examination, both of which
were performed annually by a local investigator (Figure 1).
These examinations were very likely to coincide with medical
care. By 1985, a coordinating center conducted telephone interviews, with the exception of 1 center, which interviewed its
own patients. At the time of the telephone interview in designated years, the interviewer helped to arrange the patient’s clinical examination, which, when possible, was performed at a participating center or, alternatively, at the patient’s current
dermatology department and was performed relatively independently of clinical status or care. Also, by 1985, PUVA use
had decreased substantially (Figure 1). In this report, the dermatologic examinations analyzed were performed during 4 periods (1985-1986, 1990-1991, 2000-2001, and 2003-2005). The
study provided instructions and standardized forms to all examining physicians for scoring several clinical cutaneous signs.
Each clinical examination included a 4-point assessment of PGA
(clear, mild, moderate, and severe).
STUDY POPULATION
Cohort members were included in this analysis if they had undergone 2 or more PGA assessments between 1985 and 2005.
To be eligible, patients must have undergone a second examination after 1985; therefore, they had to have received follow-up at least until 1991. In 1991, a total of 979 patients were
still participating in the study, 341 had died, 37 were unavailable for follow-up, and 23 had withdrawn from the study
(Figure 1). A comparison of the 979 cohort members who were
followed up in 1991 and the 815 patients who were eligible to
enter this study demonstrated that the study patients were significantly more likely to be male (66.6% vs 61.7%, P =.03), but
men and women were of comparable age (mean [SD], 56.7 [12.9]
years vs 55.9 [15.9] years, P=.16). Up to 1986, the cumulative
exposures to PUVA, UV-B, and methotrexate were comparable between the study patients and those not included (mean
[SD], 188.5 [137.6] PUVA treatments vs 203.3 [163.1] PUVA
treatments, P = .12; 248.6 [351.1] UV-B treatments vs 288.5
[458.5] UV-B treatments, P=.31; and 15.6 [31.2] months of
methotrexate therapy vs 17.4 [32.9] months of methotrexate
therapy, P=.27, respectively).
At time of the enrolment in the PUVA study, the 815 study
patients were significantly younger and more likely to be female than the other 565 cohort members (mean age, 41.5
years vs 47.1 years [P ⬍ .001] and 64.2% women vs 56.4%
women [P = .005], respectively). At time of the first PGA assessment (1977, N = 1192), study participants were significantly more likely to have more moderate to severe disease
compared with the remaining patients (18.9% vs 32.9%
[P⬍ .001], respectively).
STATISTICAL ANALYSIS
We used the ␹2 test to determine the statistical significance of
difference in the distribution of categorical variables and the t
test for continuous variables. For paired comparisons, the Wilcoxon signed rank test and the McNemar test were used as appropriate. To test for statistical differences between multiple
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Interviewed
Died
Lost
Withdrew
1400
1200
No. of Patients
1000
800
600
400
200
0
1975
1978
1981
1984
1987
1990
1993
1996
1999
2002
Study Year
Figure 2. Of 1380 cohort members, the number of patients who were interviewed and the cumulative number of patients who died, who were unavailable for
follow-up (Lost), and who withdrew from the study each year.
groups, 2-way analysis of variance or the Kruskal-Wallis test
was used as appropriate. To assess the intraindividual variability of the PGA scorings, we calculated turnover tables for all
intervals and pooled them. We applied multistate Markov modeling, which describes the process in which an individual moves
through a series of states in continuous time.10 The multivariate statistical modeling package for the statistical program R
was used to estimate a transition intensity matrix (hazard matrix: hazard ratios with 95% confidence intervals [CIs] [data
not shown]), which were subsequently transformed to proportions (without 95% CIs because of software limitations).11 First,
multistate Markov modeling was used to estimate the transit
rates between levels of PGA after 1, 5, and 10 years. We chose
a model that allowed changes only to subsequent PGA stages
but used a likelihood ratio test to compare it with a model that
allowed all possible changes. Second, Markov models estimated the length of stay of the total study period (20 years) in
each of the PGA levels stratified by the patients’ PGA level at
baseline in 1986.
To study the effect of aging and disease duration on the
4-point PGA, we compared the distribution of these variables
across the PGA levels at each clinical examination. Also, a multivariate ordered logistic regression model, which is a type of
logistic regression model with an ordinal-depending variable
that has more than 2 categories, was used to calculate adjusted odds ratios (ORs) and 95% CIs. For the 4 analyses, collinearity was absent and the proportional odds assumption was
tested using a likelihood ratio test and a Brant test, the results
of which were nonsignificant (P ⬎.05).
About three-quarters of the cohort members who were
followed up participated in the clinical examinations
(Table 1). Of the 979 patients, 815 (82.3%) underwent 2 or more clinical examinations between 1985 and
2005. The majority of 815 study participants were middleaged male patients who had psoriasis for more than 25
years (Table 1). The age at onset of psoriasis ranged from
0 to 68 years (mean [SD] age, 19.0 [17.8] years). Graphically, no bimodal distribution was detected. A little fewer
than 50% of the patients had PGA scores of moderate to
severe psoriasis at 1 or more of the examinations. The
distribution of PGA levels remained stable over a period
of 20 years, except that a larger percentage of patients
were reported clear of psoriasis at the 2005 examination
compared with the prior examinations (9.6% vs 4.5%,
3.9%, and 5.1%, respectively; P⬍.03). However, the percentage of patients with none to mild and moderate to
severe psoriasis was comparable at the different examinations (56.8% vs 52.1%, 52.6%, and 55.0%, respectively; P ⬎.13).
RESULTS
DISTRIBUTION
THE COHORT OVER TIME
In 1986, 1991, 2001, and 2005, the total number of clinically examined patients was 889, 979, 580, and 424, respectively. Of the patients who were followed up after
1991, 92.2% of the 884 patients who underwent 1 examination between 1985 and 2005 underwent a second
examination. Of the study patients who were followed
up in 2005, 8.8% underwent 2, 30.5% underwent 3, and
60.8% underwent 4 examinations. The likelihood that a
Figure 2 demonstrates that of the patients who were
actively followed up in each year of the PUVA study, the
overwhelming majority were interviewed, and that the
number of participants who were unavailable for follow-up or withdrew from the study was very small.
Death of the cohort members was the primary reason
for the decreasing number of participants between 1975
and 2005.
CHARACTERISTICS OF
STUDY POPULATION
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Table 1. Characteristics of Patients With Psoriasis Who Underwent 2 or More Clinical Examinations
Examination (Year)
Characteristics
1 (1985-1986)
2 (1990-1991)
3 (2000-2001)
4 (2004-2005)
865 (73.7) b
333 (38.1)
54.0 (13.9)
32.6 (13.6)
743 (74.1) b
280 (37.4)
56.1 (13.0)
34.9 (12.8)
571 (78.3) b
221 (38.1)
59.9 (12.6)
41.6 (12.2)
400 (76.0) b
151 (37.8)
63.7 (13.5)
45.0 (13.0)
40 (4.5)
404 (45.4)
308 (34.6)
121 (13.6)
29 (3.8)
340 (44.7)
270 (35.5)
109 (14.3)
29 (4.8)
289 (47.8)
193 (31.9)
63 (10.4)
38 (9.5) c
188 (47.0)
127 (31.8)
47 (11.8)
Participants, No. (%) a
Women, No. (%)
Age, mean (SD), y
Duration of disease, mean (SD), y
Physician global assessment of psoriasis, No. (%)
Clear
Mild
Moderate
Severe
a Of the patients who underwent at least 2 examinations (n = 815).
b Percentage of patients who were followed up during that period.
c Statistically significant (P ⬍ .02) on ␹² test.
None
1 Level
2 Level
3 Level
100
Patients, %
80
had severe disease in 1991, about 25% remained at this
level in 2001 and 2005, and between 65% to 85% had at
least moderate disease at subsequent examinations. About
90% of 602 patients with mild and moderate psoriasis
in 1986 remained within 1 PGA level at the subsequent
examinations. About 70% of patients with no or mild disease in 1986 had these same levels of psoriasis severity
at subsequent examinations.
PAIRED COMPARISONS
60
40
20
0
2
(n = 308)
3
(n = 266)
4
(n = 241)
No. of Clinical Examinations
The median change in PGA score between the 4 examination periods was 0 (25th percentiles of 0.0 and −1.0
and 75th percentiles of 0.0 and 1.0). Paired analyses between the 4 assessments showed no significant difference in PGA levels of patients (P⬎.06). After categorizing the PGA levels of patients with none to mild and
moderate to severe psoriasis, paired analyses showed no
statistical significant differences between periods
(P ⬎.33).
INTRAINDIVIDUAL VARIABILITY
Figure 3. Maximum level of change in physician global assessment score for
the maximum number of clinical examinations.
second examination was reported increased significantly for each year a patient was followed up after the
first examinations between 1985 and 2005 (OR, 1.31; 95%
CI, 1.27-1.36). A total of 2378 examinations were included in this study (mean, 3 examinations per patient). The mode of PGA level was mild (48.0%). Of the
815 patients, 290 (35.6%) had the exact same PGA score,
and 50.3% had a maximum difference of 1 level; 13.3%,
of 2 levels; and 0.9%, of 3 levels (ie, had an examination
reporting clear psoriasis and an examination reporting
severe psoriasis) at examinations in which they participated. The difference between the 2 broad severity categories (none or mild vs moderate or severe psoriasis)
changed in more than half of the participants (52.3%).
Although the variance increased significantly (P⬍ .001)
with the maximum number of observations (Figure 3),
the majority of patients remained within 1 level of their
baseline assessment in 1986 (Figure 4). Of the 94 patients who had severe disease in 1986, almost half still
Patients’ probability of having the same global psoriasis
severity 1 year later is about 80% but decreases at 5- and
10-year intervals (Table 2). Of patients with mild to moderate disease, about 85% were likely to still have the same
level of disease after 10 years. It was estimated that almost half the patients with moderate disease will have
mild disease after 10 years. About a third of patients with
severe psoriasis are likely to have mild or moderate disease 10 years later, and almost a quarter of those with
no psoriasis will have moderate disease.
Table 3 provides the results of our statistical model
that predicts the expected duration in years of the total
20-year study period for individual time in each PGA level
according to their baseline level (the sum of the years in
the rows equals 20 years). Patients with no psoriasis in
1986 were likely to have about 5 years with no disease
and 5 years with moderate to severe disease over a subsequent 20-year period. Patients who had mild psoriasis
in 1985 would remain in that PGA level for an average
of 12 of 20 subsequent years and be clear for 1 year. Pa-
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B
100
80
80
60
60
Patients, %
Patients, %
A
100
40
20
40
20
0
0
1
1991
2
2001
3
2005
1
1991
Clinical Examination, y
3
2005
Clinical Examination, y
No change
Worse 1 level
Improved 3 levels
Worse 2 levels
Improved 2 levels
Worse 3 levels
Improved 1 level
C
No change
D
100
100
80
80
60
60
Patients, %
Patients, %
2
2001
40
20
40
20
0
00
1
1991
2
2001
3
2005
1
1991
Clinical Examination, y
2
2001
3
2005
Clinical Examination, y
Figure 4. The distribution of change of 4-point physician global assessment (PGA) for subsequent clinical examinations stratified by PGA level at 1986
examination. A, No psoriasis (n=33). B, Mild psoriasis (n=347). C, Moderate psoriasis (n = 255). D, Severe psoriasis (n = 94).
tients with moderate psoriasis in 1986 were expected to
have moderate or severe disease in 11 of 20 subsequent
years. Those with severe disease at the initial examination would average 6 years of mild, moderate, and severe psoriasis and should be clear of psoriasis for only
half a year over 2 decades.
EFFECT OF AGING
A comparison of patients’ age and disease duration at the
time of examination between the 4 PGA levels showed
no statistical significant differences in any of the examination periods (P⬎.18). After adjustment for sex in a multivariate proportional logistic regression model, age and
disease duration were not significantly associated with
level of PGA in 1986, 1991, 2001, or 2005 (eg, age in 2005,
adjusted OR, 0.98 [95% CI, 0.96-1.02]; and duration of
disease in 2005, adjusted OR, 1.00 [95% CI, 0.981.03]).
SENSITIVITY ANALYSES
To study whether patients with active or persistent disease were more likely to accept an invitation for a studysponsored clinical examination, several sensitivity analyses were performed. The demographic and disease
characteristics of the patients who underwent all examinations during follow-up (72.2% of the study population) were comparable to those of the patients who missed
intermediate examinations (data not shown). Restricting the analysis to the 241 participants who underwent
all 4 examinations did not change the results substantially (data not shown). We compared the PGA levels of
patients who were examined only in 1986 with those of
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Table 2. The Transit Rate Between Levels of Physician
Global Assessment of Psoriasis at Consecutive
Examinations After 1, 5, and 10 Years a
Psoriasis, y
None
1
5
10
Mild
1
5
10
Moderate
1
5
10
Severe
1
5
10
a Multistate
None
Mild
Moderate
Severe
0.82
0.40
0.19
0.17
0.47
0.53
0.01
0.12
0.23
0.00
0.02
0.05
0.02
0.06
0.07
0.88
0.63
0.53
0.10
0.26
0.30
0.00
0.05
0.09
0.00
0.02
0.05
0.15
0.39
0.46
0.78
0.44
0.36
0.07
0.15
0.14
0.00
0.01
0.03
0.02
0.15
0.37
0.19
0.78
0.39
0.79
0.15
0.22
Markov modeling (see “Methods” section).
Table 3. Of the Total of 20 Years, the Expected Number
of Years That Patients Will Spend in Each of the Levels
of the Physician Global Assessment (PGA) Stratified
by PGA of Psoriasis in 1986 a
PGA of Psoriasis
in 1986
None
Mild
Moderate
Severe
None
Mild
Moderate
Severe
5.79
1.23
0.78
0.55
9.28
11.80
8.15
6.22
3.90
5.42
8.44
7.04
1.03
1.55
2.63
6.18
a Multistate
Markov modeling (see “Methods” section).
patients who were assessed in both 1986 and 1991. The
same comparison was performed for examinations in 1991
and 2001. There were no significant differences in the
distribution of the PGA levels of the patients with 1 vs 2
observations, except that patients who underwent only
1 examination were significantly more likely to have severe psoriasis than were those who underwent 2 examinations (11.9% vs 3.1%, P ⬍ .001). When we fitted a
Markov model with all transitions possible (ie, also from
PGA levels 1 to 4), the likelihood ratio test comparing
this model with the presented model showed no significant difference (df=6, P = .41).
COMMENT
Nearly all data concerning the variability in clinical psoriasis severity over time come from a few cross-sectional
studies using self-reported psoriasis severity in time or from
clinical trials with follow-up measured in weeks rather than
years or decades. The PUVA Follow-up Study cohort is
unique. Patients have been followed up for nearly 30 years
from enrollment in a clinical trial irrespective of their use
of PUVA or any other therapy. In the first 5 years of the
study, many patients still relied on PUVA and the study
protocol linked interviews and study-sponsored dermatologic examinations. By the mid-1980s, use of PUVA had
decreased significantly.9 Also beginning in 1985, the timing of interviews and study-sponsored dermatologic examinations were no longer closely linked to each other or
to patients seeking care for their psoriasis. As a result, the
structured dermatologic examinations performed from 1985
to 2005 provide a unique assessment of the distribution of
psoriasis over time in a group of patients who joined this
cohort nearly a decade earlier and of the variability in individuals’ physician-assessed psoriasis severity over a 20year period. To quantify the variation of the patients’ disease severity over these 20 years, we used new statistical
techniques to estimate transition rates and the expected
number of years that patients would be at the different PGA
levels depending on their baseline assessment.
PSORIASIS SEVERITY IN TIME
Based on nearly 2400 structured dermatologic examinations, the distribution of psoriasis severity within this
group assessed by dermatologists changed little for the
PUVA cohort as a whole over a 20-year period. Only about
25% of individual study participants had more than 1 PGA
level change (with up to 3 levels possible) in multiple
examinations. Paired comparisons demonstrated no significant differences between patients’ PGA levels over time.
Moreover, transition rate analysis estimated that patients had about an 80% chance to have the same level
of psoriasis severity after 1 year, but these rates decreased after 5 and 10 years, especially for the 2 extreme
PGA levels. At least 50% of patients with moderate to severe disease are likely to still be at this level 10 years later,
but patients with severe psoriasis will have mild to moderate disease in at least two-thirds of the follow-up years.
Therefore, at least in this heterogeneous population cared
for by many dermatologists, including many with a special interest in psoriasis, the likelihood that the extent
of disease will change more than 1 PGA level over 1 year
and over 10 years is relatively small, and fewer than 5%
will have no psoriasis. As expected, patients who had no
psoriasis at baseline, which may reflect the natural course
of their disease or may be attributable to therapy, have
the best chance of having no or mild disease in the future. Although treatment exposure and PGA examination results were not linked in this study, overall treatment use has been substantial in this cohort. For example,
from study entry to 1984, cohort members had used twice
as many PUVA as UV-B treatments, but after 1984, UV-B
was used 3 times as often (between 1985 and 2005, the
cohort used more than 200 000 UV-B treatments). Despite substantial therapy use over time, only 9.0% and
2.3% of the 815 study participants were clear of disease
at 1 or 2 examinations and only 5 (1.0%) of the 507 patients who underwent 3 or more clinical examinations
were clear at 3 examinations, which may be a spontaneous outcome or attributable to therapy. These low proportions of clearance contrast with those observed in an
older prospective study of an isolated population followed up for a median interval of 1 year as well as those
of a study that noted that 75% of patients reported a com-
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plete remission of their disease and that 2% of men and
8% of women had no signs of the disease for at least 5
years.2-4 Both of these studies relied on patient reports
rather than on examination and included a much higher
percentage of persons with mild psoriasis than did the
PUVA Follow-up Study.
EFFICACY VS EFFECTIVENESS
The study findings confirm the discrepancy between
the efficacy of treatments observed in clinical trials and
our success in controlling psoriasis over the long term.
In the original PUVA trial, 88% of the patients achieved
clearance at completion of the study,12 but 1 years or
more thereafter, including at time points close to the introduction of cyclosporine and the biologics, 55% or
fewer of those patients were described as having no or
mild psoriasis. This difference of 30% may suggest that
clearing psoriasis over the short term is quite feasible
but that it is much more difficult to substantially reduce
psoriasis over the long term, which may be attributable
to other issues such as care setting (clinical trials vs real
life), access and availability, safety, convenience, satisfaction, and costs.13-15 Although our study was unable to
differentiate which of these issues or what other factors
may be the root cause, our findings indicate that those
patients who sought a cure for their psoriasis 30 years
ago and temporarily achieved good control of their disease have suffered from substantial disease over the
long term.
Psoriasis severity reported at the first 5 examinations
after the introduction of PUVA (1976-1982), which
were excluded from the analyses, was significantly less
than that at later examinations. In the years in which
the first 5 examinations were performed, the use of
PUVA was significantly greater than in the years before
the examinations that were performed between 1985
and 2005 (Figure 1). However, this level of control diminished in association with the decline of PUVA use
after it became widely accepted to be carcinogenic in
the 1980s.16 At least in our cohort, the introduction of
new treatments from 1985 to 1998 (ie, vitamin D derivatives, retinoids, and cyclosporine) did not seem to
have substantially affected the severity of the patients’
psoriasis. However, the distribution of PGA levels of
400 patients with psoriasis who were examined in 2005
showed that a significantly larger percentage (9.6% vs
⬍5.1%) of patients were rated clear compared with the
patients at prior examinations. Fewer than one-fourth
of those who were clear in 2005 had ever used biologics, but the availability of biologics and the publicity
about psoriasis treatments may have stimulated more
patients to seek care again. Therefore, these recent data,
as well as our cohorts’ experience from 1977 to 1982,
are compatible with the hypothesis that more intensive
therapy, both new and old, is able to reduce psoriasis, at
least for short periods.
EFFECT OF AGING
A medical claims–based study that used prevalence estimates that were based on general physicians’ record-
ing diagnoses and assessing the distribution of severity
among different groups suggested that psoriasis may go
into remission in the elderly.6 Our logistic regression
model, which was based on a prospective study of a defined cohort, indicates that psoriasis severity does not decrease substantially with age. Also, our study could not
confirm that the extent of psoriasis depends on the duration of disease (ie, age at onset) but indicates that it
may depend on family history.17-19
STRENGTHS AND LIMITATIONS
To our knowledge, this is the first prospective study that
has used standardized structured dermatologic examination to assess psoriasis severity longitudinally over 2
decades at 4 time points that were not substantially related to treatment use. This is a long-term ecologic study
of a cohort with psoriasis. As such, it has several advantages and disadvantages.
Although we documented patient treatments through
nearly annual telephone interviews with members of the
cohort, the timing of dermatologic examination was not
coordinated with therapy or therapeutic decisions but
rather was arranged to suit the patient’s convenience.
Therefore, we cannot link the use of specific treatments
with specific disease states. Instead, we present a unique
perspective of physician-assessed severity in a cohort of
patients who were periodically examined over a 20-year
period. A true “natural history” study of a chronic disease such as psoriasis would need to withhold treatment from the affected individuals. Such a study would
be both impractical and unethical, particularly in a cohort such as ours. Enrollment in a clinical trial may be
associated with worsening of a disease, with subsequent
observed decreased severity a reflection of “regression to
the mean” rather than a true change in the “usual” disease severity. Since we used examination 1, which was
administered nearly a decade after enrollment, as our baseline, this potential ascertainment bias is unlikely to have
substantially influenced our results. However, this phenomenon may in part explain the relatively large proportion of patients with mild disease. Although cohort
members with persistent or active psoriasis may have been
more likely than those with less or inactive disease to accept the invitation for a clinical examination, the number of patients who were unavailable for follow-up or who
withdrew from the cohort study was small. Although several sensitivity analyses also suggest that this potential
selection bias has not substantially affected our results,
study patients had more severe psoriasis in 1977 than cohort members who were not included in this study. Despite the fact that patients were invited randomly in a follow-up cycle, the probability may have been greater that
the participating patients who attended the examination were more likely than nonparticipating patients to
be seeking medical care, including therapeutic and nontherapeutic interventions. However, this association is
not likely to be different among the 4 assessments, suggesting a nondifferential effect. The study findings are
not generalizable to all patients with psoriasis, because
this cohort included patients who sought experimental
therapy 30 years ago at tertiary referral centers. At the
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time of patients’ enrollment in the PUVA study, nearly a
decade before the first examinations included in these
analyses were performed, the patients had sufficiently severe and/or treatment-resistant psoriasis that both patients and their treating dermatologists at 16 centers,
which were selected for their expertise in the treatment
of psoriasis, deemed them appropriate candidates for a
then-experimental therapy, which included the systemic administration of drug. We believe that our results are likely to be representative of the course of psoriasis severity among patients with moderate to severe
psoriasis who at least initially had access to care at a leading dermatologic center. Although mortality may be associated with clinical psoriasis severity (owing to increased incidence of comorbidities),20 it is not likely to
be associated with the degree of disease fluctuations, which
is the objective of this study. The Markov model was used
to create the transition tables. As a statistical model, it is
based on several assumptions. The results of these kinds
of analyses should be interpreted with some caution and
applied cautiously in advising individual patients. However, a sensitivity analysis with altered assumptions confirmed the findings of the presented model. Because of
software limitations, we were unable to calculate 95% CIs
for the transition rates. However, the 95% CIs were estimated for the transition intensities (hazard matrix),
which is in an intermediate step in the process of the transition rate calculation, and were reasonably narrow (data
not shown). We believe that a 4-point PGA scale, which
was assessed by dermatologists who were trained at investigators’ meetings and through instructions, as part
of a structured dermatologic examination, is likely to be
a reliable and valid measurement in the assessment of psoriasis. However, the PGA was not strictly defined and did
not include parameters such as percentage of body surface area affected and/or plaque characteristics but is
widely used and has “face” validity.21-23 Although a global
assessment may be relatively insensitive for measuring
small changes over time, we believe it should be sensitive to clinically meaningful changes, which are the focus of this study. In addition to the intraobserver variability of the PGA, interobserver variability may also have
affected our results, because different investigators may
have assessed some patients over time. The extent to which
observer bias affects the PGA in psoriasis is not well documented.22
In conclusion, even with substantial use of psoriasis
therapies after 1984, including more than an average of
170 UV-B treatments, 50 PUVA treatments, and a year
of methotrexate therapy, our cohort was assessed by
dermatologists as having moderate or severe psoriasis at
nearly half of almost 2400 examinations performed
over a 20-year period. Although at some times the disease may improve or worsen, most individuals in our
cohort had similar extents of psoriasis at subsequent examinations. Three decades after this large diverse group
of patients sought a cure for their psoriasis, they have
not achieved consistent control of their disase. Additional prospective longitudinal studies that assess the
(natural) course of psoriasis and its determinants are
warranted.
Accepted for Publication: February 25, 2007.
Correspondence: Robert S. Stern, MD, Department of Dermatology, Beth Israel Deaconess Medical Center, 330
Brookline Ave, Boston, MA 02215 (rstern@bidmc.harvard
.edu).
Author Contributions: Dr Stern is the principal investigator of the PUVA Follow-up Study. Study concept and
design: Nijsten and Stern. Acquisition of data: Stern. Analysis and interpretation of data: Nijsten, Looman, and Stern.
Drafting of the manuscript: Nijsten. Critical revision of the
manuscript for important intellectual content: Nijsten, Looman, and Stern. Statistical analysis: Nijsten and Looman. Obtained funding: Stern. Administrative, technical,
and material support: Nijsten and Stern. Study supervision: Stern.
Financial Disclosure: None reported.
Funding/Support:This study was funded in part by Public Health Service contract N01-AR-0-2246 from the National Health Institute of Arthritis and Musculoskeletal
and Skin Diseases, National Institutes of Health, Department of Health and Human Services.
Additional Contributions: We thank the patients and
principal investigators of the multicenter PUVA Follow-up Study for their participation; M. Cosmos and S.
Paquette for collecting and managing data for this project;
D. Spiegelman for input on data analysis; and Christopher Jackson, PhD, Imperial College, London, England, for providing access to Markov modeling software. The following institutions and investigators have
participated in the recruitment and follow-up of patients in this study: Stanford University School of Medicine, Stanford, California (E. Bauer and E. Abel); University of California at San Francisco (J. H. Epstein and
J. Koo); Baylor College of Medicine, Houston, Texas
(J. Wolf); Washington Hospital Center, Washington, DC
(T. P. Nigra); University of Michigan Medical School, Ann
Arbor (T. F. Anderson); Columbia University College of
Physicians and Surgeons, New York, New York (J. Prystowsky and M. J. Stiller); Mayo Graduate School of Medicine, Rochester, Minnesota (M. McEvoy); University of
Miami Medical School, Miami, Florida (J. R. Taylor); Mt
Sinai Medical Center, Miami Beach, Florida (N. Zaias);
Temple University School of Medicine, Philadelphia,
Pennsylvania (F. Urbach); Beth Israel Deaconess Medical Center, Boston, Massachusetts (R. S. Stern); Dartmouth Medical School, Hanover, New Hampshire (R. D.
Baughman); Yale University of Medicine, New Haven,
Connecticut (I. M. Braverman); Duke University Medical Center, Durham, North Carolina (J. Murray); University of Pennsylvania Hospitals, Phildelphia (V. P.
Werth); and Massachusetts General Hospital, Boston
(T. B. Fitzpatrick [deceased], J. Parrish, C. Taylor, and
A. J. Sober).
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carries a substantial burden even when not extensive, and is associated with widespread treatment dissatisfaction. J Investig Dermatol Symp Proc. 2004;9(2):
136-139.
2. Farber EM, Bright RD, Nall ML. Psoriasis: a questionnaire survey of 2,144 patients.
Arch Dermatol. 1968;98(3):248-259.
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3. Farber EM, Nall ML. The natural history of psoriasis in 5,600 patients. Dermatologica.
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4. Molin L. Psoriasis: a study of the course and degree of severity, joint involvement, socio-medical conditions, general morbidity and influences of selection
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5. Spuls PI, Witkamp L, Bossuyt PM, Bos JD. The course of chronic plaque-type
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6. Gelfand JM, Weinstein R, Porter SB, Neimann AL, Berlin JA, Margolis DJ. Prevalence and treatment of psoriasis in the United Kingdom: a population-based study.
Arch Dermatol. 2005;141(12):1537-1541.
7. Stern RS, Laird N, Melski J, Parrish JA, Fitzpatrick TB, Bleich HL. Cutaneous squamous-cell carcinoma in patients treated with PUVA. N Engl J Med. 1984;310
(18):1156-1161.
8. Stern RS, Thibodeau LA, Kleinerman RA, Parrish JA, Fitzpatrick TB. Risk of cutaneous carcinoma in patients treated with oral methoxsalen photochemotherapy for psoriasis. N Engl J Med. 1979;300(15):809-8138.
9. Stern RS, Laird N, Melski J, Parrish JA, Fitzpatrick TB, Bleich HL. Cutaneous squamous-cell carcinoma in patients treated with PUVA. N Engl J Med. 1984;310
(18):1156-1161.
10. Gladman DD, Farewell VT. Progression in psoriatic arthritis: role of time-varying
clinical indicators. J Rheumatol. 1999;26(11):2409-2413.
11. The R project for statistical computing. http://www.r-project.org/. Accessed September 10, 2006.
12. Melski JW, Tanenbaum L, Parrish JA, Fitzpatrick TB, Bleich HL. Oral methoxsalen photochemotherapy for the treatment of psoriasis: a cooperative clinical
trial. J Invest Dermatol. 1977;68(6):328-335.
13. Krueger G, Koo J, Lebwohl M, Menter A, Stern RS, Rolstad T. The impact of psoriasis on quality of life: results of a 1998 National Psoriasis Foundation patientmembership survey. Arch Dermatol. 2001;137(3):280-284.
14. Zaghloul SS, Goodfield MJ. Objective assessment of compliance with psoriasis
treatment. Arch Dermatol. 2004;140(4):408-414.
15. Nijsten T, Margolis DJ, Feldman SR, Rolstad T, Stern RS. Traditional systemic
treatments have not fully met the needs of psoriasis patients: results from a national survey. J Am Acad Dermatol. 2005;52(3, pt 1):434-444.
16. Housman TS, Rohrback JM, Fleischer AB Jr, Feldman SR. Phototherapy utilization for psoriasis is declining in the United States. J Am Acad Dermatol. 2002;
46(4):557-559.
17. Melski JW, Stern RS. The separation of susceptibility to psoriasis from age at
onset. J Invest Dermatol. 1981;77(6):474-477.
18. Gudjonsson JE, Karason A, Runarsdottir EH, et al. Distinct clinical differences
between HLA-Cw*0602 positive and negative psoriasis patients—an analysis of
1019 HLA-C– and HLA-B–typed patients. J Invest Dermatol. 2006;126(4):740745.
19. Henseler T, Christophers E. Psoriasis of early and late onset: characterization of
two types of psoriasis vulgaris. J Am Acad Dermatol. 1985;13(3):450-456.
20. Gelfand JM, Neimann AL, Shin DB, Wang X, Margolis DJ, Troxel AB. Risk of myocardial infarction in patients with psoriasis. JAMA. 2006;296(14):1735-1741.
21. Naldi L, Svensson A, Diepgen T, et al. Randomized clinical trials for psoriasis
1977-2000: the EDEN survey. J Invest Dermatol. 2003;120(5):738-741.
22. Ashcroft DM, Wan Po AL, Williams HC, Griffiths CE. Clinical measures of disease severity and outcome in psoriasis: a critical appraisal of their quality. Br J
Dermatol. 1999;141(2):185-191.
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Dis. 2005;64:ii65-ii68.
ARCHIVES Feature
Free color publication if color illustrations enhance the
didactic value of the article.
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STUDY
Clinical, Biochemical, and Genetic Study
of 11 Patients With Erythropoietic Protoporphyria
Including One With Homozygous Disease
Carmen Herrero, MD, PhD; Jordi To-Figueras, PhD; Celia Badenas, PhD; Manuel Méndez, PhD;
Patricia Serrano, MD; Rafael Enrı́quez-Salamanca, MD, PhD; Mario Lecha, MD, PhD
Objective: To study the mutations in the ferrochelatase gene (FECH) and the phenotypic expression of
erythropoietic protoporphyria (EPP) in a group of Spanish patients.
Design: Case series.
Setting: University-based hospital.
Patients: Eleven unrelated patients with EPP and 19
asymptomatic relatives from 10 families.
Main Outcomes Measures: Measurement of protoporphyrin concentration in red blood cells and feces by
fluorometry and chromatography. Analysis of the mutations of the FECH gene by single-strand conformation
analysis. Expression of mutations in Escherichia coli.
Results: FECH gene mutations were found in all 11 pa-
tients. Ten were heterozygous and carried the IVS3-48C
low-expression allele. Three novel mutations were found:
IVS4⫹1delG, 347-351delC, and 130_147dupl 18. One
patient did not present the IVS3-48C polymorphism and
was found to harbor a novel A185T missense mutation
in both alleles. The familial study confirmed a recessive
mode of inheritance of the disease. The A185T mutation showed a residual activity 4% of normal when expressed in E coli. This patient presented cutaneous photosensitivity similar to the heterozygous cases, but a higher
protoporphyrin accumulation in erythrocytes, microcytic anemia, and early signs of liver engagement. FECH
mutations were found in 10 healthy relatives, none of
whom carried the low-expression allele. The frequency
of the IVS3-48C allele among 180 nonporphyric Spanish individuals was 5.2%.
Conclusions: These findings confirm, among a group
of Spanish patients, that most cases of EPP result from
the coinheritance of IVS3-48C and a mutation in the FECH
gene, and also document the existence of patients with
mutations in homozygosity that may present a more severe form of the disease.
Arch Dermatol. 2007;143(9):1125-1129
E
Author Affiliations:
Departments of Dermatology
(Drs Herrero, Serrano, and
Lecha) and Biochemistry and
Molecular Genetics
(Drs To-Figueras and Badenas),
Hospital Clinic of Barcelona,
University of Barcelona,
IDIBAPS (Institut
d’Investigacions Biomèdiques
August Pi i Sunyer), Barcelona,
Spain; and Centro de
Investigación, Hospital 12 de
Octubre, Madrid, Spain
(Drs Méndez and
Enrı́quez-Salamanca).
RYTHROPOIETIC PROTOPORphyria (EPP) (Mendelian Inheritance in Man 177000) is
an inherited disorder of porphyrin metabolism caused by
a partial deficiency of ferrochelatase (FECH)
(European Community 4.99.1.1), which
catalyzes the insertion of iron into protoporphyrin IX to form heme. Patients with
EPP accumulate free protoporphyrin mainly
in erythropoietic tissues, but the metabolite may also reach the skin, absorb light at
certain wavelengths, and generate free radicals, resulting in phototoxic cell injury.
Most patients with EPP develop solely photosensitivity commencing in childhood, but
in some cases liver complications also appear. The strong hydrophobic nature of the
molecule does not allow renal clearance but
only bile secretion. Therefore, massive hepatic accumulation of protoporphyrin in the
liver may cause cholestasis and liver dam-
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1125
age in a minority of patients with EPP. Hepatic involvement may vary in severity,
ranging from abnormalities in 20% of the
cases to cirrhosis and liver failure in less
than 5%.1-3 Blood disorders such as mild
anemia with hypochromia and microcytosis may also be detected in 20% to 50% of
these patients.2,4,5
See also pages 1153, 1194,
and 1209
The FECH gene is assigned to chromosome 18q21.3 (GenBank No. D00726),
with more than 110 different mutations
having been described in EPP families to
date.6 Individuals who are heterozygous
for these mutations remain asymptomatic, despite having FECH activity reduced by about 50%. Clinical expression
of the disease in most cases results from
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the coinheritance of a null FECH allele plus a wild-type
low-expressed allele, which further reduces FECH
activity to below a critical threshold of about 35%.7 In a
haplotype segregation analysis,8 it was found that the lowexpression allele is the C variant of an intronic singlenucleotide polymorphism (SNP) IVS3-48T/C in intron
3 of the FECH gene. Because the IVS3-48C allele is relatively common among European populations,6 overt
EPP is normally inherited in such a way that it resembles an autosomal dominant disease with low clinical penetrance.
Erythropoietic protoporphyria is rarely inherited as
an autosomal recessive disease with true mutations in both
alleles.9-12
In some areas of southern Europe, the prevalence of
EPP and the genetic defects underlying the disease are
not sufficiently elucidated. Therefore, we investigated the
mutations in the FECH gene and the phenotypic expression of the disease in a series of Spanish patients with
EPP. The molecular, biochemical, and clinical study included a rare case of recessive EPP.
amplification are available from the authors. All polymerase chain
reaction (PCR) analyses were carried out using the PCR Master Mix (Promega Corporation, Madison, Wisconsin) following the manufacturer’s instructions. The following PCR conditions were applied: initial denaturizing step (5 minutes at
95°C), 35 cycles (1 minute at 95°C, 1 minute at 57°C, and 1
minute at 72°C), followed by final extension (10 minutes at
72°C) and maintenance at 4°C until single-strand conformational polymorphism or sequencing studies were carried out.
Part of intron 3 was sequenced in all samples to test for the IVS348T/C polymorphism.
Single-strand conformation analysis was used to detect mutations. Three microliters of denatured PCR product was combined with loading buffer and loaded into GeneGel Excel 12.5
acrylamide gels (Amersham Biosciences, Uppsala, Sweden) and
run following the manufacturer’s instructions. The different migrations were silver stained.19 DNA samples with abnormal migrations were sequenced. The PCR products were purified using
the GFX PCR DNA and gel band purification kit (Amersham
Biosciences) and automatically sequenced using the BigDye Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems, Foster City, California) and an ABI3100 automatic sequencer (Applied Biosystems).
METHODS
PROKARYOTIC EXPRESSION
OF MUTANT FECH
PATIENTS
We studied 11 unrelated patients (6 female and 5 male, with a
mean age of 12.8 years [range, 4-26 years]) who attended the
Department of Dermatology of the Hospital Clinic of Barcelona (Barcelona, Spain) for photosensitivity and suspicion of
porphyria. The diagnosis of EPP was established initially by clinical and biochemical criteria and was later confirmed by DNA
analysis of mutations in the FECH gene. A complete hematological and biochemical profile and specific liver function tests
were performed in every case. In addition, 19 asymptomatic
relatives from 8 families were also included in the genetic study.
The study was conducted in accordance with the Declaration
of Helsinki principles and was approved by the hospital ethics
committee of the Hospital Clinic of Barcelona. Written consent was obtained from all patients.
PORPHYRIN DETERMINATION
Protoporphyrin concentration in erythrocytes was determined fluorometrically after solvent partition according to the
method described elsewhere.13-15 Protoporphyrin in feces was
extracted according to Lockwood et al16 and was analyzed by
high-performance liquid chromatography according to Lim and
Peters.17 Porphyrins in urine were analyzed by standard methods of high-performance liquid chromatography.17
LYMPHOCYTE FECH ENZYME ASSAY
FECH activity in lymphocytes was determined by incubating a
homogenate with zinc and mesoporphyrin and measuring zincmesoporphyrin formation by fluorometry according essentially
to the method of Rossi et al,18 as modified by Gouya el al.6 FECH
activity was expressed as nanomoles of zinc-mesoporphyrin
formed per hour per milligram of protein at 37°C.
DNA ANALYSIS
We analyzed exons 1 to 11 of the FECH gene and the associated splice donor and acceptor sites. The primers used for exon
Mature ferrochelatase was expressed in Escherichia coli strain
JM109 (Promega Corporation) using the expression vector
pKK223-3 (Pharmacia Biotech Inc, Piscataway, New Jersey).
The wild-type human ferrochelatase complementary DNA
(cDNA) was synthesized by PCR excluding the region encoding the mitochondrial leader sequence and including a new ATG
start site of translation, and cloned into the EcoRI-HindIII sites
of pKK223-3. This construct was designated pKK-FECH-wt.
To generate the mutant construct pKK-FECH-A185T, a fragment of FECH cDNA, containing the A185T mutation was
generated by PCR site-directed mutagenes20 using the pKKFECH-wt plasmid as templated. Then, the PCR product was
digested with the restriction endonucleases MfeI and CveI (New
England Biolabs, Beverly, Massachusetts) and the MfeI-CveI fragment was ligated as a cassette into the corresponding sites in pKKFECH-wt, and transformed in E coli strain JM109. The integrity
of each expression construct was checked by automated sequencing. The primers are available from the authors.
Bacterial clones, each of them containing one of the plasmids
pKK223-3, pKK-FECH-wt, or pKK-FECH-A185T, were grown
to log phase and were induced with 5mM isopropylthiogalactoside for 3 hours. Then, cells were harvested by centrifugation and
washed twice in phosphate-buffered saline. The pellets were resuspended in 250 µL of lysis buffer (100mM Tris hydrochloride,
pH 7.6; 0.1% Triton-X 100) and sonicated on ice. After centrifugation, ferrochelatase activity was measured in the supernatant
using protoporphyrin IX and zinc sulfate as substrates, according to the method described by Camadro and Labbe.21
RESULTS
CLINICAL CHARACTERISTICS
The main clinical and biochemical outcomes of the patients with EPP are given in the Table. All presented acute
cutaneous photosensitivity, with the symptoms beginning in early childhood in most cases. Only 3 cases presented with chronic skin thickening over the knuckles.
Microcytic anemia was present in 4 cases. Liver func-
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Table. Major Clinical and Biochemical Features and FECH Genotypes in 11 Patients With EPP
Patient No./
Sex/Age at
First Symptoms, y
1/F/4
2/F/2
3/M/1
4/M/1
5/F/6
6/M/3
7/F/8
8/M/2
9/M/2
10/F/1
11/F/6
Hemoglobin,
12-17 g/dL
MCV,
80-100 fL
Liver
Dysfunction
Erythrocyte PP
⬍1.5 µmol/L
Fecal PP
⬍100 nmol/g
of Dried Feces
FECH
Mutation
IVS3-48C/T
SNP
11.5
11.1
13.7
13.4
12.0
12.6
11.8
12.3
12.5
11.7
12.4
73
75
80
79
87
75
79
83
81
76
79
Yes a
No
No
No
No
No
No
No
No
No
No
32
12
11
10
13
18
17
11
5
10
7
1066
ND
90
715
114
327
115
ND
ND
ND
186
A185T/A185T
757del5
IVS4 ⫹ 1delG
347-351delC
757del5
130_147dupl18
I186T
H386P
843delC
R115X
P334L
T/T
C/T
C/T
C/T
C/T
C/T
C/C
C/T
C/T
C/T
C/T
Abbreviations: EPP, erythropoietic protoporphyria; MCV, medium corpuscular volume; ND, not done; PP, protoporphyrin; SNP, single-nucleotide polymorphism.
SI conversion factor: To convert the hemoglobin to grams per liter, multiply by 10.
aminotransferase, alanine aminotransferase, and ␥-glutamyltransferase levels greater than 40 U/L (to convert to microkatals per liter, multiply by
0.0167).
a Aspartate
tion test results were persistently normal in 10 cases, most
with a long clinical follow-up (mean, 8.6 years; range 1-26
years). Only 1 case showed alterations in the liver function test results. The main characteristics of this patient
are described in the “Report of a Case” subsection.
MUTATIONS IN THE FECH GENE
Ten different mutations in the FECH gene were found,
thereby confirming the molecular heterogeneity of EPP
(Table). Four novel mutations were found: 553G⬎A in exon
5 (A185T); IVS4⫹1delG and 347-351delC, both in exon
4; and 130_147dupl 18 in exon 1. The A185T mutation
was homozygous, while the other mutations were heterozygous. Only the already described 575del5 mutation was
present in 2 patients. Patients 7, 8, 9, and 10 (I186T, H386P,
843delC, and R115X, respectively) were previously studied by Gouya et al,22 but the status of the SNP of the allele
trans to mutant allele was not determined in that study. All
patients, except patient 1 who was homozygous for IVS348T/T, were heterozygous for IVS3-48C/T.
PROKARYOTIC EXPRESSION
OF GENE MUTATION
The A185T mutation was expressed in E coli. FECH specific activity was determined in 4 independent experiments. The residual activity was calculated from the value
of the normal FECH construct (pKK-FECH-wt) and was
4% of normal activity.
FAMILIAL AND POPULATION ANALYSES
Molecular analysis of 19 asymptomatic relatives from patients 1 through 6 and 8 through 10 were performed. This
allowed the identification of 10 relatives who were carriers of heterozygous mutations. Inspection of the intron 3 SNP showed that none harbored the IVS3-48C allele. All of these relatives had normal values of
protoporphyrin in blood. Analysis of 180 nonporphyric
unrelated Spanish individuals showed that the IVS348C allele was present in 10.5% (allele frequency, 5.2 %).
REPORT OF A CASE
Patient 1 was a 15-year-old girl with microcytic anemia since
she was 4 months old and photosensitive dermatitis since
she was 4 years old. When she was 10 years old, alterations in liver function had been detected, with the persistence of microcytic anemia. She presented an itchy erythema and edema on the hands and face after sun exposure.
On examination, pitted and linear scars on the nose, cheeks,
and forehead and mild skin thickening over the knuckles
were observed. There was no family history of photosensitivity and no apparent familial consanguinity.
Results from porphyrin analyses included the following: erythrocyte protoporphyrin level, 32 µmol/L (reference value, ⬍ 1.5 µmol/L; ⬎90% free protoporphyrin);
and fecal protoporphyrin level, 1066 nmol/g of dried feces (reference value, ⬍100 nmol/g), which allowed for
the diagnosis of EPP. The excretion of coproporphyrins
in urine was normal. Results from biochemical analysis
included the following: aspartate transaminase level, 52
U/L (reference value, ⬍40 U/L), alanine aminotransferase level, 109 U/L (reference value, ⬍40 U/L), and ␥-glutamyltransferase level, 57 U/L (reference value, ⬍40 U/L)
(to convert to microkatals per liter, multiply by 0.0167);
hemoglobin level, 11.5 g/dL (reference range, 12.0-17.0
g/dL) (to convert to grams per liter, multiply by 10); median corpuscular volume, 73 fL (reference range, 80100 fL); median corpuscular hemoglobin concentration, 22.7 pg (26.7-33.3 pg); serum iron level, 59 µg/dL
(reference range, 50-150 µg/dL) (to convert to micromoles per liter, multiply by 0.179); ferritin level, 28 ng/mL
(reference range, 15-200 ng/mL) (to convert to picomoles per liter, multiply by 2.247); and soluble transferrin receptor level, −0.089 mg/dL (reference range,
0.083-0.176 mg/dL) (to convert to micromoles per liter,
multiply by 0.0123). The appearance of the liver on echography was normal. A hepatic biopsy revealed normal liver
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architecture and the presence of brown material without birefringence at polarized light. Hemoglobin electrophoresis demonstrated normal percentages of hemoglobin A2 and F, and findings from DNA analysis excluded
the thalassemia trait. Bone marrow examination showed
normal percentages of the hematopoietic cell lineages with
dysplasia signs in the erythroid cells. The bone marrow
karyotype was 46,XX[20].
Findings from a molecular study of the DNA showed
that this patient was apparently homozygous for a novel
A185T missense mutation and homozygous for the T variant of the IVS3-48C/T polymorphism. The residual activity of the mutant FECH in E coli was 4% of normal activity. The FECH activity in peripheral lymphocytes was 0.4
nmol of zinc-mesoporphyrin per hour per milligram of protein at 37°C (reference value, mean±SD, 4.5±1). Two years
later, the erythrocyte protoporphyrin level had increased
to 77 µmol/L (fecal protoporphyrin level, 1221 nmol/g of
dried feces).
Familial investigation showed that both parents and
a sister were heterozygous for the A185T mutation, and
none harbored the low-expression IVS3-48C allele, thus
confirming recessive EPP. All were asymptomatic and had
an erythrocyte protoporphyrin concentration of less than
1.5 µmol/L.
COMMENT
We present the clinical, biochemical, and molecular characteristics of 11 cases of EPP and 19 asymptomatic relatives from 10 Spanish families. Among the series of patients with EPP, 1 had homozygous disease. Recessive
inheritance of EPP, with patients presenting mutations
in both alleles is rare. Only 13 cases (12 families) have
been reported to date,6,9-12 most being compound heterozygotes. To our knowledge, the patient who was homozygous for an A185T mutation is the second case of
true homozygous EPP, with the same mutation in both
alleles confirmed by molecular analysis.12 The A185T mutation is located within the ␤3-strand of the enzyme and
may produce a significant structural alteration owing to
the replacement of a hydrophobic amino acid by a polar
amino acid. Although the alanine residue at this position is not invariant among different species, it is conserved in mammals, yeast, and some prokaryotic species.23,24 Expression of the A185T allele revealed a low
but still detectable residual activity of 4% in a crude bacterial extract. These data indicate that the mutation produces important structural and/or functional consequences in the FECH enzyme but is not completely
deleterious.
It has been suggested that recessive EPP forms may
have a higher risk of liver failure than the more usual
dominant forms.10 According to published reports, severe liver disease has been observed in 4 of 13 patients
with recessive EPP detected to date.6,10,12 This is a high
proportion, taking into account that liver failure appears in only in less than 5% of patients with EPP dominant forms.6,25
The determinants of liver injury in EPP are not well
understood because genetic factors may modulate the ac-
cumulation of protoporphyrin in the liver.26 It is likely,
however, that the amount of residual FECH activity in
cells12,25 may play a key role in determining the course
of the disease. Most of the missense mutations found in
heterozygous EPP cases show a drastic reduction or even
undetectable activity when expressed in prokaryotes.27-29 In contrast, in a report of recessive EPP, all the
mutations retained a FECH residual activity ranging from
12% to 50% when expressed in E coli.12 This is in accordance with the general view that homozygous cases of
porphyria must retain a substantial residual enzyme activity to be compatible with life. The A185T mutation,
however, showed only 4% of the normal activity in E coli,
thus suggesting a severe impairment in functionality. Consequently, even if this homozygous patient is free of cholestasis signs and the liver markers remain stable to date,
the progression of the disease should be considered of
risk and advocates close clinical follow-up.
Except for the recessive case, all the other patients in
our study showed mutations in heterozygosity within the
FECH gene. Some of the new mutations can also cause
severe impairment in enzyme activity. The c.351delC mutation is a single C deletion from a stretch of 5 C that
causes a frameshift and introduces a premature termination codon of translation in exon 4. As a consequence, we can predict the rapid degradation of the mutant transcript due to nonsense-mediated messenger RNA
decay.30,31 The c.130_147dupl 18 mutation does not result in a frameshift, but its location within the mitochondrial leader sequence could result in a defective targeting to mitochondria or a deficient processing of the
polypeptide. The novel splicing defect IVS4⫹1delG affects the consensus donor splice site of intron 4.32 Unfortunately, RNA from this patient was not available for
analysis. Nonetheless, this mutation probably results in
exon 4 skipping, as was observed in a previously reported mutation (IVS4⫹ 1G⬎C) in this donor site.27
All heterozygous cases presented the low-expression
IVS3-48C allele, thereby confirming the common view
that clinically overt EPP is associated with inheritance
of this allele in trans to a severe FECH mutation.6,12,33,34
The study of the relatives yielded additional confirmation of the importance of this polymorphism in EPP, since
all asymptomatic carriers had the IVS3-48T/T genotype. Familial investigation of patient 1 showed that several relatives harbored the A185T mutation, but none had
the IVS3-48C allele. Therefore, the phenotype of a hypothetical carrier of the A185T mutation with the lowexpression allele in trans remains unknown.
In conclusion, among our series of Spanish patients with
EPP, we have found 10 cases with coinheritance of 1 FECH
gene mutation with IVS3-48C and 1 rare case with a severe homozygous mutation with very low residual activity. This patient presented a cutaneous photosensitivity
similar to the heterozygous cases but had a higher protoporphyrin accumulation, pronounced microcytic anemia, and early signs of liver involvement. These findings
emphasize the need for further research on the genotypicphenotypic relationships in porphyria.
Accepted for Publication: January 26, 2007.
Correspondence: Jordi To-Figueras, PhD, Department
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1128
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of Biochemistry and Molecular Genetics, Villarroel 170,
Hospital Clinic Barcelona, 08036 Barcelona, Spain (JTO
@clinic.ub.es).
Author Contributions: Drs To-Figueras and Carmen Herrero had full access to all the data and take full responsibility for the integrity of the data and the accuracy of
the data analysis. Study concept and design: Herrero, ToFigueras, Méndez, Enrı́quez-Salamanca, and Lecha. Acquisition of data: Herrero, To-Figueras, Badenas, Méndez, and Serrano. Analysis and interpretation of data:
Herrero, To-Figueras, and Méndez. Drafting of the manuscript: Herrero, To-Figueras, Méndez, and Serrano. Critical revision of the manuscript for important intellectual content: Badenas, Enrı́quez-Salamanca, and Lecha. Obtained
funding: Herrero and To-Figueras. Administrative, technical, and material support: Badenas. Study supervision:
Méndez, Enrı́quez-Salamanca, and Lecha.
Financial Disclosure: None reported.
Funding/Support: This study was supported in part by
grants from “Fondo de Investigación Sanitaria” (03/
0489) and “Fundación Mutua Madrileña.” Both are nonprofit organizations that supported the Universitybased research as a contribution to health progress.
Role of the Sponsors: The sponsors did not participate
in the conduction of the study; collection, management,
analysis, interpretation of the data; or preparation, review, or approval of the manuscript.
Additional Contributions: We appreciate the participation of the family members in this study. M. Bruguera,
MD, provided help in the control of hepatic disease, J.
M, Mascaró, MD, collaborated in the recruitment of patients, and M. Sala provided technical assistance.
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STUDY
Five-Year Follow-up of a Randomized, Prospective
Trial of Topical Methyl Aminolevulinate Photodynamic
Therapy vs Surgery for Nodular Basal Cell Carcinoma
Lesley E. Rhodes, MD, FRCP; Menno A. de Rie, MD; Ragna Leifsdottir, MD; Raymond C. Yu, MD, FRCP;
Ingeborg Bachmann, MD; Victoria Goulden, MD, FRCP; Gavin A. E. Wong, MRCP;
Marie-Aleth Richard, MD; Alex Anstey, MD, FRCP; Peter Wolf, MD
Objective: To compare 5-year lesion recurrence rates
in primary nodular basal cell carcinoma treated with topical methyl aminolevulinate photodynamic therapy (PDT)
or simple excision surgery.
Design: Prospective, randomized, multicenter study.
Setting: University hospital dermatology departments.
Patients: A total of 97 patients, 50 with 53 lesions treated
with methyl aminolevulinate PDT and 47 with 52 lesions
treated by excision surgery, were included in the per protocol analysis. Of the lesions treated with methyl aminolevulinate PDT and surgery, 49 and 52, respectively, showed
complete clinical response at 3 months after treatment and
were observed for long-term outcome evaluation.
Interventions: Topical methyl aminolevulinate cream,
160 mg/g, applied for 3 hours before illumination (75
J/cm2 of red light at 570 to 670 nm) on 2 or 4 occasions
(12 [23%] of 53 lesions); or excision surgery.
Main Outcome Measures: Histologically confirmed
lesion recurrence, sustained lesion complete response rate
T
Author Affiliations are listed at
the end of this article.
(time-to-event analysis), and investigator assessment of
cosmetic outcome, 5 years after the last treatment.
Results: At 5 years, recurrence was documented in 7
(14%) of 49 lesions (95% confidence interval [CI], 6%27%) treated with methyl aminolevulinate PDT vs 2 (4%)
of 52 lesions (95% CI, 1%-13%) treated with excision surgery (P = .09). Estimated sustained lesion complete response rates were 76% (95% CI, 59%-87%) and 96% (95%
CI, 84%-99%), respectively (P=.01). More patients treated
with methyl aminolevulinate PDT than surgery had an
excellent or good cosmetic outcome: 27 (87%) of 31 patients (95% CI, 70%-96%) vs 19 (54%) of 35 patients (95%
CI, 37%-71%) (P=.007).
Conclusions: Long-term follow-up indicates superior
efficacy of surgery to methyl aminolevulinate PDT in
nodular basal cell carcinoma. However, methyl aminolevulinate PDT is also an effective treatment for this
indication and exhibits a more favorable cosmetic
outcome.
Arch Dermatol. 2007;143(9):1131-1136
OPICAL PHOTODYNAMIC
therapy (PDT) is an attractive modality for the treatment of basal cell carcinoma (BCC), based on its
generally favorable efficacy and adverse
effect profile and its excellent cosmetic outcome. Moreover, because PDT is a noninvasive procedure causing minimal
damage to surrounding tissue, it offers advantages over excision surgery, particularly for the treatment of lesions in cosmetically sensitive areas, such as the face.1-3
However, long-term follow-up data of controlled clinical trials of topical PDT vs excision surgery (regarded as the treatment
of choice for nodular BCC)4,5 are lacking.
We performed a prospective, randomized, multicenter study of simple excision
surgery vs topical PDT, using methyl ami-
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nolevulinate, a drug showing highly selective uptake by malignant cells,6 in the treatment of primary nodular BCC. Initial data
covering a 2-year follow-up demonstrated
that methyl aminolevulinate PDT was an
effective treatment for nodular BCC. Clearance rates of 93% (vs 100% for excision surgery) were seen after 3 months and 85% (vs
98% for excision surgery) after 12 months,
with no significant difference between treatment groups. Methyl aminolevulinate PDT
also gave a significant superior cosmetic
outcome compared with excision surgery
at 3, 12, and 24 months.7 At 24 months, 5
lesions that initially cleared with methyl
aminolevulinate PDT had recurred, compared with 1 after surgery.
The potential for lesion recurrence following PDT is an issue of clinical concern,
particularly in the treatment of deeper
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101 Patients randomized and treated
52 In the methyl aminolevulinate PDT group (ITT population)
49 In the surgery group (ITT population)
2 Not included
1 Protocol violation
1 Discontinued because
of an adverse event
2 Not included
1 Discontinued because
of an adverse event
1 Withdrew consent
50 Patients in the PP population
47 Patients in the PP population
19 Not included
10 Experienced treatment
failure (all lesions)
6 Discontinued because
of an adverse event
1 Withdrew consent
2 Were lost to follow-up
12 Not included
2 Experienced treatment
failure (all lesions)
4 Discontinued because
of an adverse event
4 Withdrew consent
2 Were lost to follow-up
31 Patients completed the 5-y follow-up
35 Patients completed the 5-y follow-up
Figure 1. Disposition of patients 5 years after the last treatment. The protocol violation in the methyl aminolevulinate group was also a treatment failure (all
lesions). ITT indicates intention-to-treat; PDT, photodynamic therapy; and PP, per protocol.
(nodular) BCC. Nearly two-thirds of all recurrent BCC lesions appear in the first 3 years after treatment, with 18%
appearing between 5 and 10 years posttreatment.8 We therefore performed a 5-year follow-up to examine the sustained complete lesion response and recurrence rate over
time for methyl aminolevulinate PDT vs excision surgery
in patients with nodular BCC.
METHODS
European university hospital dermatology departments participated in a prospective, randomized study of methyl aminolevulinate PDT vs simple excision surgery in patients with
nodular BCC. The study design and procedures have been detailed in a prior report.7 Patients aged at least 18 years with previously untreated primary nodular BCC, suitable for simple excision surgery, were enrolled from the clinics of participating
centers. The diagnosis of nodular BCC was confirmed by histological examination. Patients with more than 10 eligible lesions; lesions in the midface region, orbital areas, and ears; lesions with a longest diameter of less than 6 mm or more than
15 mm (face or scalp), more than 20 mm (extremities or neck),
or more than 30 mm (trunk); and pigmented or morpheaform
BCCs were excluded. Patients were enrolled from October 26,
1999, to August 29, 2000, and were followed up until October
12, 2005. All patients gave written informed consent before enrollment. The study was performed in accordance with the Declaration of Helsinki, with ethical approval obtained from the
local ethics committee of each of the participating centers.
Eligible patients were randomized to treatment with PDT using
methyl aminolevulinate cream, 160 mg/g (Metvix; PhotoCure ASA,
Oslo, Norway, and Galderma, Sophia Antipolis, France), or excision surgery.7 In the PDT group, lesion surface preparation was
performed in a standardized manner between centers, before application of methyl aminolevulinate cream. Surface scale or crust
was gently removed with a curette or scalpel blade, without anesthesia, insufficient to cause pain or bleeding. An occlusive and
light-shielding dressing was applied, and after 3 hours, the area
was illuminated with noncoherent red light (wavelength, 570670 nm; total fluence, 75 J/cm2; and fluence rate, 50-200 mW/
cm2). Patients in the PDT group were treated with either 1 or 2
PDT cycles, each composed of 2 PDT sessions, with an interval
of 1 week between sessions. Simple elliptical excision surgery with
at least 5-mm margins was performed once under local anesthesia in accordance with the usual practice of the center.
Patients with a complete response at 3 months after the last
treatment (ie, complete disappearance of the lesion as evaluated on clinical inspection by the same investigator [M.A.R., V.G.,
G.A.E.W., or P.W.]) were followed up at yearly intervals for 5
years after the last treatment. Any clinically suspected recurrence was confirmed by histological examination. Investigatorassessed cosmetic outcome was judged yearly for up to 5 years
in all patients with a complete response in all lesions, using a
4-point scale7 as follows: (1) excellent: no scarring, atrophy, or
induration and slight or no redness or change in pigmentation
compared with adjacent skin; (2) good: no scarring, atrophy, or
induration and moderate redness or increase in pigmentation compared with adjacent skin; (3) fair: slight to moderate occurrence of scarring, atrophy, or induration; and (4) poor: extensive occurrence of scarring, atrophy, or induration.
Details of adverse events, including local phototoxicity reactions reported up to 3 months after last treatment, have been
provided.7 During the 5-year follow-up, any adverse events that
led to discontinuation were documented.
The primary statistical analysis was based on the per protocol (PP) population, including all eligible patients who completed surgery or the first PDT treatment cycle and had a response assessment at 3 months or who completed the second
PDT treatment cycle and received treatment in accordance with
the study procedures. In addition, an intention-to-treat analysis was performed. The analysis populations (intention-totreat and PP groups) were almost identical and gave similar results in all aspects. Two patients in each treatment group (4 of
101) were excluded from the PP population. The present study
therefore focuses on the population of primary interest (ie, the
PP population). Analyses were performed independently
(PAREXEL International GmbH, Berlin, Germany) using SAS
statistical software (SAS Institute Inc, Cary, North Carolina).
Of primary interest during long-term follow-up was the histologically confirmed lesion recurrence rate. Lesion recurrence
rates were the proportion of recurrent lesions, of all lesions that
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Table 1. Baseline Characteristics of Lesions
in the PP Population a
Methyl
Aminolevulinate
PDT Group
(n = 53)
Surgery
Group
(n = 52)
21 (40)
27 (51)
5 (9)
32 (62)
15 (29)
5 (10)
29 (55)
19 (36)
2 (4)
34 (65)
14 (27)
3 (6)
Lesion location
Face or scalp
Trunk or neck
Extremities
Longest lesion diameter, mm b
ⱕ 10
⬎ 10 and ⬍20
ⱖ 20
Abbreviations: PDT, photodynamic therapy; PP, per protocol.
a Data are given as number (percentage) of lesions for each group.
Percentages may not total 100 because of rounding or because of missing data.
b Data are missing for 3 patients in the methyl aminolevulinate PDT group
and 1 in the surgery group.
had a clinical complete response 3 months after treatment. They
were presented with 95% confidence intervals (CIs), and the treatment difference was tested with the Fisher exact test.
A time-to-event approach was used to estimate lesion complete response rates over time, using all available information
and keeping the original sample size and randomization scheme.
The event of interest was failure, defined as nonresponse at 3
months after the last treatment or recurrence at the follow-up
intervals of 1, 2, 3, 4, or 5 years.
Censoring occurred when a patient with a lesion in complete
response discontinued for reasons other than treatment failure.
Discontinuations or recurrences were only recorded at the yearly
follow-up. Thus, the exact time when the event occurred was unknown. Furthermore, some patients had more than 1 lesion. The
lesions formed clusters within these patients and therefore could
no longer be regarded as independent observations. The interval
censoring and the lesion clusters made the data unsuitable for standard procedures, such as the Kaplan-Meier or the life-table approach. Instead, a complementary log-log model suggested by Guo
and Lin9 was used. In a first step, a logistic regression using the
complementary log-log link function was run with standard software (PROC LOGISTIC; SAS Institute Inc). In a second step, the
standard errors of the estimates were adjusted for the dependencies in the data caused by the lesion clusters, as described using
computer software (IML; SAS Institute Inc).
Recurrence rates could not be derived from the time-toevent model because the failure rates were a combination of
nonresponse rates at 3 months after the last treatment and recurrence rates during later follow-ups.
The proportions of patients categorized with excellent or good
overall cosmetic outcome were summarized with 2-sided 95%
CIs. The treatment difference was tested with the Fisher exact
test using the categories of excellent or good vs fair or poor.
RESULTS
Of 103 randomized patients, 101 were treated in the study,
52 with methyl aminolevulinate PDT and 49 with surgery. The PP population comprised 97 patients, 50 with
53 lesions treated with methyl aminolevulinate PDT and
47 with 52 lesions treated with excision surgery
(Figure 1). Four patients were excluded from the PP
population, 1 in the methyl aminolevulinate PDT group
with a major protocol violation (received a light dose less
Lesion CR Rate
(Complementary Log-Log Model)
Characteristic
100
75
50
25
Surgery group
Methyl aminolevulinate
PDT group
0
12
24
36
48
60
Time, mo
Figure 2. Lesion complete response (CR) over time (time-to-event analysis)
for the per protocol population. PDT indicates photodynamic therapy.
than that stipulated) and 3 for whom response at 3 months
could not be assessed (in the surgery group, 1 died and 1
withdrew consent; and in the methyl aminolevulinate PDT
group, 1 discontinued the study prematurely because of
treatment-related pain). Forty-nine lesions in 46 patients
treated with methyl aminolevulinate PDT and 52 lesions
in 47 patients treated with excision surgery showed complete lesion response at 3 months and were included in
the long-term follow-up.
Sixty-six patients, 31 treated with methyl aminolevulinate PDT and 35 treated with surgery, completed the
5-year follow-up evaluation with at least 1 lesion in complete response. Twelve patients, 10 treated with methyl
aminolevulinate PDT and 2 treated with surgery, discontinued the study before the 5-year follow-up evaluation, with treatment failure in all lesions (Figure 1). Only
4 patients (2 in each treatment group) were truly lost to
follow-up during the 5-year period. Eight patients (4 in
each group) died during the follow-up, and 2 discontinued because of intercurrent disease.
The baseline characteristics of the 2 groups were similar.7 The mean (range) age was 69 (40-95) years in the
methyl aminolevulinate PDT group and 67 (38-82) years
in the surgery group; there were 32 men and 20 women
in the methyl aminolevulinate PDT group and 29 men
and 20 women in the surgery group. Most patients in each
group had 1 lesion (94% [47 of 50 patients] in the methyl
aminolevulinate PDT group and 89% [42 of 47 patients] in the surgery group). In each group, most lesions were less than 20 mm in diameter and were located on the face or scalp or trunk or neck (Table 1).
However, the distribution of these lesions differed between the 2 groups. In the surgery group, there were more
lesions on the face or scalp than on the trunk or neck,
whereas in the methyl aminolevulinate PDT group, the
distribution of lesions to these areas was similar (Table 1).
Most lesions in the methyl aminolevulinate PDT group
were treated with 1 PDT cycle (41 of 53 lesions [77%]).
LESION RESPONSE AND RECURRENCE
A time-to-event analysis of lesion response over time
showed that excision surgery was more favorable than
methyl aminolevulinate PDT (Figure 2). At 5 years af-
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Table 2. Lesion Complete Response and Recurrence Rates in the Per Protocol Population
Interval After Last Treatment, y
Variable
1
Missing, No. (%)
Lesion recurrence (n = 49)
No. of lesions
Proportion (95% CI) of lesions, %
Lesion size, mm d
ⱕ 10
⬎ 10 and ⬍20
Missing, No. (%)
Lesion recurrence (n = 52)
No. of lesions
Proportion (95% CI) of lesions, %
Lesion size, mm d
ⱕ 10
⬎ 10 and ⬍20
2
3
Methyl Aminolevulinate PDT Group a,b
2 (4)
9 (18)
9 (18)
4
5
10 (20)
10 (20)
2
4 (1-14)
5
10 (3-22)
7
14 (6-27)
7
14 (6-27)
7
14 (6-27) c
1
1
4
1
5
2
5
2
5
2
7 (13)
10 (19)
11 (21)
1 (2)
Surgery Group b,e
3 (6)
0
0 (0-100)
0
0 (0-100)
1
2 (0-10)
2
4 (1-13)
2
4 (1-13) c
0
0
0
0
0
1
0
2
0
2
Abbreviations: CI, confidence interval; PDT, photodynamic therapy.
a Complete response at 3 months occurred in 49 of 53 lesions (92%) (95% confidence interval, 82%-98%).
b P = .12 for the treatment difference at 3 months in lesion response rate.
c P = .09 for the treatment difference at 5 years in lesion recurrence rate.
d There were no 20-mm or larger lesions in either group.
e Complete response at 3 months occurred in 52 of 52 lesions (100%) (95% confidence interval, 93%-100%).
A
B
Figure 3. The appearance of the nodular basal cell carcinoma in a study participant in the photodynamic therapy group (a 72-year-old woman) at baseline (A) and
at 5 years, showing an excellent cosmetic outcome and complete lesion response (B). In A and B, the inset shows a close-up.
ter last treatment, the sustained lesion complete response rate, estimated by the complementary log-log
model, was 76% (95% CI, 59%-87%) for methyl aminolevulinate PDT compared with 96% (95% CI, 84%99%) for excision surgery in the PP population (P =.01).
Lesion recurrence was documented in 14% of lesions with
complete response after 3 months treated with methyl
aminolevulinate PDT, compared with 4% of lesions treated
with excision surgery (P =.09) (Table 2). The methyl
aminolevulinate PDT group recurrences included 5 of 40
lesions given 1 treatment cycle and 2 of 9 lesions given
2 treatment cycles. No recurrences in the methyl aminolevulinate PDT group were observed from 3 to 5 years,
and only 1 lesion treated with excision surgery recurred
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within this period. In the methyl aminolevulinate PDT
group, there was no evidence that lesion recurrence was
higher in larger lesions because recurrence was documented in 5 lesions with a maximum diameter of up to
10 mm and in 2 lesions with a diameter between 11 and
20 mm (Table 2). Recurrence rates at 5 years were identical in the intention-to-treat population.
COSMETIC OUTCOME
In the PP population, outcome at 3 months rated as excellent or good was found in 36 of 44 patients (82%) (95%
CI, 67%-92%) in the methyl aminolevulinate PDT group
vs 15 of 45 patients (33%) (95% CI, 20%-49%) in the surgery group (P⬍.001). The overall cosmetic outcome 5
years after last treatment was also superior with methyl
aminolevulinate PDT compared with excision surgery. At
final assessment, outcome as rated by the investigators
[L.E.R., M.A.R., R.L., R.C.Y., I.B., V.G., M.-A.R., A.A., and
P.W.]was good or excellent in 27 of 31 patients (87%) (95%
CI, 70%-96%) treated with methyl aminolevulinate PDT
compared with 19 of 35 patients (54%) (95% CI, 37%71%) treated with excision surgery (P=.007) (Figure 3).
COMMENT
Findings from this long-term follow-up study add to evidence supporting a role for methyl aminolevulinate PDT
in the treatment of primary nodular BCC. The cumulative 5-year lesion recurrence rate with methyl aminolevulinate PDT was 14% compared with 4% for excision surgery, the latter being consistent with the published low
rate for this modality.8,10,11 We anticipate that we have
captured all relevant events and that a longer than 5-year
follow-up would be unlikely to yield further recurrences because only 2 recurrent lesions were observed
in the methyl aminolevulinate PDT group and 1 in the
surgical group between 2 and 3 years’ follow-up. There
were no recurrent lesions observed in the methyl aminolevulinate PDT group and only 1 in the surgical group
from 3 to 5 years’ follow-up.
While the sustained lesion complete response rate at
5 years was statistically superior with excision surgery
compared with methyl aminolevulinate PDT (96% vs 76%;
P=.01), lesions treated with methyl aminolevulinate PDT
showed a substantially better cosmetic outcome at 5 years,
as assessed by the investigator, than those treated with
surgery (P = .007). Thus, the results of our study indicate that, whereas simple excision surgery will generally remain the treatment of choice for nodular BCC amenable to this intervention, methyl aminolevulinate PDT
is also an effective treatment. There are a number of instances (eg, when there are multiple lesions; when there
are lesions in sites such as the lower leg, where there is
poor healing; and when there are patients undergoing anticoagulation) in which excision can be challenging. Moreover, methyl aminolevulinate PDT may be more suitable for the treatment of lesions in cosmetically sensitive
areas, such as the face (involving approximately 50% of
lesions in the present study), where optimal cosmetic outcome is an important clinical consideration.
Systematic reviews4,5,8,11 of treatment modalities for
BCC highlight the lack of published long-term follow-up data from controlled clinical trials and advocate
evaluation of 5-year lesion recurrence rates as a primary
outcome in clinical studies. The lack of long-term data
from randomized PDT studies has been a particular concern among dermatologists.12 To our knowledge, we present the first randomized study to report cumulative 5-year
recurrence rates in nodular BCC comparing topical PDT
with the standard treatment of excision surgery. We conclude that the moderately low 5-year lesion recurrence
rate with methyl aminolevulinate PDT documented in
this study, together with the favorable long-term cosmetic outcome, supports a clinical role for this modality
in the treatment of nodular BCC, particularly when avoidance of scarring is a priority.
Accepted for Publication: April 4, 2007.
Author Affiliations: Photobiology Unit, Departments of
Dermatology, University of Manchester and Salford Royal
Foundation Hospital, Manchester (Dr Rhodes), University College Hospital, London (Dr Yu), Leeds General Infirmary, Leeds (Dr Goulden), and Royal Liverpool University Hospital, Liverpool (Dr Wong), England; Academic
Medical Centre, Amsterdam, the Netherlands (Dr de Rie);
Norra Älvsborgs Länssjukhus, Trollhättan, Sweden
(Dr Leifsdottir); Haukeland Hospital, Bergen, Norway
(Dr Bachmann); Hôpital Sainte-Marguerite, Marseille,
France (Dr Richard); University Hospital of Wales, Cardiff (Dr Anstey); and Medical University Graz, Graz, Austria (Dr Wolf).
Correspondence: Lesley E. Rhodes, MD, FRCP, Photobiology Unit, Department of Dermatology, University of
Manchester, Salford Royal Foundation Hospital, Manchester M6 8HD, England (lesley.e.rhodes@manchester.ac
.uk).
Author Contributions: Dr Rhodes had full access to all
the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Rhodes, de Rie, Goulden, and
Wong. Acquisition of data: Rhodes, de Rie, Leifsdottir, Yu,
Bachmann, Goulden, Wong, Richard, Anstey, and Wolf.
Analysis and interpretation of data: Rhodes, de Rie, Yu,
Anstey, and Wolf. Drafting of the manuscript: Rhodes, Yu,
and Richard. Critical revision of the manuscript for important intellectual content: Rhodes, de Rie, Leifsdottir, Yu,
Bachmann, Goulden, Wong, Richard, Anstey, and Wolf.
Statistical analysis: Rhodes. Obtained funding: Rhodes. Administrative, technical, and material support: Rhodes, de
Rie, Yu, Richard, Anstey, and Wolf. Study supervision:
Rhodes, Yu, and Wolf.
Financial Disclosure: None reported.
Funding/Support: This study received financial support from Photocure ASA.
Role of the Sponsor: Photocure ASA assisted in the
design and conduct of the study, performed the data
collection, and assisted in the preparation of the manuscript.
Additional Contributions: Parexel GmbH, Berlin, Germany, performed the data analysis.
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REFERENCES
7.
1. Horn M, Wolf P, Wulf HC, et al. Topical methyl aminolaevulinate photodynamic
therapy in patients with basal cell carcinoma prone to complications and poor
cosmetic outcome with conventional treatment. Br J Dermatol. 2003;149(6):
1242-1249.
2. Vinciullo C, Elliott T, Francis D, et al. Photodynamic therapy with topical methyl
aminolaevulinate for “difficult-to-treat” basal cell carcinoma. Br J Dermatol. 2005;
152(4):765-772.
3. Szeimies RM, Morton CA, Sidoroff A, Braathen LR. Photodynamic therapy for
non-melanoma skin cancer. Acta Derm Venereol. 2005;85(6):483-490.
4. Thissen MRTM, Neumann MHA, Schouten LJ. A systematic review of treatment
modalities for primary basal cell carcinomas. Arch Dermatol. 1999;135(10):
1177-1183.
5. Telfer NR, Colver GB, Bowers PW. Guidelines for the management of basal cell
carcinoma. Br J Dermatol. 1999;141(3):415-423.
6. Angell-Petersen E, Sørensen R, Warloe T, et al. Porphyrin formation in actinic
8.
9.
10.
11.
12.
keratosis and basal cell carcinoma after topical application of methyl
5-aminolevulinate. J Invest Dermatol. 2006;126(2):265-271.
Rhodes LE, de Rie M, Enström Y, et al. Photodynamic therapy using topical methyl
aminolevulinate vs surgery for nodular basal cell carcinoma: results of multicenter randomized prospective trial. Arch Dermatol. 2004;140(1):17-23.
Rowe DE, Carroll RJ, Day CL. Long-term recurrence rates in previously untreated (primary) basal cell carcinoma: implications for patient follow-up. J Dermatol Surg Oncol. 1989;15(3):315-328.
Guo SW, Lin DY. Regression analysis of multivariate grouped survival data.
Biometrics. 1994;50(3):632-639.
Silverman MK, Kopf AW, Bart RS, Grin CM, Levenstein MS. Recurrence rates of
treated basal cell carcinomas, part 3: surgical excision. J Dermatol Surg Oncol.
1992;18(6):471-476.
Bath-Hextall F, Bong J, Perkins W, Williams H. Interventions for basal cell carcinoma of the skin: systematic review. BMJ. 2004;329(7468):705-709.
Morton CA, Brown SB, Collins S, et al. Guidelines for topical photodynamic therapy:
report of a workshop of the British Photodermatology Group. Br J Dermatol. 2002;
146(4):552-567.
Call for Papers
Genetics and Genomic Manuscripts
In March 2008, the JAMA and Archives family of journals
will publish manuscripts in a theme issue devoted to practical applications of genetics and genomics that are currently clinically important or may become clinically relevant in the near future. We invite authors to submit
manuscripts reporting the results of original research, especially clinical trials; systematic reviews including metaanalyses; special communications; and commentaries. Evidence-based articles will be given priority.
Topics of particular interest include genetic diagnosis,
including prenatal tests, and genetic testing, especially for
illnesses for which presymptomatic intervention such as
prevention of disease or increased surveillance for disease
can be expected to change the patient’s quality of life. Other
presymptomatic interventions may include pharmacogenomics, gene therapy, evolutionary medicine such as genotypes with proven adaptive responses to emerging infections, genetic counseling, and ethical issues that
dermatologists will need to consider as the role of genetics and presymptomatic interventions expands.
Manuscripts received by October 15, 2007, will have the
best chance for consideration for this theme issue. All manuscripts will undergo our usual rigorous editorial review process.Authorsareencouragedtoconsultthe ArchivesInstructions for Authors at http://www.archdermatol.com for
guidelines on preparing and submitting manuscripts.
June K. Robinson, MD
Editor
Jeffery P. Callen, MD
Associate Editor
(REPRINTED) ARCH DERMATOL/ VOL 143 (NO. 9), SEP 2007
1136
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STUDY
Effect of Cold Air Cooling on the Incidence
of Postinflammatory Hyperpigmentation After
Q-Switched Nd:YAG Laser Treatment of Acquired
Bilateral Nevus of Ota–like Macules
Woraphong Manuskiatti, MD; Sasima Eimpunth, MD; Rungsima Wanitphakdeedecha, MD
Objective: To investigate the effect of cold air cooling
on the incidence of postinflammatory hyperpigmentation (PIH) after laser treatment in Asian patients.
a spectrometer, and it was subjectively assessed by 2 nontreating physicians before treatment and once weekly for
4 weeks.
Design: Randomized, controlled, split-face study.
Results: Of the 21 patients who completed the study,
Setting: Skin laser center of a university hospital.
Patients: Twenty-three Thai women with acquired bilateral nevus of Ota–like macules.
Interventions: Patients were treated using a 1064-nm
Q-switched Nd:YAG laser at an average fluence of 7.0
J/cm2 using a 3-mm spot size. The same laser fluence was
used on both sides of the face in individual patients. One
randomly selected face side of each patient was cooled
using a cold air cooling device during and 30 seconds
before and after laser irradiation, and the other side was
irradiated without cooling.
13 (62%) and 5 (24%) developed PIH on the cooled and
uncooled sides, respectively. One patient (5%) had PIH
on both the cooled and uncooled sides, and 2 (10%) did
not experience PIH. The cooled sides were significantly
more likely to become hyperpigmented after laser irradiation than the uncooled sides (relative risk, 2.6; 95%
confidence interval, 1.13-6.00; P=.03). The clinical evaluation corresponded to the spectrometer reading.
Conclusion: Epidermal cooling with cold air is associated with an increased risk of PIH after Q-switched Nd:
YAG laser treatment.
Trial Registration: clinicaltrials.gov Identifier:
NCT00287001
Main Outcome Measures: Occurrence of PIH was objectively evaluated by measuring the melanin index using
P
Author Affiliations:
Department of Dermatology,
Faculty of Medicine Siriraj
Hospital, Mahidol University,
Bangkok, Thailand.
Arch Dermatol. 2007;143(9):1139-1143
OSTINFLAMMATORY HYPERPIG-
mentation (PIH) is a frequently encountered problem and represents the
sequelae of various cutaneous disorders and therapeutic interventions. The pathogenesis of PIH includes an
increase in melanin production and an abnormal distribution of this pigment. After trauma or cutaneous inflammation, melanocytes can react with increased or
decreased production of melanin, reflected clinically as hyperpigmentation or
hypopigmentation.1 Postinflammatory hyperpigmentation is probably the most common adverse effect of laser treatments in
dark-skinned individuals.2,3 Treatment of
PIH is difficult because there are few, if any,
therapeutic options that are consistently
successful. Little is known about whether
PIH can be prevented or minimized.4,5
Acquired bilateral nevus of Ota–like macules (ABNOMs), or Hori nevus, is clini-
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1139
cally characterized by blue-brown macules occurring bilaterally on the forehead,
temples, eyelids, malar areas, nasal alae, and
nasal root. Unlike the nevus of Ota, these
pigmented lesions usually appear in the
fourth or fifth decade of life in women (only
rarely in men) and are not observed in the
conjunctiva or mucous membranes of the
mouth or nose.6,7 Histologically, active melanin-synthesizing dermal melanocytes are
dispersed in the papillary and middle portions of the dermis.8 Q-switched lasers have
been used successfully as a treatment modality.9-11 However, the incidence of transient PIH after laser treatment is as much
as 50% to 73%.2
Skin cooling has been used to protect the
epidermis in a variety of laser dermatologic procedures, including leg vein treatment, hair removal, and port-wine stain removal. The use of epidermal cooling during
laser treatment decreases procedureassociated pain, allows safer treatment of
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A
B
Figure 1. The left side of the face before laser treatment with cold air cooling (A) and the right side of the face before laser treatment without cooling (B).
darker-skinned individuals, and allows the use of higher
fluences.12-14 Studies to determine the benefit of epidermal cooling on the prevention of PIH after laser treatment
are limited. Epidermal cooling is thought to reduce the nonspecific thermal injury caused by the laser pulses and consequently to minimize the incidence of PIH.
The present study was performed to address the advantage of epidermal cooling on reducing the occurrence of PIH after laser treatment of ABNOMs. However, we found that epidermal cooling with cold air was
associated with an increased risk of PIH after Qswitched Nd:YAG laser treatment. An unexpected finding was a clinically and statistically significant darkening of the cooled side compared with the uncooled side.
METHODS
Twenty-three Thai women with ABNOMs (Hori nevus) were
enrolled in the study. The patients were randomized as to which
side of the face would be treated with Q-switched Nd:YAG laser and a cold air cooling device vs Q-switched Nd:YAG laser
alone by using a table of uniform random digits. The study protocol and informed consent documents were submitted and approved by the Ethics Committee on Research Involving Human Subjects, Faculty of Medicine Siriraj Hospital, Mahidol
University. Written informed consent was obtained from each
patient before enrollment.
PATIENT CHARACTERISTICS
The mean age of the patients was 43 years (range, 27-72 years).
Their skin types were III (17/23) and IV (6/23). Patients who
were pregnant or lactating, who were taking birth control pills
or undergoing hormone therapy, or who participated in major
outdoor activities were excluded. Patients who used bleaching agents, such as hydroquinone preparation, and those who
received chemical peels, laser treatment, or intense pulsed light
treatment before enrollment were also excluded.
TREATMENT
Lidocaine, 2.5%, and prilocaine, 2.5%, cream (a eutectic mixture of local anesthetic) (AstraZeneca LP, Wilmington, Delaware) was applied to the lesions 1 hour before treatment, and
a dressing (Tegaderm; 3M, St Paul, Minnesota) was used to occlude the area. Each patient received 1 Q-switched Nd:YAG laser treatment. The uncooled side of the patient’s face was always treated first, followed by the side with cold air cooling.
The clinical end point was defined as the point of immediate
whitening without bleeding and tissue splatter. The same fluence setting was used on both sides.
COOLING TECHNIQUE
A commercially available cold air cooling device (CRIOjet AIR
Mini; CRIO Medizintechnik GmbH, Birkenfeld, Germany) was
used at a cooling level of 4 for all treatments. This instrument
works with a compressor system similar to those in refrigerators and uses ambient air to generate a permanent stream of
cold air with a flow of 500 to 1000 L /min and temperatures as
low as −30°C, depending on the cooling delivery system and
the desired cooling level (range, 1-9). The nozzle-to–cooled surface distance was 5 cm (as suggested by the manufacturer). Relative humidity was 60%, and room temperature was approximately 25°C. The nozzle was held with a rotating motion during
the treatment. The cooled side was always cooled during and
30 seconds before and after laser irradiation. The skin surface
temperature, measured using an infrared thermometer (MiniTemp MT4; Raytek Corp, Santa Cruz, California) during the
treatment, was 4°C to 5°C.
Postoperatively, antibacterial mupirocin ointment (Bactroban Ointment; SmithKline Beecham Pharmaceuticals, Philadelphia, Pennsylvania) was applied to the treated area. Patients were
instructed to cleanse the treated sites gently with tap water and
to reapply the mupirocin ointment 4 times a day until all crusting had subsided. After crusting completely healed, all the patients were instructed to wear a broad spectrum sunscreen with
a sun protection factor of 40 and were also asked to avoid sun
exposure, which could cause hyperpigmentation.
CLINICAL EVALUATION
Masked assessment of the occurrence of PIH in all the patients
was made by 2 expert dermatologists from the digital photographs taken before treatment (baseline) and 1, 2, 3, 4, and 12
weeks after laser treatment. Photographs were taken using a digital camera (D70s; Nikon Corporation, Tokyo, Japan) equipped
with a 60-mm lens (Nikkor; Nikon Corporation) and Canfield
TwinFlash (Canfield Scientific Inc, Fairfield, New Jersey). All the
photographs were taken in raw format with identical conditions
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A
B
Figure 2. The left (cooled) (A) and right (uncooled) (B) sides of the face 1 week after treatment.
and camera settings. Standardized views (face front and 45° oblique) were used. The liquid crystal display monitor was calibrated for precise on-screen displays using a colorimeter (Spyder2;
Colorvision Inc, Lawrenceville, New Jersey). Clinical observations for cutaneous changes (specifically, erythema, urticaria, blistering, dyspigmentation, and scarring) were conducted at 1-hour
and 1-week intervals after cold air exposure.
Observable skin changes were graded on the following scale:
0, absent; 1, minimal (light pink; barely perceptible skin elevation; whitening of skin; no evident blister); 2, mild (light
red/pink; slight skin elevation; skin wrinkling; no wellformed blister); 3, moderate (red; clearly visible urticaria; flaccid blisters); and 4, severe (very red; pronounced urticaria; tense
blisters). Clinical evaluation for the improvement in lesional
pigmentation was subjectively graded at baseline and week 12
using a quartile grading scale as follows: poor, less than 25%;
fair, 25% to 50%; good, 51% to 75%; and excellent, more than
75% improvement.
COLOR READING
The designated lesions of pigmented macules on both sides of
the face were marked on every patient and mapped with a translucent sheet at the first visit to ensure consistency of location.
The degree of lesion lightening was defined as the percentage
of darkness reduction compared with baseline. The degree of
pigmentation was assessed using a handheld reflectance spectrometer (DermaSpectrometer; Cortex Technology, Hadsund,
Denmark). By emitting red light at 655 nm and measuring the
absorption coefficients in the skin, the instrument provides a
readout of a melanin index (M-index) based on the absorption characteristics of the skin pigmentation. During measurements, the device was placed perpendicularly on the skin;
blanching was minimized by applying light pressure. The value
used was the average of 3 measurements at each site at each
assessment. A higher M-index value indicates increased saturation toward darkness.
STATISTICAL ANALYSIS
Two-tailed paired t test analyses using statistical software (SPSS
version 14; SPSS Inc, Chicago, Illinois) were performed to compare mean M-index values for each treatment technique and
at baseline vs the 12-week follow-up visit. Relative risk was calculated using statistical software (Epi Info version 3.3.2; Centers for Disease Control and Prevention, Atlanta, Georgia).
P ⬍ .05 was considered statistically significant.
RESULTS
Of the 23 patients, 21 completed all the follow-up visits.
Two patients were withdrawn from the study because they
did not attend scheduled visits. Acute erythema was noted
in 18 of 21 patients (86%), 1⫹ erythema was observed
in 16 of 21 patients (76%), and 2⫹ erythema was present in 2 of 21 patients (10%). One hour after treatment,
the redness disappeared in 12 of 18 patients (67%) who
developed erythema. In all the patients, the erythema resolved in 24 hours. One patient each with skin types III
and IV developed 1⫹ urticaria. All urticaria resolved by
the day 1 follow-up visit. No blistering was observed in
any patients.
The crusting healed completely within 1 and 2 weeks
of treatment in 17 of 21 patients (81%) and 4 of 21 patients (19%), respectively. No difference in crusting resolution rates was observed between the cooled and uncooled sides. No patients developed hypopigmentation
or scarring. All the patients noted significant pain reduction on the cooled side during laser treatment. No postoperative analgesic treatment was required beyond the
application of mupirocin ointment and ice compresses.
As judged by the 2 expert dermatologists, of the 21
patients who completed the study, 13 (62%) developed
PIH on the cooled side, and 5 (24%) had PIH on the uncooled side (Figures 1, 2, 3, and 4). One patient (5%)
had PIH on both the cooled and uncooled sides, and 2
(10%) did not experience PIH. The cooled sides were 3
times more likely than the uncooled sides to develop PIH
after laser treatment (relative risk, 2.6; 95% confidence
interval, 1.13-6.00; P=.03). The onset of PIH was at week
1, 2, 3, and 4 in 5% (1/21), 62% (13/21), 14% (3/21), and
10% (2/21) of the patients, respectively. The PIH was completely resolved 12 weeks after laser treatment in all the
patients except 1 with skin type IV, who developed PIH
on the cooled side.
All the patients showed less than 25% overall lightening of the pigmented macules at week 12. No difference in clinical improvement was observed regarding the
cooling used on 1 side during treatment. At baseline, there
was no significant difference in the M-index values of the
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A
B
Figure 3. The left (cooled) (A) and right (uncooled) (B) sides of the face 2 weeks after treatment. Note the postinflammatory hyperpigmentation of the lesions on
the left (cooled) side of the face.
A
B
Figure 4. The left (cooled) (A) and right (uncooled) (B) sides of the face 12 weeks after treatment. Note the disappearance of the postinflammatory
hyperpigmentation on the left (cooled) side of the face.
cooled and uncooled sides (P = .17). At week 12, there
was also no significant difference in the M-index values
of the lesions on the cooled (P=.07) and uncooled (P=.55)
sides compared with baseline. The M-index value of all
areas considered to have PIH was significantly increased compared with the baseline value (P =.03).
COMMENT
Postinflammatory hyperpigmentation is one of the most
common adverse effects in dark-skinned patients after
laser treatment. It is not life threatening, but PIH may
cause substantial psychological problems. The incidence of transient PIH after carbon dioxide laser resurfacing is approximately 37% in patients with all skin
types15 and nearly 70% in those with skin type IV or
higher.16
Hori nevus or ABNOMs is a common pigmentary disorder in Asian individuals. Q-switched lasers provide favorable treatment responses, but transient PIH after laser irradiation affects as much as 50% to 73% of patients
and can last for many months.11,17 Postinflammatory hy-
perpigmentation takes a long time to dissipate. The treatment of PIH is difficult and time-consuming, often lasting many months to achieve the desired results, which
causes frustration in patients and physicians.1,2 Thus, various attempts to reduce the occurrence of PIH after skin
laser surgery have included sun avoidance, use of preoperative and postoperative treatment regimens, and techniques for epidermal protection.
Current commercial cooling methods and devices include passive cooling with aqueous gel, active cooling with
water or refrigerated air, and dynamic active cooling with
cryogen spray. Lowering the temperature of the skin’s surface is a method of selectively controlling the depth at
which heat is produced in the skin by lasers or pulsed
light sources. Cooling of the epidermis can prevent its
temperature elevation from exceeding the threshold for
thermal injury.12 Minimizing the nonspecific thermal injury to the skin surface caused by the laser pulses may
therefore lower the incidence of PIH.
A previous study18 of a freeze injury in normal human skin showed that a brief (5-second) freezing of liquid nitrogen caused hypopigmentation, with a periph-
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eral rim of hyperpigmentation in all frozen lesions.
Similarly, a recent study by Datrice et al19 also found that
transient hyperpigmentation occurred after cryogen spray
cooling exposure in individuals with skin type III or
higher, and all hyperpigmentation was resolved by 8 weeks
without medical intervention.
In trying to address the possible causes of this occurrence, we tested the effect of the cold air cooling in 2 patients with untreated ABNOMs (not in the present study).
The same cooling techniques were performed without laser irradiation on 1 side of the face of each patient. The
patients were followed up every week for 4 weeks. However, none of the patients developed PIH on the cold air–
exposed side. Thus, it is unlikely that cold air exposure
alone is the mechanism causing PIH. However, some inflammatory triggers from the laser irradiation may underlie the increased incidence of PIH in the present study.
The underlying mechanisms and the variability individuals show for developing hyperpigmentation or hypopigmentation are not well understood. An inherited individual chromatic tendency based on “strong” or “weak”
melanocytes and their tendency to respond to trauma or
inflammation with either hyperpigmentation or hypopigmentation has been postulated.1 In addition, keratinocytes probably play an active role in the regulation of melanogenesis and can stimulate melanocytes to become
dendritic and transfer melanosomes.20 We therefore hypothesize that the laser-irradiated melanocyte or keratinocyte may be more hyperactive to stimuli such as cold temperature.
In conclusion, the mechanism by which cold air cooling is associated with an increased risk of PIH after laser
treatment is unknown. It is possible that the mechanism was a melanocyte’s or keratinocyte’s responses to
the laser pulses together with cold air exposure. Future
studies should address the question of whether the other
methods of epidermal cooling are associated with an increase risk of PIH. Of particular interest is the mechanism that underlies the cause of hyperpigmentation after cold air cooling.
Accepted for Publication: March 6, 2007.
Correspondence: Woraphong Manuskiatti, MD, Department of Dermatology, Faculty of Medicine, Siriraj Hospital, Mahidol University, 2 Pran-nok Rd, Bangkok 10700,
Thailand (siwmn@mahidol.ac.th).
Authors Contributions: Study concept and design:
Manuskiatti and Wanitphakdeedecha. Acquisition of data:
Manuskiatti and Eimpunth. Analysis and interpretation
of data: Manuskiatti. Drafting of the manuscript: Manuskiatti and Eimpunth. Critical revision of the manuscript for
important intellectual content: Wanitphakdeedecha. Statistical analysis: Manuskiatti and Wanitphakdeedecha. Administrative, technical, and material support: Eimpunth.
Study supervision: Manuskiatti.
Financial Disclosure: None reported.
Previous Presentation: This study was presented at the
Annual Meeting of the American Society for Dermatologic Surgery; October 29, 2006; Palm Desert, California.
REFERENCES
1. Ruiz-Maldonado R, Orozco-Covarrubias ML. Postinflammatory hypopigmentation and hyperpigmentation. Semin Cutan Med Surg. 1997;16(1):36-43.
2. Chan HH, Alam M, Kono T, Dover JS. Clinical application of lasers in Asians. Dermatol Surg. 2002;28(7):556-563.
3. Manuskiatti W, Goldman MP. Use of lasers on Asian skin. In: Goldman MP, ed.
Cutaneous and Cosmetic Laser Surgery. Philadelphia, PA: Mosby Elsevier; 2006:
349-374.
4. Grimes P, Nordlund JJ, Pandya AG, Taylor S, Rendon M, Ortonne JP. Increasing our understanding of pigmentary disorders. J Am Acad Dermatol. 2006;
54(5)(suppl 2):S255-S261.
5. Pandya AG, Guevara IL. Disorders of hyperpigmentation. Dermatol Clin. 2000;18
(1):91-98, ix.
6. Ee HL, Wong HC, Goh CL, Ang P. Characteristics of Hori naevus: a prospective
analysis. Br J Dermatol. 2006;154(1):50-53.
7. Hori Y, Kawashima M, Oohara K, Kukita A. Acquired, bilateral nevus of Ota–like
macules. J Am Acad Dermatol. 1984;10(6):961-964.
8. Hori Y, Takayama O. Circumscribed dermal melanoses: classification and histologic features. Dermatol Clin. 1988;6(2):315-326.
9. Lam AY, Wong DS, Lam LK, Ho WS, Chan HH. A retrospective study on the efficacy and complications of Q-switched alexandrite laser in the treatment of acquired bilateral nevus of Ota–like macules. Dermatol Surg. 2001;27(11):937-942.
10. Manuskiatti W, Sivayathorn A, Leelaudomlipi P, Fitzpatrick RE. Treatment of acquired bilateral nevus of Ota–like macules (Hori’s nevus) using a combination of
scanned carbon dioxide laser followed by Q-switched ruby laser. J Am Acad
Dermatol. 2003;48(4):584-591.
11. Polnikorn N, Tanrattanakorn S, Goldberg DJ. Treatment of Hori’s nevus with the
Q-switched Nd:YAG laser. Dermatol Surg. 2000;26(5):477-480.
12. Nelson JS, Majaron B, Kelly KM. Active skin cooling in conjunction with laser
dermatologic surgery. Semin Cutan Med Surg. 2000;19(4):253-266.
13. Raulin C, Greve B, Hammes S. Cold air in laser therapy: first experiences with a
new cooling system. Lasers Surg Med. 2000;27(5):404-410.
14. Zenzie HH, Altshuler GB, Smirnov MZ, Anderson RR. Evaluation of cooling methods for laser dermatology. Lasers Surg Med. 2000;26(2):130-144.
15. Nanni CA, Alster TS. Complications of carbon dioxide laser resurfacing: an evaluation of 500 patients. Dermatol Surg. 1998;24(3):315-320.
16. Sriprachya-anunt S, Marchell NL, Fitzpatrick RE, Goldman MP, Rostan EF. Facial resurfacing in patients with Fitzpatrick skin type IV. Lasers Surg Med. 2002;
30(2):86-92.
17. Kunachak S, Leelaudomlipi P, Sirikulchayanonta V. Q-switched ruby laser therapy
of acquired bilateral nevus of Ota–like macules. Dermatol Surg. 1999;25(12):
938-941.
18. Burge SM, Bristol M, Millard PR, Dawber RP. Pigment changes in human skin
after cryotherapy. Cryobiology. 1986;23(5):422-432.
19. Datrice N, Ramirez-San-Juan J, Zhang R, et al. Cutaneous effects of cryogen spray
cooling on in vivo human skin. Dermatol Surg. 2006;32(8):1007-1012.
20. Minwalla L, Zhao Y, Le Poole IC, Wickett RR, Boissy RE. Keratinocytes play a
role in regulating distribution patterns of recipient melanosomes in vitro. J Invest Dermatol. 2001;117(2):341-347.
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STUDY
Primary Cutaneous Diffuse Large B-Cell
Lymphoma, Leg Type
Clinicopathologic Features and Prognostic Analysis in 60 Cases
Florent Grange, MD, PhD; Marie Beylot-Barry, MD, PhD; Phillipe Courville, MD; Eve Maubec, MD;
Martine Bagot, MD, PhD; Béatrice Vergier, MD, PhD; Pierre Souteyrand, MD; Laurent Machet, MD, PhD;
Sophie Dalac, MD; Eric Esteve, MD; Isabelle Templier, MD; Emmanuel Delaporte, MD; Marie-Françoise Avril, MD;
Caroline Robert, MD, PhD; Stephane Dalle, MD; Liliane Laroche, MD, PhD; Michele Delaunay, MD;
Pascal Joly, MD, PhD; Janine Wechsler, MD; Tony Petrella, MD
Objectives: To describe clinicopathologic features and
to identify prognostic factors in a large series of primary
cutaneous diffuse large B-cell lymphoma, leg type (PCLBCL
LT), as defined in the recent World Health Organization–
European Organization for Research and Treatment of Cancer classification of cutaneous lymphomas.
Design: Retrospective multicenter study from the French
Study Group on Cutaneous Lymphomas.
Setting: Nineteen departments of dermatology in 10 regions of France.
Patients: Sixty patients with a PCLBCL LT included in
the registry of the French Study Group on Cutaneous
Lymphomas.
Main Outcome Measures: Age, sex, outcome, therapy,
B symptoms, cutaneous extent, number of lesions, location (leg vs nonleg), serum lactate dehydrogenase level,
and MUM-1 and Bcl-2 expression were recorded. Diseasespecific survival was used as the main end point. Prognostic factors were identified using a Cox proportional
hazards model.
I
Author Affiliations are listed at
the end of this article.
Results: Primary cutaneous diffuse large B-cell lymphoma, leg type is characterized by a predilection for
the leg (72%), a high proportion of Bcl-2 expression
(85%), an advanced age at onset (mean age, 76 years),
and frequent relapses and extracutaneous dissemination. The overall 5-year disease-specific survival rate
was 41%. Location on the leg and multiple skin lesions
were predictive of death in multivariate analysis.
Although no variable related to therapy was significantly associated with survival, patients recently treated
with combinations of anthracycline-containing chemotherapies and rituximab had a more favorable shortterm outcome.
Conclusions: Primary cutaneous diffuse large B-cell
lymphoma, leg type is a distinct entity with a poor
prognosis, particularly in patients with multiple tumors
on the legs. Despite the advanced age of many patients,
the prognosis could be improved with combinations
of anthracycline-containing chemotherapies and
rituximab.
Arch Dermatol. 2007;143(9):1144-1150
2005, A NEW WORLD HEALTH
Organization–European Organization for Research and Treatment of Cancer (WHO-EORTC)
classification of cutaneous lymphomas was proposed1 and was widely
accepted2,3 as an important consensual advance for the characterization and management of cutaneous lymphomas. In this classification, primary cutaneous B-cell
lymphomas (PCBCLs) were divided into the
following 3 main groups: primary cutaneous marginal zone B-cell lymphoma, primary cutaneous follicle center cell lymphoma, and primary cutaneous diffuse large
B-cell lymphoma, leg type (PCLBCL LT).
Whereas the first 2 groups had been identified long before and studied in numerous
N
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large reports,4-10 the third group was newly
defined and had not yet been characterized by large multicenter studies.
Since the report of the WHO-EORTC
classification, 2 studies11,12 have included information about 40 and 51 cases of PCLBCL
LT as subgroup analyses of larger series of
PCBCLs of different subtypes. However, no
large studies specifically dedicated to
PCLBCL LT have been published to date,
to our knowledge. In addition, although
PCLBCL LT is known to have a more aggressive clinical behavior than other groups
of PCBCLs,1,11,12 we are aware of only 1
study11 that has attempted to identify prognostic factors in these patients. In this study,
we analyzed the outcome, therapy, prognostic factors, clinical characteristics, and
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immunohistologic features in a large series of patients with
PCLBCL LT.
METHODS
PATIENT SELECTION
A retrospective review of PCBCLs included in the registry of the
French Study Group on Cutaneous Lymphomas between January 1, 1988, and March 31, 2006, was carried out. Patients with
PCLBCL LT according to the WHO-EORTC classification1 were
selected for analysis after clinicopathologic review.
Primary cutaneous B-cell lymphomas were defined as Bcell lymphomas manifesting on the skin without evidence of
extracutaneous disease. Among PCBCLs, PCLBCL LT was defined histologically as cases with a predominance or confluent
sheets of centroblasts and immunoblasts, irrespective of the location of skin lesions and Bcl-2 protein expression. There were
no recorded patients with associated chronic lymphocytic leukemia or Richter syndrome.
To avoid selection biases, events occurring after diagnosis
were not used as exclusion criteria. In particular, patients unable to receive any treatment because of their poor general condition, those who developed extracutaneous dissemination
within 6 months after diagnosis, and those who died soon thereafter were included in the study.
HISTOLOGIC AND
IMMUNOHISTOCHEMICAL REVIEW
All cases were reviewed by a panel of 3 of us (B.V., J.W., and T.P.)
who were blinded to the clinical data to confirm the inclusion
criteria based on the predominance (ⱖ80%) of centroblasts (large
cells with round or oval nuclei and several small nucleoli generally sticking to the nucleus membrane) and immunoblasts (large
cells with round nuclei and ⱖ1 large central nucleoli). Cases showing a large proportion of large centrocytic cells (cleaved cells) were
excluded. For each case, hematoxylin-eosin stains and CD20- and
CD3-immunostained slides from formalin-fixed and paraffinembedded biopsy specimens were required. In all cases, tumor
cells expressed CD20 and were negative for CD3. The cases that
did not correspond to the morphological and phenotypical criteria of centroblastic or immunoblastic B-cell lymphomas were
excluded. Unstained sections or paraffin blocks were subsequently collected from each center to perform Bcl-2 and MUM-1
immunostainings. The analysis was performed in the same laboratory (that of T.P.) at the same time to avoid techniquedependent variability using an automated system (BenchMark;
Ventana Medical System, Illkich, France). We used reactive lymph
node specimens as positive and negative controls. The following
monoclonal antibodies were used for the study: clone 124 for Bcl-2
protein and clone mum1p for MUM-1 protein (Dako Company,
Globstrup, Denmark). After consensus among reviewers, an estimated quantification of the proportion of neoplastic large cells
that showed unequivocal Bcl-2 and MUM-1 positivity was given,
ranging from 0% to 100%. As in previous studies, Bcl-2 expression was considered positive when this proportion exceeded 50%.
MUM-1 expression was categorized as positive (ⱖ50% positive
tumor cells), intermediate (30%-49% positive tumor cells), or negative (⬍30% positive tumor cells).
CLINICAL AND FOLLOW-UP DATA
All medical records were reviewed. The following clinical characteristics were recorded at diagnosis and were evaluated for
prognostic value: age, sex, B symptoms, number of skin le-
sions, duration of skin lesions before diagnosis, serum lactate
dehydrogenase level, anatomical site (arm, leg, head and neck,
anterior aspect of the trunk, or posterior aspect of the trunk),
and cutaneous extent (namely, “localized” when 1 or multiple
skin lesions were restricted to 1 anatomical site and “disseminated” when several anatomical sites were involved). Follow-up data were recorded until April 1, 2006, including initial and subsequent therapies, achievement of a complete
response, cutaneous relapse, extracutaneous progression of the
disease, final status, and date and cause of death. Causes of death
were ascertained in most cases by physician members of the
French Study Group on Cutaneous Lymphomas who followed up patients and in other cases by questioning their general practitioners. Follow-up ranged from 0.3 to 155 months
(mean follow-up, 32 months). Fifty-two patients (86.7%) were
followed up until death, until the end point, or for longer than
5 years, whereas 8 patients (13.3%) were lost to follow-up after less than 5 years (range, 17-49 months).
STATISTICAL ANALYSIS
Disease-specific survival duration was calculated from diagnosis
to the date of disease-related death or censoring. Patients whose
deaths were unrelated to lymphoma were considered censored.
Prognostic factors were identified by disease-specific survival univariate and multivariate analyses using a Cox proportional hazards model.13 Factors significant at the 0.2 level in
univariate analysis were included in stepwise regression multivariate analyses. Comparisons between subgroups of patients according to factors of prognostic value were performed
using ␹2 test or Fisher exact test for categorical variables and t
test or Mann-Whitney test for continuous variables. The KaplanMeier method was used to estimate lymphoma-specific survival and to construct corresponding survival curves.14 Survival rates were compared separately for each category of
prognostic variable identified by the Cox proportional hazards model using the Mantel-Cox test.
RESULTS
BASELINE CLINICAL AND HISTOLOGIC
CHARACTERISTICS AND FOLLOW-UP DATA
Sixty patients met the inclusion criteria. Thirty-two had
been included in a previous study.15 All patients had negative staging investigations at diagnosis, including physical examination (100% of cases), routine laboratory test
results (100%), bone marrow cytologic or histologic features (90%), chest radiography or thoracic computed tomography (100%), abdominal ultrasonographic tomography or abdominal computed tomography (100%), and
lymph node histologic features in patients with clinically enlarged lymph node (13%).
The main characteristics of patients at diagnosis and the
follow-up data are summarized in Table 1. The femalemale sex ratio was 1.6. Patient age ranged from 44 to 96
years (mean age, 76 years; median age, 77 years). The performance status was 0 (fully active), 1 (ambulatory), 2 (bedridden ⬍50% of the time), 3 (bedridden ⱖ50% of the time),
and 4 (completely bedridden) in 12, 13, 4, 4, and 2 patients, respectively, and was unavailable for 25 patients.
Fifty-four patients had cutaneous nodules or tumors, 3 patients had deeply infiltrated plaques, 2 patients had large
subcutaneous tumors, and 1 patient had a leg ulcer. Twenty
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Table 1. Main Findings at Diagnosis and Follow-up Data and According to Location of Skin Tumors a
Variable
Total
No. of cases
Age, y
Mean (range)
⬎ 75
Sex
Male
Female
No. of lesions
1
⬎1
Extent
Localized
Disseminated
Serum lactate dehydrogenase level
Normal
High
Immunohistochemistry c
Bcl-2 positive, No. of patients/total No. of patients
MUM-1 positive, No. of patients/total No. of patients
Complete response
Yes
No
Relapse d
No
Yes
Extracutaneous progression
No
Yes, nodal only
Yes, visceral with or without nodal
Status
Alive, disease free
Alive with disease
Died of lymphoma
Died, other cause
Disease-specific survival rate, %
3y
5y
Leg
Nonleg
60
43
17
76 (44-96)
35 (58.3)
78 (44-92)
30 (69.8)
72 (49-96)
5 (29.4)
23 (38.3)
37 (61.7)
15 (34.9)
28 (65.1)
8 (47.1)
9 (52.9)
20 (33.3)
40 (66.7)
8 (18.6)
35 (81.4)
12 (70.6)
5 (29.4)
48 (80.0)
12 (20.0)
32 (74.4)
11 (25.6)
16 (94.1)
1 (5.9)
54 (90.0)
6 (10.0)
38 (88.4)
5 (11.6)
16 (94.1)
1 (5.9)
51/60 (85.0)
23/41 (56.1)
39/43 (90.7)
18/29 (62.1)
12/17 (70.6)
5/12 (41.7)
41 (68.3)
19 (31.7)
27 (62.8)
16 (37.2)
14 (82.4)
3 (17.6)
15 (36.6)
26 (63.4)
8 (29.6)
19 (70.4)
7 (50.0)
7 (50.0)
34 (56.7)
9 (15.0)
17 (28.3)
23 (53.5)
6 (14.0)
14 (32.6)
11 (64.7)
3 (17.6)
3 (17.6)
16
4
31
9
5 (11.6)
4 (9.3)
27 (62.8)
7 (16.3)
11 (64.7)
0
4 (23.5)
2 (11.8)
43
26
77
77
P Value b
.03
.004
.4
⬍.001
.15
.6
a Data are given as number (percentage) unless otherwise indicated.
b Leg vs nonleg primary cutaneous diffuse large B-cell lymphoma, leg
.1
.3
.2
.13
.3
.001
(26.7)
(6.7)
(51.7)
(15.0)
.002
53
41
type. For 5-year survival rates, P values were calculated from a comparison of survival
curves.
c Not available in all patients.
d Considered only in 41 patients who achieved a complete response.
patients (33.3%) had 1 lesion, 19 patients (31.7%) had 2
to 5 lesions, and 21 (35.0%) had more than 5 lesions. Eight
patients (13.3%) had lesions on the trunk, 9 patients (15.0%)
had lesions on the arm, 11 patients (18.3%) had lesions on
the head, and 43 patients (71.7%) had lesions on the leg
(in 5 of these 43 patients, lesions were located both on the
leg and at other anatomical sites). Using the previous
EORTC classification,16 all 43 of these cases would have
been classified by most authors as PCLBCL of the leg,
whereas 17 cases without leg lesions (28.3%) would have
been classified as primary cutaneous follicle center cell lymphoma. In the present study, these 17 cases are referred to
as nonleg PCLBCL LT, as defined in the WHO-EORTC
classification.1
Seven patients (11.7%) had a high serum lactate dehydrogenase level, 6 patients (10.0%) had B symptoms,
and 2 patients (3.3%) had both conditions. Bcl-2 staining was positive in 51 patients (85.0%). MUM-1 staining was scored as positive, intermediate, and negative in
23 (56.1%), 5 (12.2%), and 13 (31.7%) of 41 patients,
respectively, and was unavailable in 19 patients.
Table 2 summarizes first-line and subsequent therapies administered in our 60 patients. First-line therapy
was most often radiation therapy (38.3%) or variable combinations of systemic chemotherapies (49.9%) with or
without rituximab. In addition, 17 patients (28.3%) received second-line or third-line therapies. Overall, 39 patients (65.0%) were treated with polychemotherapies as
first-line or subsequent therapies during the course of the
disease (data not shown). These included 9 patients
(15.0%) who received polychemotherapies only without anthracycline, 18 patients (30.0%) who received anthracycline-containing chemotherapies without rituximab, and 12 patients (20.0%) who received various
combinations of anthracycline-containing chemotherapies and rituximab. No statistically significant difference with respect to therapies administered was observed between patients with leg vs nonleg PCLBCL LT.
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Table 2. Summary of Therapiesa
Therapy
First-line Therapies
(n = 60)
Subsequent Therapies
(n = 17)
23 (38.3) b
1 (1.7)
8 (13.3) c
11 (18.3) d
11 (18.3)
6 (10.0) e
3
2
5
7
1
Radiation therapy
Single-agent chemotherapy
Polychemotherapies without anthracycline
Anthracycline-containing chemotherapies without rituximab
Various combinations of anthracycline-containing chemotherapies and rituximab
Other
a Data are given as number (percentage).
b Associated with single-agent chemotherapy in 1 patient.
c Associated with radiation therapy in 1 patient.
d Associated with radiation therapy in 3 patients.
e Consisted of surgery in 3 patients, oral corticosteroid use
in 1 patient, and no therapy in 2 patients.
Table 3. Results From the Multivariate Analysis
Result
Location of skin lesions
Nonleg
Leg
No. of lesions
Single
Multiple
P = .003
Nonleg (n = 17)
0.75
P
Value
Survival
Relative Risk
(95% Confidence
Interval)
1.00
.02
1 [Reference]
3.3 (1.1-10.0)
0.50
Leg (n = 43)
0.25
.05
1 [Reference]
2.3 (1.0-5.4)
Among 41 patients (68.3%) who achieved at any time
a complete response, 26 (63.4%) experienced 1 or several relapses. Of 60 patients, 26 (43.3%) developed extracutaneous disease. The mean time until extracutaneous dissemination was 20 months. The dissemination was
restricted to the lymph nodes in 9 patients. The remaining 17 patients had visceral progression associated with
lymph node involvement (6 patients) or without (11 patients). The central nervous system was the most frequent site of visceral dissemination (7 patients). Other
sites included the bones (2 patients), kidney (2 patients), liver (1 patient), spleen (1 patient), testis (1 patient), pancreas (1 patient), breast (1 patient), pelvis (1
patient), and brachial plexus (1 patient).
Thirty-one patients (51.7%) died of lymphoma, and
9 patients (15.0%) died of unrelated disease. Of 31 diseasespecific deaths, 24 (77.4%) followed extracutaneous progression of the disease. Eight other deaths were considered disease-related despite the absence of obvious
extracutaneous involvement. These included patients who
developed fatal sepsis after chemotherapy and those who
died of secondary infection, major cutaneous tumor bulk
and ulceration, or major worsening of their general condition. The 3-year and 5-year disease-specific survival rates
were 53% and 41%, respectively.
PROGNOSTIC FACTORS
In univariate analysis, disease-related death was statistically significantly associated with location on the leg
(P=.003), disseminated distribution (P=.04), and the presence of multiple skin lesions at diagnosis (P = .004). Pa-
0
0
12
24
36
48
60
72
84
Months
Figure. Kaplan-Meier lymphoma-specific survival curves according to
location of skin lesions.
tients older than 75 years had a slightly poorer prognosis (P=.06). Sex, B symptoms, Bcl-2 expression, MUM-1
expression, performance status, serum lactate dehydrogenase level, duration of lesions before diagnosis, and variables related to therapy had no effect on survival. Multivariate analysis of lymphoma-specific survival using all
candidate variables identified location on the leg (P=.02)
and multiple skin lesions (P=.05) as independent factors
associated with a poorer prognosis (Table 3). Similar results were observed when age was forced in the model.
CHARACTERISTICS OF PATIENTS
AND OUTCOMES IN DIFFERENT
PROGNOSTIC GROUPS
Because the topographic subtype (leg vs nonleg) was the
strongest prognostic factor, the main features at diagnosis and the follow-up data were subsequently analyzed
according to the location of skin lesions (Table 1). Patients with the leg subtype were older and had more numerous skin lesions at diagnosis than patients with nonleg PCLBCL LT; they showed a tendency for less frequent
response to therapy and more frequent relapses and visceral progressions. The 3-year disease-specific survival
rates were 43% in the leg subtype group and 77% in the
nonleg subtype group (P=.002). Kaplan-Meier lymphomaspecific survival curves according to the location of skin
lesions are shown in the Figure.
The number of skin lesions at diagnosis also was a major distinctive factor for predicting survival in the entire
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series, with 3-year disease-specific survival rates of 39%
in patients with multiple skin lesions vs 77% in those with
a single lesion (P = .004). The number of lesions was related to the topographic subtype (Table 1). Only 8 of 43
patients (18.6%) in the leg subtype group had a single
lesion at diagnosis. In this subgroup, the 3-year survival
rate was 78% compared with 32% in 35 patients with multiple lesions involving 1 or both legs. No difference in
survival was observed between Bcl-2–positive cases (3year survival, 54%) and Bcl-2–negative cases (3-year survival, 43%) in the entire series (P = .8).
ROLE OF THERAPY
Although no variable related to therapy was statistically
significantly associated with survival in this retrospective study, we further analyzed patients who received at
any time various combinations of anthracyclinecontaining chemotherapies and rituximab (12 patients)
and compared them with those who received other therapies only (48 patients). These 2 groups did not differ by
age, location, or number of skin lesions. They strongly
differed by period of inclusion because rituximab was
never used before 2002 and was used only rarely before
2004. Therefore, no long-term (ⱖ3 year) survival comparison was available at the end point. The 2-year survival rate differed between the 2 groups (group receiving various combinations of anthracycline-containing
chemotherapies and rituximab, 81%; group receiving
other therapies, 59%) without reaching a statistically
significant difference (P = .3). However, the short-term
outcome was more favorable in patients treated with various combinations of anthracycline-containing chemotherapies and rituximab. Among these 12 patients, all but
1 (91.6%) achieved a complete response (compared with
62% in the group receiving other therapies) (P=.05), and
10 of 11 patients had no relapse. At the end point, 9 of
these patients were alive with a mean follow-up of 19
months (8 patients without disease and 1 patient with
disease), 2 patients had died of lymphoma (1 patient of
septicemia after chemotherapy and 1 patient of brain involvement), and 1 patient had died of unrelated disease.
A similar comparative analysis between patients treated
with anthracycline-containing chemotherapies without
rituximab and other patients failed to disclose any difference in outcomes.
COMMENT
We report herein the largest study of PCLBCL LT, to our
knowledge, and provide new data on its clinicopathologic features and prognostic factors. In addition, we provide preliminary results comparing outcomes in patients treated with classic vs new therapeutic regimens.
Most PCBCLs, including almost all small-cell lymphomas and a large proportion of large-cell lymphomas, have an indolent clinical course.4-6,9,16-18 However,
a subset of PCBCLs with a predominance of large cells
comprises aggressive lymphomas. This finding led researchers to look for discriminating prognostic factors
within this heterogeneous group of primary cutaneous
large B-cell lymphomas. Small case series first identified
the location on the leg as a criterion of aggressiveness.4,19 In further multicenter studies, round-cell morphological features20 (ie, the predominance of large cells
with round nuclei over large cells with cleaved nuclei)
and Bcl-2 protein expression15 were identified as additional adverse prognostic factors.
In the WHO-EORTC classification,1 the term primary
cutaneous diffuse large B-cell lymphoma, leg type was introduced beside primary cutaneous follicle center cell lymphoma and primary cutaneous marginal zone B-cell lymphoma to designate PCBCLs with a predominance of large
cells and a less favorable prognosis. Primary cutaneous diffuse large B-cell lymphoma, leg type was primarily defined on the basis of morphological features by the presence of confluent sheets of large cells with round nuclei
(ie, centroblasts and immunoblasts). Primary cutaneous
diffuse large B-cell lymphoma with a predominance of large
cleaved cells and fewer centroblasts was classified within
the group of primary cutaneous follicle center cell lymphoma. In addition, it was specified that PCLBCL LT arises
on the leg in most (but not all) cases and demonstrates
strong Bcl-2 expression.1 The role of Bcl-2 expression for
classifying these lymphomas remained unclear. In further studies, some authors excluded rare Bcl-2–negative
cases from the group of PCLBCL LT and included them
in the heterogeneous group termed large B-cell lymphoma, other,11 whereas other authors (as we do in the present study) included all cases with characteristic roundcell morphological features within the group of PCLBCL
LT, irrespective of Bcl-2 expression.12
Using these criteria, we found that PCLBCL LT is characterized by a poor prognosis, a high proportion of Bcl-2
expression (85%), an advanced age at onset (median age,
77 years), and a frequent location on the leg (72% in 43
cases, including 5 cases with lesions on the leg and at other
sites). The 3-year and 5-year disease-specific survival rates
in the entire group were 53% and 41%, respectively.
Survival rates in the present study (Table 1) were lower
than those in previous reports. The Italian study Group
for Cutaneous Lymphomas12 recently reported a 5-year survival rate of 73% in 51 patients with PCLBCL LT, including 6 patients without leg lesions. Kodama et al11 reported a 5-year survival rate of 61.7% in 40 Austrian patients
with Bcl-2–positive PCLBCL LT, 32 of whom had disease
on the leg. Such differences in survival may result from
variations in management and therapy or from differences in baseline characteristics of patients resulting from
various selection biases. Although patients included in the
Austrian study did not differ in age from our patients, those
included in the Italian series were younger (median age,
70 years). In addition, only patients who had 6 months of
follow-up without extracutaneous dissemination were included in the Italian series. In our study, patients were included on the basis of negative initial staging, irrespective of further outcome. Some older patients had multiple
and bulky tumors on the legs, could receive only palliative care, and died early after diagnosis. These patients were
not excluded from the study and affected the survival rate
in the entire series.
We identified location on the leg as the main negative prognostic factor. Patients with leg tumors had a
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3-year disease-specific survival rate of 43%, compared with
77% in patients with nonleg PCLBCL LT. This result confirms and extends previous reports of the aggressiveness of primary cutaneous large B-cell lymphoma of the
leg, as defined in the previous EORTC classification.16,19,20 However, the prognosis of nonleg PCLBCL LT
(Figure) seems poorer than that of primary cutaneous
follicle center lymphoma or primary cutaneous marginal zone B-cell lymphoma, which are characterized by
5-year survival rates of 95% to 100%.1,8 Therefore, it seems
preferable to classify these lymphomas on a morphological basis within the group of PCLBCL LT, as proposed
in the recent WHO-EORTC classification,1 rather than
in the group of primary cutaneous follicle center cell lymphoma, as in the previous EORTC classification.16
The second negative prognostic factor in our study was
the presence of multiple skin lesions. Although the number of skin lesions had no prognostic value in the Austrian series,11 2 previous studies15,20 on aggressive PCBCLs
identified multiple skin lesions as an important adverse
prognostic factor. This is in accord with earlier studies9,21,22 of different types of cutaneous or noncutaneous
lymphomas that underlined the prognostic value of variables related to tumor burden. In the present study, the
3-year disease-specific survival rate was 39% in patients
with multiple skin lesions vs 77% in patients with only 1
lesion (P=.004). Most patients with leg involvement had
multiple tumors. However, those with only 1 tumor on a
leg had a favorable prognosis. Whether these patients may
be first treated with less aggressive procedures such as radiation therapy alone remains questionable.
In the present study, PCLBCL LT showed intermediate or positive staining for MUM-1 protein in most cases
and consistently expressed Bcl-2 protein. This finding confirms that the expression of MUM-1 and Bcl-2 characterizes not only primary cutaneous large B-cell lymphomas
of the leg, as previously demonstrated,23-25 but also PCLBCL
LT defined on a morphological basis. Bcl-2 expression was
almost universal in cases located on the leg and was observed in most nonleg cases (Table 1). Overall, only 9 of
60 cases had negative Bcl-2 staining. Bcl-2–negative
PCLBCL LT is rare and has been poorly characterized to
date. Kodama et al11 described 9 cases using the term large
B-cell lymphoma, other. Four cases were located outside
of the leg. No difference in survival was observed between these 9 patients (5-year survival, 50%) and 40 patients with typical Bcl-2–positive PCLBCL LT (5-year survival, 61.7%). We found similar results, with 3-year survival
rates of 43% in Bcl-2–negative patients vs 54% in Bcl-2–
positive patients (P=.8). Although these results need to
be confirmed in larger series, it seems suitable to include
all of these cases within the group of PCLBCL LT as defined morphologically by confluent sheets of large round
B-cells, irrespective of Bcl-2 staining.
Primary cutaneous diffuse large B-cell lymphoma, leg
type is an aggressive lymphoma that requires effective
therapies. This seems to be a difficult challenge in view
of the advanced age of many patients. Historically, some
of these patients received only palliative care, radiation
therapy, or nonaggressive chemotherapies. However, the
report of the effectiveness of various combinations of anthracycline-containing chemotherapies and rituximab in
older patients with noncutaneous diffuse large B-cell lymphomas22 led to changes in the French practices regarding the cutaneous counterparts of these lymphomas. The
rationale for this attitude was enhanced by the demonstration that rituximab was able to overcome Bcl-2–
associated resistance to chemotherapy,26,27 which coincided with findings that most PCLBCL LT strongly
expressed Bcl-2.15,23 In the present study, 12 patients who
received various combinations of anthracyclinecontaining chemotherapies and rituximab were retrospectively compared with 48 patients who received other
treatments. Although the follow-up was insufficient to
objectively determine a statistically significant difference in survival, more favorable short-term outcomes were
observed with various combinations of anthracyclinecontaining chemotherapies and rituximab. While awaiting appropriate controlled trials to confirm these observations, we recommend that patients with PCLBCL LT
should be treated as often as possible with age-adapted
various combinations of anthracycline-containing chemotherapies and rituximab, particularly in patients with
multiple skin tumors.
Accepted for Publication: February 25, 2007.
Author Affiliations: Department of Dermatology, Hôpital Robert Debré, Reims (Dr Grange); Departments of Dermatology (Dr Beylot-Barry) and Pathology (Dr Vergier),
Hôpital du Haut Lévêque, Pessac; Departments of Dermatology (Dr Courville) and Pathology (Dr Joly), Hôpital Charles Nicolle, Rouen; Department of Dermatology, Hôpital Bichat (Dr Maubec), and Department of
Dermatology, Hôpital Tarnier (Dr Avril), Paris; Departments of Dermatology (Dr Bagot) and Pathology (Dr
Wechsler), Hôpital Henri-Mondor, Créteil; Department
of Dermatology, Hôtel Dieu, Clermont-Ferrand (Dr
Souteyrand); Department of Dermatology, Hôpital Trousseau, Tours (Dr Machet); Department of Dermatology (Dr
Dalac) and Centre de Pathologie and Department of Pathology (Dr Petrella), Hôpital du Bocage, Dijon; Department of Dermatology, Hôpital Porte Madeleine, Orléans
(Dr Esteve); Department of Dermatology, Hôpital Michallon, Grenoble (Dr Templier); Department of Dermatology, Hôpital Claude Huriez, Lille (Dr Delaporte);
Department of Dermatology, Institut Gustave Roussy,
Villejuif (Drs Avril and Robert); Department of Dermatology, Hôpital de l’Hôtel-Dieu, Lyon (Dr Dalle); Department of Dermatology, Hôpital Avicenne, Bobigny (Dr
Laroche); and Department of Dermatology and Cancerology, Hôpital Pellegrin, Bordeaux (Dr Delaunay); France.
Correspondence: Florent Grange, MD, PhD, Department
of Dermatology, Hôpital Robert Debré, Avenue du Général Koenig, Reims 51100, France (fgrange@chu-reims.fr).
Author Contributions: Study concept and design: Grange.
Acquisition of data: Grange, Beylot-Barry, Courville,
Maubec, Bagot, Vergier, Souteyrand, Machet, Dalac,
Esteve, Templier, Delaporte, Avril, Robert, Dalle, Laroche,
Delaunay, Joly, Wechsler, and Petrella. Analysis and interpretation of data: Grange and Petrella. Drafting of the
manuscript: Grange and Petrella. Critical revision of the
manuscript for important intellectual content: BeylotBarry, Courville, Maubec, Bagot, Vergier, Souteyrand,
Machet, Dalac, Esteve, Templier, Delaporte, Avril, Robert,
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Dalle, Laroche, Delaunay, Joly, and Wechsler. Statistical analysis: Grange. Study supervision: Grange and
Petrella.
Financial Disclosure: None reported.
13.
14.
15.
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5. Santucci M, Pimpinelli N, Arganini L. Primary cutaneous B-cell lymphoma: a unique
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6. Pimpinelli N, Santucci M, Mori M, Vallecchi C, Giannotti B. Primary cutaneous
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7. Rijlaarsdam JU, van der Putte SC, Berti E, et al. Cutaneous immunocytomas: a
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WWW.ARCHDERMATOL.COM
OBSERVATION
Familial Acanthosis Nigricans
Due to K650T FGFR3 Mutation
David R. Berk, MD; Elaine B. Spector, PhD; Susan J. Bayliss, MD
Background: Acanthosis nigricans is a feature of several syndromes caused by activating mutations of the fibroblast growth factor receptor 3 gene (FGFR3), including Crouzon syndrome with acanthosis nigricans,
thanatophoric dysplasia, and severe achondroplasia with
developmental delay and acanthosis nigricans (SADDAN
syndrome).
numerous affected family members was constructed.
Other than slightly short stature, no associated anomalies were found, including dysmorphic features or skeletal or neurologic defects. Genetic testing revealed a previously undescribed, heterozygous lysine to threonine
mutation at codon 650 of the FGFR3 gene in the 4 affected family members who were tested.
Observations: We describe a healthy 4-year-old Afri-
Conclusion: Extensive acanthosis nigricans in early child-
can American girl with generalized acanthosis nigricans
since infancy. Her father had a history of acanthosis nigricans since childhood, in addition to Crohn disease,
obesity, and adult-onset diabetes mellitus. A pedigree with
hood, especially with a family history of acanthosis nigricans, may warrant testing for FGFR3 mutations.
Arch Dermatol. 2007;143(9):1153-1156
N
UMEROUS GENETIC SYNdromes are associated
with acanthosis nigricans (AN), particularly
syndromes characterized by obesity, hyperinsulinemia, and/
or craniosynostosis.1 In a recent review,
Torley et al1 divided these genetic syndromes into insulin resistance syndromes
and fibroblast growth factor (FGF) defects. Insulin resistance syndromes are
caused by mutations in the insulin receptor (leprechaunism and Rabson-Mendenhall syndrome), peroxisome proliferatoractivated receptor-␥ (insulin-resistant
See also pages 1125,
1194, and 1209
Author Affiliations:
Department of Internal
Medicine, Division of
Dermatology, and Department
of Pediatrics, Washington
University School of Medicine,
St Louis, Missouri (Drs Berk
and Bayliss); and DNA
Diagnostic Laboratory and
Department of Pediatrics,
University of Colorado at
Denver and Health and Sciences
Center, Aurora (Dr Spector).
diabetes mellitus with AN and hypertension), 1-acylglycerol-3-phophate O-acyltransferase-2 (Berardinelli-Seip syndrome), seipin (Berardinelli-Seip syndrome),
lamin A/C (Dunnigan syndrome), and Alstrom syndrome genes. Fibroblast growth
factor defects associated with AN include
specific activating mutations of FGFR2
(Beare-Stevenson syndrome) and FGFR3
(Crouzon syndrome with AN and thanatophoric dysplasia [TD], and severe achondroplasia with developmental delay and AN
[SADDAN syndrome]).
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1153
We describe herein a family with AN associated with a previously undescribed lysine to threonine mutation at codon 650 of
the FGFR3 gene. All 4 affected family members who were tested demonstrated the mutation. The inheritance pattern was autosomal dominant, and there were no obvious
associated skeletal or neurological abnormalities other than short stature.
REPORT OF CASES
A 4-year-old African American girl was referred for evaluation of generalized, minimally pruritic skin thickening since infancy. She was diagnosed as having atopic
dermatitis by her pediatrician years earlier
but had not responded to treatment with
topical corticosteroids. She was otherwise
healthy without diabetes mellitus and was
taking no medications. Neurological development was normal. Her father (age, 25
years) described having a similar skin condition since early childhood. He was slightly
obese and had Crohn disease and mild adultonset diabetes mellitus (diet controlled).
There was no history of consanguinity.
On physical examination, the patient
had generalized, thick, velvety, hyperpigmented plaques that were most prominent on her neck, back, and axillae
(Figure 1). There was no erythema or li-
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A
C
A
A
G
A
A/C
G
A
C
Figure 1. Patient at age 4 years with thick, velvety, hyperpigmented plaque
involving the neck and chest.
chenification. Her oral mucosa, palms, and external genitalia were normal. Height and weight at age 5.5 years were
105.5 cm (eighth percentile) and 17.3 kg (20th percentile), respectively. Results from laboratory evaluations (complete blood cell count, urinalysis, and random glucose and
hemoglobin A1c measurements) were normal. Examination of the patient’s father revealed similarly thick, velvety, hyperpigmented plaques localized to the neck, back,
and axillae. His height was 156 cm (⬍ fifth percentile). Over
the past few years, his weight had fluctuated from 48 to
106 kg due to his Crohn disease. Neither the patient nor
her father had facial dysmorphism (eg, frontal bossing) or
tibial bowing. Familial AN was diagnosed.
Because activating FGFR3 mutations have been identified in several forms of syndromic AN, this gene was
evaluated for mutations. Genetic testing was performed
on DNA isolated from saliva (Oragene; DNA Genotek Inc,
Ottawa, Ontario, Canada) followed by sequencing of exons 10, 13, and 15 of the FGFR3 gene. A single nucleotide change was observed in exon 15 (Figure 2). The
patient and her father both demonstrated a previously
undescribed lysine to threonine mutation at codon 650
(K650T) in one FGFR3 gene, suggesting autosomal dominant inheritance. No mutation was identified in the patient’s mother or the patient’s 3-year-old sister, both of
whom were clinically unaffected. Genetic counseling was
performed. There was no change with topical pimecrolimus and steroids.
The father’s 29-year-old cousin (Figure 3) and her 11year-old daughter (Figure 4) were subsequently evaluated for the same condition and diagnosed as having familial AN, resulting in a pedigree with multiple affected
relatives (Figure 5). The daughter’s height and weight
at age 11 years were 139 cm (26th percentile) and 40.9
kg (68th percentile), respectively. Her mother’s height and
weight were 145 cm (⬍ fifth percentile) and 64.2 kg (25th50th percentile), respectively. No further associated anomalies were identified in these 2 patients or reported in their
relatives, including dysmorphic features, diabetes mellitus, Crohn disease, or skeletal or neurologic defects. Both
this child and her mother demonstrated heterozygous
K650T mutations on genetic testing, identical to their 2
relatives who had been previously tested.
B
A
C
A
A
G
A
A
G
A
C
Figure 2. Sequencing of exon 15 of the FGFR3 gene was performed using
the following primers: forward, 5⬘ GTA AAA CGA CGG CCA GT AGG TGT GGG
TGG AGT AGG; and reverse, 5⬘ CAG GAA ACA GCT ATG ACC TC AGG CGC
CAT CCA CTT 5⬘ CTG TCA CCG TAG CCG TGA AG. Sequencing was
performed using an ABI 3130 sequencer (Applied Biosystems, Foster City,
California). A, The arrow indicates K650T mutation; A→C change at
nucleotide 1950, amino acid 650. B, Normal sequence.
COMMENT
Acanthosis nigricans is characterized by velvety, hyperpigmented plaques often accentuated in the flexures. Numerous forms of AN have been described including be-
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Figure 3. Cousin (age, 29 years) demonstrating thick, velvety,
hyperpigmented plaques on the neck and posterior auricular region.
Figure 4. Cousin (age, 11 years) demonstrating thick, velvety,
hyperpigmented plaques on the neck and forehead.
nign (nonsyndromic, insulin resistance-associated AN),
malignant (paraneoplastic), obesity-associated (pseudoAN), acral, medication-induced (corticosteroids, estrogens, oral contraceptives, niacin, triazinate, somatotrophin, and diethylstilbestrol), and syndromic AN
(including isolated, “pure” familial AN).2,3
Generalized AN is rare and often paraneoplastic,4 even
in very early childhood. However, generalized AN in early
childhood may also suggest isolated (nonsyndromic, noninsulin resistance–associated) familial AN.4-8 Furthermore, there are reports of benign, generalized AN in early
childhood without a positive family history, malignancy, associated syndrome, causative medication, or comorbid condition.9-15
Only a few families with isolated (nonsyndromic, noninsulin resistance–associated) familial AN have been reported in the literature.4-8 Inheritance tends to be autosomal dominant with variable penetrance. This “pure”
familial AN usually appears in infancy, stabilizes at puberty, and is not associated with obesity or diabetes mellitus. The term familial AN is confusing because AN associated with insulin resistance also tends to be hereditary
and the term familial AN has been used in the literature
in such cases.16,17 Comorbid conditions have rarely been
reported with isolated familial AN. Chuang et al18 reported a family with AN and ectodermal defects including madarosis. In addition, 2 cases of benign AN (no family history) in early childhood have been associated with
pyramidal tract degeneration.11,15 Familial AN may be confused with ichthyosis hystrix,5 generalized epidermal nevi,
or lichenification in atopic dermatitis.
The pathogenesis of AN is poorly understood. In patients with hyperinsulinemia, excess insulin may directly or indirectly stimulate epidermal proliferation
through the insulin-like growth factor 1 receptor.19
Growth factors (particularly transforming growth factor-␣) produced by tumors may cause malignant AN
through the epidermal growth factor receptor.20
Fibroblast growth factors are involved in angiogenesis, embryogenesis, mitogenesis, and wound healing.
There are more than 20 human FGF ligands and 4 human FGF receptors. The FGFR3 gene is located at 4p16.3
and encodes a transmembrane receptor tyrosine kinase,
which down-regulates long-bone growth. FGFR3 mutations have been reported in several dermatologic conditions including seborrheic keratoses,21 epidermal nevi,22
and syndromic AN. Several autosomal dominant syndromes are caused by specific FGFR3 mutations, including achondroplasia, Muenke syndrome, hypochondroplasia, TD I and II, Crouzon syndrome with AN, and SADDAN
syndrome. The latter 3 disorders demonstrate AN.
Codon 650 of FGFR3 is located in its tyrosine kinase
domain II. Mutations of this codon have been reported
in skeletal disorders including hypochondroplasia
(K650N and K650Q), SADDAN syndrome (K650M), TD I
(K650M), and TD II (K650E), as well as malignant conditions including bladder cancer and multiple myeloma
(K650M, K650E, and K650T). Germline K650T mutations have never been reported. Bellus et al23 studied the
effects of various amino acid changes on the activation
of FGFR3 in vitro. Constructs were made that contained
all of the possible FGFR3 mutations at amino acid 650.
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port: Berk, Spector, and Bayliss. Study supervision: Berk
and Spector.
Financial Disclosure: None reported.
Of an additional 11 siblings,
4 were affected
∗
∗
∗
∗
∗
∗
Figure 5. Pedigree of family. Shaded boxes indicate affected family members.
The asterisks indicate family members tested for FGFR3 mutations.
In a [32P]-ATP autophosphorylation assay, the relative
activity of the mutations compared with that of a wildtype construct was as follows: K650R, 1.5x; K650N, 3.7x;
K650Q, 4.9x; K650T, 3.1x; K650E, 9.6x; and K650M,
18.1x. These data suggest that since the K650T mutation was a relatively weak activator of FGFR3, it would
have a less severe effect on phenotype than the mutations found in hypochondroplasia, SADDAN syndrome, TD I, and TD II, as was observed in the patients
described herein.
Activating FGFR3 mutations and/or ectopic overexpression have been reported in a number of tumors, such
as bladder,24 cervical,25 multiple myeloma,26 and colorectal cancers.27 Tyrosine kinase inhibitors of FGFR3 are
being tested in several hematologic malignancies with
positive results.26 Topical preparations of these inhibitors may prove beneficial for seborrheic keratoses, epidermal nevi, and/or AN.22
In summary, we describe a family with AN caused by
an autosomal dominant K650T mutation in the FGFR3
gene. Extensive AN in early childhood, especially with
a family history of AN, may warrant testing for FGFR3
mutations.
Accepted for Publication: March 27, 2007.
Correspondence: David R. Berk, MD, Division of Dermatology, Washington University School of Medicine, 660
S Euclid, Campus Box 8123, St Louis, MO 63110 (DBerk
@im.wustl.edu).
Author Contributions: Dr Berk had full access to all of
the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Berk and Bayliss. Acquisition of
data: Berk and Spector. Analysis and interpretation of data:
Berk and Spector. Drafting of the manuscript: Berk and
Spector. Critical revision of the manuscript for important
intellectual content: Berk, Spector, and Bayliss. Statistical
analysis: Berk. Administrative, technical, and material sup-
REFERENCES
1. Torley D, Bellus GA, Munro CS. Genes, growth factors and acanthosis nigricans.
Br J Dermatol. 2002;147(6):1096-1101.
2. Curth HO. Classification of acanthosis nigricans. Int J Dermatol. 1976;15(8):592593.
3. Curth HO. Acanthosis nigricans. Birth Defects Orig Artic Ser. 1971;7(8):31-39.
4. Inamadar AC, Palit A. Generalized acanthosis nigricans in childhood. Pediatr
Dermatol. 2004;21(3):277-279.
5. Curth HO, Aschner BM. Genetic studies on acanthosis nigricans. AMA Arch Derm.
1959;79(1):55-66.
6. Curth HO. Benign acanthosis nigricans. Arch Dermatol. 1967;96(5):603-604.
7. Tasjian D, Jarratt M. Familial acanthosis nigricans. Arch Dermatol. 1984;120(10):
1351-1354.
8. Dhar S, Dawn G, Kanwar AJ, Nada R. Familial acanthosis nigricans. Int J Dermatol.
1996;35(2):126-127.
9. Curth HO. Benign type of acanthosis nigricans. Arch Derm Syphilol. 1936;34(3):
353-366.
10. Pindborg JJ, Gorlin RJ. Oral changes in acanthosis nigricans (juvenile type): survey of the literature and report of a case. Acta Derm Venereol. 1962;42:63-71.
11. Maranon G, Alvarez Cascos M. Benign juvenile acanthosis nigricans; its relation
to congenital abnormalities. Acta Derm Venereol. 1957;37(3):249-258.
12. Skiljevic DS, Nikolic MM, Jakovljevic A, Dobrosavljevic DD. Generalized acanthosis nigricans in early childhood. Pediatr Dermatol. 2001;18(3):213-216.
13. Uyttendaele H, Koss T, Bagheri B, et al. Generalized acanthosis nigricans in an
otherwise healthy young child. Pediatr Dermatol. 2003;20(3):254-256.
14. Rai VM, Balachandran C. Generalized acanthosis nigricans in childhood. Dermatol Online J. 2006;12(6):14.
15. Curth HO. Significance of acanthosis nigricans. AMA Arch Derm Syphilol. 1952;
66(1):80-100.
16. Taylor G, James MP, Simpson H. Familial acanthosis nigricans. J R Soc Med.
1994;87(3):169.
17. Friedman CI, Richards S, Kim MH. Familial acanthosis nigricans: a longitudinal
study. J Reprod Med. 1987;32(7):531-536.
18. Chuang SD, Jee SH, Chiu HC, Chen JS, Lin JT. Familial acanthosis nigricans with
madarosis. Br J Dermatol. 1995;133(1):104-108.
19. Cruz PD Jr, Hud JA Jr. Excess insulin binding to insulin-like growth factor receptors: proposed mechanism for acanthosis nigricans. J Invest Dermatol. 1992;
98(6)(suppl):82S-85S.
20. Haase I, Hunzelmann N. Activation of epidermal growth factor receptor/ERK signaling correlates with suppressed differentiation in malignant acanthosis nigricans.
J Invest Dermatol. 2002;118(5):891-893.
21. Logié A, Dunois-Larde C, Rosty C, et al. Activating mutations of the tyrosine kinase receptor FGFR3 are associated with benign skin tumors in mice and humans.
Hum Mol Genet. 2005;14(9):1153-1160.
22. Hafner C, van Oers JM, Vogt T, et al. Mosaicism of activating FGFR3 mutations
in human skin causes epidermal nevi. J Clin Invest. 2006;116(8):2201-2207.
23. Bellus GA, Spector EB, Speiser PW, et al. Distinct missense mutations of the FGFR3
lys650 codon modulate receptor kinase activation and the severity of the skeletal dysplasia phenotype. Am J Hum Genet. 2000;67(6):1411-1421.
24. van Rhijn BW, van Tilborg AA, Lurkin I, et al. Novel fibroblast growth factor receptor 3 (FGFR3) mutations in bladder cancer previously identified in non-lethal
skeletal disorders. Eur J Hum Genet. 2002;10(12):819-824.
25. Cappellen D, De Oliveira C, Ricol D, et al. Frequent activating mutations of FGFR3
in human bladder and cervix carcinomas. Nat Genet. 1999;23(1):18-20.
26. Grand EK, Chase AJ, Heath C, Rahemtulla A, Cross NC. Targeting FGFR3 in multiple myeloma: inhibition of t(4;14)-positive cells by SU5402 and PD173074.
Leukemia. 2004;18(5):962-966.
27. Jang JH, Shin KH, Park JG. Mutations in fibroblast growth factor receptor 2 and
fibroblast growth factor receptor 3 genes associated with human gastric and colorectal cancers. Cancer Res. 2001;61(9):3541-3543.
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OBSERVATION
Eczematoid Graft-vs-Host Disease
A Novel Form of Chronic Cutaneous Graft-vs-Host Disease
and Its Response to Psoralen–UV-A Therapy
Daniel Creamer, MD; Claire L. Martyn-Simmons, MRCP(England); Genevieve Osborne, MRCP(England);
Michelle Kenyon, MSc; Jon R. Salisbury, MD; Stephen Devereux, MD; Antonio Pagliuca, MD;
Aloysius Y. Ho, MD; Ghulam J. Mufti, MD; Anthony W. P. du Vivier, MD
Background: Chronic cutaneous graft-vs-host disease
(GVHD) is generally classified by whether lesions have
a lichenoid or sclerodermatous morphology. Other unusual clinical forms have been reported that exhibit the
features of dermatomyositis and lupus erythematosus.
Within a large population of individuals who underwent allogeneic stem cell transplantation because of hematologic malignancy, a group of patients was identified in whom severe and persistent eczema developed.
Observations: We prospectively evaluated 10 adult patients with unexplained eczematous dermatosis after allogeneic hematopoietic stem cell transplantation. The dermatosis developed between 2 and 18 months (mean, 7.5
months) after receipt of the transplant, exhibited the typical clinical features of dermatitis, and became erythrodermic in each case. The patient group had strong risk
factors for chronic cutaneous GVHD: 8 had received a
transplant from an unrelated donor, 7 had evidence of
extracutaneous GVHD, and 7 had a history of acute cutaneous GVHD. Sampling of lesional skin revealed the
histologic features of GVHD coexisting with the changes
of dermatitis. The patients were treated with topical corticosteroid and systemic immunosuppressive agents. Six
patients also received psoralen–UV-A. Four patients
achieved prolonged remission. Six patients died, 5 of infective complications and 1 of relapsed leukemia.
Conclusions: The eczematous dermatosis observed represents a novel form of chronic cutaneous GVHD that
we named eczematoid GVHD. Eczematoid GVHD is an
aggressive, chronic dermatosis that requires substantial
immunosuppression therapy to achieve control. It is associated with a poor prognosis. Although atopy can be
transmitted to an individual from a hematopoietic stem
cell transplant, none of the donors in this series gave a
history of an atopic disorder. Therefore, other factors must
be implicated in provoking the expression of an eczematous phenotype in individuals with underlying chronic
graft-vs-host activity.
Arch Dermatol. 2007;143(9):1157-1162
G
Author Affiliations:
Departments of Dermatology
(Drs Creamer, MartynSimmons, Osborne, and du
Vivier) and Histopathology
(Dr Salisbury), King’s College
Hospital; and Department of
Haematological Medicine,
King’s College Hospital and
King’s College London
(Ms Kenyon and Drs Devereux,
Pagliuca, Ho, and Mufti),
London, England.
RAFT - VS - HOST DISEASE
(GVHD) is a multisystem disease initiated by allogeneic T lymphocytes
that recognize foreign tissue antigens in the host.1 The disease usually develops after hematopoietic stem cell
transplantation (HSCT), a therapeutic
method used primarily to treat hematologic malignancy. However, it may also occur after transfusion of nonirradiated blood
products, transplantation of solid organs,
and maternal blood transfer in an immunodeficient fetus. Graft-vs-host disease results in complications in 40% to 80% of allogeneic HSCTs and is a major cause of
morbidity and mortality.2
Graft-vs-host disease is divided into
acute and chronic forms that have distinct
disease patterns and are conventionally differentiated by whether onset is before or after 100 days following transplantation.
Acute GVHD follows a graft-vs-host (GVH)
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reaction targeted against epithelia of skin,
gastrointestinal tract, and liver and is manifested with rash and diarrhea and with abnormal liver function test results. The eruption of acute GVHD is characterized by
maculopapular exanthem with acral accentuation or, rarely, is manifested as widespread epidermal necrolysis.3 Clinically,
chronic cutaneous GVHD has been classified by whether lesions have a sclerodermoid or lichenoid appearance.4 Sclerodermoid GVHD has many clinicopathologic
patterns including cases resembling morphea, lichen sclerosus, and eosinophilic
fasciitis.5 The diffuse form of sclerodermoid GVHD is associated with deepseated fibrosis and joint contractures. Lichenoid GVHD is characterized by the
presence of violaceous, indurated papules
and plaques that resemble lichen planus.
Other papulosquamous GVHD subtypes
have been reported including psoriasiform, keratosis pilaris–like, and asteatotic
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A
B
Figure 1. Widespread, intensely pruritic, eczematous eruption in patient 7 (A) and patient 2 (B). During the course of the illness, all patients developed
erythroderma with thermoregulatory dysfunction and dependent edema (B).
forms.5 Rarely, GVHD variants occur that exhibit the features of autoimmune connective tissue diseases such as
dermatomyositis and lupus erythematosus.6,7 Two reports cite eczemalike GVHD.8,9
We studied patients who developed cutaneous GVHD
after HSCT performed in the Department of Haematological Medicine at King’s College Hospital, London, England. Patterns of GVHD manifestation, natural history,
response to treatment, and outcome were recorded for
all patients. Within this population, a distinct group has
been identified characterized by persistent, widespread,
chronic eczematous dermatosis occurring several months
after allogeneic HSCT. The eruption demonstrates the histopathologic changes of both dermatitis and a GVH reaction, and we, therefore, suggest that it represents a manifestation of chronic cutaneous GVHD that warrants
reporting and further investigation.
METHODS
PATIENTS
Between January 1, 2001, and December 31, 2004, 254 patients
underwent allogeneic HSCT in the Department of Haematological Medicine at King’s College Hospital. Of these patients, 10 were
identified who developed chronic eczematous dermatosis after
HSCT (eTable; available at: http://www.archdermatol.com). The
group consisted of 8 men and 2 women, with a mean age at onset of dermatosis at 54.5 years (age range, 18-65 years). All patients had undergone allogeneic HSCT for the treatment of a hematologic malignancy (acute myeloid leukemia, 3 patients;
chronic myeloid leukemia, 1; myelodyplastic syndrome, 2; chronic
myelomonocytic leukemia, 2; myelofibrosis, 1; and acute lymphoblastic leukemia, 1). Dermatosis developed between 2 and
18 months (mean, 7.5 months) after HSCT. One patient had a
history of atopic dermatitis, 2 had a history of asthma and hayfever, and 1 had a history of psoriasis. Drugs being taken by patients at the onset of dermatosis included prednisolone cyclosporine, tacrolimus, phenoxymethyl-penicillin, fluconazole,
amphotericin B, and acyclovir.
HEMATOPOIETIC STEM
CELL TRANSPLANTATION
All 10 patients received an allogeneic stem cell transplant. Stem
cells were derived from the peripheral blood in 7 patients and
bone marrow in 3. In 8 patients, the transplant was from a volunteer unrelated donor; in 2, the donor was a sibling (eTable).
There was a donor-recipient sex mismatch in 3 of 10 transplantations and a donor-recipient cytomegalovirus mismatch
in another 3 transplantations (eTable). None of the donors reported a history of atopy (atopic dermatitis, asthma, or eczema). One donor reported a history of mild psoriasis (the recipient was patient 5). The conditioning regimen, described
previously,10 included alemtuzumab (Campath; Genzyme Corp,
Cambridge, Massachusetts) in all patients but was otherwise
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A
B
Figure 2. Palmoplantar hyperkeratosis was present in 7 of 10 patients. A, Patient 4. B, One patient (patient 3) had marked ichthyotic scaling overlying the eczema.
of reduced intensity in 9 patients (fludarabine phosphate, 150
mg/m2; busulfan, 8 mg/kg; and alemtuzumab, 100 mg) and of
standard intensity in patient 7 (total body irradiation; cyclophosphamide; busulfan, 8 mg/kg; and alemtuzumab, 100 mg).
RISK FACTORS FOR GVHD
All 10 patients had received GVHD prophylaxis with cyclosporine and all transplants were T cell depleted in vivo using alemtuzumab in the conditioning regimen. Matching for donor relation, sex, and cytomegalovirus status is described above in
“Hematopoietic Stem Cell Transplantation” subsection of the
“Methods” section (eTable). Four patients had evidence of chronic
hepatic, gastrointestinal GVHD, or both, occurring concurrently with the eczematous dermatosis. Seven patients were known
to have had preceding acute cutaneous GVHD (eTable), and, in
these patients, the eczematous dermatosis occurred 2 to 16 months
(mean, 7.7 months) after acute GVHD. In 6 patients, the eruption appeared some months after acute GVHD (quiescent pattern), and in 1 patient (patient 3), it developed immediately after the acute episode (progressive pattern). Three patients (patients
4, 7, and 9) received donor lymphocyte infusions after HSCT
(eTable). In these patients, the donor lymphocyte infusion was
administered 13 weeks (patient 7) or 14 weeks (patients 4 and
9) after HSCT and 2 to 6 weeks before the onset of eczematous
dermatosis. All patients received standard GVHD prophylaxis with
cyclosporine and prednisolone in the first few months after HSCT.
In 5 patients, the eczematous dermatosis developed as prophylactic immunosuppression therapy was being tapered in the 2 to
4 months after HSCT.
CLINICAL FEATURES
The eruption was similar in each patient and consisted of diffuse erythema and fine scaling, suggestive of eczema (Figure 1).
Signs of impetiginization (colonization by Staphylococcus aureus) were frequently observed. Weeping in involved skin was
common. Vesicles or pustules were not seen. Pruritus was usually severe and accompanied by excoriation. One patient had
marked ichthyotic scaling, especially on the face and scalp
(Figure 2). Palmoplantar hyperkeratosis was prominent in 7
of 10 patients (Figure 2). In all patients, the eczema rapidly became widespread, leading to erythroderma (exfoliative dermatitis). Erythrodermic involvement was complicated by thermoregulatory dysfunction, thirst, and dependent edema
(Figure 1).
HISTOPATHOLOGIC FEATURES
Biopsy specimens were obtained from the affected skin in all
patients. In each case, the histologic features of GVHD coexisted with the changes of dermatitis (Figure 3). The GVH reaction was indicated by satellite cell necrosis, and the presence of parakeratosis, lymphocyte exocytosis, and epidermal
spongiosis reflected the clinical appearance of eczema (Figure 3).
The dermal changes were less marked, often showing a sparse
perivascular lymphocytic infiltrate. Eosinophils were admixed in the infiltrate in 4 patients. The combined features were
not always present in the first biopsy specimen, and, in some
patients, as many as 3 samples were necessary to indicate the
eczematoid pattern of GVHD.
TREATMENT
First-line therapy for all patients was a regimen of an emollient, a potent topical corticosteroid ointment, and a sedating
antihistamine taken at bedtime. Oral antibiotics were given when
the dermatosis was complicated by secondary bacterial infection. Nine of 10 patients required hospital admission at least
once during the course of their illness. Inpatient management
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A
B
Figure 3. A, Note parakeratosis, mild acanthosis, and an upper dermal and
intraepidermal lymphocytic infiltrate (hematoxylin-eosin, original
magnification ⫻40). B, The dermatopathologic condition exhibits the
combined features of both eczema and a graft-vs-host reaction. There is
spongiosis (short arrow) and satellite cell necrosis (long arrows)
(hematoxylin-eosin, original magnification ⫻100).
was considered necessary when systemic symptoms arising from
the erythroderma (eg, thirst, shivering, or malaise) were prominent or if first-line therapy was ineffective in controlling the
dermatosis. As well as delivering maximal topical therapy, erythroderma was treated with systemic immunosuppression with
one or more of the following: psoralen–UV-A (PUVA), prednisolone, methylprednisolone, azathioprine, cyclosporine, tacrolimus, or mycophenolate mofetil (Table).
In an attempt to limit systemic immunosuppression, 6 patients were treated with PUVA using oral psoralen (5methoxypsoralen) and a UV-A dosimetry regimen similar to
that used to treat atopic dermatitis (Table). Psoralen–UV-A was
delivered twice weekly starting at a dose of 0.5 J/cm2 and increasing the dose by 0.5 J/cm2 increments at each treatment to
a maximum dose of 5 J/cm2. The duration of PUVA therapy was
12 to 20 weeks.
RESULTS
The course of dermatosis was prolonged in all 10 patients and did not tend to remit spontaneously. The shortest period of active involvement was 4 months, in 2 patients; both patients died with active eczematoid GVHD
4 months after the onset of dermatosis. The longest period of active involvement was 20 months (mean, 9.2
months; Table). The shortest follow-up was 4 months,
and the longest was 42 months (mean, 15.5 months).
Seven of the 10 patients also developed features of extracutaneous chronic GVHD, with hepatic involvement
in 5 patients, bronchiolitis obliterans in 2, and involvement of the gastrointestinal tract in 2 (Table).
In 2 patients, the dermatosis was controlled with topical agents and systemic immunosuppressant agents (prednisolone and mycophenolate mofetil in patient 8 and prednisolone, tacrolimus, and mycophenolate mofetil in
patient 10). Four of the 6 patients treated with PUVA responded successfully, achieving complete cutaneous clearance, and remission was maintained with only low-dose
systemic immunosuppression therapy (eg, prednisolone, 1-5 mg/d) or no systemic immunosuppression
therapy. In 2 of the patients who responded to PUVA (patients 2 and 6), treatment was hampered by the presence of secondary infection with methicillin-resistant
S aureus, and the dermatosis resolved only after staphylococcal eradication.
Six patients died. The cause of death was considered
to be bacterial sepsis in 2 patients, disseminated Aspergillus species infection in 2, and cryptococcosis in 1
(Table); 1 patient had a relapse of acute myelocytic leukemia. Two patients (patients 4 and 7) who died of septic complications had required prolonged exposure to high
doses of systemic immunosuppressant agents to control
the cutaneous GVHD. Secondary skin infection in patient 4 was probably the source of fatal overwhelming
sepsis.
Four patients1,5,8,10 have achieved long-term remission (12-42 months; mean, 24 months) of the eczematoid GVHD; 2 (patients 1 and 5) received PUVA and 2
(patients 8 and 10) did not (Table). In these patients,
the hematologic malignancy has also remained in remission.
COMMENT
We describe 10 patients in whom a widespread, chronic
dermatitic eruption developed after allogeneic HSCT.
The striking feature in all of our patients was the coexistence of eczematous histopathologic features with
changes of GVHD. All of the patients had risk factors
for the development of chronic cutaneous GVHD: 8 had
received a transplant from an unrelated donor, 7 had
evidence of extracutaneous GVHD, and at least 5 had a
history of acute cutaneous GVHD. We believe there is
compelling evidence to suggest that the eczematous
dermatosis observed in our patients represents a novel
form of chronic cutaneous GVHD that we have named
eczematoid GVHD.
The differential diagnosis of a dermatitic eruption
occurring after allogeneic HSCT should include the following: an eczematous drug reaction, the precipitation
of preexisting dermatitis, or the acquisition of atopic
diathesis from donor stem cells. Each potential cause of
eczema was considered in our patients. All of the patients were receiving multiple drugs, but none of these
were known to be associated with the induction of an
eczematous drug eruption. Three patients had allergic
disorders and 1 had mild eczema during childhood;
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Table. Treatment and Follow-up of Patients With Chronic Eczematoid GVHD
Patient
No.
Treatment
Response
Duration of
Disease, mo
Duration of
Follow-up, mo
Outcome; Extracutaneous GVHD
1
2
3
4
5
6
7
8
9
10
PUVA, prednisolone, tacrolimus
PUVA, prednisolone, tacrolimus
Prednisolone, cyclosporine
PUVA, methylprednisolone, cyclosporine
PUVA
PUVA, prednisolone, cyclosporine
PUVA, prednisolone, cyclosporine
Prednisolone, MMF
Prednisolone
Prednisolone, tacrolimus, MMF
Good
Good
Good
Poor
Good
Good
Poor
Good
Good
Good
20
17
4
12
8
6
9
6
4
6
24
20
4
12
12
7
9
42
4
20
Remission (skin and blood); no extracutaneous GVHD
Died (relapse of AML); hepatic GVHD
Died (cryptococcosis); hepatic GVHD
Died (bacterial sepsis); hepatic and GI tract GVHD
Remission (skin and blood); no extracutaneous GVHD
Died (aspergillosis); hepatic GVHD
Died (aspergillosis); hepatic GVHD
Remission (skin and blood); bronchiolitis obliterans
Died (bacterial sepsis); GI tract GVHD
Remission (skin and blood); bronchiolitis obliterans
Abbreviations: AML, acute myeloid leukemia; GI, gastrointestinal; GVHD, graft-vs-host disease; MMF, mycophenolate mofetil; PUVA, psoralen–UV-A.
however, the remaining 7 patients had no history suggestive of an atopic susceptibility. None of the patients
were known to have another eczematous dermatosis
(eg, seborrhoeic dermatitis or allergic contact dermatitis) before HSCT. Although it is recognized that atopy
can be transmitted to an individual from HSCT,11 none
of the donors in this series gave a history of an atopic
disorder. We, therefore, suggest that in these patients,
eczema, observed both clinically and histopathologically, was expressed as a manifestation of chronic
GVHD. Although the pathophysiology of chronic
GVHD remains poorly understood, it is recognized that
both alloreactive and autoreactive T cells have a role in
mediating tissue damage.12 Thymic injury from acute
GVHD may prevent the deletion of autoreactive clones,
which can, therefore, promote a range of inflammatory
responses.13 In murine chronic cutaneous GVHD, uncontrolled collagen synthesis is driven by transforming
growth factor–␤ generated by an inflammatory process
with a Th2-predominant cytokine profile.14 In many eczematous diseases, a Th2 response is also typical.15 A
model to explain the development of an eczematous
GVH response in our patients will, therefore, need to
incorporate the complex interaction between antigenpresenting cells (including epidermal dendritic cells of
donor origin) and autoreactive and allogenic T cells
stimulated in the presence of Th2 cytokines. External
stimuli, most notably, bacterial antigens, will influence
the severity of eczematoid GVHD, as with other forms
of eczema. Alemtuzumab, a monoclonal antibody that
targets CD52 on mature T lymphocytes, was administered to all patients as a part of the conditioning regimen before HSCT. Alemtuzumab-induced T-cell depletion may be central to the development of eczematoid
GVHD; however, larger studies are needed to explore
the relation between conditioning regimens and GVH
reactions.
The development of GVHD after allogeneic HSCT has
potential clinical benefits because concomitant graft-vsleukemia effects can control residual malignancy. In our
series, only 1 patient had a relapse of the original hematologic malignancy. Nevertheless, the severity of this form
of GVH reaction resulted in substantial morbidity and
mortality. All of the patients with eczematoid GVHD de-
veloped erythroderma, which was poorly tolerated. The
severity of the skin involvement necessitated, in most
cases, admission to the hospital for intensive topical
therapy and treatment with systemic immunosuppressant agents. Six patients died; in 5, the cause of death was
considered to be an infective complication. Three patients had systemic fungal infections, and 1 died of overwhelming bacterial sepsis. In one of these patients, septicemia was probably a complication of intractable skin
infection. The need to control the GVHD with systemic
immunosuppression therapy may have had a permissive effect in the progression to fatal sepsis. Problems encountered with systemic immunosuppression therapy
prompted the use of more effective skin-directed treatment. Six patients were treated with PUVA, and 4 of these
responded well, achieving complete cutaneous clearance. Psoralen–UV-A is, therefore, recommended as a useful adjunctive and immunosuppression-sparing treatment in this form of GVHD.
Eczematoid GVHD is a severe, often erythrodermic
eruption associated with considerable morbidity and mortality. While this dermatosis represents a complex management problem for dermatologists treating patients with
hematologic malignancies, the eczematous phenotype
points to immunopathologic pathways previously unexplored in the GVH reaction.
Accepted for Publication: May 3, 2007.
Correspondence: Daniel Creamer, MD, Department of
Dermatology, King’s College Hospital, Denmark Hill, London SE5 9RS, England (daniel.creamer@kingsch.nhs.uk).
Author Contributions: Dr Creamer had full access to all
the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Creamer, Salisbury, Mufti, and
du Vivier. Acquisition of data: Creamer, MartynSimmons, Osborne, Kenyon, Salisbury, Devereux, Pagliuca, Ho, Mufti, and du Vivier. Analysis and interpretation of data: Creamer, Martyn-Simmons, Osborne,
Salisbury, Pagliuca, and Mufti. Drafting of the manuscript: Creamer, Salisbury, Mufti, and du Vivier. Critical
revision of the manuscript for important intellectual content: Creamer, Martyn-Simmons, Osborne, Kenyon, Salisbury, Devereux, Pagliuca, Ho, Mufti, and du Vivier. Sta-
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tistical analysis: Mufti. Administrative, technical, or material
support: Creamer, Martyn-Simmons, Osborne, Salisbury, Devereux, and Mufti. Study supervision: Creamer,
Salisbury, Ho, Mufti, and du Vivier.
Financial Disclosure: None reported.
Additional Information: The eTable is available at http:
//www.archdermatol.com.
8.
9.
10.
REFERENCES
1. Billingham RE. The biology of graft-versus-host reactions. Harvey Lect. 1966-1967;
62:21-78.
2. Ferrara JL, Deeg HJ. Graft-versus-host disease. N Engl J Med. 1991;324(10):667674.
3. Johnson ML, Farmer ER. Graft-versus-host reactions in dermatology. J Am Acad
Dermatol. 1998;38(3):369-396.
4. Hood AF, Soter NA, Rappeport J, Gigli I. Graft-versus-host reaction: cutaneous
manifestations following bone marrow transplantation. Arch Dermatol. 1977;
113(8):1087-1091.
5. Hymes SR, Turner ML, Champlin RE, Couriel DR. Cutaneous manifestations of
chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2006;12
(11):1101-1113.
6. Ollivier I, Wolkenstein P, Gherardi R, et al. Dermatomyositis-like graft-versushost disease. Br J Dermatol. 1998;138(3):558-559.
7. Girardi M, Herreid P, Tigelaar R. Specific suppression of lupus-like graft-versus-
11.
12.
13.
14.
15.
host disease using extracorporeal photochemical attenuation of effector
lymphocytes. J Invest Dermatol. 1995;104(2):177-182.
Tanasescu S, Balguerie X, Thomine E, et al. Eczema-like cutaneous graft versus
host disease treated by UV-B therapy in a 2-year-old child [in French]. Ann
Dermatol Venereol. 1999;126(1):51-53.
Sloane JP, Thomas JA, Imrie SF, Easton DF, Powles RL. Morphological and immunohistological changes in the skin in allogeneic bone marrow recipients.
J Clin Pathol. 1984;37(8):919-930.
Ho AY, Pagliuca A, Kenyon M, et al. Reduced-intensity allogeneic hematopoietic
stem cell transplantation for myelodysplastic syndrome and acute myeloid leukemia with multilineage dysplasia using fludarabine, busulphan, and alemtuzumab (FBC) conditioning [published online ahead of print April 1, 2004]. Blood.
2004;104(6):1616-1623. doi:10.1182/blood-2003-12-4207.
Bellou A, Kanny G, Fremont S, Moneret-Vautrin DA. Transfer of atopy following
bone marrow transplantation. Ann Allergy Asthma Immunol. 1997;78(5):513516.
Sullivan KM, Parkman R. The pathophysiology and treatment of graft-versushost disease. Clin Haematol. 1983;12(3):775-789.
Weinberg K, Blazar BR, Wagner JE, et al. Factors affecting thymic function after
allogeneic hematopoietic stem cell transplantation. Blood. 2001;97(5):14581466.
McCormick LL, Zhang Y, Tootell E, Gilliam AC. Anti-TGF-beta treatment prevents skin and lung fibrosis in murine sclerodermatous graft-versus-host disease: a model for human scleroderma. J Immunol. 1999;163(10):5693-5699.
van Reijsen FC, Bruijnzeel-Koomen CA, Kalthoff FS, et al. Skin-derived aeroallergenspecific T-cell clones of Th2 phenotype in patients with atopic dermatitis. J Allergy Clin Immunol. 1992;90(2):184-193.
Announcement
Manuscript Submission
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review the Instructions for Authors available at http://
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the Archives by Web access at http://manuscripts
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WEB-ONLY CONTENT
eTable. Chronic Eczematoid GVHD: Patient and Donor Characteristics a
Patient No./
Sex/Age, y
1/M/54
2/M/65
3/M/46
4/M/62
5/F/56
6/F/64
7/M/18
8/M/54
9/M/63
10/M/62
Diagnosis
Donor Type
Donor Sex/
Age, y
CMV
Status R/D
Acute
GVHD
DLI
Onset of Eczematoid GVHD
After Transplantion, mo
MDS/RAEB
MDS/AML
Myelofibrosis
CML
AML
MDS
ALL
CMML
CML/AML
CMML
Unrelated
Unrelated
Unrelated
Sibling
Unrelated
Unrelated
Unrelated
Unrelated
Unrelated
Sibling
M/26
M/44
M/25
M/70
M/37
F/34
M/40
M/43
F/26
F/63
−/−
−/−
⫹/⫹
⫹/−
−/⫹
−/−
⫹/−
⫹/⫹
−/−
−/−
Yes
No
Yes
Yes
Yes
No
No
Yes
No
Yes
No
No
No
Yes
No
No
Yes
No
Yes
No
18
2
3
5
10
4
4
6
4
18
Abbreviations: ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; CML, chronic myeloid leukemia; CMML, chronic myelomonocytic leukemia;
CMV, cytomegalovirus; DLI, donor lymphocyte infusion; GVHD, graft-vs-host disease; MDS, myelodysplastic syndrome; RAEB, refractory anemia with excess
blasts; R/D, recipient/donor; −, negative; ⫹, positive.
a All patients underwent a conditioning regimen with alemtuzumab (Campath; Genzyme Corp, Cambridge, Massachusetts) and received GVHD prophylaxis.
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OBSERVATION
Epidermolysis Bullosa Nevus
An Exception to the Clinical and Dermoscopic Criteria for Melanoma
Sarah H. Cash, MD; Tara T. Dever, MD; Patrice Hyde, MD; Jason B. Lee, MD
Background: Large acquired melanocytic nevi that oc-
cur in patients with epidermolysis bullosa (EB), referred to as EB nevi, may pose a diagnostic challenge because of their clinical and dermoscopic resemblance to
melanoma. These unconventional melanocytic nevi have
been encountered in all categories of hereditary EB, most
of them in childhood. Although some of the reported cases
have an alarming clinical appearance that is indistinguishable from melanoma, long-term follow-up has confirmed the benign nature of these rarely encountered melanocytic lesions. The histopathologic patterns of these
nevi range from a banal congenital pattern to the problematic persistent pseudomelanoma pattern.
Observation: We describe the clinical, dermoscopic,
and histopathologic features of a large EB nevus in a tod-
R
Author Affiliations:
Department of Dermatology
and Cutaneous Biology, Thomas
Jefferson University Hospital,
Philadelphia, Pennsylvania
(Drs Cash, Hyde, and Lee); and
National Naval Medical Center,
Bethesda, Maryland (Dr Dever).
Dr Cash is now in private
practice in Dermatology Group
of the Carolinas, Concord,
North Carolina.
dler. Clinically, the lesion was markedly asymmetrical
and irregularly pigmented with foci of stippled pigmentation and scarring, which easily fulfilled the ABCD criteria for melanoma. Accordingly, a false-positive score
resulted when dermoscopy was performed. Histopathologically, a pattern of persistent melanocytic neoplasm
was observed. In the following 18 months, dynamic
changes of the lesion included near-complete disappearance of the pigment, which was replaced by scar, milia,
and areas of healing ulcers.
Conclusion: Epidermolysis bullosa nevi are dynamic me-
lanocytic lesions that may simulate melanoma.
Arch Dermatol. 2007;143(9):1164-1167
ECENTLY, BAUER ET AL1 PRO-
posed the term epidermolysis bullosa (EB) nevi for
large acquired melanocytic nevi that are encountered in all forms of hereditary EB. Their
clinical importance lies in the fact that they
may simulate melanoma clinically and dermoscopically. In that 20-year prospective study of patients with EB nevi, however, no melanoma arose in association
with these melanocytic nevi. We herein describe the clinical, dermoscopic, and histopathologic features of a large EB nevus
in a toddler. After 18 months of followup, the pigment almost completely disappeared, with replacement by scar, milia,
and areas of healing ulcers.
REPORT OF A CASE
A 3-year-old Korean boy with a known
mutation for recessive dystrophic EB was
noted on a routine follow-up visit to have
a large pigmented lesion on the right thigh.
The mother reported a rapid development of the pigmented lesion during a pe-
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1164
riod of several months that coincided with
repeated blistering at the site. Physical examination revealed a large (9 ⫻ 10-cm),
markedly asymmetric, irregularly pigmented patch on the right lateral thigh
(Figure 1). In addition, areas of scarring with stippled pigmentation and regressive changes (ie, hypopigmentation
and scarring) were found within the lesion (Figure 1). Results of the examination revealed no palpable lymph nodes.
Dermoscopic findings included an atypical network and irregular dots and globules with colors that ranged from blue to
varying shades of brown and black
(Figure 2). Examination of a shave biopsy specimen from an area with multiple colors revealed a cleft at the dermoepidermal junction consistent with the
patient’s known recessive dystrophic EB
and increased pigment within the epidermis and dermis (Figure 3). Within the
epidermis, there was an uneven distribution of solitary melanocytes and a mild degree of scatter (ie, pagetoid spread) accompanied by the presence of melanin at
all levels of the epidermis, including the
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Figure 3. A shave biopsy specimen shows a cleft between the
dermoepidermal junction, effaced rete ridges, and pigmented nested
melanocytes in the superficial dermis (hematoxylin-eosin, original
magnification ⫻40).
100 µm
Figure 1. A large pigmented lesion with an irregular border, color
variegation, and areas of regression, scarring, and stippled pigmentation
(arrow).
Figure 4. Higher-power magnification of the specimen from Figure 3 shows
fibrosis of the dermis, the presence of numerous melanophages, and nested
monomorphous melanocytes (hematoxylin-eosin, original magnification
⫻200).
mitotic figures, normal proliferative index, and knowledge of the EB nevus phenomenon eventually led to the
diagnosis of EB nevus. Because of the reported benign
clinical course of these nevi, no therapeutic intervention was offered, only close clinical follow-up. To our surprise, during 18 months of follow-up, there was complete regression of epidermal pigment. What remained
were areas of healing ulcers, hypopigmented scars, and
a subtle hue of dermal pigmentation in some foci
(Figure 5). Whether or not the melanocytic lesion actually regressed completely was not confirmed by histopathologic evaluation. At 24 months, the patient was well,
and development of additional melanocytic lesions was
not observed.
Figure 2. Dermoscopic image (original magnification ⫻10) shows irregular
dots and globules, blue-gray pigment, and hypopigmented areas.
cornified layer. Within the dermis, there were discretely
nested, heavily melanized monomorphous melanocytes
enveloped in fibrosis accompanied by numerous melanophages (Figure 4). No mitotic figures were observed. Immunohistochemical staining for Ki-67 showed
no increase in the proliferative index. The histopathologic pattern was consistent with a persistent melanocytic neoplasm and, hence, the differential diagnosis was
between a persistent melanocytic nevus and persistent
melanoma. The monomorphous melanocytes, lack of any
COMMENT
Although rarely encountered, EB nevi may not be so rare
among patients with EB. Bauer et al1 reported a prevalence rate of 14% (12 of 86) among the patients in their
EB registry. The lesions are usually encountered in children with all major categories of hereditary EB. The mean
ages of patients in reported cases of recessive dystrophic EB and EB simplex are 7 and 11 years, respectively.1-5 No predilection for sex or site appears to exist,
except that the lesions are encountered at the sites of repeated blisters. They are often eruptive in nature, ie, they
appear rapidly and enlarge within a few weeks to a few
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Figure 5. The lesion from Figure 1 after 18 months of follow-up shows
regression of epidermal pigment.
months. The reported lesions have ranged from 3 to 15
cm in diameter with an appearance that ranged from congenital melanocytic nevus to melanoma. The alarming
clinical features included not only their large size but also
the presence of marked asymmetry, irregular and/or
stippled pigmentation, variegation in color, scarring, and
foci of regression. On a morphologic basis alone, without the benefit of knowing the clinical context, the EB
nevus may be indistinguishable from melanoma at times.
Although Gallardo et al5 observed no melanomaassociated dermoscopic features in their series of EB nevi
in a single patient, Lanschuetzer et al6 observed melanomaassociated dermoscopic features that included a multicomponent pattern, an atypical pigment network, and irregular dots and globules in many of the patients in their
EB registry. Even the milky red areas highly characteristic of melanoma were present in several of their nevi.
When dermoscopic algorithms were performed, a falsepositive score resulted in most of the lesions in their series. According to the authors,6 these apparently alarming clinical and dermoscopic findings can be explained
by the known pathogenesis of EB nevi, ie, the repeated
disruption of the dermoepidermal junction, fibrosing inflammation, scar formation, and neovascularization
account for their clinical and dermoscopic features.
Marghoob and Kopf 7 have previously reported that a persistent melanocytic nevus frequently yields a falsepositive dermoscopic score. It should be no surprise then
that asymmetrical and irregularly pigmented EB nevi with
a histopathologic pattern of persistent melanocytic neoplasm yield a false-positive dermoscopic score.
The histopathologic pattern of EB nevus ranges from
the readily recognizable congenital pattern to a problematic persistent/pseudomelanoma pattern.1-5 Most persistent patterns occur in patients with recessive dystrophic EB, whereas the congenital pattern occurs more
frequently in patients with EB simplex. Obviously, the
fibrosing inflammation that is more frequently encountered in recessive dystrophic EB accounts for this observation. Some of the large lesions, even those with an ominous clinical appearance, display a banal compound
congenital pattern, ie, monomorphous melanocytes in
nests and fascicles spanning the papillary and reticular
dermis with angiotropism and adnexotropism.1,3,8 Other
patients, like ours, have shown the persistent pattern, ie,
uneven distribution of melanocytes within the epidermis and dermal melanocytes enveloped in fibrosis. The
persistent pattern raises the differential diagnosis of persistent melanoma vs persistent melanocytic nevus. Diagnosing persistent nevus becomes problematic if sections from the previous procedure are not available and/or
if only the portion of the persistent melanocytic neoplasm is biopsied, which may lack the readily recognizable conventional benign melanocytic pattern. In cases
of large EB nevi, in which the entire lesion often cannot
be sampled, the problem of the persistent pattern may
not be resolvable on the basis of histologic sections alone
because there are no previous sections to review and the
entire lesion may not be available for review. Our patient represented such a dilemma. The clues that the lesion on our patient was benign included melanocytes in
the dermis that were monomorphous, a lack of mitosis,
and, accordingly, a normal proliferative index. In addition, the lesion in our patient had a striking clinical resemblance to a large superficial spreading melanoma,
but this clinical and histopathologic pattern of melanoma, although common in adults, is exceedingly rare
in children. Melanomas in children are usually papular
or nodular and thus have a prominent vertical orientation clinically and histopathologically rather than the
horizontal orientation that is typical of the superficial
spreading type of melanoma.9,10 The knowledge of the
EB nevus phenomenon and the histopathologic features
eventually convinced us of the benign nature of the lesion on our patient.
Although it is obvious that the recurrent blisters and
the subsequent inflammation and/or fibrosis alter the morphologic features of melanocytic nevi in patients with EB,
the exact mechanism by which the recurrent blisters
achieve the alteration is unknown. Speculations include
(1) induction by the Koebner phenomenon, meaning that
disruption of melanocytes at the site of blisters somehow induces proliferation during reepitheliazation,2 and
(2) seeding of a blister cavity by melanocytes from a preexisting nevus, which then proliferates owing to cytokines that are released by the inflammatory process caused
by the blisters.8 Irrespective of the mechanism, the repeated blisters at the site of the nevi result in a dynamic
growth pattern that may lead to clinical lesions, which
may be asymmetrical and multicolored and have regressive changes due to chronic fibrosing inflammation rather
than to specific immune-mediated process mounted
against melanocytes.
An EB nevus represents a collision between an inflammatory disease and a melanocytic nevus that results in unconventional phenotypic expression of the nevus. Collision between lichen sclerosus et atrophicus and melanocytic
nevus represents an analogous phenomenon.11,12 These collision phenomena have led to diagnostic difficulties for the
clinicians and histopathologists because the expected clinical and histopathologic findings of the melanocytic lesions are significantly altered. Similar to the EB nevus, the
persistent melanocytic pattern is observed histopathologically in cases of collision with lichen sclerosus.11 The well-
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circumscribed nature of these lesions allows for correct
interpretation in most instances. In cases of a large EB nevus, however, circumscription often cannot be assessed
because only a portion of the lesion is available for interpretation. This adds to the diagnostic difficulty compared with the cases of lichen sclerosus. Previously reported cases of eruptive melanocytic nevi that appeared
shortly after episodes of Stevens-Johnson syndrome and
bullous erythema multiforme have been suggested as analogous phenomena.13-16 In these instances, there is no collision, per se; rather, the 2 phenomena occur metachronously rather than synchronously. Accordingly, diagnostic
difficulties are not reported because there are no significant clinical and histopathologic alterations of the nevi’s
morphologic features. Curiously, analogous phenomena
have not been reported with any frequency in other blistering diseases known to occur in childhood, such as linear IgA dermatosis. In 1 reported case of an 8-year-old girl
with bullous pemphigoid of the vulva, a melanocytic lesion at the site of the blisters eventually regressed completely. As in our patient, the lesion resembled melanoma clinically and dermoscopically.17
Although the association between squamous cell carcinoma and chronic scarring inflammatory dermatosis
is well known, it is unclear whether such an association
exists for melanoma in general. Data suggest that a higher
incidence of melanoma may exist in patients with EB,18-20
especially recessive dystrophic EB, but there are no detailed, well-documented cases in the literature, in contrast to the well-documented and now well-known higher
incidence of squamous cell carcinoma in patients with
EB. Furthermore, the higher incidence has not been corroborated by experience in other countries. Because EB
nevi may simulate melanoma, they have the potential to
falsely increase the incidence and prevalence of melanoma among patients with EB if they are misconstrued
as such. Clinicians and histopathologists should be aware
of this phenomenon to avoid misdiagnosis and unnecessary therapeutic intervention. An EB nevus should be
considered a distinct diagnostic possibility and should
be excluded if melanoma is suspected in a child with EB.
Once it has been established clinically, dermoscopically, and histopathologically that a lesion is an EB nevus, close clinical follow-up of these unconventional melanocytic nevi is an acceptable option, especially for nevi
that are not amenable to simple excision owing to their
large size.
Accepted for Publication: February 20, 2007.
Correspondence: Jason B. Lee, MD, Department of Dermatology and Cutaneous Biology, Thomas Jefferson University Hospital, 833 Chestnut St, Ste 704, Philadelphia,
PA 19107 (Jason.b.lee@jefferson.edu).
Author Contributions: Dr Lee had full access to all the
data in the study and takes responsibility for the integ-
rity of the data. Study concept and design: Lee. Acquisition of data: Cash and Hyde. Analysis and interpretation
of data: Cash, Dever, and Lee. Drafting of the manuscript:
Cash, Dever, Hyde, and Lee. Critical revision of the manuscript for important intellectual content: Dever, Hyde, and
Lee. Administrative, technical, and material support: Cash
and Hyde. Study supervision: Cash, Hyde, and Lee.
Financial Disclosure: None reported.
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1. Bauer JW, Schaeppi H, Kaserer C, Hantich B, Hintner H. Large melanocytic nevi
in hereditary epidermolysis bullosa. J Am Acad Dermatol. 2001;44(4):577584.
2. Soltani K, Pepper MC, Simjee S, Apatoff BR. Large acquired nevocytic nevus induced by the Koebner phenomenon. J Cutan Pathol. 1984;11(4):296-299.
3. Hoss DM, McNutt NS, Carter DM, Rothaus KO, Kenet BJ, Lin AN. Atypical melanocytic lesions in epidermolysis bullosa. J Cutan Pathol. 1994;21(2):164169.
4. Stavrianeas NG, Katoulis AC, Moussatou V, et al. Eruptive large melanocytic nevus in a patient with hereditary epidermolysis bullosa simplex. Dermatology. 2003;
207(4):402-404.
5. Gallardo F, Toll A, Malvehy J, et al. Large atypical melanocytic nevi in recessive
dystrophic epidermolysis bullosa: clinicopathological, ultrastructural, and dermoscopic study. Pediatr Dermatol. 2005;22(4):338-343.
6. Lanschuetzer CM, Emberger M, Laimer M, et al. Epidermolysis bullosa naevi reveal distinctive dermoscopic pattern. Br J Dermatol. 2005;153(1):97-102.
7. Marghoob AA, Kopf AW. Persistent nevus: an exception to the ABCD rule of
dermoscopy. J Am Acad Dermatol. 1997;36(3, pt 1):474-475.
8. Lanschuetzer CM, Emberger M, Hametner R, et al. Pathogenic mechanisms in
epidermolysis bullosa naevi. Acta Derm Venereol. 2003;83(5):332-337.
9. Ferrari A, Bono A, Baldi M, et al. Does melanoma behave differently in younger
children than in adults? a retrospective study of 33 cases of childhood melanoma from a single institution. Pediatrics. 2005;115(3):649-654.
10. Mones JM, Ackerman AB. Melanomas in prepubescent children: review comprehensively, critique historically, criteria diagnostically, and course biologically.
Am J Dermatopathol. 2003;25(3):223-238.
11. Carlson JA, Mu XC, Slominski A, et al. Melanocytic proliferations associated with
lichen sclerosus. Arch Dermatol. 2002;138(1):77-87.
12. El Shabrawi-Caelen L, Soyer HP, Schaeppi H, et al. Genital lentigines and melanocytic nevi with superimposed lichen sclerosus: a diagnostic challenge. J Am
Acad Dermatol. 2004;50(5):690-694.
13. Shoji T, Cockerell CJ, Koff AB, Bhawan J. Eruptive melanocytic nevi after StevensJohnson syndrome. J Am Acad Dermatol. 1997;37(2, pt 2):337-339.
14. Kirby JD, Darley CR. Eruptive melanocytic naevi following severe bullous disease.
Br J Dermatol. 1978;99(5):575-580.
15. Burns DA, Sarkany I. Junctional naevi following toxic epidermal necrolysis. Clin
Exp Dermatol. 1978;3(3):323-326.
16. Kopf AW, Grupper C, Baer RL, Mitchell JC. Eruptive nevocytic nevi after severe
bullous disease. Arch Dermatol. 1977;113(8):1080-1084.
17. Lebeau S, Braun RP, Masouyé I, Perrinaud A, Harms M, Borradori L. Acquired
melanocytic naevus in childhood vulval pemphigoid. Dermatology. 2006;213
(2):159-162.
18. Chorny JA, Shroyer KR, Golitz LE. Malignant melanoma and a squamous cell
carcinoma in recessive dystrophic epidermolysis bullosa. Arch Dermatol. 1993;
129(9):1212.
19. Fine JD, Johnson LB, Tien H, et al. Skin cancer and inherited epidermolysis bullosa (EB): analysis of the National EB Registry cohort by disease type and subtype [abstract 12]. J Invest Dermatol. 1994;103(6):846.
20. Fine JD, Johnson LB, Tien H, et al. Risk of skin cancers and inherited epidermolysis bullosa (EB): determination of differences across major EB subtypes,
as assessed by lifetable analysis techniques [abstract 21]. J Invest Dermatol.
1994;103(6):848.
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OBSERVATION
Herpes Gestationis in a Mother and Newborn
Immunoclinical Perspectives Based on a Weekly Follow-up
of the Enzyme-Linked Immunosorbent Assay Index
of a Bullous Pemphigoid Antigen Noncollagenous Domain
Yumi Aoyama, MD; Kanako Asai, MD; Kana Hioki, MD; Michinori Funato, MD;
Naomi Kondo, MD; Yasuo Kitajima, MD
Background: Herpes gestationis (HG) is a rare, autoimmune, bullous disease that occurs during the second or
third trimester and usually resolves over weeks or months
after delivery. Neonates with HG are rare (estimated at 1
per 100 000 cases). Although anti–180-kDa bullous pemphigoid (BP180) autoantibody and transfer of this autoantibody are known as the cause, to our knowledge, no
coordinated analysis of clinical symptoms and antiBP180 antibody enzyme-linked immunosorbent assay titers has been reported in a mother and neonate with HG.
Observations: We describe a 33-year-old woman with
HG and her neonate with vesicular erythematous lesions and the weekly follow-up results of the BP180 noncollagenous domain (NC16a) enzyme-linked immunosorbent assay.
H
Author Affiliations:
Departments of Dermatology
(Drs Aoyama, Asai, Hioki, and
Kitajima) and Pediatrics
(Drs Funato and Kondo), Gifu
University School of Medicine,
Gifu City, Japan.
Conclusions: Almost the same titer of pathogenic antibody as that in the mother is transferred to the neonate.
The plasma elimination half-life of anti-BP180 antibody is
approximately 15 days in mother and neonate. An abrupt
twin peak increase in the BP180 enzyme-linked immunosorbent assay index from maternal serum was observed just
before and after delivery, possibly explaining why HG usually occurs in the last trimester of pregnancy and exacerbates postpartum. Lesions in the neonate resolve without
treatment far before pathogenic antibody disappears, suggesting that factors other than anti-BP180 antibodies may
be involved in the generation of eruptions. Frequent testing of the BP180 enzyme-linked immunosorbent assay
greatly facilitates therapeutic planning.
Arch Dermatol. 2007;143(9):1168-1172
ERPES GESTATIONIS (HG),
also known as pemphigoid gestationis, is a rare,
autoimmune, bullous disease that occurs during
the second or third trimester, but it has
been reported in the first trimester.1 It flares
at delivery and usually resolves spontaneously over weeks or months after delivery. Herpes gestationis is clinically characterized by pruritic urticarial papules or
plaques, polymorphous eruptions, and annular or figured erythematous-edematous lesions evolving into vesicles and tense
blisters. These skin eruptions usually start
on the abdomen and spread over the whole
body, including the extremities; the face,
scalp, and mucous membranes are much
less involved.2,3 Immunologically, HG is
characterized by linear deposition of C3
with or without associated IgG at the basement membrane zone on direct immunofluorescence4,5 and by the presence on serum of antibodies to the 180-kDa bullous
pemphigoid (BP) antigen (BP180), which
is type 17 collagen contained in the
hemidesmosomal components. 6,7 Epitope mapping has revealed that HG and
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BP autoantibodies primarily bind at a common antigenic site within the noncollagenous domain (NC16a) of BP180.8 Most
HG serum samples are positive for the
NC16a domain on immunoblot analysis
(93%), with enzyme-linked immunosorbent assay (ELISA) (88%) using the BP180
NC16a domain as the antigen.9
We describe herein a mother and neonate with HG, with precise weekly follow-up studies of the BP180 NC16a ELISA
(BP180 ELISA) index during treatment.
The present case displayed BP180 ELISA
titers in the umbilical artery and vein of
1224.5 and 1021.6, respectively, compared with 1521.8 in maternal venous
blood; the plasma elimination half-life of
BP180 antibody was approximately 15 days
during the first 33 days after birth in the
mother and neonate. The BP180 ELISA activity had been eliminated by day 112 after delivery in the neonate, but the maternal level remained higher than normal
(at 44.3) as of 19 months after delivery.
We present an immunoclinical perspective of HG based on BP180 ELISA analysis of the present case.
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A
B
Figure 1. Exudative and erythematous lesions with clusters of vesicles on the abdomen (A) and vesicles on the palm (B) of the mother.
REPORT OF A CASE
A 33-year-old woman with a 1-week history of itchy
exudative or urticarial erythema in a figurate and annular pattern, with tense vesicles on the abdomen, presented in gestational week 18 of her third pregnancy
(Figure 1A). Examination of the skin revealed palmar
plantar pruritic dyshidrosislike vesicles (Figure 1B). Her
medical history included a presumptive diagnosis of pruritic urticarial papules and plaques of pregnancy in the
first pregnancy, with delivery of a healthy neonate, and
a spontaneous abortion with pruritic urticarial papules
and plaques of pregnancy in her second pregnancy. No
other history of diseases was elicited. Because severe itching and extension of lesions to the entire body were identified, the patient was admitted to Gifu University Hospital, Gifu City, for corticosteroid treatment. The otherwise
healthy newborn boy, weighing 2264 g, had developed
annular erythema, with vesicles ranging from coin to walnut size and appearing when he was 3 days old, involving the face, trunk, and extremities (Figure 2A and B).
The neonate also developed dyshidrosislike vesicles on
the soles, as did the mother (Figure 2C). These lesions
resolved in the neonate by the time he was 10 days old,
without treatment. A previous study10 of HG revealed that
HLA-DR3 and HLA-DR4 are 2 predominant histocompatibility complex II molecules that are common to patients with HG. In our case, the mother and neonate shared
a common HLA-DR antigen, because the mother expressed DR4/15 and the neonate expressed DR4.
Skin biopsy specimens were obtained from the edge
of erythema with vesicles on the arm of the mother. A
histopathological examination using hematoxylineosin staining demonstrated marked subepidermal edema
and blisters, with an inflammatory infiltrate mainly comprising eosinophils in blisters and the upper dermis
A
B
C
Figure 2. Annular erythematous-edematous lesions on the face (A) and
abdomen (B) and vesicles on the soles (C) of the neonate.
(Figure 3A). Direct immunofluorescence of the skin biopsy specimens showed linear C3 deposits in the basement membrane zone (Figure 3B), whereas IgG was
weakly positive and IgA and IgM were not detected.
The BP180 ELISA titers were determined using a BP180
NC16a ELISA kit (MBL, Nagoya, Japan). Briefly, each well
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B
A
Figure 3. Hematoxylin-eosin staining of a vesicular erythematous lesion from the mother (A) and a clear linear deposit of C3 shown on direct immunofluorescence
of biopsy specimens from perilesional skin of the mother (B). In A, papillary dermis shows marked edema associated with eosinophils and blisters in which
eosinophils and fibrin strands are contained. The epidermis appears intact.
Prednisolone, mg/d
30
25
20
35
15
Azathioprine, mg/d
Minomycin, mg/d
Erythema
50 100
Vesicles
6000
5500
5000
b
4500
BP180 ELISA Index
4000
3500
a
3000
2500
2000
1500
1000
500
c
Delivery
0
Oct Nov Dec Jan
12 12 12 12
2004
Feb Mar Apr May Jun
12 12 12
12 12
Jul
12
Aug
12
2005
Figure 4. Time course of clinical symptoms, treatments, and the 180-kDa
bullous pemphigoid (BP180) enzyme-linked immunosorbent assay (ELISA)
index of the mother: an abrupt twin peak increase in the BP180 ELISA index
is seen in maternal serum just before (a) and after (b) delivery; oral
prednisolone, 20 to 30 mg/d, sustains remission, whereas marked
exacerbation is seen at the second peak of the BP180 ELISA index just after
delivery and mild exacerbation is present 4 months after delivery (c).
of standard 96-well microtiter plates was coated with recombinant glutathione S-transferase NC16a or the same
amount of recombinant glutathione S-transferase. Serum samples, diluted 101-fold, 16 times 101-fold, or 64
times 101-fold, were incubated in duplicate for reaction, and ELISA indexes were determined in accordance
with the instructions of the manufacturer.
The mother was initially treated with 30 mg/d (0.6
mg/kg per day) of prednisolone for the first 2 weeks,
when the BP180 ELISA index was 2500. By approximately 3 weeks after the initiation of treatment with
oral prednisolone at this dosage, eruptions had resolved
despite 1 occasion of exacerbation and the ELISA index
had also increased once to 5950 before decreasing to
2360 (Figure 4). Because eruptions had mostly resolved, the prednisolone dosage was gradually tapered
to 20 mg/d over the following 4 weeks, although the
ELISA index remained somewhat higher (approximately ⬎2360) than normal, and this dosage was maintained until delivery, because any further decrease in
prednisolone dosage led to flares in disease activity. At
1 week after delivery, prednisolone was decreased by 5
mg/d, resulting in severe clinical recurrence with a
marked increase in the BP180 ELISA index. Given this
severe recurrence of clinical symptoms and the increased ELISA index, the prednisolone dosage was increased to 35 mg/d for 1 week and gradually decreased
to 15 mg/d over 5 months. The mother has been clinically in remission with treatment of 15 mg/d of prednisolone and 100 mg/d of azathioprine. The time course
of the BP180 ELISA index in the mother revealed that
anti-BP180 activity increased dramatically 1 month before and 2 weeks after delivery to maximum indexes of
2955 and 4300, respectively, and gradually decreased
with prednisolone treatment to approximately 50 by 9
months after delivery.
The BP180 ELISA indexes in the umbilical artery
and vein were 1225 and 1022, respectively, compared
with 1522 in maternal venous blood. Furthermore, the
plasma elimination half-life of the BP180 antibody in
the neonate was approximately 15 days during the initial 33 days after delivery (Figure 5). Anti-BP180 antibody activity in the neonate, as determined by the
BP180 ELISA, was completely eliminated by the time
the neonate was 112 days old. Eruptions in the neonate
resolved even when the titer of pathogenic antibody
was still high (BP180 ELISA index, approximately 770),
far before the pathogenic antibody titer disappeared.
This may suggest that anti-BP180 antibody is insufficient to generate skin lesions.
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COMMENT
The present case study of a mother and neonate with HG
focused on the follow-up of BP180 ELISA levels, providing several novel insights that may lead to a better understanding of HG. This was an extreme rare opportunity to
be able to follow the BP180 ELISA index in a mother and
neonate, because most neonates of mothers with HG are
born with normal skin and neonates with vesicular lesions are rare (estimated at 1 per 100 000 cases).11,12
Our case clearly proves that vesicular erythematous
lesions in the neonate are caused by transplacental passage of pathogenic antibodies against BP180 NC16a, from
the mother to the neonate, as shown by the fact that BP180
ELISA indexes in the umbilical artery and vein were 1225
and 1022, respectively, compared with 1522 in maternal venous blood. Interestingly, indexes from the neonate at 1 and 4 days after birth were 1154 and 784, respectively. Also, eruptions in the neonate disappeared by
the age of 8 days, much faster than the disappearance of
anti-BP180 activity, suggesting that some unknown factors may be involved in the generation of blisters.
The plasma elimination half-life of IgG is thought to be
around 14 days in the average human adult. The present
neonatal case revealed for the first time, to our knowledge, a plasma elimination half-life for anti-BP180 antibody of approximately 15 days during the first 33 days after birth. The pathway of anti-BP180 antibody elimination
from plasma may involve consumption by binding to antigen in patients with BP in addition to physiological degradation of other IgG levels. Antibody bound to BP180,
which is expressed over the entire basal cell surface and
on hemidesmosomes in the basement membrane zone, is
degraded by internalization from the membrane surface into
basal cells13 and by several proteolytic enzymes generated
during the inflammation process because of compliment
activation at the basement membrane zone. However, the
present study suggests that the consumption of pathogenic IgG in the basement membrane zone is not substantial, because the 15-day elimination half-life of pathogenic IgG in the first 33 days is approximately the same as
the physiological elimination half-life of IgG.
Herpes gestationis occurs during the second or third
trimester (mean onset, 21 weeks) or, in some cases, during the first trimester.1 It flares at delivery in 75% of cases.14
In most cases, it regresses spontaneously over weeks or
months after delivery. This seems to be associated with
anti-BP180 antibody activity, as shown in an abrupt twin
peak increase in the BP180 ELISA index from maternal
serum just before and after delivery (Figure 4). Exactly
why pathogenic antibody increases before and after delivery remains unclear, but the chorionic membrane,
which is rich in BP180 antigen, may become labile at this
stage of pregnancy and delivery, resulting in the release
of antigen into the maternal bloodstream, in turn activating the production of pathogenic antibody.
The elimination rate of pathogenic antibody from the
second peak on day 40 (shown as “b” in Figure 4) to the
trough level on day 64 after delivery in maternal serum
closely parallels that in the neonate (Figure 5), for the
baseline BP180 ELISA indexes of the mother (2955) and
BP180 ELISA Index, %
100
Mother
Neonate
80
60
50
40
25
20
0
0
8~11
33
50
100
150
Time After Delivery, d
Figure 5. Elimination curve of the 180-kDa bullous pemphigoid (BP180)
enzyme-linked immunosorbent assay (ELISA) index for mother and neonate.
Starting points for the ELISA index of the mother (2955) and neonate (1154)
were normalized as 100%. The elimination half-life of anti-BP180 antibody is
initially approximately 15 days in mother and neonate in the first 33 days
after delivery.
neonate (1154) normalized to 100%. After postdelivery
day 60, pathogenic antibody disappeared from the neonate, whereas antibody in the mother continued to show
a mild up-and-down slope (peak “c” in Figure 4) and
stayed in the abnormal range, with a BP180 ELISA index of 43.3, suggesting that the disease activity to produce pathogenic antibody remains present, although much
less extensive. This suggests a diagnosis of chronic persistent HG or progression to bullous pemphigoid.
Monitoring the ELISA index is useful when corticosteroid tapering is planned after all skin lesions are gone.
Even if all the lesions are gone, we may have to think of
keeping a minimum dosage of corticosteroids to suppress antibody production to prevent recurrence, when
ELISA indexes remain in high titer, as shown in the mother’s case (Figure 4).
In summary, we have presented herein an interesting
coordinate analysis of clinical severity and time course of
the BP180 ELISA index, demonstrating the following: (1)
almost the same titer of pathogenic antibody as that in the
mother is transferred to the neonate; (2) the plasma elimination half-life of anti-BP180 antibody is approximately
15 days during the first 33 days after delivery in mother
and neonate; (3) an abrupt twin peak increase in the BP180
ELISA index from maternal serum was observed just before and after delivery, possibly explaining why HG usually occurs in the last trimester of pregnancy and exacerbates postpartum; (4) lesions in the neonate resolve far
before pathogenic antibody disappears, and without treatment, suggesting that factors other than anti-BP180 antibodies may be involved in the generation of the eruption;
and (5) frequently testing the BP180 ELISA index greatly
facilitates treatment planning.
Accepted for Publication: February 20, 2007.
Correspondence: Yumi Aoyama, MD, Department of Dermatology, Gifu University School of Medicine, Yanagido 1-1,
Gifu City 501-1194, Japan (ymaoyama@gifu-u.ac.jp).
Author Contributions: Dr Aoyama had full access to all
the data in this study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Aoyama. Acquisition of data:
Aoyama, Asai, Hioki, Funato, and Kondo. Analysis and
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interpretation of data: Aoyama and Kitajima. Drafting of
the manuscript: Aoyama. Critical revision of the manuscript for important intellectual content: Aoyama, Asai,
Hioki, Funato, Kondo, and Kitajima. Obtained funding:
Aoyama. Administrative, technical, and material support:
Kondo. Study supervision: Kitajima.
Financial Disclosure: None reported.
Funding/Support: This study was supported by grantsin-aid for scientific research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; Health and Labor Sciences Research Grants for
Research on Measures for Intractable Disease; and the
Ministry of Health, Labor, and Welfare of Japan.
REFERENCES
1. Jenkins RE, Hern S, Black MM. Clinical features and management of 87 patients
with pemphigoid gestationis. Clin Exp Dermatol. 1999;24(4):255-259.
2. Shornick JK, Bangert JL, Freeman RG, Gilliam JN. Herpes gestationis: clinical
and histologic features of twenty-eight cases. J Am Acad Dermatol. 1983;8
(2):214-224.
3. Lin MS, Arteaga LA, Diaz LA. Herpes gestationis. Clin Dermatol. 2001;19(6):697702.
4. Provost TT, Tomasi TB Jr. Evidence for complement activation via the alternate
pathway in skin diseases, I: herpes gestationis, systemic lupus erythematosus,
and bullous pemphigoid. J Clin Invest. 1973;52(7):1779-1787.
5. Bushkell LL, Jordon RE, Goltz RW. Herpes gestationis: new immunologic findings.
Arch Dermatol. 1974;110(1):65-69.
6. Giudice GJ, Wilske KC, Anhalt GJ, et al. Development of an ELISA to detect antiBP180 autoantibodies in bullous pemphigoid and herpes gestationis. J Invest
Dermatol. 1994;102(6):878-881.
7. Matsumura K, Amagai M, Nishikawa T, Hashimoto T. The majority of bullous pemphigoid and herpes gestationis serum samples react with the NC16a domain of
the 180-kDa bullous pemphigoid antigen. Arch Dermatol Res. 1996;288(9):
507-509.
8. Lin MS, Gharia M, Fu CL, et al. Molecular mapping of the major epitopes of BP180
recognized by herpes gestationis autoantibodies. Clin Immunol. 1999;92(3):
285-292.
9. Sitaru C, Powell J, Messer G, Brocker EB, Wojnarowska F, Zillikens D. Immunoblotting and enzyme-linked immunosorbent assay for the diagnosis of pemphigoid gestationis. Obstet Gynecol. 2004;103(4):757-763.
10. Shornick JK, Stastny P, Gilliam JN. High frequency of histocompatibility antigens HLA-DR3 and DR4 in herpes gestations. J Clin Invest. 1981;68(2):553555.
11. Chorzelski TP, Jablonska S, Beutner EH, Maciejowska E, Jarzabek-Chorzelska
M. Herpes gestations with identical lesions in the newborn: passive transfer of
the disease? Arch Dermatol. 1976;112(8):1129-1131.
12. Katz A, Minto JO, Toole JW, Medwidsky W. Immunopathologic study of herpes
gestationis in mother and infant. Arch Dermatol. 1977;113(8):1069-1072.
13. Kitajima Y, Nojiri M, Yamada T, Hirako Y, Owaribe K. Internalization of the 180
kDa bullous pemphigoid antigen as immune complexes in basal keratinocytes:
an important early event in blister formation in bullous pemphigoid. Br J Dermatol.
1998;138(1):71-76.
14. Baxi LV, Kovilam OP, Collins MH, Walther RR. Recurrent herpes gestationis with
postpartum flare: a case report. Am J Obstet Gynecol. 1991;164(3):778-780.
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EVIDENCE-BASED DERMATOLOGY: STUDY
SECTION EDITOR: MICHAEL BIGBY, MD; ASSISTANT SECTION EDITORS: DAMIANO ABENI, MD, MPH; ROSAMARIA CORONA, DSc, MD;
URBÀ GONZÁLEZ, MD, PhD; ABRAR A. QURESHI, MD, MPH; HYWEL WILLIAMS, MSc, PhD, FRCP;
CRITICALLY APPRAISED TOPIC FEATURE EDITOR: MICHAEL J. SLADDEN, MAE, MRCP(UK)
Balancing the Benefits and Risks of Drug Treatment
A Stated-Preference, Discrete Choice Experiment With Patients With Psoriasis
Elizabeth M. Seston, PhD; Darren M. Ashcroft, PhD; Christopher E. M. Griffiths, MD, FRCP
Objective: To examine the extent to which the
attributes of a treatment affect patients’ choice of treatment for psoriasis and the magnitude and nature of
trade-offs between risks and benefits of treatment.
Design: A questionnaire, including a stated-preference,
discrete choice experiment, was used to elicit patients’ preferences for the treatment of psoriasis.
Setting: Dermatology clinics in England.
Patients: A total of 126 patients with psoriasis.
the mean duration of psoriasis was 23 years. All 6 attributes were important factors affecting choice of treatment. The results indicated that patients with psoriasis prioritized low risk of skin cancer (␤=−0.054; P⬍.01) and
liver damage (␤ = −0.054; P ⬍ .01) and preferred treatment that resulted in a shorter time to achieve a moderate
improvement (␤=−0.034; P⬍.01) over a longer time to relapse (␤=0.028; P⬍.01). Patients were most willing to wait
longer for a treatment to work if the likelihood of skin cancer or liver damage was reduced.
Main Outcome Measures: Preferences of patients for,
and trade-offs between, the 6 attributes of time to moderate (50%) improvement, relapse, and risks of experiencing skin irritation, high blood pressure, liver damage, and skin cancer.
Conclusions: This study shows that treatment attributes influence patients with psoriasis in their choice
of treatment. The results of the discrete choice experiment presented herein indicate that most respondents
would be willing to trade between different aspects of treatment to achieve improvements in their psoriasis and minimize the risks of adverse events.
Results: The mean age of respondents was 47.6 years, and
Arch Dermatol. 2007;143(9):1175-1179
P
Author Affiliations: School of
Pharmacy and Pharmaceutical
Sciences (Drs Seston and
Ashcroft) and Dermatology
Centre, Hope Hospital
(Dr Griffiths), University of
Manchester, Manchester,
England.
SORIASIS IS A CHRONIC IN -
flammatory, hyperproliferative skin disease that affects
approximately 1% to 2% of
the general population in the
United Kingdom.1 The morbidity associated with psoriasis is well documented in
terms of its impact on patients’ quality of
life.2-4 Many patients experience problems with body image, self-esteem and selfconcept, poor psychological adaptation,
and feelings of stigmatization, shame, and
embarrassment concerning their appearance.2,5,6 The disease also places an economic burden on patients, particularly
those with severe psoriasis, because they
incur out-of-pocket expenses.7
There is currently no cure for psoriasis,
although a wide range of therapies are available, varying considerably in terms of efficacy and toxic effects.8 Levels of adherence to treatment among patients with
psoriasis are low, with nonadherence rates
reported in 40% of patients.9,10 Factors such
as efficacy9,11 and duration of treatment10 can
influence the decision whether to con-
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tinue with treatment. Previous studies12,13
have shown that many patients with psoriasis often feel frustrated with the ineffectiveness of current therapies and want treatment to be more aggressive. It has also been
suggested that dermatologists (and other
physicians) may not appreciate fully the impact that skin diseases have on individual
patients.14,15
Little is known about how patients with
psoriasis evaluate the risks and benefits of
the treatments they are offered. Given the
low levels of adherence among these patients, information about the decisionmaking process could be useful for physicians considering which treatment to offer.
This study used a stated-preference, discrete choice experiment (DCE)16 to explore the attitudes of patients toward the
risks and benefits of drug treatment for psoriasis. The objectives were to (1) identify the
extent to which the attributes of a treatment (eg, degree of improvement, duration of remission, and adverse effects) affected patients’ choice of treatment for their
psoriasis, (2) determine the hierarchical im-
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Section Editor’s Note
Table 1. Treatment Attributes, Definitions, and Levels
Used in the Discrete Choice Experiment
Treatment Attribute
Definition
Time to achieve
moderate (50%)
improvement in
psoriasis
Time to relapse
Time taken for psoriasis
to improve by 50%
following treatment
4, 8, 12, or
24 wk
Time taken to lose the
improvement in
psoriasis obtained
from the treatment
once the treatment is
stopped
Percentage risk of
experiencing skin
irritation while using
treatment
Percentage risk of
experiencing high
blood pressure while
using treatment
Percentage risk of liver
damage from
treatment over a 20-y
period
Percentage risk of
developing squamous
cell or basal cell skin
cancer as a result of
treatment over a 20-y
period
2, 6, 12, or
24 wk
Risk of experiencing skin
irritation during
treatment
Risk of high blood
pressure during
treatment
20-y risk of experiencing
liver damage
20-y risk of experiencing
skin cancer
0%, 10%, 20%,
or 50%
1. Ryan M, Scott DA, Reeves C, et al. Eliciting public preferences for
healthcare: a systematic review of techniques. Health Technol Assess.
2001;5(5):1-186..
2. Ryan M, Bate A, Eastmond CJ, Ludbrook A. Use of discrete choice
experiments to elicit preferences. Qual Health Care. 2001;(10 suppl
1):i55-i60.
0% or 10%
0% or 20%
Table 2. Example of Choice Set Used
in the Discrete Choice Experiment
Time to achieve moderate (50%)
improvement in psoriasis, wk
Time to relapse, wk
Risk of experiencing skin irritation during
treatment, %
Risk of high blood pressure during
treatment, %
20-y risk of experiencing liver damage,%
20-y risk of experiencing skin cancer, %
Which treatment would you prefer?
(Please choose 1 only.)
Michael Bigby, MD
0% or 10%
a See the “Methods” section.
Treatment Attribute
Does determining patients’ preferences have to be so complicated? Probably. Ryan et al1 reviewed the state of the art
of eliciting public preferences for health care. Quantitative
techniques include ranking exercises, rating scales, and
choice-based techniques (as used in this article by Seston
et al). Qualitative techniques include interviews, case study
analyses, the Delphi technique, complaints procedures, focus groups, concept mapping, citizens’ juries, consensus
panels, public meetings, and nominal group techniques.
All techniques have strengths and limitations that were well
reviewed by Ryan et al.1 A thorough description of discrete
choice experiments and an example of their use in rheumatology can be found in a second article by Ryan et al.2
Attribute
Levels a
Treatment A
Treatment B
4
12
2
0a
24
10 b
10 b
0a
0a
20 c
A
10 b
0a
B
a No risk.
b One in 10 people.
c Two in 10 people.
portance of these attributes, and (3) explore the extent to
which patients make trade-offs between risks and benefits
of drug treatment for psoriasis.
METHODS
TREATMENT ATTRIBUTES
Using a DCE, we explored patients’ preferences.16 In a DCE,
key attributes of a good or service are identified. Realistic and
tradable levels are assigned to these attributes, and scenarios
containing the attributes are created. Scenarios are paired together, and respondents are asked to choose between the scenarios on the basis of the levels presented. The exercise is then
repeated with the values of the attributes within the scenarios
being altered systematically.
The treatment attributes used in the DCE were derived from
a review of the published literature, and their relevance was
confirmed through discussions with 3 consultant dermatologists (one of whom was C.E.M.G.).17-21 In all, 6 attributes were
included, namely: (1) time to achieve a moderate (50%) improvement, (2) time to relapse, (3) risk of skin irritation, (4)
risk of high blood pressure, (5) 20-year risk of liver damage,
and (6) 20-year risk of skin cancer. Our survey was administered to patients currently being treated for psoriasis in routine practice and not in a trial setting. We therefore chose a 50%
improvement as one of the attributes because this has previously been acknowledged to be a clinically important end point
in the assessment of psoriasis.22,23 The levels used for each of
these attributes are shown in Table 1.
The levels were organized into treatment scenarios using a fractional factorial design. This type of design was used because a full
factorial design would have produced 512 (4⫻4 ⫻ 4⫻2 ⫻ 2⫻2)
treatment scenarios, which was felt to be too burdensome for respondents. Using experimental design theory, we were able to identify 16 pair-wise treatment choices in which the levels were varied independently, thus avoiding multicollinearity24 (a situation
in which 2 variables within the model are highly correlated).
These 16 choice sets were split randomly into 2 separate versions of the questionnaire, each containing 8 choice sets, which
were distributed to patients. For each choice set, the respondents were asked to select which treatment scenario they would
prefer for the management of their psoriasis. Each version of
the questionnaire also included a single choice set in which 1
of the treatment options would always be expected to be chosen as a test for consistency. Each patient, therefore, completed 8 pair-wise choices and 1 test of consistency. Table 2
shows an example of a choice set presented to respondents.
Demographic data were also collected from each patient relating to age, sex, duration of psoriasis, and age at onset. The
Self-Assessment Psoriasis Area and Severity Index, which has
a 0 to 72-point scale, was used to determine clinical severity of
a patient’s psoriasis, with a higher score indicating greater se-
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Table 3. Regression Results From Random Effects Probit Model and Marginal Rates of Substitution in 126 Patients With Psoriasis
Coefficient
(95% CI) a
Trade-offs Relative
to Time to Improvement, wk
Preference
Interpretation
−0.034 (−0.042 to −0.026)
0.028 (0.020 to 0.035)
−0.010 (−0.017 to −0.007)
−0.038 (−0.051 to −0.026)
−0.054 (−0.068 to −0.042)
−0.054 (−0.0629 to −0.049)
1.331 (1.135 to 1.555)
NA
0.8 (0.6 to 1.0)
0.3 (0.2 to 4.0)
1.1 (0.8 to 1.5)
1.6 (1.2 to 1.9)
1.6 (1.4 to 1.8)
NA
NA
1-wk increase in time to relapse
1% Reduction in risk of skin irritation
1% Reduction in risk of high blood pressure
1% Reduction in 20-y risk of liver damage
1% Reduction in 20-y risk of skin cancer
NA
Treatment Attribute
Time to achieve moderate (50%) improvement
Time to relapse
Risk of experiencing skin irritation during treatment
Risk of high blood pressure during treatment
20-y risk of experiencing liver damage
20-y risk of experiencing skin cancer
Constant term b
Abbreviations: CI, confidence interval; NA, not applicable.
a Data are presented as ␤ values (range).
b The constant term is automatically included
in the Stata software model (StataCorp LP, College Station, Texas) and indicates that unobserved attributes (ie,
attributes not included in our model) are also influencing treatment choices.
verity.25 In addition, respondents were asked to rank the 6 treatment attributes in order of importance ranging from 1 (most
important) to 6 (least important). The study was approved by
the local National Health Service research ethics committees
in the 3 areas where the study was conducted and also by the
University of Manchester Ethics Committee.
STUDY SAMPLE
AND DATA ANALYSIS
Patients were recruited from the dermatology departments of
3 Acute National Health Service Hospital Trusts located in northwest England. Questionnaires were distributed to patients who
were attending a dermatology outpatient clinic, and postagepaid envelopes were provided for the returns.
Because each respondent provided up to 8 responses (having completed 8 choice sets), a random effects probit model
was considered appropriate, as this accounts for correlations
between responses given by the same individual. A probit
model is a popular specification of a generalized linear model,
using the probit link function. Because the response is a series
of binomial results, the likelihood is often assumed to follow
the binomial distribution. Let Y be a binary outcome variable,
and let X be a vector of regressors. The probit model assumes
that
all expected to have negative coefficients, whereas the longer
the time to relapse was expected to have a positive coefficient.
The trade-offs that patients were willing to make were determined by calculating the marginal rate of substitution, that
is, the ratio of any 2 attributes.27 Trade-offs were calculated by
dividing the coefficients of the attributes by the coefficient for
time to improvement (␤1), giving the estimated trade-offs in
time to improvement for a 1-unit change in each of the other
attributes. Confidence intervals for coefficients and the marginal rate of substitution were derived using nonparametric bootstrapping with Stata software (StataCorp LP).28 Bootstrapping
allows the confidence intervals to be determined through repeated sampling with replacement, using parameter point estimates and their estimated variance-covariance matrix.
The respondents’ treatment choices were explored to see if
they showed evidence of nontrading behavior among the different treatment attributes. Respondents were classified as having a dominant preference if they always chose the “best” level
of a particular attribute and if they also ranked that attribute
as the most important in the ranking exercise.29 To determine
whether including respondents with dominant preferences affected the results of the random effects probit model, the data
were analyzed in 2 separate models by including and excluding these respondents.
RESULTS
Pr (Y=1|X=x)=⌽(x⬘␤),
where ⌽ is the cumulative distribution function of the standard normal distribution. Parameters for ␤ are typically estimated by maximum likelihood.26
All calculations were conducted using Intercooled Stata statistical software (version 8.0; StataCorp LP, College Station,
Texas). In the model, the choice of treatment option was the
binary-dependent variable, and the differences in levels for each
of the 6 attributes were the independent variables. Differences
were calculated by subtracting the levels. A main-effects linear additive model was estimated in which ⌬␤ is the dependent variable; ␤o is the constant, representing unobserved influences on choices, ␤j is the coefficient of the attributes included
in the design, e represents the error term due to differences
among observations, and u represents the error terms due to
differences among respondents26:
⌬␤ = ␤o ⫹␤1IMPROVE⫹␤2RELAPSE⫹␤3SKIN
⫹␤4BLOOD ⫹␤5LIVER⫹␤6CANCER⫹ e⫹ u.
The theoretical validity of the model was tested by examining the signs and significance of coefficient estimates in relation to a priori hypotheses. The longer the time to improvement and increased risks of adverse effects of treatment were
INFLUENCE OF ATTRIBUTES
ON TREATMENT CHOICES
In all, 126 patients with psoriasis completed the questionnaire. A total of 64 respondents (51%) were female, and
62 (49%) were male. Their mean age was 47.6 years (range,
21-82 years), the mean duration of their psoriasis was 22.8
years (range, 1-63 years), their mean age at onset of psoriasis was 24.9 years (range, birth to 67 years), and the mean
Self-Assessment Psoriasis Area and Severity Index score was
11.1 (range, 0.4-55.2). All 126 respondents passed the consistency test, suggesting that they had understood the DCE.
Twenty-nine respondents (23%) showed evidence of dominant preferences for specific treatment attributes. Most of
these (19/29) always chose the option for which there was
no risk of experiencing skin cancer. A few respondents also
showed evidence of dominant preferences for time to relapse (5 subjects), no risk of liver damage (3 subjects), and
no risk of high blood pressure (2 subjects).
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TRADE-OFFS BETWEEN THE BENEFITS
AND RISKS OF TREATMENT
Table 4. Ranking of Attributes by 103 Respondents a
Treatment Attribute
Time to achieve moderate (50%) improvement
Time to relapse
Risk of experiencing skin irritation during
treatment
Risk of high blood pressure during treatment
20-y risk of experiencing liver damage
20-y risk of experiencing skin cancer
a There
Respondents
Ranking It as
“Most Important,”
No. (%)
30 (29.1)
17 (16.5)
2 (1.9)
9 (8.7)
17 (16.6)
28 (27.2)
are some missing values.
Two random effects probit models were estimated; 1
with all respondents and 1 with “dominant” respondents excluded. A comparison of the models indicated
no significant differences in coefficient estimates, relative size of the coefficients, or the significance of the fit
of the models. Therefore, only the model that included
all respondents is presented in Table 3. The coefficients for all 6 treatment attributes were statistically significantly different from zero (P ⬍.01), indicating that
all the attributes were important factors affecting patients’ choice of treatment. The constant term was also
significant (P ⬍ .05), indicating that other unobserved
attributes were also likely to influence treatment preferences.
The size and direction of the coefficients were in accordance with our a priori hypotheses. The negative signs
on the coefficient for the adverse effects indicated that
the higher the risk of experiencing these events, the less
likely patients were to choose this scenario. Similarly, the
negative sign for the time to improvement attribute indicated that the longer the time to achieve a moderate
improvement, the less likely the patients were to choose
that scenario. Positive values for the time to relapse indicated that the greater the duration of time to relapse,
the more likely the patients were to choose that scenario.
RELATIVE IMPORTANCE
OF THE TREATMENT ATTRIBUTES
Comparison of the magnitude of the coefficients indicated that respondents considered both the long-term risks
of experiencing skin cancer and liver damage to be the most
important adverse events influencing their choice of treatment, followed by the risk of experiencing high blood pressure. The risk of skin irritation was considered to be least
important. The patients also prioritized time to moderate
improvement over time to relapse. This corresponds with
the results of the ranking exercise in which 30 of 103 respondents ranked the time to achieving a moderate improvement in psoriasis as the most important attribute
(29.1%), whereas 17 of 103 (16.5%) ranked time to relapse as the most important, as shown in Table 4. (It should
be noted that 23 respondents [18.3%] did not complete the
ranking exercise.)
Table 3 also shows the marginal rates of substitution between time to achieve a moderate improvement in the
severity of psoriasis and the other attributes; that is, how
much more time to improvement the respondents were
willing to trade off to achieve an improvement in 1 level
of the other treatment attributes. For example, the results show that respondents were willing to wait 0.8 weeks
longer to achieve a moderate improvement if the treatment prolonged the time to relapse following such improvement by 1 week. The least important marginal rates
of substitution were for the risk of skin irritation during
treatment, and the most important were for the 20-year
risks of liver damage and skin cancer.
COMMENT
This study has shown that treatment attributes, such as
adverse effects, time to improvement, and time to relapse, influence the treatment preferences of patients with
psoriasis. Most respondents would be willing to trade
among different aspects of treatment to achieve an improvement in their psoriasis with minimal adverse effects. In other words, patients indicated that they would
wait longer for a treatment to work if the chance of a severe adverse effect, such as skin cancer or liver damage,
was considerably reduced. Respondents considered the
long-term risks of skin cancer and liver damage to be the
most important adverse effects and were prioritized above
short-term risks of drug-induced hypertension or skin
irritation.
Almost a quarter of the sample were unwilling to trade
among the attributes and always chose the treatment option with a particular level of their chosen attribute, most
often no risk of skin cancer. The level of nontrading in this
study was low compared with other DCE studies16,29 in
which nontrading respondents have accounted for 30% to
71% of all respondents. It is important to take these into
account because they reveal strong preferences on the part
of some respondents. These studies suggest that some patients may not accept a treatment offered to them, no matter how efficacious, if they have serious concerns about adverse effects. These findings may provide some insight into
why patients demonstrate intentional nonadherence to treatments for psoriasis and provide a useful starting point for
meaningful dialogue between patients and physicians about
choice of treatment.
Previous studies have explored attitudes to risks and
benefits of treatments in patients with rheumatoid arthritis and other musculoskeletal conditions. Fraenkel
et al30 found that as many as 60% of respondents would
not accept an arthritis treatment if there was a risk, however small, of developing cancer. Another study31 showed
that patients would be willing to accept the risk of treatment if the benefits were seen to be high. More recently,
it was reported that patients with arthritis prioritized eliminating the risk of adverse effects, whether short- or longterm, much more highly than the chance of the treatment providing benefit.32
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To our knowledge, this is the first study to examine
the nature and extent of some of the specific trade-offs
that patients routinely face when choosing among the risks
and benefits of drug treatments for psoriasis. However,
there are several limitations that should be taken into account in interpreting the findings. First, the patients were
presented with scenarios in which we systematically manipulated specific treatment attributes. Respondents were
making decisions based on the state of their psoriasis at
the time of the study; however, their attitudes may have
varied according to the severity of their psoriasis. In the
words of one patient, who provided written comments
to support her answers, “If my psoriasis was severe, which
indeed it has been at various times of my life, if I look
back . . . I would probably, in desperation, have agreed
to any treatment that would improve my skin condition.” The results were averaged across the sample, and
as a result there is inevitable variation between patients.
It is likely that our sample does not represent fully the
general population of patients with psoriasis; rather, it
is more representative of those being treated in dermatology clinics in the hospital setting. Future work should
explore whether these findings are mirrored by those derived from patients who are being cared for in ambulatory care alone. Likewise, it would also be of interest to
explore patients’ preferences toward other treatment attributes, such as the route or mode of administration and
the associated treatment costs.
Nonetheless, this study has provided novel insight into
the attitudes of patients with psoriasis toward the risks
and benefits of the treatments they receive. Given the
heavy psychological burden associated with psoriasis, the
high levels of dissatisfaction with the effectiveness of current treatment, and poor levels of adherence, a greater
understanding of how these patients perceive their treatment may enhance the dialogue between them and their
physicians.
Accepted for Publication: March 16, 2007.
Correspondence: Elizabeth M. Seston, PhD, School of
Pharmacy and Pharmaceutical Sciences, Stopford Building, Oxford Road, University of Manchester, Manchester M13 9PT, England (liz.seston@gmail.com).
Author Contributions: Dr Ashcroft had full access to all
the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Seston, Ashcroft, and Griffiths. Acquisition of data: Seston and Ashcroft. Analysis
and interpretation of data: Seston, Ashcroft, and Griffiths. Drafting of the manuscript: Seston and Ashcroft. Critical revision of the manuscript for important intellectual content: Seston, Ashcroft, and Griffiths. Statistical analysis:
Seston and Ashcroft. Obtained funding: Ashcroft and Griffiths. Administrative, technical, and material support: Ashcroft. Study supervision: Ashcroft and Griffiths.
Financial Disclosure: None reported.
Funding/Support: Galderma International Ltd provided financial support for the study via an unrestricted
educational grant.
Disclaimer: The views expressed in this article are those
of the authors alone.
Additional Contributions: The staff at the hospitals as-
sisted with the distribution of questionnaires. We thank
all of the patients who took part in the study.
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17. Griffiths CEM, Clark CM, Chalmers RJ, Li Wan Po A, Williams HC. A systematic
review of treatments for severe psoriasis. Health Technol Assess. 2000;4(40):
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18. Ashcroft DM, Li Wan Po AL, Williams HC, Griffiths CEM. Systematic review of
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30. Fraenkel L, Bogardus ST, Concato J, Felson DT. Unwillingness of rheumatoid arthritis patients to risk adverse effects. Rheumatology (Oxford). 2002;41(3):253-261.
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EVIDENCE-BASED DERMATOLOGY: RESEARCH COMMENTARY
Use of Antibiotic Ointment
After Clean Cutaneous Surgery
Michael Bigby, MD; Department of Dermatology, Harvard Medical School, Boston, Massachusetts, and
Beth Israel Deaconess Medical Center, Boston
Commentary on: Randomized clinical trial of
the effect of applying ointment to surgical
wounds before occlusive dressing
Dixon AJ, Dixon MP, Dixon JB
Br J Surg. 2006;93(8):937-943
Ointments are often applied to surgical wounds after clean
cutaneous surgery in the belief that they speed and improve wound healing. The effectiveness of this practice
was tested in a large randomized control trial.
Question: Does application of no ointment, paraffin ointment, or mupirocin ointment lower complication rates
or improve wound healing after clean cutaneous surgery when occlusive dressings are applied?
Design: A blinded randomized clinical trial was undertaken to evaluate the effect of applying mupirocin ointment to a wound before occlusive dressing, in comparison with no ointment or sterile paraffin.
Setting: Skincanceronly Clinic, Geelong, Alfred Hospital, Melbourne, Australia.
Patients: All patients were newly referred to the Skincanceronly Clinic from July 1, 2002, to December 31,
2003. One surgeon performed all procedures, which included punch biopsy, elliptical excision, incisional biopsy, skin grafts, and skin flaps.
Interventions: No ointment, paraffin ointment, or mupirocin ointment was placed on sutured wounds of patients prior
to application of moist occlusive dressings. All patients were
given a detailed instruction sheet regarding wound treatment, warning signs, and details of return appointments.
At 6 to 9 months after surgery, patients were surveyed to
assess the wounds, with a response rate of 74.0%.
Main Outcome Measures: The primary outcome was development of a wound infection defined as purulent suture site, suture abscess, cellulitis, infective necrosis, large
subcuticular abscess, regional lymphadenitis, or septicemia assessed at suture removal. When there was abscess formation or evidence of involvement beyond the
local site, a wound swab was taken for culture; otherwise, the infection was assessed clinically. In the absence of suppuration, a wound was considered infected
if 3 of the following 4 signs were present: discharge, pain,
erythema, or induration. Secondary outcomes included
scarring, suture markings, suture reaction, hypertrophy, keloid formation, discoloration, wound depres-
sion, wound elevation, dog ears, and contracture. Recorded adverse reactions included postoperative bleeding,
allergy to dressing, allergy to skin preparation, contact
dermatitis, local recurrence, subcutaneous fibrosis, granuloma, dehiscence, pruritus, persistent pain, nerve damage, ectropion, nodal involvement, and distant metastases. All key outcome incidences were analyzed with the
␹2 test.
Results: Some 778 patients with 1801 surgical wounds
following excision of skin lesions were enrolled in the
trial. No ointment was placed on 510 sutured wounds
of 247 patients, paraffin ointment was placed on 729
wounds of 269 patients, and mupirocin ointment on 562
wounds of 262 patients. There were no significant differences in outcome for all primary end points evaluated (Table 1). The infection rate was 1.4% with no ointment, 1.6% for paraffin, and 2.3% for mupirocin (P= .49).
Total complication rates were 3.5%, 4.7%, and 4.8% for
no ointment, paraffin, and mupirocin, respectively
(P= .59). Skin necrosis occurred in 0, 1, and 6 patients,
respectively. There was a clinical and statistical increase
in wound infections in lower limb lesions.
At 6 to 9 months after surgery, patients were surveyed to assess the wounds, with a response rate of 74.0%.
Some 10.9%, 10.3%, and 8.2% of patients had a neutral
or negative perception of their wounds at 6 to 9 months
after surgery with no ointment, paraffin ointment, and
mupirocin ointment, respectively (P= .65). There was no
difference in postoperative pain, degree of inconvenience, or overall level of satisfaction with treatment.
Authors’ Conclusions: Putting ointment on a surgical
wound before occlusive dressing does not benefit the patient. In view of the risk of antibiotic resistance, mupirocin ointment is not indicated for clean surgical wounds.
Comment
The trial was well reported. A sample size calculation was
performed, and adequate numbers of patients were recruited. Patients (not wounds) were randomized prospectively. The randomization process (an independent
person drew 1 of 150 disks [50 each of 3 different colors
from a barrel] without replacement) was well described. Drawing disks without replacement results in
“block randomization,” designed to produce groups of
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Table 1. Postoperative Occlusive Dressinga
Complication
Wound
infection
Skin
necrosis
No Ointment
(n = 510 Wounds)
95% CI
Paraffin
(n = 729 Wounds)
95% CI
Mupirocin
(n = 562 Wounds)
95% CI
7 (1.4)
(0.4-2.4)
12 (1.6)
(0.7-2.6)
13 (2.3)
(1.1-3.6)
.49
0 (0)
(0-0.6)
6 (1.1)
(0.2-1.9)
.007,
1 (0.1)
(0-0.4)
P Valueb
Abbreviation: CI, confidence interval.
a
Data are given as the number of events (percentage).
b
For the ␹2 test.
Table 2. Postoperative Nonocclusive Dressing
Complication
Infection (evaluable)
Infection (ITT)
Contact dermatitis (evaluable)
Contact dermatitis (ITT)
White Petrolatum a
(n = 610 Wounds)
Bacitracin a
(n = 597 Wounds)
Difference (95% CI)
NNT (95% CI)
9 (2.0)
9 (1.5)
0 (0)
0 (0)
4 (0.9)
4 (0.7)
4 (0.9)
4 (0.7)
0.011 (−0.004 to 0.027)
0.008 (−0.004 to 0.019)
−0.009 (NP)
−0.007 (−0.015 to 0.002)
91 (−250 to 37)
127 (−280 to 52)
−112 (NP)
−150 (−68 to 667)
Abbreviations: CI, confidence interval; ITT, intention to treat; NNT, number needed to treat; NP, not provided.
a Data are given as number (percentage).
equal size. The authors state on page 938 that, “The surgeon and the patients were not aware of the allocation”
but the means of concealment of allocation were not described. Multiple wounds were evaluated in randomized patients. Because 1 group received no ointment,
masking was not entirely possible. Intention-to-treat
analysis (ITT) was performed for wound healing and development of infection because all wounds were followed up until healing was complete (to time of suture
removal or longer if healing was slow or complications
were experienced). Intention-to-treat analysis was not performed but was calculable for long-term results with the
data provided from survey results. Equal numbers of patients failed to return surveys of long-term results from
the groups receiving no ointment, paraffin ointment, and
mupirocin ointment.
All patients had a “moist occlusive dressing,” although the specifics of the dressing and its aftercare were
not described. The corresponding author supplied the information on my request. The dressings were variable but
were all of a moist occlusive type as described by Eaglestein et al.1 In the main, an initial cover like Melolin or
Telfa was used. Then the dressing was sealed with tape
circumferentially. Patients were asked to leave the dressing on until review. If they wanted to take it off, they were
encouraged to reinforce the dressing and leave it on.
This trial was well conducted and reported. Two flaws
deserve comment. The first is the lack of detailed description of the occlusive dressing used in the published report. The second relates to the unit of analysis.
Although individual patients were randomized into the
study, analysis was performed using the wound as the
unit of analysis—an approach that is problematic if responses to treatment are clustered within a few individuals with multiple wounds who might be overrepresented in one of the treatment groups. The number of
wounds was quite different in the 3 groups (510, 729,
and 562 wounds compared with 247, 269, and 262 individual patients, respectively), yet no adjustment for clustering effects was made in the analysis. The authors recognized this flaw and commented that the differences in
infection rates for just the first wound were similar to the
findings when all wounds were considered.
The results (Table 1) fully justify the authors’ conclusions. This article should lead to a paradigm shift in
the management of postoperative wound care.
In a similar randomized, double-blind study published more than 10 years ago, Smack et al2 demonstrated that, compared with bacitracin ointment, white
petrolatum is a safe, effective wound care ointment for
postoperative wound care using nonocclusive dressings
that are changed daily. Procedures included shave and
punch biopsy, electrodessication and curettage, excision, Mohs surgery, and dermabrasion. Compared with
bacitracin ointment, white petrolatum possesses a nearly
equally low infection rate and minimal risk for induction of allergy (Table 2). Their data2 indicated that using
white petrolatum would produce an insignificantly higher
infection rate (number needed to harm [NNH] 91, evaluable; 127 ITT) and a lower rate of contact allergy (NNH
−112, evaluable; −150 ITT).
This study was also well reported. A power calculations was performed; however, adequate numbers of subjects were not recruited because the actual infection rate
was lower than the 3% that was assumed in the calculation. Because of the less-than-adequate number of subjects recruited, the authors could not exclude the possibility that using white petrolatum would produce a higher
infection rate with an NNH as high as 37, evaluable or
52 ITT. The method of randomization and concealment
of allocation were adequate. Patient and evaluator blinding was successful. An ITT analysis was not performed
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but was calculable. The results (Table 2) justify the authors’ conclusions.
Bottom Line: No ointment is necessary when postoperative wounds are covered with occlusive dressings.
Petrolatum is an acceptable ointment for use when nonocclusive dressings that are changed daily are used.
Adoption of these changes instead of using antibiotic
ointments on postoperative wounds will result in considerable cost savings.
Accepted for Publication: March 14, 2007.
Correspondence: Michael Bigby, MD, Department of Dermatology, Beth Israel Hospital, 330 Brookline Ave, Boston, MA 02215 (mbigby@bidmc.harvard.edu).
Financial Disclosure: None reported.
1. Eaglstein WH, Davis SC, Mehle AL, Mertz PM. Optimal use of an occlusive dressing to enhance healing: effect of delayed application and early removal on wound
healing. Arch Dermatol. 1988;124(3):392-395.
2. Smack DP, Harrington AC, Dunn C, et al. Infection and allergy incidence in ambulatory surgery patients using white petrolatum vs. bacitracin ointment: a randomized controlled trial. JAMA. 1996;276(12):972-977.
Archives Web Quiz Winner
C
ongratulations to the winner of our June quiz, Farzam Gorouhi, MD, Center for Research and Training in Skin Diseases and Leprosy, Medical Sciences, University of Tehran, Tehran, Iran. The correct answer to
our May challenge was factitial dermatitis. For a complete discussion of this case, see the Off-Center Fold section in the July Archives (Heydendael VMR, Hoekzema
R. Acute blue patch on the forearm. Arch Dermatol. 2007;
143[7]:937-942).
Be sure to visit the Archives of Dermatology Web site
(http://www.archdermatol.com) to try your hand at the
interactive quiz. We invite visitors to make a diagnosis
based on selected information from a case report or other
feature scheduled to be published in the following month’s
print edition of the Archives. The first visitor to e-mail
our Web editors with the correct answer will be recognized in the print journal and on our Web site and will
also receive a free copy of The Art of JAMA II.
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EDITORIAL
Evidence-Based Dermatology Section Welcomes
a New Feature: Critically Appraised Topic
S
INCE 1999, THE EVIDENCE-BASED DERMATOL-
ogy (EBD) section has fulfilled its purpose
of alerting clinicians to important advances
in dermatology to help them use the best and
most up-to date evidence when making decisions about patient care. My assistant editors and I select original articles from the biomedical literature to summarize in structured, value-added abstracts, and clinical
experts comment on them. The procedures we follow as
we attempt to achieve this purpose are (1) detecting, using
prestated criteria, the best original and systematic review articles, which may or may not include metaanalysis, on the cause, course, diagnosis, prevention, and
treatment of disorders and quality of care or economics
in dermatology; (2) introducing these articles with declarative titles and summarizing them accurately in structured abstracts that describe their objectives, methods,
results, and evidence-based conclusions; (3) adding brief,
Michael Bigby, MD, Section Editor
Damiano Abeni, MD, MPH
Abrar A. Qureshi, MD, MPH
highly expert commentaries to place each of these summaries in its proper clinical and health care context; and
(4) disseminating the summaries to clinicians in a timely
fashion.
See also page 1187
In this issue of the Archives, we introduce critically
appraised topics (CATs) and the CATs’ feature editor,
Michael J. Sladden, MAE, MRCP(UK), to the EBD section. CATs are written summaries of the application of
the practice of evidence-based medicine to specific problems that are commonly encountered in clinical practice (ie, translating the problem into an answerable, 4-part,
well-built question; finding the best evidence to answer
the question; critically appraising the evidence for its validity, magnitude, and precision; and applying the evidence to specific patients). In short, CATs are mini-
Rosamaria Corona, DSc, MD
Michael J. Sladden, MAE, MRCP(UK)
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Urbà González, MD, PhD
Hywel Williams, MSc, PhD, FRCP
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systematic reviews of narrow, patient-focused questions
that are not easy to find in a textbook. For example, after a
clinical encounter, a patient-oriented question might be
developed, which would then be followed by a search for
relevant high-quality information to answer that question. The studies that are found will be briefly and critically appraised and then applied back to the patient along
with the commentary.
If you are interested in contributing to the EBD section and wish to discuss the topic with the section editor, please e-mail your note of interest to mbigby@bidmc
.harvard.edu. Please specify which kind of contribution
you are interested in providing:
v Critical Appraisal of published articles, whose authors are invited to reply.
v Systematic Reviews, which may or may not include meta-analysis.
v Original Contributions.
v Evidence-Based Reports, which are original manuscripts that are often the work of a consensus conference using the evidence-based approach to evaluate the
status of a disease and its therapy or to formulate a public health policy.
v CATs.
Once the manuscript is complete, it is submitted via Webbased process at http://manuscripts.archdermatol.com.
The author designates 1 of the 5 categories of submissions to the EBD section. The assistant section editors
and I look forward to reviewing your submissions.
Michael Bigby, MD
Section Editor
Correspondence: Dr Bigby, Beth Israel Deaconess Medical Center, TCC-2, 330 Brookline Ave, Boston, MA 02215
(mbigby@bidmc.harvard.edu).
Correction
Error in Byline. In the article titled “Breaking Strength
of Barbed Polypropylene Sutures: Rater-Blinded, Controlled Comparison With Nonbarbed Sutures of Various Calibers,” by Rashid et al, published in the July issue of the Archives (2007;143[7]:869-872), the first
author’s name should have read as follows: Rashid M.
Rashid, MD, PhD.
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EVIDENCE-BASED DERMATOLOGY: CRITICALLY APPRAISED TOPIC
What Is the Chance of a Normal Pregnancy
in a Woman Whose Fetus Has Been Exposed
to Isotretinoin?
Michael J. Sladden, MAE, MRCP(UK); Karen E. Harman, MD, MRCP; Department of Medicine, University of Tasmania,
Launceston, Australia (Dr Sladden), and Department of Dermatology, Leicester Royal Infirmary, Leicester, England
(Dr Harman)
Clinical Question: Recently, one of our patients who was
taking isotretinoin became pregnant. This occurred despite appropriate counseling, a negative pregnancy test
result before commencing treatment, and use of the combined oral contraceptive pill Microgynon 30 (Schering
Health Care, West Sussex, England) (levonorgestrel, 150
µg, ethinylestradiol, 30 µg). The patient did not want to
terminate her pregnancy. The aim of this Critically Appraised Topic is to explore the literature to determine the
chance of delivering a healthy child after fetal exposure
to isotretinoin; the types of fetal malformations associated with it; and what monitoring should be performed.
Background
Since introduction of the drug in 1982, over 2000 pregnancies in the United States have been affected by fetal
exposure to isotretinoin,1 most resulting in spontaneous or elective abortions.2-6
Literature Search
We searched the Medline and EmBase databases from
1966 to March 2007 using the terms isotretinoin or Accutane or Roaccutane and pregnancy or birth defect.
Appraisal of the Evidence
We found 469 articles in the literature search and chose
2 case series3,4 that prospectively identified and followed up pregnancies in which the fetus was exposed to
isotretinoin for which abortion was not elected.3,4 We extracted data from these 2 prospective studies to develop
our clinical bottom line because these studies are likely
to be less biased than the retrospective studies. These 2
studies collected data from a combined total of 151 pregnant women in the United States aged 14 years to older
than 35 years whose fetuses were exposed to isotretinoin.
v In one study3 of 115 pregnancies, there were 21 spontaneous abortions (18%). Of the 94 live births, 61 were
healthy infants (65% of births, 53% of pregnancies), 26
had congenital malformations consistent with isotretinoin embryopathy (28% of births, 23% of pregnancies),
and 7 had other problems (7% of births). Therefore, 28%
of live births had congenital malformations consistent with
isotretinoin embryopathy (95% confidence interval, 19%37%).3
v In the second study4 of 36 pregnancies, there were
8 spontaneous abortions (22%). Of the 28 live births, 23
were healthy infants (82% of births, 64% of pregnancies), and 5 had congenital malformations (18% of births,
14% of pregnancies).
The main abnormalities found in isotretinoin embryopathy are craniofacial, central nervous system, cardiovascular, and thymic.1,3,4,7,8
v Craniofacial: ear defects, dysmorphism, cleft palate, depressed nasal bridge, hypertelorism;
v Central nervous system: hydrocephalus, microcephaly, facial nerve palsy, cortical and cerebellar defects;
v Cardiovascular: Fallot’s tetralogy, transposition of
great vessels, septal defects, aortic arch hypoplasia;
v Thymic: ectopia, hypoplasia, aplasia; and
v Miscellaneous: spina bifida, limb reduction.
In addition, fetal exposure to isotretinoin is associated with high risk of adverse outcome with respect to
mental functioning.9 The United Kingdom National Teratology Information Service10 estimates that in fetal exposure to isotretinoin, 30% of infants with no gross malformations have mental retardation, and up to 60% have
impaired neuropsychological function.
For editorial comment
see page 1185
The National Teratology Information Service recommends that women who wish to continue their pregnancy after fetal exposure to isotretinoin should have alpha-fetoprotein testing at 16 to 19 weeks’ gestation and
undergo a targeted ultrasound scan and echocardiography at 20 to 21 weeks’ gestation.10 These investigations
would give some indication of the risks of structural malformations so that parents can plan support services and,
in rare instances, in utero intervention could be performed, if appropriate.
The high rate of fetal exposure to isotretinoin and its
serious teratogenicity are clearly illustrated. The US Food
and Drug Administration has recently approved the
“iPLEDGE” risk management program,11 which is designed to reduce the risk of fetal exposure to isotreti-
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noin. However, it is also important that dermatologists
prevent pregnant women from taking the medication
(document proof of no pregnancy) and prevent women
who are taking it from getting pregnant (use of 2 forms
of birth control).
v Women who choose to continue their pregnancy require careful support and monitoring.
Finally, it is important that dermatologists prevent
pregnant women from taking isotretinoin and prevent
women who are taking it from getting pregnant.
Limitations
There is no dose of oral isotretinoin that is safe for use in
pregnant women3,12 and, consequently, there are no published studies of women who took isotretinoin throughout pregnancy. Therefore, information about safety must
be obtained from studies in which isotretinoin was taken
for acne during some portion of pregnancy.13
Reported outcomes of retrospectively and prospectively ascertained cases differ considerably.3 Therefore,
we have based our conclusions on data from prospective studies because of the strong likelihood of bias (especially reporting bias) associated with retrospective studies. Published prospective outcome data are available for
only a small proportion of pregnancies in which the fetus was exposed to isotretinoin because most of these pregnancies are not reported in the literature.
The level of fetal exposure to isotretinoin varies from
pregnancy to pregnancy so it is possible that isotretinoinrelated problems may be higher for women who continue taking isotretinoin for a longer duration before discovering that they are pregnant. However, there is
insufficient data to address this issue. There is little information about the timing of spontaneous abortions,
either in weeks or trimesters. There is little follow-up data
on infants with no gross malformation to determine the
risk of developmental disabilities later in life.
Clinical Bottom Line
In pregnancies in which the fetus is exposed to isotretinoin,
v The risk of spontaneous abortion is approximately
20%;
v In pregnancies that progress, 65% to 82% of neonates appear normal at birth, but there is insufficient data
to determine how many will later develop isotretinoinrelated problems;
v There is an 18% to 28% risk of isotretinoin embryopathy;
v There is no safe level of exposure: any exposure can
cause malformation;
v The main abnormalities are craniofacial, cardiac, central nervous system, and thymic; and
What Happened to Our Patient?
Our patient ceased taking isotretinoin as soon as she
discovered that she was pregnant, at approximately 6 to
7 weeks’ gestation. We discussed with her the evidence
regarding isotretinoin and birth defects. She elected to
continue with her pregnancy and underwent regular
ultrasound scans, performed by her obstetrician. She
delivered a healthy baby girl, with no apparent birth
defect. At age 18 months, her daughter was developing
normally.
REFERENCES
1. Lindstrom J. Isotretinoin: background and regulatory history. FDA Joint Dermatologic and Ophthalmic Drugs & Drug Safety and Risk Management Advisory
Committee Meeting; February 26–27, 2004; Gaithersburg, MD. http://www.fda
.gov/ohrms/dockets/ac/04/slides/4017s1.htm. Accessed March 12, 2007.
2. Abroms L, Maibach E, Lyon-Daniel K, Feldman SR. What is the best approach to
reducing birth defects associated with isotretinoin? PLoS Med. 2006;3(11):
e483.
3. Dai WS, LaBraico JM, Stern RS. Epidemiology of isotretinoin exposure during
pregnancy. J Am Acad Dermatol. 1992;26(4):599-606.
4. Lammer EJ, Chen DT, Hoar RM, et al. Retinoic acid embryopathy. N Engl J Med.
1985;313(14):837-841.
5. Mitchell AA, Van Bennekom CM, Louik C. A pregnancy-prevention program in
women of childbearing age receiving Isotretinoin. N Engl J Med. 1995;333
(2):101-106.
6. Bérard A, Azoulay L, Koren G, Blais L, Perreault S, Oraichi D. Isotretinoin, pregnancies, abortions and birth defects: a population-based perspective. Br J Clin
Pharmacol. 2007;63(2):196-205.
7. Lynberg MC, Khoury MJ, Lammer EJ, Waller KO, Cordero JF, Erickson JD.
Sensitivity, specificity, and positive predictive value of multiple malformations
in isotretinoin embryopathy surveillance. Teratology. 1990;42(5):513-519.
8. Stern RS, Rosa F, Baum C. Isotretinoin and pregnancy. J Am Acad Dermatol.
1984;10(5, pt 1):851-854.
9. Adams J, Lammer EJ. Neurobehavioral teratology of isotretinoin. Reprod Toxicol.
1993;7(2):175-177.
10. National Teratology Information Service. Exposure to Isotretinoin During Pregnancy.
Newcastle upon Tyne, England: National Teratology Information Service, Regional Drug and Therapeutics Centre; 2001.
11. Food and Drug Administration. iPLEDGE update. 2006. http://www.fda.gov/cder
/drug/infopage/accutane/iPLEDGEupdate200603.htm. Accessed May 28, 2007.
12. Goldsmith LA, Bolognia JL, Callen JP, et al. American Academy of Dermatology
Consensus Conference on the safe and optimal use of isotretinoin: summary and
recommendations [published correction for a dosage error appears in J Am Acad
Dermatol. 2004;51(3):348]. J Am Acad Dermatol. 2004;50(6):900-906.
13. Rothman KF, Pochi PE. Use of oral and topical agents for acne in pregnancy.
J Am Acad Dermatol. 1988;19(3):431-442.
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ON THE HORIZON
SECTION EDITOR: GARY S. WOOD, MD; ASSISTANT SECTION EDITORS: CRAIG A. ELMETS, MD; MOLLY A. HINSHAW, MD;
JAY C. KLEMME, MD, MPH; MARK R. PITTELKOW, MD; MARTIN A. WEINSTOCK, MD, PhD; DAVID T. WOODLEY, MD
Accessible Evidence-Based Medicine
Critically Appraised Topics
David A. Barzilai, MD, PhD; Martin A. Weinstock, MD, PhD; Department of Dermatology (Drs Barzilai and Weinstock),
Brown University, and Department of Veterans Affairs Medical Center (Dr Weinstock), Providence, Rhode Island
Learning Evidence-Based Veterinary Medicine
Through Development of a Critically
Appraised Topic
Hardin LE, Robertson S
J Vet Med Educ. 2006;33(3):474-478
Evidence-based veterinary medicine is a relatively new
field of study. Increased knowledge of medicine coupled
with the increased ability of computers and other electronic devices present overwhelming information. The
critically appraised topic (CAT) is one method to gather
and evaluate information related to a clinical question.
CATs in informatics are short summaries of evidence, usually found through literature searches, in response to a
specifically stated, clinically oriented problem or question. This article describes a study in which each firstyear veterinary student developed a CAT as a class project.
The results of this project indicate that students were able
to successfully develop CATs and that this exercise helped
them understand evidence-based veterinary medicine concepts. Though some modification in this project will be
made in the future, overall it was a worthwhile effort and
will remain as an activity in the course.
COMMENT
The cumulative knowledge base of pertinent data for patient management is tremendous and rapidly growing in
dermatology. To facilitate efficient and accurate acquisition of the best current knowledge, evidence-based medicine (EBM) has emerged as the science of integrating “the
best research evidence with our clinical expertise and our
patient’s unique values and circumstances.”1(p1) CATs and
CAT banks (collections of CATs) will become an important part of this effort in the future. In the evidencebased hierarchy, CATs are between narrative reviews and
systematic reviews in quality and come in handy when
systematic reviews are not available.
See also page 1187
While a full discussion of EBM is beyond the scope
of this brief discussion,1-5 using EBM to answer a clinical query involves the following steps: (1) formalizing
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1189
tion; (2) systematically searching out the best evidence
available; (3) critically appraising the evidence; (4) integrating the data with clinical expertise and patient values; and (5) archiving the results and learning from steps
1 through 4. In clinical practice, steps 2 and 3 (searching out and critically appraising the best evidence) are
often the most challenging. Step 5 is essential to allow
others to benefit from an EBM review, and this is where
the CATs and a CAT bank are useful.
The quality of clinical evidence can be categorized in a
continuum ranging from lower-level evidence such as a
colleague’s subjective opinion or a solitary case report to
systematic reviews based on double-blind, randomized,
controlled trials. Systematic reviews are regarded as the
highest level of data because they involve comprehensive
searches of the literature and use explicit criteria for evaluating and incorporating data into the conclusions. A frequent challenge in clinical practice, however, is to find a
systematic review that addresses a particular query. Such
Editor’s Note
Critically Appraised Topics
How wonderfully appropriate that the benefits of CATs
are recognized in evidence-based veterinary medicine!
The medical care providers for our feline friends wrap
the methods of informatics around clinical questions just
as those felines that we share living space with wrap themselves around our legs. In this issue, the Archives introduces the CATs feature of the Evidence-Based Dermatology section. Our planning for this feature began in
January 2007. We are delighted to be able to implement
this clinically relevant feature for our readers and invite
you to send your suggestions for topics to be addressed
to the CATs feature editor, Michael Sladden, MAE,
MRCP(UK) at m.sladden@doctors.org.uk.
Now our canine pals are begging for equal representation, and who can resist those wet noses and wagging
tails. We must recognize DOGs, disease-oriented groups.
In recent years, the Archives published the work of several multicenter groups who focus on a single disease to
perform randomized clinical trials to provide the highest level of evidence for therapeutic interventions. The
challenging work of these visionary seeing eye DOGs is
leading the way to improve therapy for our patients.
June K. Robinson, MD
WWW.ARCHDERMATOL.COM
Table. Critically Appraised Topic (CAT) Web Sites
Name
BestBets
CAT bank
Dermatoscopia
ebDerm.org (evidence-based dermatology)
Description
URL
CATs in a variety of clinical areas
CATs in a variety of clinical areas
Spanish language dermatology CATs
Will host English language CATs in August 2008
www.bestbets.org
www.minervation.com/cebm2/cats/allcats.html
www.dermatoscopio.cl
ebDerm.org
reviews are often not available, and to create one could
take a year or more to reach a conclusion (by which
time the question might no longer be relevant to the
case that prompted the query). Narrative reviews are
more likely to have some answer, but these are a poor
solution because they do not reliably, comprehensively,
or critically appraise the evidence and hence ultimately
resemble expert opinion. In practice, dermatologists
may use medical search engines like PubMed or even
Web search engines like Google to find their answers,
but the first answer is often not the most current, representative, or accurate. Finally, none of these methods
permits an easy system for storing the answer for future
reference or sharing results with colleagues.
What if a tool existed to help rapidly identify valuable data, critically appraise its quality, and then store it
as a 1-page summary for future reference? There is such
a tool, the CAT. Literally speaking, CATs are 1-page summaries of evidence, but what makes them so powerful is
the standardized approach to conducting evidencebased searches and appraising the evidence. The other
premise behind CATs is that they are educational. The
best way to learn EBM is through answering real-life clinical queries developed in practice.
The Centre for Evidence-Based Medicine, Headington, England, has developed publicly accessible and free
software for generating CATs, CATMaker. This software
can be downloaded to any personal computer
with access to the Web (www.cebm.net/catmaker.asp).
CATMaker software facilitates data entry, helps carry out
calculations to determine the clinical importance of differences detected in the study, and generates an output file
that can be edited by a word processor. In addition, the software is equipped with an online help system designed for
novices to EBM searches. The output of this process is a
simple 1-page CAT summary that can readily be shared with
colleagues. With this software, the output can be converted to HTML format for Web-based searching, printed
out locally for filing away the results, and saved as a “Kitten,” which serves as the basis of future updates to the CAT.
The clinical bottom-line section of the CAT summarizes
the results.
Multiple online CAT banks are currently available
(Table). By August 2007, ebDerm.org will be releasing
a user community–generated international database of
dermatology CATs. The ebDerm.org CATs will be constructed using CATMaker software.
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Several important limitations of CATs should be noted.
First, the study or studies under inquiry, in contrast with
systematic reviews, may not represent the best or only
data on a subject.1 Second, because CATs are userdriven and generally not subject to the highest level of
peer review, they are vulnerable to bias. Third, CATs, like
other data sources, may no longer represent the most recent best data if they are not periodically updated. For
these reasons, if a systematic review can be found to answer a clinical question (such as through the Cochrane
Skin Group), this, rather than a CAT, would be the best
source of data. Finally, the generalizability of a CAT to
any individual practice setting must be considered. CAT
summaries of severe psoriasis cases seen in the dermatology department of an urban tertiary medical center
might have limited application to moderate psoriasis cases
found in a rural middle class setting.
Despite these limitations, the CAT is a powerful tool
for improving the quality of evidence-based searches and
for practicing EBM skills. CATs can also save tremendous time when a previously generated CAT resembles
your query and can be quickly updated to reflect the best
current data. In the future, CATs may also be incorporated as a method for practicing evidence-based search
and critical appraisal skills in dermatology residency or
as continuing medical education for dermatologists.
Correspondence: David A. Barzilai, MD, PhD, Department of Dermatology, Brown University, 593 Eddy St,
APC 10th Floor, Providence, RI 02903 (david
@skinresearch.org).
Financial Disclosure: Dr Barzilai is the founder of
ebDerm.org. Dr Weinstock is on the advisory board of
ebDerm.org.
REFERENCES
1. Straus SE, Richardson WS, Glasziou P, Haynes RB. Evidence-Based Medicine: How
to Practice and Teach EBM. 3rd ed. New York, NY: Churchill Livingstone; 2005.
2. Hardin LE, Robertson S. Learning evidence-based veterinary medicine through development of a critically appraised topic. J Vet Med Educ. 2006;33(3):474-478.
3. Barzilai DA, Freiman A, Dellavalle RP, Weinstock MA, Mostow EN. Dermatoepidemiology. J Am Acad Dermatol. 2005;52(4):559-578.
4. Barzilai DA. Evidence-based dermatology: a brief introduction. http://www.vgrd
.org/archive/cases/2007/ebd/ebd.htm. Accessed May 2, 2007.
5. Bigby M. Evidence-based medicine in a nutshell: a guide to finding and using the
best evidence in caring for patients. Arch Dermatol. 1998;134(12):1609-1618.
WWW.ARCHDERMATOL.COM
EDITORIAL
Long-term Treatment for Severe Psoriasis
We’re Halfway There, With a Long Way to Go
O
VER THE LAST 30 YEARS, THE LANDMARK
PUVA [psoralen–UV-A] Follow-up
Study has demonstrated the importance of clinical epidemiology research
in making informed treatment decisions for patients with psoriasis. When PUVA was first
introduced, psoriasis was widely believed to be an epidermal cell proliferation disorder, and there were few systemic treatment options available at that time.1 Thirty years
later, psoriasis is believed to be an immunologic disorder, and more new systemic therapies have been approved to treat it in the last 4 years than in the previous
30 years combined.2-8 Our objective criterion regarding
which patients have severe psoriasis and therefore are candidates for systemic therapy has also evolved during this
period, declining from 20% to 30% body surface area
(BSA) in the 1970s to 1990s to 5% more recently.9,10 With
the increasing recognition of the impact of psoriasis on
health-related quality of life and the advent of novel therapies targeting its immunopathogenesis, the treatment of
psoriasis is undergoing a revolution. As patients with psoriasis are increasingly being treated with systemic agents
on a long-term basis, the PUVA study provides an important reminder of the challenge involved in making
clinical decisions based on a scientific understanding of
the disease’s natural history and the robust long-term
safety and efficacy data of its treatments.
See also page 1113
First, the PUVA experience exemplifies the critical importance of long-term studies to fully define the risks and
benefits of a novel treatment. In 1974, years before the
importance of PUVA in targeting T cells and dendritic
cells was recognized, this treatment was first shown to
be effective for severe psoriasis in 21 patients who had
at least 50% BSA involvement.1,11 The use of PUVA for
treating very severe psoriasis was a major development,
as all patients in the trial achieved complete clearance
and reported adverse effects were minimal. In 1977, a large
multicenter clinical trial involving more than 1300 patients who received more than 45 000 treatments demonstrated that only 3% of patients failed to achieve clearance with this regimen and that adverse effects due to
PUVA therapy were uncommon, temporary, and generally mild.12 Although PUVA therapy was considered an
experimental technique, with limited long-term safety
data, it was widely used in the United States, with an estimated 35 000 patients being treated in 1978 alone.13 In
1979, the first observations of cutaneous carcinoma were
reported in the cohort; however, it was not clear if PUVA
therapy was responsible for the excess number of skin
cancers, as affected patients had a history of treatment
with ionizing radiation or a history of skin cancer.13 In
1984, about 2 years after being approved by the Food and
Drug Administration, PUVA was definitively linked to
an excess risk of squamous cell carcinoma when the cohort had an average follow-up of 5.7 years.14 In 1997, when
the median follow-up of patients reached 19 years, PUVA
use was associated with an increased risk of melanoma,
a finding that remains controversial.15
Although it took 10 years to clearly demonstrate the
risk of squamous cell carcinoma from PUVA therapy and
even longer to detect a potential association with melanoma, the PUVA study represents a success in defining
the long-term safety of a systemic psoriasis treatment. Currently, the most robust safety data for psoriasis treatments are derived predominantly from randomized controlled clinical trials. However, these trials are generally
of short duration, measured in weeks to months, whereas
psoriasis is a lifelong disease that requires several decades of treatment for control.16 Although clinical trials
are well suited to define the efficacy of an agent, they are
particularly prone to miss the effects of drugs that are
delayed and/or uncommon (eg, cancer, cardiovascular disease, and serious infections).17 The current drug approval process leaves us with wide gaps in our knowledge of treatment safety, which is particularly problematic
when the therapy is to be used in large populations of
patients on a long-term basis.18 In particular, existing safety
data of systemic therapies for severe psoriasis are limited in the duration of drug exposure and in the number
of patients who are receiving follow-up. Therefore, the
potential risks associated with truly long-term treatment of psoriasis remain to be further defined for serious end points such as malignancy.19
The current PUVA Follow-up Study, as analyzed by
Nijsten et al,20 also provides unique data regarding the
effectiveness of long-term treatment of severe psoriasis.
During the follow-up of 815 patients who underwent 2378
skin examinations from 1985 to 2005, approximately 50%
of such examinations demonstrated that patients had mild
to no skin disease. Moreover, Nijsten and coauthors note
that the likelihood that the extent of psoriasis will change
more than 1 physician global assessment level over 1 year
and over 10 years is relatively small. These observations
suggest that our treatment approach is about 50% effective over the long term, given that the average BSA of patients who initially entered the multicenter PUVA trial
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was 33%. Based on the ecological design used for the
PUVA study, in which treatment use and psoriasis severity were not linked at the individual level, it is unclear if these patients had mild or no psoriasis because
of the natural history of psoriasis or because of the use
of psoriasis treatments. The natural history and determinants of psoriasis remission and flare remain poorly
understood as reviewed by Nijsten and colleagues. This
study therefore underscores the need for further prospective epidemiological investigations to determine the
true rate and determinants of spontaneous psoriasis improvement and flare, as well as how psoriasis may lead
to other disease states that are associated with chronic
TH1 inflammation, such as psoriatic arthritis, metabolic
disease, atherosclerosis, and myocardial infarction.21-24
Such information would better inform patients about the
natural history of their psoriasis, would improve clinical trial designs and the interpretation of safety data, and
would allow clinicians and patients to make more informed decisions about long-term vs intermittent therapy.
Remarkably, Nijsten et al20 report that despite having
access to a wide array of dermatologic therapeutic modalities, including extensive use of phototherapy and
methotrexate in the study population, about 50% of patients continued to have moderate to severe psoriasis on
their follow-up examinations. This observation demonstrates that we still have a long way to go when it comes
to consistently controlling severe psoriasis. For example, a recent study of 1657 contacts of the National
Psoriasis Foundation demonstrated that 37% of patients with moderate psoriasis (defined as 3%-10% BSA)
and 39% of patients with severe disease (⬎10% BSA) were
not receiving any therapy.25 Furthermore, more than 80%
of patients with severe psoriasis were not receiving systemic therapy or phototherapy. These data suggest that
severe psoriasis remains uncontrolled in the majority of
patients affected. Further studies are necessary to determine the degree to which this is attributable to patient
factors (such as changing treatment preference, adherence, or access to therapies) or to factors related to treatment failure over time. Although short-term clinical trials
in highly selected patient populations have shown the
efficacy of systemic therapies for psoriasis, we have large
gaps in our knowledge of the long-term effectiveness of
these treatments when they are used on a long-term basis in a broader population of patients with psoriasis. For
example, the limited data we have on methotrexate suggest that the drug is highly efficacious over the short term
(16 weeks) but that over 1 year of follow-up about 25%
of patients discontinue therapy because of adverse effects, indicating that long-term effectiveness is well below short-term efficacy.26 Similarly, long-term studies of
biologic antibody therapy (chimeric and humanized) for
inflammatory diseases show high short-term efficacy but
lower long-term effectiveness as a result of drug discontinuation associated with adverse effects or loss of treatment response during extended periods of treatment.7,27,28
Dermatologists and patients have scant data to make
head-to-head comparisons of systemic therapies, and our
general assumptions about which treatments are most safe,
efficacious, and cost-effective based on short-term trial
data may not be valid when the end point is more clinically relevant (eg, long-term effectiveness). The burden
of treatment success and failure over the patient’s lifetime is eloquently described by John Updike,29 who
wrote,“ . . . when I am at last too ill for all of these demanding and perilous palliatives, the psoriasis like a smoldering fire in damp peat will break out and spread triumphantly; in my dying I will become hideous, I will
become what I am.”
Over the last 30 years, tremendous progress has been
made in our knowledge of the pathogenesis of psoriasis
and in the development of systemic therapies to treat this
disease. This progress has been well documented by the
more than 20 000 medical publications related to psoriasis since PUVA was introduced. Despite this progress,
we still have major gaps in our basic knowledge of the
natural history of psoriasis, and a large percentage of patients with extensive psoriasis will continue to suffer from
the burden of this disease for decades.
Joel M. Gelfand, MD, MSCE
Correspondence: Dr Gelfand, Department of Dermatology and Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, 3600 Spruce St, 2 Maloney Bldg, Philadelphia, PA 19104 (Joel.Gelfand@uphs
.upenn.edu).
Financial Disclosure: Dr Gelfand has been a consultant
for Genentech, Centocor, Amgen Inc, Wyeth, WarnerChilcott, Novartis, Signum, Follica, and Therakos and
has received honoraria from CME Consultants and Emeritus Educational Sciences as well as grants from Biogenidec, AMGEN, Astellas, Centocor, and Longport Inc. He
is also on the Medical Advisory Board for the National
Psoriasis Foundation and on the Clinical Guidelines Committee for the American Academy of Dermatology.
Funding/Support: Dr Gelfand is supported by grant
K23AR051125 from the National Institute of Arthritis and
Musculoskeletal and Skin Diseases.
Role of the Sponsor: The sponsor had no role in this editorial.
Additional Contributions: John R. Stanley, MD, and
Daniel Roling, MD, provided helpful feedback on early
drafts of this manuscript.
REFERENCES
1. Parrish JA, Fitzpatrick TB, Tanenbaum L, Pathak MA. Photochemotherapy of psoriasis with oral methoxsalen and longwave ultraviolet light. N Engl J Med. 1974;
291(23):1207-1211.
2. Gottlieb AB. Immunologic mechanisms in psoriasis. J Am Acad Dermatol. 1988;
18(6):1376-1380.
3. Krueger JG, Bowcock A. Psoriasis pathophysiology: current concepts of
pathogenesis. Ann Rheum Dis. 2005;64(suppl 2):ii30-ii36.
4. Leonardi CL, Powers JL, Matheson RT, et al. Etanercept as monotherapy in patients with psoriasis. N Engl J Med. 2003;349(21):2014-2022.
5. Gordon KB, Papp KA, Hamilton TK, et al. Efalizumab for patients with moderate
to severe plaque psoriasis: a randomized controlled trial. JAMA. 2003;290(23):
3073-3080.
6. Ellis CN, Krueger GG. Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes. N Engl J Med. 2001;345(4):248-255.
7. Menter A, Feldman SR, Weinstein GD, et al. A randomized comparison of continuous vs. intermittent infliximab maintenance regimens over 1 year in the treatment of moderate-to-severe plaque psoriasis. J Am Acad Dermatol. 2007;56
(1):31.e1-e15.
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8. Gordon KB, Langley RG, Leonardi C, et al. Clinical response to adalimumab treatment in patients with moderate to severe psoriasis: double-blind, randomized
controlled trial and open-label extension study. J Am Acad Dermatol. 2006;
55(4):598-606.
9. Roenigk HH Jr, Auerbach R, Maibach H, Weinstein G, Lebwohl M. Methotrexate
in psoriasis: consensus conference. J Am Acad Dermatol. 1998;38(3):478485.
10. Pariser DM, Bagel J, Gelfand JM, et al. National Psoriasis Foundation clinical consensus on disease severity. Arch Dermatol. 2007;143(2):239-242.
11. Baker BS, Swain AF, Griffiths CE, Leonard JN, Fry L, Valdimarsson H. Epidermal
T lymphocytes and dendritic cells in chronic plaque psoriasis: the effects of PUVA
treatment. Clin Exp Immunol. 1985;61(3):526-534.
12. Melski JW, Tanenbaum L, Parrish JA, Fitzpatrick TB, Bleich HL. Oral methoxsalen photochemotherapy for the treatment of psoriasis: a cooperative clinical
trial. J Invest Dermatol. 1977;68(6):328-335.
13. Stern RS, Thibodeau LA, Kleinerman RA, Parrish JA, Fitzpatrick TB. Risk of cutaneous carcinoma in patients treated with oral methoxsalen photochemotherapy for psoriasis. N Engl J Med. 1979;300(15):809-813.
14. Stern RS, Laird N, Melski J, Parrish JA, Fitzpatrick TB, Bleich HL. Cutaneous squamous-cell carcinoma in patients treated with PUVA. N Engl J Med. 1984;310
(18):1156-1161.
15. Stern RS, Nichols KT, Vakeva LH. Malignant melanoma in patients treated for
psoriasis with methoxsalen (psoralen) and ultraviolet A radiation (PUVA): the
PUVA Follow-up Study. N Engl J Med. 1997;336(15):1041-1045.
16. Naldi L, Svensson A, Diepgen T, et al. Randomized clinical trials for psoriasis
1977-2000: the EDEN survey. J Invest Dermatol. 2003;120(5):738-741.
17. Gelfand JM. Pharmacovigilance: verifying that drugs remain safe. In: Wolverton
S, ed. Comprehensive Dermatologic Drug Therapy. 2nd ed. Philadelphia, PA:
Elsevier; 2007:1017-1026.
18. Okie S. Safety in numbers—monitoring risk in approved drugs. N Engl J Med.
2005;352(12):1173-1176.
19. Gelfand JM, Shin DB, Neimann AL, Wang X, Margolis DJ, Troxel AB. The risk of
lymphoma in patients with psoriasis. J Invest Dermatol. 2006;126(10):21942201.
20. Nijsten T, Looman CWN, Stern RS. Clinical severity of psoriasis in last 20 years
of PUVA Study. Arch Dermatol. 2007;143(9):1113-1121.
21. Gelfand JM, Neimann AL, Shin DB, Wang X, Margolis DJ, Troxel AB. Risk of myocardial infarction in patients with psoriasis. JAMA. 2006;296(14):1735-1741.
22. Neimann AL, Shin DB, Wang X, Margolis DJ, Troxel AB, Gelfand JM. Prevalence
of cardiovascular risk factors in patients with psoriasis. J Am Acad Dermatol.
2006;55(5):829-835.
23. Gelfand JM, Gladman DD, Mease PJ, et al. Epidemiology of psoriatic arthritis in
the population of the United States. J Am Acad Dermatol. 2005;53(4):573.
24. Ludwig RJ, Herzog C, Rostock A, et al. Psoriasis: a possible risk factor for development of coronary artery calcification. Br J Dermatol. 2007;156(2):271276.
25. Horn EJ, Patel KM, Fox C, Chiou F, Dann F, Lebwohl M. Treatment patterns and
utilization of systemic therapy and phototherapy among psoriasis patients
[abstract]. J Am Acad Dermatol. 2007;56:2725.
26. Heydendael VM, Spuls PI, Opmeer BC, et al. Methotrexate versus cyclosporine
in moderate-to-severe chronic plaque psoriasis. N Engl J Med. 2003;349(7):
658-665.
27. Bartelds GM, Wijbrandts CA, Nurmohamed MT, et al. Clinical response to adalimumab: the relationship with anti-adalimumab antibodies and serum adalimumab concentrations in rheumatoid arthritis [published online ahead of print
March 9, 2007]. Ann Rheum Dis.
28. Hyrich KL, Lunt M, Watson KD, Symmons DP, Silman AJ. Outcomes after switching from one anti–tumor necrosis factor alpha agent to a second anti–tumor necrosis factor alpha agent in patients with rheumatoid arthritis: results from a large
UK national cohort study. Arthritis Rheum. 2007;56(1):13-20.
29. Updike J. Self-Consciousness. New York, NY: Alfred A Knopf Inc; 1989.
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EDITORIAL
Dermatology and the Human Genome
An Epidemiologic Approach
A
S THE BODY’S MOST ACCESSIBLE ORGAN, SKIN
provides a unique window on physiologic processes governed ultimately by
the genome. Cutaneous signs have long
been used to diagnose systemic disease,
from hypothyroidism to syphilis,1 and many genetic syndromes include pathognomonic skin findings. The field
of medical genetics extends the search for patterns beyond individual patients to inheritance within families;
statistical genetics and genetic epidemiology use quantitative methods to analyze these patterns in families and
populations. Now the tools of molecular genetics are being
used to identify thousands of mutations associated with
hundreds of mostly rare genetic diseases. In the process, they are revealing unexpected genetic complexity,
blurring the distinction between Mendelian and complex disorders.2 New approaches are needed to find meaningful patterns in the outpouring of genomic data; we believe that epidemiology will provide a crucial link between
dermatology and the human genome.
Three articles in this issue of the Archives describe novel
mutations in genes associated with inherited dermatoses: FGFR3 with acanthosis nigricans (AN),3 CYLD with
See also pages 1125, 1153,
and 1209
multiple familial trichoepithelioma,4 and FECH with erythropoietic protoporphyria (EPP).5 Each of these findings
adds incrementally to the growing web of knowledge that
connects variations in genetic sequences with biologic
processes, clinical findings, and epidemiologic observations. For example, some FGFR3 mutations that produce amino acid substitutions at position 650 are known
to cause severe skeletal dysplasias; association of the
K650R mutation with AN, a relatively mild condition, is
consistent with its small effect on function in a systematic study of all possible FGFR3 missense mutations at
that locus.3 Variation in CYLD affects its negative regulation of nuclear factor–kappa B, a key signaling protein
in a pathway that has been implicated in cancer and many
other diseases.6 Confirmation that FECH mutations cause
EPP only when coinherited with another lowexpression allele is consistent with the autosomal dominant inheritance pattern observed in European populations, where one such allele is common.7
How will larger patterns emerge from the accumulation of thousands of small studies? The first systematic
catalog of inherited diseases and their genetic causes was
published in 1966 by Victor A. McKusick,8 a founder of
modern medical genetics. Now in its 12th edition, Mendelian Inheritance in Man8 has a continuously updated,
online counterpart known as OMIM (Online Mendelian
Inheritance in Man).9 The OMIM editors regularly append newly reported findings, creating essentially chronological summaries. Currently, OMIM includes more than
2000 summaries that refer to genes or syndromes associated with skin changes. In addition, various diseaseor gene-focused databases have been created to serve
particular research communities, such as the Human
Intermediate Filament Database, which catalogs mutations in epithelial keratin and related genes.10 Several journals, including Human Mutation and Human Genetics, publish brief descriptions of novel mutations along with names
of authors and digital object identifiers (DOIs) that permit their retrieval by PubMed. The Human Genome Variation Society (HGVS), which promotes the “collection, documentation and free distribution of genomic variation
information and associated clinical variations,”11 recently
announced a new initiative, the Human Variome Project,
which aims to catalog all human mutations worldwide and
make the information freely available online.12
Most mutation databases are essentially lists based on
investigations of the genetic characteristics of individual persons and families—the information equivalent of a case series. In contrast, epidemiologic studies
that link a genotype with phenotypic and environmental variables produce multidimensional data. The epidemiologic approach, which is based on precise definitions, careful sampling, and systematic analysis, allows
investigators to interpret their findings in a context larger
than that of individual persons or families. Molecular genetic analysis became practical for use in epidemiologic
studies only in the last 10 years or so; however, published reports already number in the thousands. The most
popular design for studies of genetic associations compares the distributions of genotypes between affected and
unaffected groups, which is equivalent to an epidemiologic case-control study. Because the inherited genotype is invariant, studies of gene-disease associations are
able to avoid bias related to concurrent ascertainment of
cause and effect, which is an important limitation of traditional case-control studies. When based on sound epidemiologic research methods, such studies can provide
a strong basis for inference.13
The term human genome epidemiology (HuGE) was proposed to distinguish population-based analyses of genotype frequencies, gene-disease associations, and genegene and gene-environment interactions from the
traditional studies of genetic epidemiology, which fo-
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cus on heritability analysis and gene discovery.14 The
HuGE Network (HuGENet) is an international, voluntary collaboration for promoting this population perspective and encouraging the synthesis of published and
unpublished data by consortiums of investigators.15 In
addition to devising a “road map” for this endeavor,16
HuGENet has focused on developing tools to support researchers, including a curated, searchable, online database of PubMed abstracts reporting studies in human genome epidemiology.17,18 As of April 16, 2007, the database
contained abstracts for 26 635 articles, including 247 related to dermatology. These articles, which were published in more than 50 journals in the United States, Europe, and Asia, examined 145 genes and more than 100
conditions, of which the most frequently studied were
psoriasis (61 articles), melanoma (34 articles), and atopic
dermatitis (22 articles).
The systematic review and synthesis of information
on human genetic variation in relation to health and disease is increasingly recognized as crucial to realizing the
promised medical and public health benefits of genomic research.16 This challenge is too large and complex to undertake individually or to base on a single discipline, methodology, database, or other infrastructure;
a networked approach may have a better chance of success.19 Advocacy groups like PXE International can play
an important role by creating registries and organizing
research consortiums.20 By promoting partnerships among
clinicians, basic scientists, and epidemiologists, the field
of dermatology can help promote the productive integration and translation of research findings into better
preventive medicine and clinical care. The editors of the
Archives of Dermatology would like to encourage the submission of articles that synthesize information on genetic variants in relation to diseases, both common and
rare, in the form of HuGE reviews and meta-analyses that
will integrate these findings into a larger context. An online handbook published by HuGENet and available online provides methodologic guidance in developing, conducting, and reporting individual associations and their
integration into systematic reviews.21
Marta Gwinn, MD, MPH
Muin J. Khoury, MD, PhD
Correspondence: Dr Gwinn, National Office of Public
Health Genomics, Centers for Disease Control and Pre-
vention, 4770 Buford Hwy, MS K-89, Atlanta, GA 30341
(mgwinn@cdc.gov).
Financial Disclosure: None reported.
REFERENCES
1. Templeton HJ Skin lesions as diagnostic aids in general medicine. http://www
.pubmedcentral.nih.gov/articlerender.fcgi?artid=1655038. Accessed April 16, 2007.
2. Sidransky E. Heterozygosity for a Mendelian disorder as a risk factor for complex disease. Clin Genet. 2006;70(4):275-282.
3. Berk DR, Spector EB, Bayliss SJ. Familial acanthosis nigricans due to K650T FGFR3
mutation. Arch Dermatol. 2007;143(9):1153-1156.
4. España A, Garcı́a-Amigot F, Aguado L, Garcı́a-Foncillas J. A novel missense mutation in the CYLD gene in a Spanish family with multiple familial trichoepithelioma.
Arch Dermatol. 2007;143(9):1209-1210.
5. Herrero C, To-Figueras J, Badenas C, et al. Clinical, biochemical, and genetic study
of 11 patients with erythropoietic protoporphyria including one with homozygous disease. Arch Dermatol. 2007;143(9):1125-1129.
6. Courtois G, Gilmore TD. Mutations in the NF-kappaB signaling pathway: implications for human disease. Oncogene. 2006;25(51):6831-6843.
7. Gouya L, Puy H, Robreau AM, et al. The penetrance of dominant erythropoietic
protoporphyria is modulated by expression of wildtype FECH. Nat Genet. 2002;
30(1):27-28.
8. McKusick VA. Mendelian Inheritance in Man: A Catalog of Human Genes and Genetic Disorders. Baltimore, MD: Johns Hopkins University Press; 1998.
9. OMIM—Online Mendelian Inheritance in Man. http://www.ncbi.nlm.nih.gov
/entrez/query.fcgi?db=OMIM. Accessed April 16, 2007.
10. Human Intermediate Filament Database. http://www.interfil.org. Accessed April
16, 2007.
11. HGVS—Human Genome Variation Society. http://www.hgvs.org. Accessed April
16, 2007.
12. Cotton RG; Participants in the 2006 Human Variome Project meeting. Recommendations of the 2006 Human Variome Project meeting. Nat Genet. 2007;
39(4):433-436.
13. Hattersley AT, McCarthy MI. What makes a good genetic association study? Lancet.
2005;366(9493):1315-1323.
14. Khoury MJ, Little J, Burke W, eds. Human Genome Epidemiology: A Scientific
Foundation for Using Genetic Information to Improve Health and Prevent Disease.
New York, NY: Oxford University Press; 2004.
15. National Office of Public Health Genomics. Human Genome Epidemiology Network.
http://www.cdc.gov/genomics/hugenet/. Accessed April 16, 2007.
16. Ioannidis JP, Gwinn M, Little J, et al. A road map for efficient and reliable human
genome epidemiology. Nat Genet. 2006;38(1):3-5.
17. GDPInfo. Genomics and Disease Prevention Information System. http://apps
.nccd.cdc.gov/genomics/GDPQueryTool/default.asp. Accessed April 16, 2007.
18. Lin BK, Clyne M, Walsh M, et al. Tracking the epidemiology of human genes in
the literature: the HuGE Published Literature database. Am J Epidemiol. 2006;
164(1):1-4.
19. Ioannidis JP, Bernstein J, Boffetta P, et al. A network of investigator networks in
human genome epidemiology. Am J Epidemiol. 2005;162(4):302-304.
20. Terry SF, Terry PF, Rauen KA, Uitto J, Bercovitch LG. Advocacy groups as research organizations: the PXE International example. Nat Rev Genet. 2007;
8(2):157-164.
21. Little J, Higgins J, eds. The HuGENet HuGE Review Handbook, Version 1.0. http:
//www.genesens.net/_intranet/doc_nouvelles/HuGE%20Review%20Handbook
%20v11.pdf. Accessed April 16, 2006.
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Editor’s Note
The Next Frontier of Dermatologic Research
Recently, dermatology research has identified new genetic alterations associated with diseases. In 2005, the Archives was
privileged to publish the first of these reports, which can be summarized as “name that tune” by identifying the single erroneous note causing the disease.1 Clinicians longed for progress beyond the stupefying identification of variants of genetic
disorders, dared to hope for gene therapy for dermatologic diseases, and questioned the relevance of ever increasing reports
of 2 or 3 cases with a few codons different from other cases of the same disease. The “tune” can be named in 1 note. Now, we
hear the sweet melody of therapy in at least 1 case of junctional epidermolysis bullosa!2
Our next frontier is prevention of dermatologic diseases by the identification and modification of environmental risk factors
among persons susceptible to disease due to genotype.3 To realize this goal, the principles of epidemiologic research will be applied to molecular genetic analysis of populations.4 The Archives invites HuGE Reviews and meta-analyses submitted under the
article category “Reviews” as described in our Instructions for Authors at http://archderm.ama-assn.org/misc/ifora.dtl.
June K. Robinson, MD
Editor
1. Gao M, Wang PG, Yang S, et al. Two frameshift mutations in the RNA-specific adenosine deaminase gene associated with dyschromatosis symmetrica hereditaria.
Arch Dermatol. 2005;141(2):193-196.
2. Mavilio F, Pellegrini G, Ferrari S, et al. Correction of junctional epidermolysis bullosa by transplantation of genetically modified epidermal stem cells.
Nat Med. 2006;12(12):1397-1402.
3. Coughlin SS. The intersection of genetics, public health, and preventive medicine. Am J Prev Med. 1999;16(2):89-90.
4. Gwinn M, Khoury MJ. Dermatology and the human genome: an epidemiologic approach. Arch Dermatol. 2007;143(9):1194-1195.
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OFF-CENTER FOLD
SECTION EDITORS: MICHAEL E. MING, MD, MSCE; ASSISTANT SECTION EDITORS: CARRIE ANN R. CUSACK, MD; SENAIT W. DYSON, MD;
JACQUELINE M. JUNKINS-HOPKINS, MD; VINCENT LIU, MD; KARLA S. ROSENMAN, MD
Hyperpigmented Keratotic Nodules
Ser Ling Chua, MRCP; Kusum Kulkarni, MRCPath; Eric Saihan, FRCP; Queen’s Medical Centre, Nottingham, England
A 59-year-old woman of Indian descent presented with
a 6-month history of an increasing number of itchy hyperpigmented nodules on her trunk and limbs. The lesions were preceded by pruritus. Treatment with topical 0.05% clobetasone butyrate cream and oral cetirizine
reduced the pruritus but did not affect the appearance
of the lesions. The patient had a history of type 2 diabetes mellitus and hypertension. Ultrasonography showed
that her liver was enlarged, with a fatty echo texture.
Physical examination revealed multiple 3- to
15-mm-diameter hyperpigmented lesions with a central
keratotic plug (Figure 1). The Koebner phenomenon
was seen (Figure 2). There was sparing of her back
in “difficult-to-reach” areas. A 4-mm punch biopsy
specimen obtained from a lesion on the left upper
back area was sent for histopathologic examination
(Figure 3).
What is your diagnosis?
Figure 1.
Figure 2.
Figure 3.
REPORT OF A CASE
Verrucous Papules and Plaques in a Pediatric Patient
Mercedes E. Gonzalez, MD; Fiona P. Blanco, MD; Maria C. Garzon, MD; Columbia University, New York, New York
extensor surface of the left forearm (Figure 2), from
which a shave biopsy specimen was obtained.
REPORT OF A CASE
A 12-year-old boy presented with a several-month history of enlarging verrucous lesions on his face and left
forearm. Similar lesions had first appeared on the central area of his face 3 years earlier and had been excised.
His medical history included failure to thrive, which required gastrostomy tube feeding; Arnold-Chiari malformation, which had been corrected when he was 1 year
old; idiopathic hypertrophic subaortic stenosis, which required 2 corrective surgical procedures; global developmental delay; and hypertension, which required propranolol therapy. His family history was unremarkable.
Physical examination revealed coarse facial features,
large lips, a short neck, and 4 facial verrucous papules
(Figure 1). Follicular papules were present over the
lateral surface of both arms and on the face. The palms
were hyperkeratotic, with accentuation of the creases.
There was a large 2 ⫻ 2-cm verrucous plaque on the
Figure 1.
What is your diagnosis?
Figure 2.
Diffuse Nodules in a Woman With Renal Failure
Erin B. Lesesky, MD; Michelle T. Pelle, MD; Terence C. O’Grady, MD; University of California, San Diego
A 47-year-old woman presented with a 1-year history of
an erythematous plaque on her left leg. The plaque was
not painful when it first developed, but it became tender when it ulcerated. She denied trauma and systemic
symptoms. There was no previous treatment. Her medical history was significant for type 2 diabetes, chronic
renal failure, cardiomyopathy, and gouty arthritis.
Physical examination revealed an 11 ⫻ 21-cm erythematous plaque on the lower area of the left leg, with
scattered firm, white papules and areas of ulceration
(Figure 1), and a 7-cm, rubbery, nontender, reddish yellow nodule on the dorsal aspect of the right hand
(Figure 2). Also, pink to white firm nodules were seen
in a linear distribution on the lateral aspect of the fingers, the dorsal aspect of both hands, and the extensor
aspect of the forearms. A punch biopsy specimen was
obtained from the plaque on the left lower leg area
(Figure 3).
What is your diagnosis?
Figure 1.
Figure 2.
Figure 3.
REPORT OF A CASE
Tender Nodules on the Palms and Soles
Lisa Esler-Brauer, MD; Ilene Rothman, MD; University at Buffalo School of Medicine and The Women and Children’s Hospital of Buffalo, Buffalo, New York
A 10-year-old white boy presented with a 3-day history
of painful, red, swollen hands. Physical examination
revealed multiple, erythematous, 1- to 3-cm, tender nodules on his palms (Figure 1). A few similar smaller
nodules were present on the plantar aspect of the middle
of both heels. The patient had an associated low-grade
fever but was otherwise healthy and active. He had
recently spent a lot of time in ice hockey practice. His
primary care physician had initially evaluated him, and
the results of rapid streptococcal screening were
negative, no murmur was appreciated, and no treatment
had been initiated. A 4-mm punch biopsy specimen was
obtained from a palmar lesion for microscopic evaluation (Figure 2 and Figure 3).
What is your diagnosis?
Figure 1.
Figure 2.
Figure 3.
REPORT OF A CASE
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Hyperpigmented Keratotic Nodules
Diagnosis: Acquired perforating collagenosis.
MICROSCOPIC FINDINGS
Microscopic examination showed a cup-shaped deformity of the epidermis that was filled with a plug consisting of collagen, parakeratosis, and inflammatory exudate. The underlying epidermis was atrophic, but the
adjacent epidermis was acanthotic. Dermal collagen at
the base of the plug was almost perpendicular to the overlying epidermis. There was a sparse mixed inflammatory exudate around the upper dermal vessels.
DISCUSSION
The main histologic abnormality in perforating dermatoses is the transepithelial elimination of material from
the dermis. There are 4 main types of primary perforating dermatoses: Kyrle disease, elastosis perforans serpiginosa, reactive perforating collagenosis, and perforating folliculitis. Perforating dermatoses have also been
reported in association with chronic renal failure and diabetes mellitus. The term acquired perforating dermatoses
has been used to describe them. The lesions are typically dome-shaped papules and nodules with a central
keratotic plug. They have been considered a distinct
entity from primary perforating dermatoses owing to their
differences in clinical and histologic presentation from
the original descriptions of the primary perforating dermatoses.1-3
Acquired perforating dermatosis has been reported to
occur in 4.5% to 10% of patients receiving hemodialysis
in North America. In Dundee, Scotland, the reported
prevalence was 11% in patients who were undergoing dialysis, 78% of whom were diabetic.2 In most patients, pruritus precedes or develops at the same time as the skin
lesions. The Koebner phenomenon is frequently observed. Acquired perforating dermatosis is also associated with lymphoma, nephropathy of various causes (including obstructive nephropathy, glomerulonephritis,
hypertensive nephrosclerosis, heroin use, and human immunodeficiency virus infection), hypothyroidism, hyperparathyroidism, neurodermatitis, liver dysfunction,
and hypertension.4
The pathogenesis of acquired perforating dermatosis
is unknown. Trauma due to scratching has been postulated as a precipitating factor. This theory is supported
by the linear distribution and reproducibility of the lesions by scratching of the skin.4 In diabetic patients, it
has been suggested that scratching results in localized dermal necrosis due to poor blood supply as a result of diabetic vasculopathy. The necrotic tissue is then extruded
through the epidermis.5 In patients with renal impairment, the dermal microdeposition of substances such as
uric acid has been suggested as a cause of acquired perforating dermatosis.6
To our knowledge, there is no well-established therapy
for acquired perforating dermatosis. In some patients, the
skin lesions resolve spontaneously. There have been reports of successful treatment of both primary and acquired perforating dermatoses with topical, intradermal, and systemic corticosteroids; topical and systemic
retinoids; UV-B phototherapy; methotrexate; and allopurinol.1,2,4
REFERENCES
1. Patterson JW, Richmond VA. The perforating disorders. J Am Acad Dermatol. 1984;
10(4):561-581.
2. Morton CA, Henderson IS, Jones MC, et al. Acquired perforating dermatosis in a
British dialysis population. Br J Dermatol. 1996;135(5):671-677.
3. Rapini RP, Hebert AA, Drucker CR. Acquired perforating dermatosis. Arch Dermatol.
1989;125(8):1074-1078.
4. Faver IR, Daoud MS, Daniel Su WP. Acquired reactive perforating collagenosis.
J Am Acad Dermatol. 1994;30(4):575-580.
5. Cochran RJ, Tucker SB, Wilkin JK. Reactive perforating collagenosis of diabetes
mellitus and renal failure. Cutis. 1983;31(1):55-58.
6. Haftek M, Euvrard S, Kanitakis J, et al. Acquired perforating dermatosis of diabetes mellitus and renal failure: further ultrastructural clues to its pathogenosis.
J Cutan Pathol. 1993;20(4):350-355.
Verrucous Papules and Plaques in a Pediatric Patient
Diagnosis: Cutaneous papillomas associated with
Costello syndrome.
MICROSCOPIC FINDINGS
AND CLINICAL COURSE
Histopathologic examination of the left arm lesion showed
a hyperplastic epidermis with vascular ectasia and a mononuclear cell infiltrate in the dermis. The findings were
consistent with verrucous acanthoma (papilloma). The
patient was referred to the plastic surgery department to
discuss treatment options for the facial papillomas.
DISCUSSION
Approximately 150 cases of Costello syndrome have
been identified since the condition was described in 1977
by Costello1 and later named by Der Kaloustian et al2 in
1991. The major features include growth and mental retardation, with a sociable personality; coarse facies
(macrocephaly, thick lips, big tongue, depressed nasal
bridge, and low-set ears with thick lobes); short neck;
musculoskeletal abnormalities (tight Achilles tendon, hyperextensible fingers, and limited joint mobility), cardiac defects (hypertrophic cardiomyopathy, cardiac
malformations, and supraventricular arrhythmias); increased risk for malignant tumors (rhabdomyosarcoma,
ganglioneuroblastoma, neuroblastoma, and bladder
carcinoma); and distinctive cutaneous findings.3 Cutaneous papillomas are a unique skin manifestation of Costello syndrome, although they are present in only about
50% of patients.4 Papillomas occur on the face, anus, axillae, elbows, knees, vocal cords, and abdomen and usually develop between the 2nd and 15th years of life. The
pathogenesis is unknown, but mechanical stress and human papillomavirus have been implicated.5 Clinically, the
papillomas resemble verrucae, but histologically, verrucae can be distinguished by the presence of koilocytes,
vertical columns of parakeratosis, and foci of clumped
keratohyaline granules. In addition to verrucae, the differential diagnosis includes epidermal nevus, verrucous
carcinoma, keratoacanthoma, actinic keratosis, squamous cell carcinoma, lipoid proteinosis, deep fungal infections, and epidermodysplasia verruciformis. Treatment options are limited to destruction and excision of
the lesions, both of which may result in profound scarring. Patients with Costello syndrome also invariably have
loose, redundant skin, especially of the neck, hands, and
feet, which results in the appearance of deep creases on
the palms and soles, as seen in our patient. Acanthosis
nigricans, pigmented acral nevi, vascular birthmarks, hyperkeratosis, hyperpigmentation of the skin, thin deepset nails, thick eyebrows, and sparse curly scalp hair also
frequently occur.4
Historically, Costello syndrome was considered a
variant of Noonan syndrome and was synonymous with
cardiofaciocutaneous syndrome, but these 3 conditions
were found to have separate genetic loci.6 The derangement in Costello syndrome is a de novo mutation of the
HRAS gene (v-Ha-ras Harvey rat sarcoma viral oncogene homologue), located on chromosome 11, resulting
in permanent activation of the HRAS protein and
uncontrolled cell division.7 Our patient was diagnosed
as having both Noonan syndrome and cardiofaciocutaneous syndrome before receiving the diagnosis of Costello syndrome at the age of 6 years. The average age at
diagnosis in 1 review was 14 years, which further indicates that establishing the correct diagnosis may be a
challenge.8 Genetic testing is now possible, but the
diagnosis of Costello syndrome still relies heavily on
clinical recognition of the pattern of malformations.
Characteristic skin features provide early clues to the
diagnosis, thereby facilitating the prevention and management of the more serious systemic effects of Costello
syndrome.
REFERENCES
1. Costello JM. A new syndrome: mental subnormality and nasal papillomata. Aust
Paediatr J. 1977;13(2):114-118.
2. Der Kaloustian VM, Moroz B, McIntosh N, Watters AK, Blaichman S. Costello
syndrome. Am J Med Genet. 1991;41(1):69-73.
3. Costello syndrome. http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi
?id=218040. Accessed June 11, 2007.
4. Hennekam RC. Costello syndrome: an overview. Am J Med Genet C Semin Med
Genet. 2003;117(1):42-48.
5. Torrelo A, Lopez-Avila A, Medeiro IG, Zambrano A. Costello syndrome. J Am Acad
Dermatol. 1995;32(5, pt 2):904-907.
6. Wieczorek D, Majewski F, Gillessen-Kaesbach G. Cardio-facio-cutaneous (CFC)
syndrome—a distinct entity? report of three patients demonstrating the diagnostic difficulties in delineation of CFC syndrome. Clin Genet. 1997;52(1):37-46.
7. Gripp KW, Lin AE, Stabley DL, et al. HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation. Am J Med Genet A. 2006;140(1):
1-7.
8. White SM, Graham JM Jr, Kerr B, et al. The adult phenotype in Costello syndrome.
Am J Med Genet A. 2005;136(2):128-135.
Diffuse Nodules in a Woman With Renal Failure
DISCUSSION
Diagnosis: Chronic tophaceous gout.
MICROSCOPIC FINDINGS
AND CLINICAL COURSE
The biopsy specimen revealed amorphous pink to gray
material in the dermis, surrounded by lymphocytes and
multinucleated foreign body–type giant cells, with no evidence of vasculitis or panniculitis. A von Kossa stain was
negative for calcium. These microscopic findings were
consistent with a diagnosis of a gouty tophus. Laboratory data revealed normal levels of serum calcium and
phosphorus and an elevated level of uric acid (12.2 mg/dL
[to convert to micromoles per liter, multiply by 59.485];
reference range, 2.6-7.5 mg/dL).
Oral allopurinol therapy (100 mg every other day; alternate-day dosing because of renal failure) was initiated, and hemodialysis was started 3 months later. The
patient’s uric acid level decreased markedly to 5.6 mg/dL
over a 5-month period. No new tophi have developed since
the allopurinol therapy was begun. In this case, transepidermal elimination of the tophi caused multiple large
ulcers and subsequent pyodermas that yielded methicillinresistant Staphylococcus aureus and vancomycinresistant Enterococcus faecalis on culture. Meticulous
wound care, frequent surveillance for infection, allopurinol, and antibiotics as needed are the mainstays of our
patient’s treatment.
Gout, one of the cutaneous deposition disorders, is a metabolic disease in which the underlying abnormality is hyperuricemia. The clinical manifestations include acute
gouty arthritis, cutaneous tophi, and uric acid nephrolithiasis and nephropathy.1 Hyperuricemia can result from
overproduction or underexcretion of uric acid, which is
the end product of the catabolism of purines and is primarily excreted by the kidneys.1 Predisposing factors for
the development of gout include dietary overindulgence, obesity, excessive alcohol intake, renal insufficiency, and ingestion of certain medications, including
diuretics and cyclosporine.2,3 The 3 classic stages of gout,
which can occur after years of asymptomatic hyperuricemia, are acute gouty arthritis; intercritical gout, which
includes the intervals between attacks; and chronic tophaceous gout.2
Chronic tophaceous gout has a prevalence of less than
5% among patients with gout because of the availability
of effective antihyperuricemic medications.2 The average interval from the first gouty attack to the onset of tophi is 12 years.4 Tophi present as firm, smooth or multilobulated, white to red dermal or subcutaneous nodules.
They are most commonly located in the skin overlying
joints or the helix of the ear and are often nontender.1
Diagnosis of gout during an acute attack is made by
demonstration of urate crystals in synovial fluid.
However, urate crystals can also be obtained from a
tophus or visualized histologically in excised tissue.
Ideally, specimens are placed in alcohol, which preserves the crystals, but formalin-fixed tissue also exhibits key features, including deposits of amorphous material containing needlelike clefts within the dermis or
subcutis and a surrounding infiltrate of lymphocytes
and foreign body–type giant cells.1 Treatment of acute
attacks includes colchicine and nonsteroidal antiinflammatory drugs. Chronic tophaceous gout is best
treated by allopurinol and reduction of risk factors,
with a goal of lowering the serum uric acid level to less
than 6 mg/dL, which will prevent further attacks and
can lead to resorption of tophi.5 Our patient improved
markedly with allopurinol therapy and the discontinuation of diuretic treatment once hemodialysis was
started.
REFERENCES
1. Franke I, Gollnick H. Deposition diseases. In: Bolognia J, Jorizzo J, Rapini R, eds.
Dermatology. New York, NY: Mosby Elsevier Ltd; 2003:669-672.
2. O’Duffy JD, Hunder GG, Kelly PJ. Decreasing prevalence of tophaceous gout. Mayo
Clin Proc. 1975;50(5):227-228.
3. Fam AG, Assaad D. Intradermal urate tophi. J Rheumatol. 1997;24(6):1126-1131.
4. Gutman AB. The past four decades of progress in the knowledge of gout, with an
assessment of the present status. Arthritis Rheum. 1973;16(4):431-445.
5. Yamanaka H, Togashi R, Hakoda M, et al. Optimal range of serum urate concentrations to minimize risk of gouty attacks during anti-hyperuricemic treatment.
Adv Exp Med Biol. 1998;431:13-18.
Tender Nodules on the Palms and Soles
Diagnosis: Palmoplantar eccrine hidradenitis
(PEH).
MICROSCOPIC FINDINGS
Examination of the hematoxylin-eosin–stained skin biopsy specimen from the erythematous tender nodule revealed a dense neutrophilic inflammatory infiltrate around
the eccrine sweat glands.
DISCUSSION
Palmoplantar eccrine hidradenitis is a distinct entity with
characteristic clinical findings. First reported in 1988, it
was named traumatic plantar urticaria.1 Since then, 47 cases
have been reported under 5 different names, including idiopathic (palmo)plantar hidradenitis and recurrent palmoplantar hidradenitis.2 It primarily affects healthy children and is characterized by an abrupt appearance of
erythematous, tender nodules on the palms and soles that
may last 1 to 4 weeks and cause considerable difficulty in
walking.2 Most eruptions are limited to the plantar surfaces, although palmar lesions have been documented.3
Typical histiologic findings include a neutrophilic perieccrine infiltrate in the setting of varying degrees of superficial and deep perivascular infiltrates of neutrophils, lymphocytes, and histiocytes as well as septal panniculitis.3
The etiology of PEH remains unknown. Local mechanical or thermal trauma, moisture, recent streptococcal infection, and hypersensitivity reaction have all been
considered.3 Naimer et al4 postulate that it is exposure
to wet footwear that triggers PEH, as a correlation was noted
between the eruption and strenuous activity, such as ballet dancing. Interestingly, the majority of the lesions in our
case were on the palmar surface and may be attributed to
the effect of hockey glove use that created a moist environment similar to a shoe. Some speculate that excessive
sweating, whether intrinsic (hyperhidrosis) or extrinisic
(exertion induced), may cause obstruction of the eccrine
duct, with subsequent rupture leading to the inflammatory cascade.5 This could explain eruptions related to hot
tub use. The differential diagnosis of PEH includes erythema nodosum or other atypical panniculitis, erythema
multiforme, insect bites, vasculitis, chilblains, migratory
angioedema, embolic disease, and cellulitis.
Most patients respond to bed rest, which presumptively decreases sweat secretion to allow resolution of inflammation. Gradual resumption of activity after resolution of lesions is recommended. Relapses occur in 50% of
patients.6 Topical and systemic steroids as well as systemic antibiotics and nonsteroidal anti-inflammatory drugs
have been used to treat PEH, without clear benefit.2,3 Palmoplantar eccrine hidradenitis is a characteristic clinical
entity that is benign and self-limiting. It is likely more common than has been realized in the pediatric population and
should be recognizable by dermatologists based on its distinctive presentation and clinical findings.
REFERENCES
1. Metzker A, Brodsky F. Traumatic plantar urticaria—an unrecognized entity? J Am
Acad Dermatol. 1988;18(1, pt 1):144-146.
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2. Rubinson R, Larralde M, Santos-Munoz A, Parr V, de Parra NP. Palmoplantar eccrine hidradenitis: seven new cases. Pediatr Dermatol. 2004;21(4):466-468.
3. Landau M, Metzker A, Gat A, Nen-Amitai D, Brenner S. Palmoplantar eccrine hidradenitis: three new cases and review. Pediatr Dermatol. 1998;15(2):97-102.
4. Naimer SA, Zvulunov A, Ben-Amitai D, Landau M. Plantar hidradenitis in children
induced by exposure to wet footwear. Pediatr Emerg Care. 2000;16(3):182-183.
5. Ben-Amitai D, Hodak E, Landau M, Metzker A, Feinmesser M, David M. Idiopathic
palmoplantar eccrine hidradenitis in children. Eur J Pediatr. 2001;160(3):189-191.
6. Simon M Jr, Cremer H, von den Driesch P. Idiopathic recurrent palmoplantar hidradenitis in children: report of 22 cases. Arch Dermatol. 1998;134(1):76-79.
Submissions
Clinicians, local and regional societies, and residents and
fellows in dermatology are invited to submit quiz cases
to this section. Cases should follow the established pattern of a Report of a Case section of less than 150 words,
followed by the Diagnosis, Microscopic Findings, and Discussion. The discussion should be between 285 and 350
words. References are limited to 9. The text should be submitted double-spaced, with the right margin ragged. Photomicrographs and illustrations must be wider than they
are tall (horizontal orientation), sharply focused with good
color balance, and submitted as separate JPG files with each
file numbered with the figure number. Material must be
accompanied by the required copyright transfer statement (see authorship form in Instructions for Authors
[http://archderm.ama-assn.org/misc/auinst_crit.pdf]).
Manuscripts should be submitted via our online manuscript submission and review system (http://manuscripts
.archdermatol.com). Please indicate in your cover letter
that the manuscript is a submission to Off-Center Fold.
CORRESPONDENCE
ase chain reaction; and further sequencing analysis was
performed. We identified 1 mutation not previously reported. The mutation was found in all patients but not
in the healthy members of this family. The change was a
point mutation in exon 20 (G2687C) that resulted in substitution of glycine at 896 by alanine (Figure 2). The
mutation was not detected in 110 unrelated controls.
RESEARCH LETTERS
A Novel Missense Mutation
in the CYLD Gene in a Spanish Family
With Multiple Familial Trichoepithelioma
Comment. Herein, we report a novel CYLD gene
mutation at nucleotide 2687 that carries out 1 amino
acid change at glycine 896 in the 4 affected members
of this family but not in the proband. The fact that we
have not detected this change in 110 unaffected controls
makes a contribution to the genotype-phenotype correlation in MFT.
The CYLD gene is considered a negative regulator of
nuclear factor kappa B(NF-␬B).5 Thereby, inhibition or
B
rooke-Spiegler syndrome (BSS) includes the combination of spiradenomas, cylindromas, and
trichoepitheliomas. It has been postulated that
BSS results from defects in the regulation of putative stem
cells of the folliculosebaceous-apocrine unit.1 This follicular dysregulation may give rise to 3 different genodermatoses: familial cylindromatosis (FC), multiple familial trichoepithelioma (MFT), or the classic triad of BSS.
See also pages 1125, 1153,
and 1194
A
B
I.
The gene for FC was mapped to chromosome
16q12-q13.2 At present, 32 different germline mutations in the CYLD gene have been described,3 20 in
families with FC, 8 in families with MFT, and 4 in families with BSS. Taken together, these observations suggest that these inherited syndromes associated with skin
appendage tumors not only share a common genetic basis but also may represent phenotypic variation of the same
disease.4
1
G/A
II.
1
G/A
1
G/G
C T
C
T G T G C
Figure 1. Clinical picture (A) and family pedigree (B) for the present case. A,
Multiple trichoepitheliomas are present on the upper eyelids, nose, nasolabial
folds, and the upper lip in the mother of the proband. B, Pedigree of the
family: for individuals whose DNA samples have been analyzed, the allele
sequences at codon 896 have been indicated as G (glycine) or A (alanine).
The proband (arrow) encodes for a G on both alleles (G/G), whereas the
affected family members are heterozygous for the mutation (black circles)
encode an A on the mutant allele.
B
Wild-type sequence
Intron 19
Mutant sequence
G896A
Exon 20
C A T A
G
G
T G
G T
C A
G
A
A
T G
3
G/A
III.
Report of a Case. An 8-year-old girl came to our department with her parents. Her mother, grandmother, and 2
aunts were diagnosed as having trichoepithelioma since
childhood (Figure 1). The parents of our patient wanted
to know if their daughter might harbor any genetic susceptibility for these cutaneous lesions.
Blood samples were obtained from available family
members and 110 unrelated controls. Genomic DNA was
extracted; all coding exons were amplified by polymerA
2
G/A
C T
C
T G T G C
C A
T A
G
S
T G
G T
C
A G A
A
T G
Figure 2. Genetic analysis of the family with multiple familial trichoepithelioma. Shown are wild-type DNA (A) and mutant sequences (B) of exon 20 of CYLD from
control and affected members, respectively.
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inactivation of CYLD enhances the action of NF-kB and leads
to increased resistance to apoptosis and carcinogenesis.6
To our knowledge, this mutation has not been previously described. The known mutations of the CYLD gene
are mostly located in the C-terminal portion.
Germline mutations display tissue-specific function
loss. Another possibility would be that the germline mutation determines the tissues where the preferred second hit occurs. When the second hit occurs in eccrineapocrine cells, the patients become susceptible to multiple
cylindromas; in hair follicle cells, the patients exhibit susceptibility to multiple cylindromas or MFT.6
Our study shows the importance of mutation screening of the CYLD gene in patients affected with FC and MFT
as well as their relatives to identify early clinical manifestations. Analysis of control volunteers in this report confirms the role of this missense mutation as the cause of this
syndrome. Further studies evaluating the effect of this mutation in animal models must be considered.
Agustı́n España, MD
Fermin Garcı́a-Amigot, PhD
Leyre Aguado, MD
Jesús Garcı́a-Foncillas, MD
Correspondence: Dr España, Department of Dermatology, University Clinic of Navarra, University of Navarra, PO Box 31080, Pamplona, Navarra, Spain (aespana
@unav.es).
Financial Disclosure: None reported.
Funding/Support: This study was supported in part by
the Spanish Academy of Dermatology.
Role of the Sponsor: The sponsor had no role in the design and conduct of the study, in the collection, analysis
and interpretation of data, or in the preparation review,
or approval of the manuscript.
1. Clarke J, Ioffreda M, Helm KF. Multiple trichoepithelioma: a folliculosebaceousapocrine genodermatosis. Am J Dermatopathol. 2002;24(5):402-405.
2. Fenske C, Banerjee P, Holden C, Carter N. Brooke-Spiegler syndrome locus
assigned to 16q12-q13. J Invest Dermatol. 2000;114(5):1057-1058.
3. The Human Gene Mutation Database at the Institute of Medical Genetics in
Cardiff [registration required]. http://www.hgmd.cf.ac.uk/ac/all/php
?gene=CYLD. Accessed February 9, 2007.
4. Bowen S, Gill M, Lee DA, et al. Mutations in the CYLD gene in BrookeSpiegler syndrome, familial cylindromatosis, and multiple trichoepithelioma: lack of genotype-phenotype correlation. J Invest Dermatol. 2005;124
(5):919-920.
5. Regamey A, Hohl D, Liu JW, et al. The tumor suppressor CYLD interacts with
TRIP and regulates negatively nuclear factor kB activation by tumor necrosis
factor. J Exp Med. 2003;198(12):1959-1964.
6. Liang YH, Gao M, Sun LD, et al. Two novel CYLD gene mutations in Chinese
families with trichoepithelioma and a literature review of 16 families with trichoepithelioma reported in China. Br J Dermatol. 2005;153(6):1213-1215.
phatase, nonreceptor type 11), a gene encoding a tyrosinephosphatase protein named SHP-2, with 2 particular “hot
spots” in exons 7 and 12.2-5 Despite overlapping clinical
manifestations, LS is distinct from Noonan syndrome, another PTPN11 gene mutation–related disorder but with
a different mutation spectrum. Herein we report the first
case to our knowledge of typical LS featuring a new
PTPN11 gene mutation.
Report of a Case. A 39-year-old woman with a medical
history of deafness and a familial background of Down
syndrome in a sister was referred for evaluation of pigmentary changes that first appeared during infancy associated with mild facial dysmorphism. Clinical examination disclosed multiple light or dark brown macules
of varied sizes scattered throughout her whole body surface including her face, palmoplantar areas, lips, and conjunctiva (Figure 1). There were no lentigines on the other
mucous membranes. Facial examination revealed hypertelorism. Electrocardiography showed a first-degree atrioventricular block, whereas heart ultrasound evaluation did not find any valve abnormality. Hearing
investigations confirmed sensorineural deafness. There
were no urogenital abnormalities, endocrinopathy, or
growth retardation. A diagnosis of LS was established
based on the presence of 4 criteria.
After obtaining the patient’s consent, we undertook
direct sequencing of the PTPN11 coding region and discovered a previously undescribed (to our knowledge) heterozygous missense mutation in exon 13, namely a
G1493T transversion leading to an R498L change in amino
acid sequence (Figure 2). No genetic analysis of her relatives could be carried out to establish a diagnosis of de
novo or inherited mutation.
Comment. The SHP-2 phosphatase plays several important roles in cellular physiologic function, mainly in cell
proliferation, differentiation, migration, and adhesion.6-8 This protein contains 2 main domains: a Cterminal protein-tyrosine phosphatase (PTP) domain involved in catalytic activity and 2 N-terminal Src homology
2 (SH2) domains interacting with the PTP domain, keeping it folded and inactive (Figure 2).3 To our knowledge, only 7 PTPN11 mutations have been reported in
patients with LS, all of them in the PTP domain in exons
7 (Y279C and Y279S), 12 (T468M and A461T), and 13
A Novel PTPN11 Gene Mutation
in a Patient With LEOPARD Syndrome
I
n 1969, Gorlin et al1 described an autosomal dominant syndrome encompassing multiple lentigines,
electrocardiographic abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness, currently
known as LEOPARD syndrome (LS). Recently, it has been
reported that most cases of LS are probably related to heterozygous mutations of PTPN11 (protein-tyrosine phos-
Figure 1. Numerous lentiginous elements scattered throughout the trunk.
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1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
5′
3′
Y279
N
N-SH2
3
T468M
C-SH2
104 112
R498L
Catalytic region (PTP)
216 221
C
524
Figure 2. Genomic structure of the PTPN11 gene and corresponding functional organization of the PTPN11-encoded SHP-2 phosphatase. Exons are represented
as shaded boxes. Also shown are the main LEOPARD syndrome–associated mutations (hot spots Y279C and T468M) and our patient’s R498L mutation affecting
exon 13. N and C are terminal indicators; PTP indicates protein-tyrosine phosphatase; SH2, Src homology 2.
(Q506P, Q510E, and Q510G).2,4,9-11 Two of them (Y279C
and T468M) represent more than 90% of the identified
changes. The mutational site in our patient is close to the
PTP-SH2 domains interacting tract and to the previously reported mutations affecting exon 13. Accordingly, this change is probably relevant as to LS pathomechanisms. PTPN11 mutations in Noonan syndrome
are likely to result in a gain of function with “permanent” catalytic activity of the protein, whereas recent results unexpectedly suggest that LS-related PTPN11 mutations result in a decrease in the phosphatase function
of SHP-2.12-14 Understanding why topographically closely
related mutations on the same gene may have opposite
functional consequences but still result in close phenotypes will be a rewarding challenge.
Aurélie Du-Thanh, MD
Hélène Cave, PharmD, PhD
Didier Bessis, MD
Carine Puso, MD
Jean-Jacques Guilhou, MD
Olivier Dereure, MD, PhD
Correspondence: Dr Dereure, Department of Dermatology, University of Montpellier I, Hôpital Saint-Eloi, 80
Ave A. Fliche, 34295 Montpellier CEDEX 5, France
(o-dereure@chu-montpellier.fr).
Financial Disclosure: None reported.
1. Gorlin RJ, Anderson RC, Blaw M. Multiple lentigenes syndrome. Am J Dis
Child. 1969;117(6):652-662.
2. Digilio MC, Conti E, Sarkozy A, et al. Grouping of multiple-lentigines/
LEOPARD and Noonan syndromes on the PTPN11 gene. Am J Hum Genet.
2002;71(2):389-394.
3. Legius E, Schrander-Stumpel C, Schollen E, Pulles-Heintzberger C, Gewillig M, Fryns JP. PTPN11 mutations in LEOPARD syndrome. J Med Genet.
2002;39(8):571-574.
4. Keren B, Hadchouel A, Saba S, et al. PTPN11 mutations in patients with
LEOPARD syndrome: a French multicentric experience. J Med Genet. 2004;
41(11):e117.
5. Ogata T, Yoshida R. PTPN11 mutations and genotype-phenotype correlations in Noonan and LEOPARD syndromes. Pediatr Endocrinol Rev. 2005;
2(4):669-674.
6. Kroll J, Waltenberger J. The vascular endothelial growth factor receptor
KDR activates multiple signal transduction pathways in porcine aortic endothelial cells. J Biol Chem. 1997;272(51):32521-32527.
7. Chang Y, Ceacareanu B, Dixit M, Sreejayan N, Hassid A. Nitric oxide-induced
motility in aortic smooth muscle cells: role of protein tyrosine phosphatase SHP-2
and GTP-binding protein Rho. Circ Res. 2002;91(5):390-397.
8. Maheshwari M, Belmont J, Fernbach S, et al. PTPN11 mutations in Noonan
syndrome type I: detection of recurrent mutations in exon 3 and 13. Hum
Mutat. 2002;20(4):298-304.
9. Conti E, Dottorino T, Sarkozy A, et al. A novel PTPN11 mutation in LEOPARD
syndrome. Hum Mutat. 2003;21(6):654.
10. Sarkozy A, Obregon MG, Conti E, et al. A novelPTPN11 gene mutation bridges
Noonan syndrome, multiple lentigines/LEOPARD syndrome and Noonanlike/multiple giant cell lesion syndrome. Eur J Hum Genet. 2004;12(12):
1069-1072.
11. Digilio MC, Sarkozy A, Pacileo G, Limongelli G, Marino B, Dallapiccola B.
PTPN11 gene mutations: linking the Gln510Glu mutation to the “LEOPARD
syndrome phenotype.” Eur J Pediatr. 2006;165(11):803-805.
12. Hanna N, Montagner A, Lee WH, et al. Reduced phosphatase activity of SHP-2
in LEOPARD syndrome: consequences for PI3K binding on Gab1. FEBS Lett.
2006;580(10):2477-2482.
13. Tartaglia M, Martinelli S, Stella L, et al. Diversity and functional consequences of germline and somatic PTPN11 mutations in human disease. Am
J Hum Genet. 2006;78(2):279-290.
14. Kontaridis MI, Swanson KD, David FS, Barford D, Neel BG. PTPN11 (SHP2)
mutations in LEOPARD syndrome have dominant negative, not activating,
effects. J Biol Chem. 2006;281(10):6785-6792.
COMMENTS AND OPINIONS
Sponsorship of Graduate Medical
Education: One Successful Model
I
n the March 2007 issue of the Archives, Loo et al1 discuss the recruitment and retention of academic dermatologic clinician-educators. They call for new ideas
to help provide needed support for teaching and mentorship, suggesting that this will lead to better job satisfaction and retention rates. It is my strong belief that robust
departmental mentoring programs supported by active,
dedicated senior faculty members working in concert with
junior faculty members and residents is the key to increasing recruitment and retention of academic dermatologists.
Implementing effective role modeling and mentorship involves a wide array of necessary elements that I
will not expand on other than to say that the educational environment requires the philosophical, physical, and monetary support of the leadership. From where
does the last of these, money, become available?
Medical schools and institutions concerned with the
advancement of medicine and the development of the next
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Paul Gross, MD
generation of physicians cite their commitment to the triad
of patient care, research, and education. The relative value
an institution places on each of these areas dictates which
will be most scrutinized in evaluation, promotion, and
retention decisions. If research is the driving value, National Institutes of Health grants and other funding sources
provide the currency to support these endeavors. Institutions that claim superior patient care as their driving
force have an obvious source of funds—those generated
by the activity itself. Education alone among the triumvirate is an unfunded priority.
How has graduate medical education survived to this
point without a sponsor, a source of dollars seemingly
necessary to support any endeavor? Excess funds from
clinical revenue helped support education until the 1990s,
but certainly such funds have disappeared with the advent of managed care. There has been a move among a
small number of institutions to dedicate dollars to this
mission and provide graded stipends based on teaching
time. However, this is not a widespread phenomenon,
and the compensation is sparse relative to the effort expended. Generally, then, graduate medical education is
an unfunded priority that has been considered a calling
and kept alive by the volunteer efforts of dedicated, supportive practitioners from the community as well as idealistic, committed faculty educators.
In Philadelphia, Pennsylvania, Paul Gross, MD
(Figure), is an example of the former and an innovator
of a welcome new kind of support for graduate medical
education. Dr Gross graduated from the University of
Pennsylvania School of Medicine in 1962 and completed his residency in dermatology at the same institution in 1968. From then until 2006, he headed the dermatology service at one of our affiliated teaching hospitals,
Pennsylvania Hospital, in the Center City neighborhood of Philadelphia. Without compensation, Paul anchored the dermatology residency teaching rotation, provided in-patient consultation services, and educated scores
of internists, family practitioners, and interns in his private practice office. He is a stalwart attendee at our weekly
“Duhring Conference” grand rounds, sharing his clinical expertise to help diagnose and treat patients with uncommon clinical diseases. He and his wife, Anita, are regular attendees at all of our departmental get-togethers,
graduation dinners, named lectures, and alumni reunions. In short, he is the epitome of the dedicated, supportive practitioner who daily contributes voluntarily of
his time and expertise to help guarantee the future of our
specialty.
Dr Gross has, however, taken his support to a higher
level, one that might also serve as a model to promote muchneeded funding for full-time dermatologic clinicianeducators and departmental education initiatives. He astutely recognizes not only that we need to educate young
academic clinician-educators but also that to do so requires financial support. Acting on this insight, he has been
able to secure philanthropic contributions from his grateful patients to support an innovative Clinical-Educator Fellowship at the University of Pennsylvania. This postresidency experience helps interested dermatologists obtain
needed skills to excel in academic medicine.
In addition, Dr Gross understands that the teaching
of dermatology residents requires the program director
to spend a growing amount of time to effectively fulfill
this role. A grateful patient has donated the funds to endow a chair for dermatologic education, with the condition that it be named in Dr Gross’ honor. Endowment
of professorial chairs to support basic science researchers and/or chairs of departments is the most common
among these types of generous philanthropic ventures.
Chairs for directors of education are unusual, and it is a
testament of Dr Gross’ vision that he was able to establish one at the University of Pennsylvania. Such professorships help the department to ensure that the third pillar of excellence, education, will be supported in
perpetuity. While education is a shared responsibility
among faculty members, as are all areas of scholarship,
these gifts guarantee the permanent presence of a dedicated expert whose main mission is to bolster the training program, mentor the young, fulfill the educational
administrative requirements, and initiate innovative learning experiences and techniques.
Dr Gross has provided a role model to our residents
of how important private practice volunteer educators
are to academic departments. We are fortunate to have
more than 50 volunteers from the community who give
at least 50 hours of teaching a year to the University of
Pennsylvania Department of Dermatology. I see a direct
connection between these exceptional men and women
and the fact that the vast majority of our graduates over
the past 10 years are involved in full-time or voluntary
teaching activities.
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The overlay of philanthropic monetary support directed to fellowships and professorships will help sustain
our next generation of learners and educators in a different way. As has been documented, approximately 10% of
our clinician-educators leave academic medicine yearly.1
Residency program directors have a 15% to 20% turnover
(unpublished data, W.D.J., 2004). Chairs for mid-level and
senior educators validate the importance of this method
of scholarship to the department and the university. They
provide a tangible goal to aspire to, help sustain careers,
and stabilize tenure in important positions such as residency program directorships.
I hope that Dr Gross’ vision, and the resulting positive experience at the University of Pennsylvania, stimulates additional discussion of support for resident and student education and invigorates funding of their endeavors
in innovative ways.
William D. James, MD
Correspondence: Dr James, Department of Dermatology, Hospital of the University of Pennsylvania, 3600
Spruce St, 2 Rhoads Pavilion, Philadelphia, PA 19104
(william.james@uphs.upenn.edu).
Financial Disclosure: None reported.
1. Loo DS, Liu CL, Geller AC, Gilchrest BA. Academic dermatology manpower:
issues of recruitment and retention. Arch Dermatol. 2007;143(3):341-347.
Narrowband UV-B Phototherapy
for Extragenital Lichen Sclerosus
I
n the January issue of the Archives, Colbert and colleagues1 report on the successful use of narrowband (NB) UV-B phototherapy in a patient with
widespread extragenital lichen sclerosus (LS). We fully
agree that NB UV-B is an attractive alternative for patients with extragenital LS if UV-A1 devices are not available. After having treated several patients with NB UV-B,
we believe that at least 30 irradiation sessions (similar
to NB UV-B treatment for localized scleroderma) are necessary to produce significant changes in the clinical status.2 Importantly, patients must be advised that their skin
disease might appear “deteriorated” during phototherapy because the healthy surrounding skin tans more
strongly than LS lesions.
Colbert and colleagues1 have speculated that the main
mechanism of action of NB UV-B in LS might be the increase of matrix metalloproteinase (MMP) levels, finally resulting in a reduction of skin sclerosis. This inspired us to perform MMP-1 immunostaining in a patient
with LS treated with NB UV-B. The Figure shows strong
MMP-1 immunopositivity in the cytoplasm of several fibroblasts after NB UV-B phototherapy. Our research
group3 has recently demonstrated that interleukin 6 (IL6), a multifunctional cytokine that has been shown to
increase the production of collagen and glycosaminoglycans, is significantly down-regulated during UV-A1 phototherapy in morphea.3 Since IL-6 concentration has also
been reported to be increased in LS,4 the efficacy of NB
UV-B might be explained by a depletion of proinflammatory cytokines such as IL-6 in addition to the induc-
A
B
Figure. Immunohistochemical staining for matrix metalloproteinase (MMP)
1 in a patient with extragenital lichen sclerosus before (A) and after (B)
narrowband UV-B phototherapy (hematoxylin-eosin, original magnification
⫻40 for both panels). B, The cytoplasm of lesional fibroblasts (arrows)
shows strong immunopositivity for MMP-1 after phototherapy.
tion of MMPs. Data recently reported by Choi et al5 indicate that NB UV-B irradiation reduces type 1 collagen
concentrations in human skin fibroblasts by inhibiting
transforming growth factor ␤1 expression and stimulating the release of MMP-1.
The good tolerability and low carcinogenicity linked to
NB UV-B should also give rise to future studies on phototherapy for genital LS,6 which is much more common and
more afflicting for the patient than extragenital disease.
Alexander Kreuter, MD
Thilo Gambichler, MD
Correspondence: Dr Kreuter, Department of Dermatology and Allergology, Ruhr University Bochum, Gudrunstrasse 56, D-44791 Bochum, Germany (a.kreuter@derma
.de).
Financial Disclosure: None reported.
1. Colbert RL, Chiang MP, Carlin CS, Fleming M. Progressive extragenital lichen sclerosus successfully treated with narrowband UV-B phototherapy. Arch
Dermatol. 2007;143(1):19-20.
2. Kreuter A, Hyun J, Stücker M, et al. A randomized controlled study of low-dose
UVA1, medium-dose UVA1, and narrowband UVB phototherapy in the treatment
of localized scleroderma. J Am Acad Dermatol. 2006;54(3):440-447.
3. Kreuter A, Hyun J, Skrygan M, et al. Ultraviolet A1-induced downregulation
of human beta-defensins and interleukin-6 and interleukin-8 correlates with
clinical improvement in localized scleroderma. Br J Dermatol. 2006;155(3):
600-607.
4. Romero LI, Pincus SH. In situ localization of interleukin-6 in normal skin and
atrophic cutaneous disease. Int Arch Allergy Immunol. 1992;99(1):44-49.
5. Choi CP, Kim YI, Lee JW, Lee MH. The effect of narrowband ultraviolet B on
the expression of matrix metalloproteinase-1, transforming growth factorbeta1 and type I collagen in human skin fibroblasts. Clin Exp Dermatol. 2007;
32(2):180-185.
6. Gambichler T, Breuckmann F, Boms S, Altmeyer P, Kreuter A. Narrowband
UVB phototherapy in skin conditions beyond psoriasis. J Am Acad Dermatol.
2005;52(4):660-670.
Exclusively Benign Dermoscopic Pattern
in a Patient With Acral Melanoma
T
he article by Saida et al1 on the significance of
dermoscopic patterns in detecting malignant
melanoma is of great importance to us. Based on
the results of this large multicenter study conducted in
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Figure 1. Clinical image of an acquired pigmented lesion on the right heel of
a 28-year-old woman.
Figure 3. Histologic image of the lesion showing a very atypical melanocytic
pattern at the dermoepidermal junction with numerous confluent nests of
atypical melanocytes (Fontana-Masson stain, original magnification ⫻5).
sion, then, and only then, should he or she look for the
presence of benign dermoscopy patterns.
Figure 2. Dermoscopy image of the same lesion shown in Figure 1 showing
a benign dermoscopy pattern throughout the lesion. The pigmentation
follows the furrows, and the ridges are relatively hypopigmented (double-line
parallel furrow pattern associated with dots and globules). No malignant
dermoscopy pattern can be observed.
Japan, the authors reported that 2 dermoscopic patterns, the parallel ridge pattern and irregular diffuse pigmentation pattern, were highly specific for the diagnosis of acral melanoma.
They found that 7 of 103 melanomas revealed a benign dermoscopic pattern consisting of either a parallel
furrow pattern or a latticelike pattern.2 However, the authors1 also mention that in all melanomas displaying benign dermoscopy patterns, this benign pattern was observed only focally and that the predominant pattern was
the malignant pattern.
We completely agree that both benign and malignant
patterns can coexist within the same lesion. Thus, to avoid
misdiagnosing acral melanoma, we recommend that acral lesions be scanned in their entirety, under dermoscopy, to determine the presence or absence of malignant patterns and to ensure that no focal area within the
lesion with a malignant pattern is overlooked. Biopsy is
recommended for any lesion that reveals a malignant pattern, no matter how small the focus.3 If after scanning
the entire lesion the dermoscopist is reassured that no
malignant patterns are present within any part of the le-
Report of a Case. Unfortunately, exceptions occur: on
rare occasions, melanomas can present with an exclusively benign dermoscopy pattern. We describe a 28year-old woman of Italian descent who presented with a
pigmented lesion on the heel, which first appeared 2 years
earlier and progressively enlarged. Clinical examination revealed a 13-mm, brown, homogeneous, and symmetric macule (Figure 1). Under dermoscopy, no malignant dermoscopy patterns were evident anywhere
within the lesion (Figure 2). The lesion displayed a homogeneous, parallel furrow pattern with dots and globules, which best fit the double-line parallel furrow pattern associated with dots and globules, a variant of the
benign parallel furrow pattern.4,5
However, owing to the disconcerting history of its recent onset and growth we were prompted to override our
dermoscopic diagnosis and take biopsy specimens of the
lesion. The lesion was surgically removed and histopathologic analysis revealed the presence of an atypical
melanocytic proliferation at the dermoepidermal junction with confluent nests of atypical melanocytes and pagetoid spread—findings consistent with a diagnosis of melanoma in situ (Figure 3 and Figure 4).
Comment. What can we learn from this case? First, it is
important to remember not to disregard a patient’s medical history. Our patient reported that her heel lesion was
relatively new and was enlarging. This fact alone should
raise suspicion, since a new or changing lesion is a sensitive indicator of melanoma. Despite the fact that the lesion had a benign dermoscopy pattern, the patient’s medical history was the main impetus for us to take biopsy
specimens and correctly identify her melanoma.
Second, the size of an acral lesion appears to be important. Several studies have shown that acquired acral
lesions larger than 7 mm in diameter have a higher probability of being melanoma, regardless of other morphologic criteria.6-8
Third, the presence of large globules is an unusual feature for benign lesions on palms and soles. It is our sin-
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Figure 4. Detail ofFigure 3 showing confluent nests of atypical melanocytes
as well as pagetoid spread of suprabasal cells. There is some fibrosis as well
as pigment incontinence in the dermis. Histopathologic diagnosis was
melanoma in situ (hematoxylin-eosin, original magnification ⫻20).
cere hope that some of our observations will result in the
timely detection of acral melanomas.
Ralph P. Braun, MD
Olivier Gaide, MD
Andreas M. Skaria, MD
Alfred W. Kopf, MD
Jean-Hilaire Saurat, MD
Ashfaq A. Marghoob, MD
Correspondence: Dr Braun, Department of Dermatology, University Hospital Zürich, Gloriastr 31, Zürich 8091,
Switzerland (braun@melanoma.ch).
Financial Disclosure: None reported.
1. Saida T, Miyazaki A, Oguchi S, et al. Significance of dermoscopic patterns in
detecting malignant melanoma on acral volar skin: results of a multicenter
study in Japan. Arch Dermatol. 2004;140(10):1233-1238.
2. Menzies SW, Zalaudek I. Why perform dermoscopy? the evidence for its role
in the routine management of pigmented skin lesions. Arch Dermatol. 2006;
142(9):1211-1212.
3. Altamura D, Altobelli E, Micantonio T, Piccolo D, Fargnoli MC, Peris K.
Dermoscopic patterns of acral melanocytic nevi and melanomas in a white
population in central Italy. Arch Dermatol. 2006;142(9):1123-1128.
4. Saida T, Oguchi S, Miyazaki A. Dermoscopy for acral pigmented skin lesions.
Clin Dermatol. 2002;20(3):279-285.
5. Marghoob AA, Braun RP, Kopf AW. Atlas of Dermoscopy. New York, NY: Taylor Francis; 2005.
6. Saida T, Yoshida N, Ikegawa S, Ishihara K, Nakajima T. Clinical guidelines
for the early detection of plantar malignant melanoma. J Am Acad Dermatol.
1990;23(1):37-40.
7. Saida T, Ishihara Y, Tokuda Y. Effective detection of plantar malignant
melanoma. Int J Dermatol. 1993;32(10):722-725.
8. Saida T. Malignant melanoma on the sole: how to detect the early lesions
efficiently. Pigment Cell Res. 2000;13(suppl 8):135-139.
In reply
I enjoyed reading the comments from Braun et al on the significance of the dermoscopic patterns seen in acral melanocytic lesions. Acral volar skin is the most prevalent site
of malignant melanoma in nonwhite populations. In Japanese patients, about half of all cutaneous melanomas affect
this anatomic site. Therefore, early accurate detection of malignant melanoma of this site is essential to improve the prognosis, particularly for nonwhites.
The introduction of dermoscopy has immensely contributed to the early detection of acral melanoma. Early acral
melanoma shows a unique dermoscopic pattern of bandlike
pigmentation on the ridges of the skin markings, which my
research groups have called the parallel ridge pattern.1,2 A
previous study performed by my group revealed that, in early
acral melanoma, the sensitivity and the specificity of this
pattern is 86% and 99%, respectively.3 Irregular diffuse pigmentation is another important pattern, also often detected in more or less advanced acral melanoma. In contrast, the major dermoscopic patterns of melanocytic nevi
on acral volar skin are the parallel furrow pattern, the latticelike pattern, and the fibrillar pattern.4
I completely agree with Braun et al in emphasizing the
importance of careful examination of an entire lesion because the malignant patterns of acral melanoma are only
partly detected in some cases. I also agree with them that
the benign dermoscopic patterns can be detected also in acral melanoma. However, in melanoma, the benign patterns
are found only focally or irregularly distributed within a
lesion. In my experience, if a melanocytic lesion on volar
skin exhibits 1 of these benign dermoscopic patterns in a monotonous fashion, the lesion is histopathologically diagnosed as a benign nevus without exception.
Thus, the case presented by Braun et al is very interesting. Clinically, the lesion was oval in shape and regular in
shades of brown color. However, the rapid growth and the
larger size, 13 mm in diameter, are exceptional in a benign
nevus. The dermoscopic finding of this lesion was the typical feature of the parallel furrow pattern associated with the
brown globules regularly distributed along both sides of the
sulci. No malignant dermoscopic patterns were detected
within the lesions. Except for the larger size and the rapid
growth, all of these clinical and dermoscopic findings strongly
suggested that this was a benign nevus. Unexpectedly, however, histopathologic examination revealed confluent nests
of atypical melanocytes as well as pagetoid spread in the
lower epidermis. Braun et al finally diagnosed this case as
melanoma in situ.
Histopathologic analysis is still the gold standard to determine the diagnosis of melanocytic neoplasm. Thus, this
case could really be melanoma in situ. Under the principle
that every rule has its exceptions, acral melanoma could exceptionally show the typical parallel furrow pattern. But in
this particular case, I wish to be prudent and agree with the
diagnosis of Braun et al.
Conflict between dermoscopic and histopathologic findings is emerging as an important subject. Soyer et al5 have
noted that dermoscopy could challenge the monopoly of dermatopathology in determining the diagnosis of malignant
melanoma. In my opinion, the lesion described by Braun et
al shows completely regular, symmetric, homogeneous, and
orderly dermoscopic features, thereby strongly suggesting
a benign nature.
Furthermore, regarding the histopathologic findings of
this case, I want to add 1 comment. My group has recently
noticed that despite banal clinical features, some melanocytic nevi located at transition portions between glabrous
and nonglabrous skin and also in interdigital areas often
histopathologically exhibit random, irregular distribution
of melanocytes as solitary units as well as in nests within
the epidermis, mimicking the findings of melanoma in situ
(unpublished data, 2007). Owing to these histopathologic
findings, melanocytic nevi on these areas could be overdi-
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agnosed as melanoma (“pseudomelanoma”), as is the case
of melanocytic nevus of a young woman’s genitalia. The melanocytic lesion described by Braun et al seems to be located at this transition zone, and thus, in my view, the histopathologic findings must be carefully interpreted. Of course,
validity of this concept of pseudomelanoma at the transition areas must be critically evaluated in further studies.
Toshiaki Saida, MD, PhD
Correspondence: Dr Saida, Department of Dermatology, Shinshu University School of Medicine, 3-1-1 Asahi,
Matsumoto 390-8621, Japan (tosaida@hsp.md.shinshu-u
.ac.jp).
1. Oguchi S, Saida T, Koganehira Y, Ohkubo S, Ishihara Y, Kawachi S. Characteristic epiluminescent microscopic features of early malignant melanoma on
glabrous skin. Arch Dermatol. 1998;134(5):563-568.
2. Saida T, Oguchi S, Miyazaki A. Dermoscopy for acral pigmented skin lesions.
Clin Dermatol. 2002;20(3):279-285.
3. Saida T, Miyazaki A, Oguchi S, et al. Significance of dermoscopic patterns in
detecting malignant melanoma on acral volar skin. Arch Dermatol. 2004;140
(10):1233-1238.
4. Saida T, Oguchi S, Ishihara Y. In vivo observation of magnified features of
pigmented lesions on volar skin using video macroscope. Arch Dermatol. 1995;
131(3):298-304.
5. Soyer HP, Massone C, Ferrara G, Argenziano G. Limitations of histopathologic analysis in the recognition of melanoma: a plea for a combined diagnostic approach of histopathologic and dermoscopic evaluation. Arch Dermatol.
2005;141(2):209-211.
noma is not a trivial matter. Much more evidence than
was provided by Matichard et al1 is needed before it can
be recommended.
Thomas B. Newman, MD, MPH
M. Jeffrey Maisels, MB BCh
Correspondence: Dr Newman, Department of Epidemiology and Biostatistics, 185 Berry St, Ste 5700, San Francisco, CA 94107-1762 (newman@epi.ucsf.edu).
Financial Disclosure: None reported.
1. Matichard E, Le Henanff A, Sanders A, Leguyadec J, Crickx B, Descamps V.
Effect of neonatal phototherapy on melanocytic nevus count in children. Arch
Dermatol. 2006;142(12):1599-1604.
2. Wiecker TS, Luther H, Buettner P, Bauer J, Garbe C. Moderate sun exposure
and nevus counts in parents are associated with development of melanocytic
nevi in childhood: a risk factor study in 1,812 kindergarten children. Cancer.
2003;97(3):628-638.
3. Bauer J, Buttner P, Luther H, Wiecker TS, Mohrle M, Garbe C. Blue-light phototherapy of neonatal jaundice does not increase the risk for melanocytic nevus development. Arch Dermatol. 2004;140(4):493-494.
4. Berg P, Lindelof B. Is phototherapy in neonates a risk factor for malignant
melanoma development? Arch Pediatr Adolesc Med. 1997;151(12):1185-1187.
5. Dean AG, Dean JA, Burton AH, Dicker RC. Epi Info: a general-purpose microcomputer program for public health information systems. Am J Prev Med.
1991;7(3):178-182.
In reply
1
Evidence Insufficient to Recommend
Melanoma Surveillance Following
Phototherapy for Jaundice
M
atichard et al1 reported an association between receipt of blue-light phototherapy for
neonatal jaundice and numbers of melanocytic nevi at least 2 mm in diameter at age 8 or 9 years.
Although they stated that their results “should be interpreted with caution,”1(p1603) they concluded that exposed children “should undergo dermatologic preventive measures and surveillance for the development of
melanoma.”1(p1599)
We believe that this recommendation is premature. The
authors studied only 18 children who had been exposed
to phototherapy, and the selection of these exposed children was via an entirely different mechanism from the selection of the control group. This could easily have introduced confounding factors that were not measured. It
appears that the original hypothesis that the authors sought
to test was that phototherapy might increase the total nevus count, which it did not: mean counts, 28.5 vs 28.7
(P=.88). The association was present only when attention was restricted to nevi 2 to 5 mm in diameter. The authors do not provide a biological rationale for restriction
of the association to nevi of that size. Finally, a larger study
of this issue failed to find any association between phototherapy and nevi,2,3 and a study of whether phototherapy
was a risk factor for melanoma4 found that 0 of 30 melanoma cases had included exposure to phototherapy, compared with 11 of 120 controls (odds ratio, 0; upper limit
of 95% confidence interval, 1.55).5
Counseling families of infants exposed to phototherapy that their child needs to be watched for mela-
My group’s study demonstrates that the number of melanocytic nevi larger than 2 mm in diameter is higher in children aged between 8 and 9 years who were exposed to neonatal phototherapy than in those who were not exposed. In
a multivariate analysis, we have studied the respective roles
of both sun exposure and neonatal phototherapy (Table).
As summarized in the Table, sun exposure is the major
factor for nevi smaller than 2 mm. In addition, the data in
the Table support the fact that neonatal phototherapy is the
major risk factor for nevi larger than 2 mm in diameter.
It can be postulated that sun exposure is the major risk
factor for the most recent melanocytic nevi (< 2 mm). Nevi
larger than 5 mm might represent congenital nevi for
which the genetic predisposition could be the most important risk factor.
This classification of melanocytic nevi into different diameters (larger than 2 mm, 2-5 mm, and larger than 5 mm)
is usual in studies evaluating the prevalence of common melanocytic nevi in children and its relationship with pigmentary characteristics and sun exposure.2-5 In most studies, small
nevi (< 2 mm) and small dark brown pigmented freckles
called lentigo simplex are excluded. But until now, the issue of the size of the nevi has not been totally resolved. However, some authors5 include these small nevi in the total number of nevi, as my group did.1
Retrospective documentation of neonatal phototherapy is
often very difficult to find and often lacks important details
(eg, bilirubin level throughout therapy, duration of exposure, and dose of phototherapy). Hence the entry criteria for
my study group was the presence of complete phototherapy
documentation and the ability to find the child. The control
group was selected to match for age, geographic area, and
Fitzpatrick skin type, thus decreasing both the likelihood of
bias and the number and influence of confounding factors. Our
method of case selection avoided the problems of recall bias
that are inherent in studies based on interviews, as conducted by Bauer and colleagues.6 The different conclusions
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Table. Statistical Multivariate Analysis of Nevus Risk Factor
P Value in the Variance Analysis Model by Lesion Size
Exposure Category
Intensive phototherapy
Solar exposure during holidays
Severe sunburns
Any Size
⬍2 mm
2-5 mm
⬎ 2 mm
⬎ 5 mm
.50
.02
.94
.18
.02
.84
⬍.001
.40
.51
⬍.001
.46
.47
.29
.80
.45
drawn by my group’s study and by Bauer et al may be the
result of the different methods used to obtain the data.
Although the relatively small sample size of my group’s
study1 suggests caution in interpreting these data (particularly our multivariate analysis) and may limit generalization of the results, the study poses an important question:
can it now be simply stated that phototherapy dose not induce a modification of nevus count?
Nonetheless, we strongly recommend that all neonatal
phototherapy sessions be meticulously documented for use
in further research and risk stratification in patients’ records. We believe that individuals who receive intensive phototherapy should undergo periodic dermatologic follow-up
if they develop nevi.
Vincent Descamps, MD, PhD
Correspondence: Dr Descamps, Bichat-Claude Bernard
Hospital, Department of Dermatology, Assistance
Publique des Hôpitaux de Paris, 46 rue Henri Huchard,
75018 Paris, France (vincent.descamps@bch.ap-hop-paris
.fr).
1. Matichard E, Le Henanff A, Sanders A, Leguyadec J, Crickx B, Descamps V.
Effect of neonatal phototherapy on melanocytic nevus count in children. Arch
Dermatol. 2006;142(12):1599-1604.
2. Siskind V, Darlington S, Green L, Green A. Evolution of melanocytic nevi on
the faces and necks of adolescents: a 4 y longitudinal study. J Invest Dermatol.
2002;118(3):500-504.
3. Autier P, Severi G, Pedeux R, et al; European Organisation for Research and
Treatment of Cancer Melanoma Group. Number and size of nevi are influenced by different sun exposure components: implications for the etiology of
cutaneous melanoma (Belgium, Germany, France, Italy). Cancer Causes Control.
2003;14(5):453-459.
4. MacLennan R, Kelly JW, Rivers JK, Harrison SL. The Eastern Australian Childhood Nevus Study: site differences in density and size of melanocytic nevi in
relation to latitude and phenotype. J Am Acad Dermatol. 2003;48(3):367-375.
5. Valiukeviciene S, Miseviciene I, Gollnick H. The prevalence of common acquired melanocytic nevi and the relationship with skin type characteristics
and sun exposure among children in Lithuania. Arch Dermatol. 2005;141
(5):579-586.
6. Bauer J, Buttner P, Luther H, Wiecker TS, Mohrle M, Garbe C. Blue light phototherapy of neonatal jaundice does not increase the risk for melanocytic nevus development. Arch Dermatol. 2004;140(4):493-494.
Allergic Contact Dermatitis:
Another Adverse Effect of Over-the-counter
Topical Hydrocortisone
W
e read with interest the commentary in the
March 2007 issue of the Archives of Dermatology titled “Topical Hydrocortisone From Prescription to Over-the-Counter Sale.”1 While this article aptly
describes the historical debate regarding approval for overthe-counter drug (OTC) use, it neglects to include allergic
contact dermatitis from corticosteroids as 1 of the adverse
effects of topical hydrocortisone.2-9
Corticosteroid allergy was first described in 1959 by
Burckhardt10 but has become more widely recognized
since the introduction of tixocortol-21-pivalate as a patchtest marker in the late 1980s. Prevalence of allergy to tixocortol, a marker for allergy to hydrocortisone and other
group A corticosteroids, has ranged from 2.3% to 2.9%
in large patch-tested populations in North America. Clinical relevance to the presenting dermatitis is documented in more than 80% of cases.
The ready availability of OTC hydrocortisone products likely contributes to this high prevalence and clinical relevance. Clues to the diagnosis of steroid contact
allergy include worsening of dermatitis with use or a
change in the clinical pattern of the disease. Importantly, this allergen is not available in commercial patchtest kits such as the T.R.U.E. test (Allerderm, Phoenix,
Arizona) in the United States. Clinicians should be aware
of the risk of allergic contact dermatitis (ACD) from corticosteroids and be prepared to refer patients for comprehensive patch testing.
Kalman L. Watsky, MD
Erin M. Warshaw, MD, MS
Correspondence: Dr Watsky, 330 Orchard St, Ste 103,
New Haven, CT 06511 (kwatsky@snet.net).
Financial Disclosure: None reported.
1. Ravis SM, Eaglstein WH. Topical hydrocortisone from prescription to overthe-counter sale. Arch Dermatol. 2007;143(3):413-415.
2. Lutz ME, el-Azhary RA, Gibson LE, Fransway AF. Contact hypersensitivity
to tixocortol pivalate. J Am Acad Dermatol. 1998;38(5, pt 1):691-695.
3. Scheuer E, Warshaw E. Allergy to corticosteroids: update and review of epidemiology, clinical characteristics, and structural cross-reactivity. Am J Contact Dermat. 2003;14(4):179-187.
4. Marks JG, Belsito DV, DeLeo VA, et al. North American Contact Dermatitis
Group standard tray patch test results (1992 to 1994). Am J Contact Dermat.
1995;6:160-165.
5. Marks JG, Belsito DV, DeLeo VA, et al. North American Contact Dermatitis
Group patch test results for the detection of delayed-type hypersensitivity
to topical allergens. J Am Acad Dermatol. 1998;38(6, pt 1):911-918.
6. Marks JG Jr, Belsito DV, DeLeo VA, et al. North American Contact Dermatitis Group patch test results, 1996-1998. Arch Dermatol. 2000;136(2):
272-273.
7. Marks JG Jr, Belsito DV, DeLeo VA, et al. North American Contact Dermatitis Group patch test results, 1998 to 2000. Am J Contact Dermat. 2003;
14(2):59-62.
8. Pratt MD, Belsito DV, DeLeo VA, et al. North American Contact Dermatitis
Group patch test results, 2001-2002 study period. Dermatitis. 2004;15
(4):176-183.
9. Warshaw EM, Rietschel RL, Sasseville D, et al. North American Contact Dermatitis Group patch test results 2003-2004 study period. Dermatitis. In press.
10. Burckhardt W. Contact eczema caused by hydrocortisone. Hautarzt. 1959;
10:42.
In reply
We thank Watsky and Warshaw for their interest and insightful comments. As they point out, ACD was not listed
as an adverse effect of treatment with topical hydrocorti-
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sone in our commentary.1 We did not mention the potential
adverse effect of ACD to topical hydrocortisone because it
did not play a role in the debate regarding the appropriateness of permitting OTC sale of topical hydrocortisone preparations.
As pointed out by Watsky and Warshaw, the ready
availability of OTC hydrocortisone products (especially in
structural class A) likely contributes to a high prevalence
of clinically significant positive patch test results to corticosteroid markers in selected patch-tested populations.
How this translates to the prevalence of corticosteroidinduced ACD in the population at large is apparently not
known. At what level corticosteroid-induced ACD might be
a public health concern requiring consideration of removing products from the market is not only an intriguing
question but one that could, depending on the answer, result—following the law of unintended consequences—in
proving correct, after all, the initial reaction of the dermatology community.
William H. Eaglstein, MD
Scott M. Ravis
Correspondence: Dr Eaglstein, Research and Development, Stiefel Laboratories Inc, 255 Alhambra Cir, Coral
Gables, FL 33134 (weaglstein@stiefel.com).
1. Ravis SM, Eaglstein WH. Topical hydrocortisone from prescription to overthe-counter sale. Arch Dermatol. 2007;143(3):413-415.
A
VIGNETTES
Successful Treatment of Pityriasis Versicolor
With 5-Aminolevulinic Acid
Photodynamic Therapy
P
ityriasis versicolor is a common chronic superficial fungal infection caused by the organism Malassezia furfur. Although many conventional treatments have been shown to be successful in treating
pityriasis versicolor, therapy of long-term duration may
be needed in many cases, and recurrence is not uncommon. In vitro experimental investigations have demonstrated that several fungal strains can be effectively inactivated by irradiation with visible light wavelengths in
the presence of photosensitizer.1-3 However, to our knowledge, there have been no clinical trials of photodynamic
therapy (PDT) against pityriasis versicolor.
Report of a Case. A 37-year-old man presented with a
2-year history of asymptomatic, light brown, scaly patches
on both axillae (Figure 1A). Microscopic examination
of samples stained with 10% potassium hydroxide revealed short, thick, fungal hyphae and spores of various
sizes (Figure 2A). We tried to treat the lesions with
B
Figure 1. A 37-year-old man with a 2-year history of scaly patches on both axillae. A, Sharply marginated, light brown hyperpigmentation with fine scales on the
axilla. B, Clearance of pityriasis versicolor without reinfection after 16 weeks of follow-up after treatment with 5-aminolevulinic acid in combination with
photodynamic therapy.
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A
B
Figure 2. Microscopic examination of samples stained with 10% potassium hydroxide (original magnification ⫻400 for both panels). A, Before treatment,
numerous short, thick fungal hyphae and spores of various sizes are seen. B, No fungal hyphae or spores are present 10 weeks after the last treatment.
5-aminolevulinic acid (ALA) in combination with PDT.
Topical 20% ALA (Medac, Hamburg, Germany) in petrolatum vehicle was applied to the lesions and covered
with an occlusive polyurethane film (Tegaderm; 3M,
St Paul, Minnesota). After 4 hours, excess ALA was removed, and the lesions were irradiated with light from
light-emitting diodes (mean ± SD wavelength, 630 ± 50
nm). The light intensity was 100 mW/cm2, and the light
doses were 70 J/cm2 for the left axilla and 80 J/cm2 for
the right axilla. The procedure was repeated 2 weeks later
with increased light dose increments of 10 J/cm2 on each
side. The area cleared within 4 weeks, and the patient
was observed for an additional 3 months without reinfection (Figure 1B). One week after the first treatment
and 10 weeks after the last treatment, samples stained
with 10% potassium hydroxide were again taken from
both axillae and these smears showed no fungal
hyphae or spores (Figure 2B). Of note, the clearance
was maintained throughout the warm and humid
summer of Korea.
Comment. To our knowledge, only 1 clinical trial of PDT
treatment for mycotic infection has been reported.4 In that
study, interdigital mycosis of the feet was irradiated with
75 J/cm2. The clearance was seen in 6 of 9 patients after
1 (n=4) or 4 (n = 2) treatments. However, 4 patients reported recurrences 4 weeks after the last treatment. The
authors suggested that in vivo environmental conditions such as temperature, humidity, and pH of the interdigital skin could induce a poor cell uptake of ALA
and a deficient biosynthesis of protoporphyrin IX. In addition, the irregular tridimensional shape of this peculiar anatomic area could lead to a nonuniform delivery
of light and/or ALA cream. The better outcome in our
case with a similar light dose may be due to the different
causative fungal strain and relatively uniform delivery of
light and ALA cream to the affected sites.
In the treatment of pityriasis versicolor, standard drug
treatments are prolonged, and the appearance of drugresistant strains is becoming more frequent. The multiplicity of cellular targets in fungi should reduce the risk
of selection of photomutant, resistant strains after PDT,
and this risk should be further minimized by the lack of
mutagenic effects of PDT.5 Our results of prompt clearance and no recurrence of pityriasis versicolor after PDT
indicate that this approach may be a promising treatment for pityriasis versicolor.
Young Jin Kim, MD
You Chan Kim, MD, PhD
Correspondence: Dr Y. C. Kim, Department of Dermatology, Ajou University School of Medicine, 5 WonchonDong, Yeongtong-Gu, Suwon 443-721, South Korea
(maychan@ajou.ac.kr).
Financial Disclosure: None reported.
1. Wainwright M. Photodynamic antimicrobial chemotherapy (PACT). J Antimicrob Chemother. 1998;42(1):13-28.
2. Strakhovskaya MG, Shumarina AO, Fraikin GY, Rubin AB. Synthesis of protoporphyrin IX induced by 5-aminolevulinic acid in yeast cells in the presence of 2,2;-dipyridyl. Biochemistry (Mosc). 1998;63(6):725-728.
3. Smijs TG, van der Haas RN, Lugtenburg J, Liu Y, de Jong RL, Schuitmaker
HJ. Photodynamic treatment of the dermatophyte Trichophyton rubrum and
its microconidia with porphyrin photosensitizers. Photochem Photobiol. 2004;
80(2):197-202.
4. Calzavara-Pinton PG, Venturini M, Capezzera R, Sala R, Zane C. Photodynamic therapy of interdigital mycoses of the feet with topical application of
5-aminolevulinic acid. Photodermatol Photoimmunol Photomed. 2004;20(3):
144-147.
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5. Calzavara-Pinton PG, Venturini M, Sala R. A comprehensive overview of photodynamic therapy in the treatment of superficial fungal infections of the skin.
J Photochem Photobiol B. 2005;78(1):1-6.
Leukemia Cutis: A Presenting Sign
in Acute Promyelocytic Leukemia
Report of a Case. A 63-year-old woman developed 3 erythematous, pruritic plaques on her left lower extremity.
She called her dermatologist and was prescribed prednisone for likely contact dermatitis from poison ivy. Two
weeks later, the patient developed fatigue and bruising.
Findings from a complete blood cell count were abnormal, demonstrating blasts (promyelocytes predominant), anemia, and thrombocytopenia. The patient was
admitted for workup.
On admission, her white blood cell count was 4500
cells/µL (normal range, 4500-11 000 cells/µL); hematocrit level was 31.4% (normal range, 35%-45%); and platelet count was 33⫻ 103/µL (normal range, 153⫻103/µL
to 367 ⫻ 103/µL). A manual differential count demonstrated 62% promyelocytes. Analysis of bone marrow biopsy specimens showed markedly hypercellular marrow with 90% promyelocytes and a positive translocation
of 15:17 on fluorescence in situ hybridization. Flow cytometry revealed cells positive for CD13, CD33, CD38,
and CD117 and negative for CD14, CD64, CD2, CD11,
CD3, CD20, CD7, CD34, and HLA-DR, which was consistent with acute promyelocytic anemia. Polymerase chain
reaction revealed a 0.436 ratio of the PML-RAR-α oncogene in her bone marrow.
A dermatology consultant was called to evaluate 3 erythematous, nontender, indurated plaques with necrotic
centers on her left calf, ranging in size from 5 to 9 mm
(Figure 1). Scattered petechiae and ecchymoses were
present. The differential diagnosis included vasculitis, leukemia cutis, arthropod assault, panniculitis, deep fungal infection, and atypical mycobacteria. Tissue cultures were negative for bacteria, fungal elements, and
mycobacteria. Histopathologic analysis revealed, pandermally and in the subcutaneous fat, dense, perivascular, and interstitial infiltrate of malignant, immature,
granulocytic cells with extensive tissue hemorrhage. These
tumor cells contained polymorphic nuclei with abundant granular cytoplasm. Occasional mitotic figures were
present. The immature hematopoietic cells stained diffusely positive for chloracetic esterase by Leder stain and
were CD34 negative. A few immature cells contained eosinophilic, cytoplasmic granules. No epidermotropism
or vascular or neural invasion was noted (Figure 2). The
findings confirmed the diagnosis of leukemia cutis, and
the morphologic features were consistent with promyelocytic leukemia.
The patient underwent a chemotherapeutic regimen
of daunorubicin and all-trans retinoic acid (ATRA) followed by cytarabine, daunorubicin, and arsenic trioxide. Four months after her initial presentation, a bone
marrow biopsy specimen showed no abnormalities, and
her disease is currently in remission. The leukemia cutis lesions on her calf are well healed.
Figure 1. Three erythematous, nontender, indurated plaques with necrotic
centers ranging in size from 5 to 9 mm were present on the patient’s left calf.
Figure 2. In a biopsy specimen taken from a lesion on the patient’s calf,
immature hematopoietic cells stained diffusely positive for chloracetic
esterase by Leder stain (original magnification ⫻40).
Comment. Leukemia cutis is the dissemination of systemic leukemia and a poor prognostic sign. It presents
as papules, plaques, or nodules, with a characteristic violaceous color.
Diffuse infiltration of leukemic cells into the dermis,
subcutis, blood vessels, and skin adnexa are seen on histologic examination.1 Immunohistochemical study characterizes the immunophenotypes of leukemic cells.
Acute promyelocytic leukemia (APL), classified as
AML-M3 (acute myeloid leukemia, subtype M3) in the
French-American-British classification system, accounts for approximately 10% to 15% of acute myeloid
leukemia in adults.2 Patients may have abundant abnormal progranulocytes, severe coagulopathy, and a balanced reciprocal translocation, t(15;17)(q22;q12), in leukemic cells.3 Fusion of the promyelocytic leukemia gene
(PML) on chromosome 15 and the retinoic acid receptor ␣ (RAR-␣) on chromosome 17 to form the oncogene
PML-RAR-␣ occurs.2 At 5 years, 70% to 80% of patients
with APL are disease free with treatment, which includes ATRA and anthracycline-based chemotherapy.2
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From 2% to 20% of patients with lymphocytic and
granulocytic leukemia and 10% to 50% with monocytic
leukemia develop leukemia cutis.4 To our knowledge,
fewer than 25 cases of skin infiltration by APL cells have
been previously described.5 Interestingly, extramedullary involvement tends to occur after the first remission
in APL, perhaps as a complication of ATRA therapy. In
contrast, our patient presented with lesions of leukemia
cutis prior to diagnosis and treatment.
To our knowledge, this represents the first case of leukemia cutis as a presenting sign of APL. Clinicians should
have a high suspicion for cutaneous findings in a patient with weakness and fatigue because it may herald
the diagnosis of malignancy.
Tania R. Markowski, BA
Donna Bilu Martin, MD
Grace F. Kao, MD
Linda Lutz, MD
April Deng, MD, PhD
Anthony A. Gaspari, MD
Figure 1. Bulla on the fourth toe due to mechanical trauma.
Correspondence: Dr Martin, Department of Dermatology, University of Maryland School of Medicine,
405 W Redwood St, Sixth Floor, Baltimore, MD 21201
(dbilumartin@gmail.com).
Financial Disclosure: None reported.
1. Gambichler T, Herde M, Hoffmann K, Altmeyer P, Jansen T. Poor prognosis
of acute myeloid leukemia associated with leukemia cutis. J Eur Acad Dermatol Venereol. 2002;16(2):177-188.
2. Löwenberg B, Griffin JD, Tallman MS. Acute myeloid leukemia and acute promyelocytic leukemia. Hematology Am Soc Hematol Educ Program. 2003:82101.
3. Giralt S, O’Brian S, Weeks E, et al. Leukemia cutis in acute promyelocytic leukemia: reports of three cases after treatment with all-trans retinoic acid. Leuk
Lymphoma. 1994;14(5-6):453-456.
4. Ratnam KV, Khor CJL, Su WPD. Leukemia cutis. Dermatol Clin. 1994;12(2):
419-431.
5. Ueda K, Kume A, Furukawa Y, Higashi N. Cutaneous infiltration in acute promyelocytic leukemia. J Am Acad Dermatol. 1997;36(1):104-106.
Necrolytic Migratory Erythema:
The Outermost Marker
for Glucagonoma Syndrome
Report of a Case. A 56-year-old woman presented with
significant loss of weight, a painful oral inflammation,
and a skin eruption on the trunk, lower extremities, and
the intertriginous and genital areas. The physical examination showed a patient with cachexia and striking eruptions on the skin and mucous membranes. The lesions
consisted of annular, confluent, superficially eroded erythematous plaques with elevated, well-demarcated edges
and bullas at the sites of friction (Figure 1). Faint areas
of lacy erythema were noted on the buttocks and arms.
Severe stomatitis, painful glossitis, and bilateral angular
cheilitis were present (Figure 2). Annular erythematous lesions with slightly elevated borders were seen on
the genital area.
An elevated erythrocyte sedimentation rate (65 mm/h;
normal, ⬍12 mm/h), high fasting serum glucose level
(155 mg/dL; normal, 63-108 mg/dL) (to convert to millimoles per liter, multiply by 0.0555), and low hemoglo-
Figure 2. The tongue is red and atrophic; bilateral angular cheilitis is seen.
bin level (100 g/L; normal, 120-140 g/L) were detected.
A peripheral blood smear showed microcytic, hypochromic red blood cells with anisocytosis.
Histopathologic findings revealed severe parakeratosis, mild acanthosis, and persistent loss of granular layer.
Necrosis of keratinocytes in the squamous layer and subcorneal blistering were present. Mild vascular dilatation
and perivascular lymphocytic infiltrate were seen in the
dermis.
An abdominal computed tomographic scan suggested a pancreatic lesion and showed multiple hypoechogenic lesions with diameters of 2 to 3 cm. Magnetic resonance imaging of the pancreas revealed a diffuse mass
in the tail. The plasma glucagon level was elevated at 127
ng/L (normal, ⬍ 60 ng/L).
The patient underwent pancreatic debulking and
partial metastasectomy of the liver. The histologic and
immunohistochemical investigations revealed a differentiated endocrine tumor with vascular invasion and
somatostatin receptor immunopositivity. Treatment
with intramuscular octreotide (30 mg every 28 days)
and interferon alfa (6 MU subcutaneously 3 times per
week) was introduced together with 6 cycles of hepatic
chemoembolization. No remission was achieved, and
the patient died 14 months after the first physical examination.
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Comment. Necrolytic migratory erythema (NME) pathogenesis is quite controversial. In vitro studies have demonstrated that glucagon stimulates epidermal arachidonic acid synthesis1 thus directly affecting the skin
structures.
The cellular protein p62 (which is an adapter in signaltransducing pathways and a component of the inclusion bodies of various chronic degenerative disorders)
is either absent from, or only focally expressed in, glucagonomas in contrast to its abundance in a wellfunctioning pancreas. Since p62 is involved in proapoptotic signal transduction, its loss probably renders tumor
cells less sensitive to apoptosis.2
At the same time, p16 and p27 levels are decreased
consistently in pancreatic endocrine neoplasms, and
because these proteins act as inhibitors of cyclindependent kinases, their insufficiency may stimulate their
transformation and migration.3
Very often NME precedes the onset of systemic symptoms and identifies the main pathologic process.4 Owing to its distinct clinical picture and well-defined histopathologic findings, NME seems to be a dependable
morphologic clue to a subtle diagnosis.5 Remarkably, clinical presumption and histologic findings were the bases
in the present case for the detection of this localized neoplastic proliferation and to confirm the sophisticated clinical entity.
Mary L. Gantcheva, MD, PhD
Valentina K. Broshtilova, MD
Adriana I. Lalova, MD, PhD
Correspondence: Dr Gantcheva, Department of Dermatology and Venereology, Faculty of Medicine, Sofia Medical University, 1 St Georgi Sofiisky St, 1431 Sofia, Bulgaria (mary_gant@yahoo.com).
Financial Disclosure: None reported.
1. Peterson LL, Shaw JC, Acott KM, Mueggler PA, Parker F. Glucagonoma syndrome increases epidermal arachidonic acid. J Am Acad Dermatol. 1984;11
(3):468-473.
2. Lackner C, Dlaska D, Fuchsbichler A, et al. p62 Protein is expressed in pancreatic beta cells J Pathol. 2005;206(4):402-408.
3. Tomita T. Cyclin-dependent kinase (cdk6) and p16 in pancreatic endocrine
neoplasms. Pathology. 2004;36(6):566-570.
4. Chastain MA. The glucagonoma syndrome: a review of its features and discussion of new perspectives. Am J Med Sci. 2001;321(5):306-320.
5. Kheir SM, Omura EF, Grizzle WE, Herrera GA, Lee I. Histologic variation in
the skin lesions of the glucagonoma syndrome. Am J Surg Pathol. 1986;10
(7):445-453.
Lymphomatoid Granulomatosis Induced
by Imatinib-Treatment
Report of a Case. An 89-year-old woman with liver metastases from a gastrointestinal stromal tumor (GIST) was
treated with imatinib mesylate, initial dose of 400 mg/d.
Three months later, the liver tumors decreased. Again 3
months later, a computed tomographic (CT) scan revealed 3 intrapulmonary lesions that radiologically resembled an infectious complication or metastases of the
GIST. Owing to the age of the patient and continuous
decline of her physical status, a lung biopsy was excluded. The progressing pulmonary tumors were clini-
A
B
Figure 1. Histologic images demonstrating large blastic B cells surrounding
the necrosis under hematoxylin-eosin (A) (original magnification ⫻ 20) and
CD20 stain (B) (original magnification ⫻ 200).
cally interpreted as metastases of the GIST, and therefore imatinib mesylate treatment was continued.
Nine months later, the patient presented with multiple subcutaneous nodules as large as 25⫻ 30 mm on
both legs and the lower back. Histologic findings revealed a dense lymphocytic infiltrate, mainly of the subcutis, extending through the dermis into the epidermis,
with central necrosis and scattered giant cells. The infiltrate was both angiocentric and angiodestructive. Immunohistochemically, the lymphocytes were mainly CD20
positive (Figure 1). Epstein-Barr virus (EBV) in situ hybridization revealed EBV RNA in a distinct population
of infiltrating lymphocytes.
Clonality analysis of the CDR3 region of the immunoglobulin heavy-chain gene revealed the identical clone
in 2 distant biopsy specimens. A large B-cell lymphoma
resembling lymphomatoid granulomatosis (LYG) was
diagnosed.
Whole-body CT scan revealed, in addition to hepatic
GIST tumor metastasis, progressive pulmonary tumors that
resembled lymphomas or granulomas (Figure 2). Blood
cell count findings showed leukopenia (2600 white blood
cells/µL) and lymphopenia (10.8% lymphocytes). Immunophenotyping of the peripheral blood showed an increased CD4/CD8 ratio of 9:1 and 1.9% B cells.
Cutaneous and most likely pulmonary LYG was diagnosed. As the pulmonic lymphomas lead to progressive dyspnea, imatinib mesylate therapy was discontinued and replaced by a symptomatic dexamethasone
treatment, which was stopped by the patient after 4 weeks.
Two months after discontinuation, the subcutaneous nodules had vanished completely, and the pulmonary infiltrates could be detected only as small residual nodules
(Figure 2). The patient’s physical condition continuously improved, and the leukocyte and lymphocyte counts
returned to normal range. The liver metastases of GIST
did not show any change in size.
Comment. Lymphomatoid granulomatosis is a rare, angiocentric, angioinvasive, EBV-positive, B-cell lymphoproliferative disease that primarily involves the lung and
skin,1 histologically characterized by angiocentric and an-
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A
B
C
Figure 2. Radiologic images. A, Computed tomographic scan showing multiple large pulmonary tumors. B and C, Chest radiographs taken during imatinib therapy
(B) and after discontinuation of imatinib treatment (C).
gioinvasive lymphoid infiltrates. The presence of EBVpositive B cells is critical for the diagnosis.
Imatinib mesylate, a tyrosine kinase inhibitor targeting the Bcr-Abl fusion tyrosine kinase,2 is currently used
in the management of metastatic and inoperable GIST.
Common adverse effects include eosinophilia, fasciitis,
and mycosis fungoides–like reactions.3 Bekkenk et al4 observed the occurrence of EBV-positive, primary, cutaneous, B-cell lymphoma during imatinib mesylate treatment that resolved after the therapy was discontinued.
Epstein-Barr virus–associated lymphomas occur most
commonly in severely immunosuppressed patients and
often spontaneously resolve after reconstitution of the
immune system. Imatinib mesylate may act through
T-cell depletion; it can inhibit T-cell proliferation and
T-cell activation in vitro and reduce the expansion of cytotoxic T lymphocytes in response to EBV.5 Since, in the
present case, cutaneous and pulmonary LYG occurred
during imatinib mesylate therapy and resolved entirely
after the treatment was discontinued, modulation of
T-cell function was most likely critically involved in the
development of LYG.
Amir S. Yazdi, MD
Gisela Metzler, MD
Susanne Weyrauch, MD
Mark Berneburg, MD
Michael Bitzer, MD
Hans-Konrad Müller-Hermelink, MD
Martin Röcken, MD
Correspondence: Dr Yazdi, Department of Dermatology,
University of Tübingen, Liebermeisterstr 25, 72076 Tübingen, Germany (Amir.Yazdi@med.uni-tuebingen.de).
Financial Disclosure: None reported.
1. Fauci AS, Haynes BF, Costa J, et al. Lymphomatoid granulomatosis: prospective clinical and therapeutic experience over 10 years. N Engl J Med. 1982;
306(2):68-74.
2. Druker BJ, Sawyers CL, Kantarjian H, et al. Activity of a specific inhibitor of
the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia
and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl
J Med. 2001;344(14):1038-1042.
3. Jardin F, Courville P, Lenain P, et al. Concomitant eosinophilia, fasciitis, and
mycosis fungoides-like reaction with antinuclear autoantibodies in chronic
myeloid leukaemia: role of a T-cell clone induced by imatinib. Lancet Oncol.
2005;6(9):728-729.
4. Bekkenk MW, Vermeer MH, Meijer CJ, et al. EBV-positive cutaneous B-cell
lymphoproliferative disease after imatinib mesylate. Blood. 2003;102(12):
4243.
5. Seggewiss R, Lore K, Greiner E, et al. Imatinib inhibits T-cell receptormediated T-cell proliferation and activation in a dose-dependent manner. Blood.
2005;105(6):2473-2479.
Focal Acne During Topical Tacrolimus
Therapy for Vitiligo
T
acrolimus is a macrolide antibiotic produced by
Streptomyces tsukubaensis and with strong Tspecific immunosuppressant activity. Primarily
used for treatment of atopic dermatitis, it has been used
to treat other inflammatory and immunologic skin disorders, including vitiligo, with encouraging results.1 Focal hypertrichosis has been reported during topical tacrolimus therapy for childhood vitiligo,2 but acne does
not seem to be a frequently reported adverse effect.
Report of a Case. An 18-year-old woman presented with
vitiligo on the left side of her chin and neck and on both
sides of the dorsum. The lesions had been present for 4
months and had been enlarging progressively. Findings
of clinical evaluation and laboratory tests were all normal. As a first treatment, she had undergone a 3-month
course of topical 0.05% desonide cream without any clinical response. She was put on a regimen of topical 0.1%
tacrolimus, applied at bedtime, for 3 months, resulting
in repigmentation of nearly 90% of the chin and cervical
lesions and 50% of the dorsal spots.
However, at the end of 3 months, the cervical and chin
spots showed an extensive eruption of inflammatory and
noninflammatory lesions of acne, with papules, pustules, and closed comedones (Figure) not present previously. The macules of the dorsum did not present any
acne lesions. Tacrolimus treatment was discontinued, and
the patient was treated with oral doxicycline and topical
adapalene, with complete clearance of the eruption in 2
months.
Comment. Treatment with topical calcineurin inhibitors is considered a safe and useful therapeutic option
for several dermatoses. Rosaceiform reactions have been
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ment of atopic dermatitis in adults, II: safety. J Am Acad Dermatol. 2001;44
(1)(suppl):S39-S46.
Pneumocystis carinii Pneumonia
in Infant Treated With Oral Steroids
for Hemangioma
I
Figure. Inflammatory papules, pustules, and closed comedones over
partially repigmented lesions of vitiligo on the cervical region and chin.
described after topical tacrolimus and even pimecrolimus treatment for inflammatory disorders of the face.3,4
Used in a vehicle-controlled study for atopic dermatitis
in adults, 0.1% topical tacrolimus therapy resulted in acne
as an adverse event at a mean ± SE rate of 7.1%±2.02%
(P⬍.05).5
As mechanisms and incidence of these adverse findings are not well established, a more accurate follow-up
of patients undergoing long-term topical therapy with
these drugs would perhaps be advisable, to search for possible, although infrequent, unwanted effects on the pilosebaceous units such as acne, hypertrichosis, and rosaceiform reactions.
nfantile hemangiomas are common, benign, and selflimited tumors of infancy. A recent multi-institution
study found that 30% of infants experience complications related to their hemangioma.1 Of those seen in tertiary medical centers, 12% require treatment with oral corticosteroids.1 Ulceration, ocular compromise, and risk of
permanent disfigurement are the most frequent reasons for
intervention. There are no agents approved by the US Food
and Drug Administration for the treatment of hemangiomas, but current practice includes the use of high-dose corticosteroids. The beneficial effects of corticosteroids were
first described in the 1960s, and despite decades of treatment, the literature consists primarily of case reports and
small case series. The effects of steroid administration to
such a young patient population have not been systematically evaluated. High-dose corticosteroids are an independent risk factor for the development of Pneumocystis carinii pneumonia (PCP).2 However, most physicians treating
infants with oral steroids for hemangiomas do not use antimicrobial prophylaxis. We report the second known case
of PCP developing in an infant treated with oral corticosteroids for a hemangioma.
Correspondence: Dr L. Bakos, Department of Dermatology, Hospital de Clı́nicas de Porto Alegre–
Universidade Federal do Rio Grande do Sul, Ramiro Barcellos 2350, Porto Alegre RS 90035003, Brazil (lbakos
@portoweb.com.br).
Financial Disclosure: None reported.
Report of a Case. A girl with a large facial infantile hemangioma not affecting her airway was treated by an outside institution with 15 mg of oral prednisolone daily beginning at age 2 months (Figure). Attempts to wean her
from steroids had failed owing to rapid growth of the
hemangioma.
At age 7 months, she developed severe respiratory distress with fever, increased respiratory rate, intercostal retractions, grunting, and bilateral lung infiltrates on chest
radiograph. She was transferred to a pediatric intensive
care unit and required mechanical ventilation. Analysis
of endotracheal tube aspirates revealed the presence of
PCP. She responded well to treatment with intravenous
trimethoprim sulfamethoxazole but still required intubation for 10 days.
By day 15, she had made a full recovery and was discharged home on a gradual oral corticosteroid taper and
oral trimethoprim sulfamethoxazole twice weekly for PCP
prophylaxis. An extensive laboratory workup revealed no
underlying primary immunodeficiency, and her infection was attributed to immunosuppression secondary to
oral corticosteroid therapy.
1. Travis LB, Weinberg JM, Silverberg NB. Successful treatment of vitiligo with
0.1% tacrolimus ointment. Arch Dermatol. 2003;139(5):571-574.
2. Prats Caelles I, Pinto PH, Casado ELA, Laguna RL. Focal hypertrichosis during topical tacrolimus therapy for childhood vitiligo. Pediatr Dermatol. 2005;
22(1):86-87.
3. Antille C, Saurat JH, Lübbe J. Induction of rosaceiform dermatitis during treatment of facial inflammatory dermatoses with tacrolimus ointment. Arch
Dermatol. 2004;140(4):457-460.
4. El Sayed F, Ammoury A, Dhaybi R, et al. Rosaceiform eruption to pimecrolimus.
J Am Acad Dermatol. 2006;54(3):548-549.
5. Soter NA, Fleiscer AB, Webster GF, et al. Tacrolimus ointment for the treat-
Comment. Pneumocystis carinii pneumonia is a potentially devastating opportunistic infection that is common in patients with AIDS. Less frequently, PCP is seen
in patients with hematologic malignancies, organ transplantation, inflammatory disorders, and solid tumors. In
patients without AIDS who develop PCP, greater than 90%
of them were undergoing treatment with systemic corticosteroids when diagnosed.2
Lucio Bakos, MD, PhD
Renato Marchiori Bakos, MD, MSc
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phylaxis for Pneumocystis carinii pneumonitis. N Engl J Med. 1987;316(26):
1627-1632.
Clinical and Dermoscopic Features
of Agminated Blue Nevus
B
lue nevi are usually solitary but may rarely appear grouped in an agminated pattern. Clinically, they present as a group of multiple blue nevi
in a circumscribed skin area smaller than 10 cm in diameter.1 The skin between the papules may not be discolored and may show a speckled or uniform blueblack or brown pigmentation.1 We report a case of
agminated blue nevus.
Report of a Case. A 59-year-old woman presented with
an asymptomatic dermatosis localized on the anterior
lower extremity of her left leg characterized by brownblue macules and papules. It initially developed during
her late teens, and although its size had increased slightly
over the earlier years, during the last 20 years, its size,
color, and texture had not changed. No family history
Figure. Girl with large facial infantile hemangioma.
To our knowledge only 1 similar case has been reported.3 A 2-month-old infant developed severe respiratory distress from diffuse airway hemangiomas and was
treated with 3.5 mg/kg per day of prednisone. After 5
weeks of therapy, she was readmitted to the hospital with
labored breathing and required mechanical ventilation.
A bronchoalveolar lavage revealed PCP. Intravenous trimethoprim sulfamethoxazole was administered, and mechanical ventilation was discontinued after 3 days.3
Trimethoprim sulfamethoxazole is effective prophylaxis against the development of PCP. The most accepted regimen is 150 mg of trimethoprim/m2 per day
plus 750 mg of sulfamethoxazole/m2 per day divided twice
daily on 3 consecutive days weekly.4 Currently, there are
no PCP prophylaxis guidelines for infants undergoing oral
corticosteroid treatment for hemangiomas. Prophylaxis
for PCP should be a consideration in this setting, given
the 2 case reports now in the literature.
Figure 1. Clinical image revealing numerous grouped pigmented lesions on
the left leg of a 59-year-old woman. A cluster of about 20 blue-brown to slate
gray macules and papules of various sizes, some of which were confluent,
can be observed (original magnification ⫻10).
∗
Mandi L. Maronn, MD
Timothy Corden, MD
Beth A. Drolet, MD
Correspondence: Dr Maronn, Department of Dermatology, Medical College of Wisconsin, 9200 W Wisconsin
Ave, Milwaukee, WI 53226 (mmaronn@mcw.edu).
Financial Disclosure: None reported.
1. Haggstrom A, Drolet BA, Chamlin SL, et al. Prospective study of infantile hemangiomas: demographic, prenatal and perinatal characteristics. J Pediatr. 2007;
150(3):291-294.
2. Yale SH, Limper AH. Pneumocystis carinii pneumonia in patients without acquired immunodeficiency syndrome: associated illnesses and prior corticosteroid therapy. Mayo Clin Proc. 1996;71(1):5-13.
3. Aviles R, Boyce TG, Thompson DM. Pneumocystis carinii pneumonia in a
3-month-old infant receiving high-dose corticosteroid therapy for airway
hemangiomas. Mayo Clin Proc. 2004;79(2):243-245.
4. Hughes WT, Rivera GK, Schell MJ, et al. Successful intermittent chemopro-
Figure 2. Dermoscopic image of part of the lesion exhibiting a cluster of blue
nevi on the anterior lower extremity on the left leg of a 59-year-old woman.
Multiple, grouped, homogeneous, confluent, steel blue to brown-blue
pigmented areas fading into the surrounding skin can be seen. On the surface of
some steel blue areas, linear pigmented structures appear as darker sulci
(diamond). In addition, blue areas, some globules and dots (black arrow), a
brown veil (black arrowhead), and brown-blue and out-of-focus pseudopods
(white arrows) can be recognized. A small rim of tan pigmentation (asterisk)
can also be seen around some blue nevi (original magnification ⫻10).
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A
B
C
Figure 3. Histopathologic examination revealed a superficial type of blue nevus characterized by a bandlike proliferation of dendritic melanocytes in the superficial
dermis. A, Dense, diffuse, bandlike proliferation of dendritic melanocytes in the superficial dermis. Note that there is no junctional involvement at all. An increased
melanin pigmentation of the epidermal basal layer can also be seen (hematoxylin-eosin, original magnification ⫻ 40). B, Higher magnification reveals morphologic
details of numerous dendritic melanocytes and also a few melanophages (hematoxylin-eosin, original magnification ⫻ 400). C, Scanning magnification nicely
shows that all the dendritic melanocytes are clearly S-100 positive (S-100 staining, original magnification ⫻ 40).
of melanoma or similar nevi was reported. Clinical examination revealed a group of approximately 20 bluebrown to slate gray macules and papules of various sizes,
some confluent, and within a perimeter of 4 ⫻2 cm; the
skin between the macules and papules had either the color
of the surrounding normal skin or a brown-gray pigmentation (Figure 1).
In the dermoscopic image (Figure 2), a cluster of
lesions was recognizable, all with a homogeneous pattern, the morphologic hallmark of blue nevus, characterized by multiple, grouped, homogeneous, confluent,
steel blue to brown-blue pigmented areas. On the surface of some of the steel blue areas, typical linear pigmented structures2 were present (Figure 2). A brown veil,
a small rim of tan pigmentation, gray-blue globules and
dots, and out-of-focus pseudopods were also seen within
the diffuse pigmentation (Figure 2).
Two biopsy specimens were taken with a 5-mm skin
punch, one of a steel blue macule, the other of a brownblue papule. The histopathologic examination revealed
a superficial type of blue nevus characterized by a bandlike proliferation of dendritic melanocytes in the superficial dermis (Figure 3). Both biopsy specimens showed
identical features of a superficial blue nevus, but the second one showed a slightly more pronounced melanin pigmentation of the epidermal basal layer (Figure 3A). Using
both the clinical and dermoscopic images, we diagnosed the lesion as a speckled or agminated blue nevus.
Comment. The few cases of agminated nevi described in
the literature have been reported as plaque type,3 eruptive,4 and patch type,5 corresponding histopathologically to common or cellular blue nevus.1 Our case was
clinically similar to one described by Hendricks4 as an
eruptive blue nevus.
Dermoscopically, in addition to structureless areas, our
case presented the local features associated with blue nevi
already reported in the literature.2
Agminated blue nevi may present a diagnostic problem in that the differential diagnosis includes agminated blue nevus or agminated intradermal Spitz nevus
combined with speckled lentiginous nevus.5 Since differential diagnosis of these nevi must also include melanoma and malignant blue nevus, a biopsy and histopathologic examination are necessary for the diagnosis.4
Our case is of special interest because for the first time
to our knowledge, the dermoscopic features of this rare
entity are described.
Maria A. Pizzichetta, MD
H. Peter Soyer, MD
Cesare Massone, MD
Lorenzo Cerroni, MD
Correspondence: Dr Pizzichetta, Division of Medical Oncology C–Preventive Oncology, Centro di Riferimento Oncologico, Via Pedemontana Occidentale 12, I-33081 Aviano, Italy (pizzichetta@cro.it).
Financial Disclosure: None reported.
Additional Contributions: Anna Maria Colussi, RN, performed editing for this article.
1. Vélez A, del-Rio E, Martin-de-Hijas C, Furio V, Sanchez Yus E. Agminated
blue nevi: case report and review of the literature. Dermatology. 1993;186
(2):144-148.
2. Stolz W, Braun-Falco O, Bilek P, Landthaler M, Burgdorf WC, Cognetta AB.
Color Atlas of Dermoscopy. 2nd ed. Berlin, Germany: Blackwell Publishing;
2002.
3. Pittman JL, Fisher BK. Plaque-type blue nevus. Arch Dermatol. 1976;112(8):
1127-1128.
4. Hendricks WM. Eruptive blue nevi. J Am Acad Dermatol. 1981;4(1):50-53.
5. Misago N, Narisawa Y, Kohda H. A combination of speckled lentiginous nevus with patch-type blue nevus. J Dermatol. 1993;20(10):643-647.
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skINsight
SECTION EDITOR: JAMES M. GRICHNIK, MD, PhD
Subungual Exostosis
Marı́a Elena Sánchez-Castellanos, MD; Cecilia Sandoval-Tress, MD; Patricia Ramı́rez-Bárcena, MD;
Instituto Dermatológico de Jalisco “Dr. José Barba Rubio,” Jalisco, Mexico (Drs Sánchez-Castellanos
and Ramı́rez-Bárcena). Dr Sandoval-Tress is in private practice in Jalisco.
S
UBUNGUAL EXOSTOSIS IS AN OUTGROWTH OF
normal bone or calcified cartilaginous remains characterized by the triad of pain, nail
dystrophy, and characteristic radiographic
features.
Case 1 involves a 13-year-old boy who presented
with a 12-month history of an enlarging and painful
lesion localized on the dorsum of the right great toe that
appeared after a trauma. Physical examination revealed
the presence of a flesh-colored, well-circumscribed
elevation that measured 2.0 ⫻1.5 cm that caused onycholysis of the affected nail (Figure 1A).
In case 2, a 17-year-old boy presented with a 4-year
history of an asymptomatic growth localized on
A
the third right toe. Physical examination revealed an
erythematous, well-defined growth that measured
1.5 ⫻1.0 cm that caused onycholysis of the affected nail
(Figure 2A).
In both cases, clinical diagnosis of subungual exostosis was established and confirmed by radiographic examination that showed a well-defined osseous growth
(Figure 1B and Figure 2B). Histologic analysis showed a
proliferative fibrocartilaginous cap that merged into hyaline cartilage forming mature trabecular bone at its base
by enchondral ossification. Both lesions were removed
surgically, resulting in complete relief of symptoms with
no signs of recurrence.
B
Figure 1.
A
B
Figure 2.
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