Dermatologia revista edicion ingles 20110121.indd

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ISSN 1515-8411 (Graphical version) - ISSN 1669-1636 (Online version)
Special Edition | Volume XV | 2009
Volumen XV | Noviembre-Diciembre 2009 | Número 6
Research Articles
Retrospective study of
dermatomyositis. Discussion
of 40 cases consulting a
Dermatology Department
M. L. Hassan, A. Capecce, M. E. Melloni,
M. Saposnik, I. Ruzzi, J. Gramajo,
J. Lorenzo, R. Schroh, C. Corbella
Epidemiological study of
basal cell carcinoma in a
community hospital
V. M. González, S. P. Busso, R. Leitner,
G. Casas, M. Larralde
Cutaneous metastasis of
internal carcinomas, our
experience in 94 cases
R. Azcune, M. G. Spelta, J. Moya,
M. L. Lado Jurjo, M. I. Fontana,
A. M. Barbarulo, S. Gavazza, M. Barrera,
S. M. Ortega, S. Martínez, S. Vanzulli,
E. Zeitlin
Reactional leprosy
L. M. Olivares, G. E. A. Pizzariello,
G. D’Atri, A. Martínez, C. Casas,
M. B. Jalo, G. Rodríguez Prados
Cutaneous manifestations of
acromegaly
M. Dahbar, K. Danilowicz, M. Malavela,
D. Velásquez, M. Allevato, H. Cabrera,
O. D. Bruno
Cutaneous manifestations in
alcoholic patients. Relation
with cirrhosis
Y. Murga, V. Parra, A. Aredes,
M. Alasino, A. Torres, L. Santolín,
S. Salomón, J. Carena
Original Articles
Mucous membrane
pemphigoid: our 14 years’
experience
Unilateral nevoid
telangiectasia. Report of four
cases
Subcutaneous fat necrosis of
the newborn, report of five
cases
M. del P. Beruschi, M. Bolatti,
S. Marinescu, C. Ardissone, L. López,
J. O. Zárate, E. Zeitlin, A. Kaminsky,
E. Dancziger
M. Arias, R. González, R. Retamar,
M. C. López Santoro, M. Demarchi,
M. C. Kien, E. Chouela
M. Larralde, M. E. Abad, C. Corbella,
C. A. Ferrari, R. Plafnik
Susceptibility of different
mouse strains to Leishmania
amazonensis infection
M. A. Falú, M. F. García Bustos,
C. M. Parodi Ramoneda, E. Molina de
Raspi, R. M. Cardozo, R. Cimino,
J. F. Gil, J. L. Vasvari, M. A. Basombrío
Psoriasis: comorbidities in
our community
M. M. Lustia, P. C. Luna, M. J. Nocito,
M. J. Soutelo, M. L. Castellanos Posse,
C. Marchesi, N. G. Cañadas, R. Garuti,
M. Á. Mazzini
Primary vasculitis in children:
A clinical-epidemiological
study
M. F. Stringa, C. Castro, A. D. Olivera,
P. Bonavía, O. J. Stringa, R. Valdez
Palmoplantar melanocytic
nevi: dermoscopic and
histopathological correlation
M. A. Barengo, M. P. Gutiérrez,
E. Valente, A. Ruiz Lascano
HTLV-1 -associated infective
dermatitis in an adult
L. Olivares, G. D’Atri, C. Martinetti,
L. Ciccia, O. Forero, J. Anaya
Verrucous melanoma:
differences and similarities
between primary and
secondary varieties
Periorificial dermatitis in
children
M. Larralde, M. E. Abad, P. Luna,
R. Plafnik, B. Pagotto
Rare tumors of difficult initial
diagnosis
M. I. Sanz, D. Feinsilber, C. Corbella,
R. Schröh, M. L. Hassan
D. Feinsilber, N. Kogan, O. M. Rosati,
C. Corbella, R. Schröh, I. Calb
Vulvar squamous cell
carcinoma. Presentation of
28 patients
Multiple miliary osteoma of
the face. Three cases treated
with carbon dioxide laser
V. Parra, F. Flores, C. Sánchez de
Giménez, P. Daguerre, V. García Llaver,
F. Galdeano, N. Driban
R. A. Retamar, M. I. Hernández, V. Battista,
D. Kaplan, G. Giavino, M. C. Kien,
G. Pellerano, E. N. Chouela
Pyoderma gangrenosum
associated with ulcerative
colitis treated with
Infliximab
D. Malieni, A. C. Torre, M. C. Baztán,
C. Anselmi, R. Galimberti
HLA patients with an
association of familial
lupus-psoriasis
B. A. Paniagua, M. E. Fiad,
A. S. Quenardelle, M. F. Giménez,
P. M. F. Motta, A. M. Habegger de
Sorrentino
www.dermatolarg.org.ar
Hydroa vacciniforme-like
cutaneous T/NK-cell
lymphoma, nasal type
M. Dacal, E. Formentini, A. Vaccarezza,
A. Arra, L. Gagliardi
Merkel cell carcinoma. Study
of five cases
N. G. Cañadas, P. C. Luna, M. J. Nocito,
M. M. Lustia, M. D. Etcheverry,
M. L. Castellanos Posse, C. Marchesi,
R. A. Garuti, G. Carabajal, M. Á. Mazzini
ISSN 1515-8411 (Graphical version) - ISSN 1669-1636 (Online version)
Publication of the Sociedad Argentina de Dermatología
Editor
Alejandra Abeldaño
Director Emeritus
Alberto Woscoff
Associate Editors
Liliana Olivares
Roberto Retamar
Assistant Editors
Ariel Blaustein
José Brusco
Myriam Alejandra Dahbar
Cristina Echeverría
María Inés Hernández
Viviana Leiro
Andrea Santos Muñoz
Sociedad Argentina
de Dermatología
Board of Directors
2009-2011
Chairman of the Board
Ricardo Galimberti
Board of Directors
Roberto Glorio
Viviana Parra
Jorge Laffargue
María Antonia Barquin
Ana Kaminsky
Alberto Woscoff
Mario A. Marini
Editorial Board
Argentina
Biagini, Roberto
Cabrera, Hugo
Casalá, Augusto
Chouela, Edgardo
Hassan, Mercedes
Jaimovich, León
Kaminsky, Ana
Stringa, Sergio
Viglioglia, Pablo
Australia
Cooper, Alan
Austria
Wolff, Klaus
Bolivia
Sangüeza, Martín
Sangüeza, Pastor
Brazil
Rivitti, Evandro
Canada
Krafchik, Bernice
Mexico
Domínguez Soto, Luciano
Ruiz Maldonado, Ramón
Chile
Cabrera, Raúl
Honeyman, Juan
Spain
Camacho Martínez, Francisco
De Moragas, José María
Mascaró, José María
Colombia
Chalela, Juan Guillermo
Falabella, Rafael
France
Belaich, Stéphane
Civatte, Jean
Ortonne, Jean
Revuz, Jean
Germany
Czarnetzki, Beate
Orfanos, Constantin
Plewig, Gerard
Italy
Caputo, Ruggero
Lotti, Torello
Tosti, Antonella
United Kingdom
Marks, Ronald
Ryan, Terence
United States of America
Bergfeld, Wilma
Eaglestein, William
Katz, Stephen
Kopf, Alfred
Price, Vera
Strauss, John
Zaias, Nardo
Uruguay
De Anda, Griselda
Macedo, Néstor
Vignale, Raúl
Summary
Vol XV, January-February 2009, Nº 1
Research Article
007
Research Article
044
R. Azcune, M. G. Spelta, J. Moya, M. L. Lado Jurjo, M. I. Fontana,
A. M. Barbarulo, S. Gavazza, M. Barrera, S. M. Ortega, S. Martínez,
S. Vanzulli, E. Zeitlin
Retrospective study of dermatomyositis.
Discussion of 40 cases consulting a Dermatology
Department
M. L. Hassan, A. Capecce, M. E. Melloni, M. Saposnik, I. Ruzzi,
J. Gramajo, J. Lorenzo, R. Schröh, C. Corbella
Research Article
017
024
Cutaneous metastasis of internal
carcinomas, our experience in 94 cases
Research Article
052
Reactional leprosy
L. M. Olivares, G. E. A. Pizzariello, G. D’Atri, A. Martínez, C. Casas,
M. B. Jalo, G. Rodríguez Prados
Epidemiological study of basal cell carcinoma
in a community hospital
V. M. González, S. P. Busso, R. Leitner, G. Casas, M. Larralde
Vol XV, May-June 2009, Nº 3
Original Article
Research Article
Unilateral nevoid telangiectasia. Report
of four cases
058
Cutaneous manifestations of acromegaly
M. Dahbar, K. Danilowicz, M. Malavela, D. Velásquez, M. Allevato,
H. Cabrera, O. D. Bruno
M. Arias, R. González, R. Retamar, M. C. López Santoro,
M. Demarchi, M. C. Kien, E. Chouela
Original Article
Original Article
029
063
HTLV-1 - associated infective dermatitis
in an adult
Pyoderma gangrenosum associated with
ulcerative colitis treated with infliximab
D. Malieni, A. C. Torre, M. C. Baztán, C. Anselmi, R. Galimberti
L. Olivares, G. D’Atri, C. Martinetti, L. Ciccia, O. Forero, J. Anaya
Original Article
Vol XV, March-April 2009, Nº 2
068
Original Article
034
HLA patients with an association of familial
lupus-psoriasis
B. Á. Paniagua, M. E. Fiad, A. S. Quenardelle, M. F. Giménez,
P. M. Fabiana Motta, A. M. Habegger de Sorrentino
Verrucous melanoma: differences
and similarities between primary
and secondary varieties
Original Article
D. Feinsilber, N. Kogan, O. M. Rosati, C. Corbella, R. Schröh, I. Calb
072
Original Article
039
Multiple miliary osteoma of the face. Three
cases treated with carbon dioxide laser
R. A. Retamar, M. I. Hernández, V. Battista, D. Kaplan, G. Giavino,
M. C. Kien, G. Pellerano, E. N. Chouela
Subcutaneous fat necrosis of the newborn,
report of five cases
M. Larralde, M. E. Abad, C. Corbella, C. A. Ferrari, R. Plafnik
6 | Sumario
Vol XV, July-August 2009, Nº 4
Research Article
077
Original Article
109
V. Parra, F. Flores, C. Sánchez de Giménez, P. Daguerre, V.
García Llaver, F. Galdeano, N. Driban
Cutaneous manifestations in alcoholic
patients. Relation with cirrhosis
Y. Murga, V. Parra, A. Aredes, M. Alasino, A. Torres, L. Santolín,
S. Salomón, J. Carena
Research Article
082
Vulvar squamous cell carcinoma.
Presentation of 28 patients
Original Article
114
Hydroa vacciniforme-like cutaneous
T/NK-cell lymphoma, nasal type
Mucous membrane pemphigoid: our 14
years’ experience
M. Dacal, E. Formentini, A. Vaccarezza, A. Arra, L. Gagliardi
M. del P. Beruschi, M. Bolatti, S. Marinescu, C. Ardissone,
L. López, J. O. Zárate, E. Zeitlin, A. Kaminsky, E. Dancziger
Vol XV, November-December 2009, Nº 6
Research Article
Original Article
089
Periorificial dermatitis in children
118
M. Larralde, M. E. Abad, P. Luna, R. Plafnik, B. Pagot
M. F. Stringa, C. Castro, A. D. Olivera, P. Bonavía, O. J. Stringa,
R. Valdez
Original Article
094
Research Article
Rare tumors of difficult initial diagnosis
M. I. Sanz, D. Feinsilber, C. Corbella, R. Schröh, M. L. Hassan
A clinical-epidemiological study
127
Vol XV, September-October 2009, Nº 5
Palmoplantar melanocytic nevi:
dermoscopic and histopathological
correlation
M. A. Barengo, M. P. Gutiérrez, E. Valente, A. Ruiz Lascano
Research Article
100
Original Article
Susceptibility of different mouse strains
to Leishmania amazonensis infection
M. A. Falú, M. F. García Bustos, C. M. Parodi Ramoneda,
E. Molina de Raspi, R. Marino Cardozo, R. Cimino,
J. Fernando Gil, J. L. Vasvari, M. Á. Basombrío
Research Article
106
Psoriasis: comorbidities in our community
M. M. Lustia, P. C. Luna, M. J. Nocito, M. J. Soutelo,
M. L. Castellanos Posse, C. Marchesi, N. G. Cañadas,
R. Garuti, M. Á. Mazzini
135
Merkel cell carcinoma. Study of five cases
N. G. Cañadas, P. C. Luna, M. J. Nocito, M. M. Lustia,
M. D. Etcheverry, M. L. Castellanos Posse, C. Marchesi,
R. A. Garuti, G. Carabajal, M. Á. Mazzini
Research Article
Retrospective study of dermatomyositis. Discussion
of 40 cases consulting a Dermatology Department
Mercedes Lidia Hassan1, Ana Capecce2, María E. Melloni2, Miriam Saposnik2, Ivana Ruzzi3, Josefina Gramajo4, Juana Lorenzo5,
Roberto Schröh6, Cristina Corbella7
Abstract
Background. Dermatomyositis (DM) is included in idiopathic inflammatory miopathies, together with polymyositis, although clinical variants without muscle involvement are recognized, exclusively showing cutaneous involvement during variable periods of time, or remaining definitely amyopathic. Cutaneous manifestations are so characteristic that a diagnosis may be made even before any muscular involvement occurs. Association to internal malignancy, organ involvement, and evolution possibilities arouse interest of physcicians and dermatologists.
Material and methods. We retrospectively studied 40 patients (33 females) consecutively seen at the Dermatology Department of Hospital Ramos
Mejía of Buenos Aires between June 1991, and June 2007.
Objective. To analyse this population composition, cutaneous and systemic involvement characteristics, and disease evolution.
Results. The following was found: 23 percent of amyopathic forms (9 of 40), 16.6 percent associated with internal malignancy (6/36), excluding four
cases of childhood/juvenile DM. Malignancies were exclusively gynecological: breast (3), cervix (2), and ovary (1). Lapse between diagnosis of cancer
and DM was from 0 to 2 years.Infrequent skin lesions and complications of these patients were described, in addition to currently accepted cutaneous criteria for the diagnosis of dermatomyositis. No “flagellated” erythema lesions or complete antisynthetase syndrome were found. Unsuspected
interstitial lung disease with simple chest X-ray was detected in two cases, both non-positive for anti-Jo1 antibodies. One case of this series appeared
three years after silicone mammary implant as amyopathic dermatomyositis (ADM). One of 4 deaths was caused by breast cancer metastasis and another by aspiration pneumonia with pharyngeal muscle involvement; in the other two cases the cause was not related to DM.
Conclusions. The analysis of the observed cases enables us to understand data about this population composition (prevalence of ADM, prevalence of
internal malignancy, negative results for anti-Jo1 antibodies), to include unusual skin aspects, and to detect unsuspected respiratory diseases requiring
special studies for early diagnosis. The lack of previous original reported series of DM in our country is highlighted (Dermatol Argent 2009;15(1):27-36).
Key words: dermatomyositis, polymiositis.
Introduction
Reception date: 12/8/08 | Approval date: 11/9/08
1. Named Professor UBA, and Head of Dermatology Department.
2. Medical Dermatologist of Collagenopathy Sector.
3. Medical Resident, 2nd year, Specialist Course UBA.
4. Attending Physician, 2nd year, Specialist Course UBA.
5. Medical Course Physician, 1st year, Specialist Course UBA.
6. Staff Physician, in charge of Pathology Sector.
7. Staff Physician, Histopathology.
Dermatology Department. Hospital “J. M. Ramos Mejía”, Associated to Universidad de
Buenos Aires. Autonomous City of Buenos Aires. Argentine Republic.
Correspondence
Mercedes Lidia Hassan. Arcos 2273 1º B, (1428) Autonomous City of Buenos Aires, Argentine Republic. | E-mail: [email protected]
Dermatomyositis (DM) is included in idiopathic inflammatory myopathies, together with polymyositis (PMs),1-6
although exclusively cutaneous clinical forms without muscular involvement are recognized for a variable period of time,
and even definitely amyopathic (ADM) forms.7-15
It is characterized by the involvement of upper limb proximal striated muscle and neck flexor muscles, with or without
dysphagia, and involvement of respiratory muscles. The association with neoplasias and involvement of internal organs
arouse interest in clinical physicians and dermatologists; however, the latter rarely see any form of PM.
Bohan and Sontheimer classifications
DM diagnosis criteria in Bohan’s classification (Table 1)
do not include patient subgroups with exclusively or predominantly cutaneous lesions;8,13 therefore, a broader pathological category has been suggested, designated as “idiopathic inflammatory dermatomyopathies” 14,15 (Table 2).
According to Sontheimer, the adult-onset DM forms encompass:
8 | M. L. Hassan, A. Capecce, M. E. Melloni, M. Saposnik, I. Ruzzi, J. Gramajo, J. Lorenzo, R. Schröh, C. Corbella
ABBREVIATIONS
LAA: leukocytoclastic allergic angiitis.
ACL: anticardiolipins.
CPK: creatine phosphokinase.
DM: dermatomyositis.
ADM: amyopathic dermatomyositis.
EMG: electromyogram.
FAN: antinuclear antibodies.
TNF: tumor necrosis factor.
IFN: interferon.
ILD: interstitial lung disease.
LDH: lactic dehydrogenase.
MTS: metastasis.
PM: polymyositis.
NMR: nuclear magnetic resonance.
Rx: X-ray.
CAT: computed axial tomography.
HRCT: high resolution computed tomography.
GOT: glutamic-oxalacetic transaminase.
Classic DM. It shows the two cutaneous and muscular components simultaneously or with a lapse not exceeding 6
months between them. Three presentations are included: exclusive, as part of a collagenopathy, or associated with internal
malignancy.
Clínically amyopathic DM. It comprises amyopathic DM (synonym of without myositis): distinctive classic DM skin lesions
confirmed by biopsy of 6 or more months evolution (provisional) to 2 years (definite) previous to muscular involvement; and
hypomyopathic DM: specific cutaneous involvement, without
clinical evidence of muscular involvement, but with some altered supplementary studies (enzymes, electromyogram [EMG]
and/or muscle biopsy).
Childhood/juvenile DM forms include classic DM and clinically amyopathic DM with its two variants (amyopathic and
hypomyopathic) defined similarly to the adult onset DM amyopathic and hypomyopathic forms.
Incidence
Incidence in this country is unknown. In the United States,
the annual incidence estimation is 1/100,000 inhabitants;6 for
childhood/juvenile DM, 0.06 to 0.32/100,000.16 According
to the Joint Committee of the American Association of
Dermatology, in 1998 the annual incidence was 5 cases per million inhabitants.17
Etiology
Family-genetic risk of suffering idiopathic inflammatory
myopathies (adult and juvenile DM) related to homocygocity for HLADQA1, nucleotide polymorphism in tumor necrosis factor (TNF) promoter (TNF-α 308-A) was found associated with chronicity, calcinosis, and high titers of TNF-α
in classic juvenile DM in Caucasian population.1Association
of DM with lung disease is known, more frequent in Japanese,
TABLE 1. BOHAN’S CLASSIFICATION OF POLYMYOSITIS/DERMATOMYOSITIS.4
• Clinical subgroups
º Polymyositis.
º Dermatomyositis.
º Polymyositis or dermatomyositis associated with malignancy.
º Childhood dermatomyositis.
º Polymyositis or dermatomyositis with an associated connective tissue disorder.
• Diagnostic criteria5
º Typical skin rash.
º Symmetrical proximal muscle weakness with or without dysphagia or respiratory involvement.
º EMG compatible with primary muscular involvement.
º Alterations in muscle biopsy compatible with primary muscular involvement.
º Elevation of muscle enzimes (creatin phosphokinase [CPK], glutamic oxalacetic transaminase [GOT], lactic dehydrogenase [LDH], aldolase).
Confidence limits for diagnosis of dermatomyositis:
Definite DM: rash and three of the four other diagnostic criteria.
Probable DM: rash and two of the four other diagnostic criteria.
Possible DM: rash and one of the four other diagnostic criteria.
TABLE 2. GLOBAL CLASSIFICATION OF IDIOPATHIC INFLAMMATORY DERMATOMYOPATHIES (SONTHEIMER 2002).1
1. Dermatomyositis (DM)
• Adult onset DM:
Classic DM:
exclusive.
as part of an overlap connective tissue disorder
associated with internal cancer.
Clinically amyopathic DM: amyopathic (provisional or definitive).
hypomyopathic.
•
Juvenile onset DM:
Classic DM.
Clinically amyopathic DM: amyopathic.
hypomyopathic.
2. Polymyositis (PM):
exclusive.
as part of an overlap connective tissue disorder.
associated with internal cancer.
3. Inclusion bodies myositis
4. Other clinical-pathological subgroups of myositis:
focal myositis, proliferative myositis, orbital myositis, eosinophilic myositis,
and granulomatous myositis.
and occasional genetic deficit of C5 has been reported in DM.
Etiology also involves virus (parvovirus B19, Epstein Barr),
drugs (such as cholesterol-lowering agents), D-penicillamine,
phenytoin, chloroquine, hydroxyurea, interferon (IFN), which
may cause myopathy and/or compatible skin lesions.18-21
Ultraviolet light has been accepted as a trigger, but no photoinduction of the lesion has been attained.
Antibody-associated subgroups
A HLA DR52-related group has been identified, with higher prevalence of Jo-1 antibodies (20-30 percent of PM/
DM), characterized by lung fibrosis, arthritis, Raynaud’s
phenomenon, mechanic’s hands, poor prognosis, higher
Retrospective study of dermatomyositis. Discussion of 40 cases consulting a Dermatology Department | 9
mortality, and poor response to treatment (antisynthetase syndrome); and another DR53-related group, Dw7 with
Mi-2 antibodies, present in 15 percent of DM, with florid skin involvement and better response to treatment.
PM/Scl present in 25 percent overlaps and in 8 to 12 percent of PM is associated with myopathy plus sclerodermia.
Anti-SRP (signal recognition particle) present in 5 percent of PM relates to cardiac involvement without lung fibrosis, resistance to corticoid treatment, and severe myositis.1,5 DR3, B8, and B14 have been related to juvenile DM;
and B14 and B40, to overlap syndrome in adults. Recently,
antibodies of 155 kDa (Se) and 140 kDa (US) have been
TABLE 3. CLASSIC CUTANEOUS MANIFESTATIONS OF DM.14
Pathognomonic
1. Gottron’s papules.
2. Gottron’s sign: symmetric confluent macular violaceous erythema on the dorsal
aspect of the interphalangeal or metacarpophalangeal joints, oleocranon, patellae and medial malleoli.
Characteristics
1. Heliotrope erithema.
identified in sera of amyopathic DM related to interstitial
lung disease or paraneoplasia, respectively. 22
Cutaneous manifestations
Table 3 describes the distinctive cutaneous manifestations of
DM.14
Signs of poor prognosis3,9,11,23-25 (acute, progressive, and severe
forms) are: early and rapid respiratory, pharingeal, or esophagic
involvement, resistance to early corticoid treatment, blisters or
necrotic skin lesions in trunk, systemic vasculitis, high erythrosedimentation rate (more than 35 mm in the 1st hour), and old age.
Mortality varies about 21 percent in adults and 3-31 percent in children, according to diverse case-control studies and
authors.14Causes of death are respiratory failure and those related to associated malignancies in adults (metastasis).1,3,9,11,25,26
Incidence of internal malignancies was found in various case-control studies (between 11 and 43 percent).34 Relative
risk for internal malignancy ranges between 1.7 and 7.7, and is
maximal in the term of one year.10,25,26-34
Material and methods
2. Periungual telangiectasia.
3. Symmetric confluent macular violaceous erythema on the dorsal aspect of the
hands, extensor aspect of arms and forearms, deltoid areas, posterior part of
shoulders and neck (shawl sign), anterior neck and upper chest (V sign), central
aspect of the face and the forehead, and scalp.
4. Mechanic’s hand.
Compatible with DM
1. Vascular atrophic poikilodermia.
2. Cutaneous calcinosis.
A retrospective observational analysis was carried out in 40 patients (7 males and 33 females) studied in the 1991-2007 period in the Dermatology Department of Hospital “J. M. Ramos
Mejía” of Buenos Aires, with confirmed diagnosis of DM. Nine
of them were amyopathic (ADM), and 4 were childhood or juvenile cases. Excluded from computation were the cases of difficult differential diagnosis: a mycosis fungoides (photosensitive
5%
18%
Femenino
23%
Classic
Masculino
Amyopathic
72%
82%
Chart 1. Dermatomyositis per gender.
Hypomyopathic
Chart 3. Dermatomyositis per clinical form.
3%
Number of patients
12
10
21- 30 years
31- 40 years
41- 50 years
51- 60 years
61- 70 years
71- 80 years
8
6
4
2
15%
Muscular
25%
Cutaneous
Concomitant
Overlap
0
21-30 31-40 41-50 51-60
years years years years
Chart 2. Dermatomyositis per age at diagnosis.
61-70 71-80
years years
57%
Chart 4. Dermatomyositis per onset form.
Clincal features are summarized in Table 4, and in Charts 1, 2,
3, and 4. Thirty three females and 7 males were studied (F:M
ratio = 4.71:1). Four of them had diagnosis of childhood/juvenile DM, with age of onset 5, 12, 14, and 15 years, respectively;
two were females and two were males. The amyopathic juvenile forms, like calcinosis, were found in three cases, two females.
As a whole, 9 (23 percent) had diagnosis of ADM, and 31 were
classic forms. The period of time lapsing from the cutaneous
manifestations to the onset of muscular manifestations lasted
up to 11 years; the initial diganosis of these patients was lupus
erythematosus (seen at our Department by another observator). In addition to major and minor criteria,14 in our case-control study we found: rare lesions: blister lesions (in 2 patients),
follicular lesions (2), extended diffuse alopecia, with whitish
scales on scalp (1), gingival and lip telangiectasia (1), “milliary”
calcinosis (1), “punch-biopsy scar”-like lesions (3), cutaneous
vasculitis (2) (Figures 1, 2, 3, 4, 5, and 6).
Complications not previously reported in this pathology: nontropical pyomyositis (1) (Figures 7 and 8), adult tinea (1), and
episodic abdominal distension related to peritoneal adherences
evidenced by abdominal computed axial tomography (CAT)
(1) (Figure 9).
No case was found of antisynthetase syndrome (association
of Jo-1 antibodies, lung fibrosis o interstitial pneumonitis,
Raynaud’s phenomenon, and mechanic’s hands), or flagellated lesions. Lung involvement was found in two patients
with Jo-1, without mechanic’s hands in an overlap and a
classic DM.
Association with internal malignancy was observed in 16.6
percent (6 of 36), excluding childhood/juvenile cases.
Treatment was carried out based on oral systemic corticosteroids, mostly meprednisone 1-2 mg/kg/day for months, with progressive variable dose reductions to complete 2 years. Not all
patients completed this regimen, or complied with it regularly.
Occasionally, in special cases due to resistance, irregular intake
of corticoids, or concomitant contraindicated conditions, oral
methotrexate 7.5 to 12.5 mg/week was used, or low dose intravenous gammaglobulin (0.5 g per kg/day) for two days once a
month, with good initial response, but they were discontinued
on cost grounds. Mycophenolate mofetil was use in refractary
myositis, 2 g/day, starting with 0.5 g/day. Thalidomide, 200
mg/day, and chloroquine phosphate, 200 mg/day, were used in
other patients.
Figure 1. Poikiloderma. “Punch-biopsy” like lesions.
Figure 2. Follicular lesions.
lesions, facial erythema with eyelid edema, poikiloderma, high
reumatoid factor, arthralgia, and Raynaud’s phenomenon, together with neurological disease); and 3 female patients in whom
the study was not completed. Also not included was a case associated with simvastatin intake, which generated uncertainty
about the role of this drug in the appearance of manifestations.
Results
TABLE 4. CLINICAL CHARACTERISTICS AND EVOLUTION OF PATIENTS WITH DM DIAGNOSIS IN HOSPITAL “RAMOS MEJÍA”. PERIOD 1991-2007.
Pat
Age
Sex
Clinical form
Onset
Antibodies
1
50
F
Classic
Muscular
-
Cervix
2
60
F
Classic
Cutaneous
-
-
Systemic condition
or other feature
Neoplasia
Evolution
Loss of weight LAA
Resp. failure
Loss of weight
-
3
57
F
Classic
Concomitant
-
-
-
-
4
37
F
Classic
Cutaneous
-
-
-
Resp. failure
5
35
F
Amyopathic
Cutaneous
ACL
-
Follicular lesions
Remission
6
58
F
Classic
Cutaneous
-
Breast
7
43
F
Classic
Concomitant
-
-
LAA
-
-
-
Blisters
-
8
43
F
Classic
Cutaneous
-
-
9
48
F
Classic
Cutaneous
-
Breast
-
Bone MTS
10
50
M
Classic
Cutaneous
-
-
-
Remission
11
68
F
Classic
Muscular
-
-
-
Resp. failure
12
54
F
Amyopathic
Cutaneous
-
-
-
-
13
12
F
Classic
Muscular
-
-
Loss of weight
Remission
14
36
F
Classic
Muscular
-
-
-
-
15
14
F
Amyopathic
Cutaneous
-
-
Acne due to corticoids
Remission
16
64
F
Classic
Muscular
-
-
-
-
17
15
M
Amyopathic
Cutaneous
-
-
Calcinosis
Irreg. Tt.
18
54
F
Amyopathic
Cutaneous
-
Breast
-
-
Respiratory
Post-silicone
Remisión.
19
32
F
Amyopathic
Cutaneous
20
56
F
Classic
Concomitant
-
-
Mild resp esoph
Remission
21
15
F
Amyopathic
Cutaneous
FAN+
-
Calcinosis+++
Improvement
22
5
M
Classic
Concomitant
-
-
Loss of weight
-
23
27
F
Classic
-
Cutaneous
-
-
Abdominal distension
Steatosis
Dry Sd
Lipodystrophy
24
46
F
Classic
Cutaneous
FAN 1/2560 Mo
-
-
-
25
33
F
Classic
Concomitant
FAN 1/320 Mo
-
Blisters
Pyomyositis
-
Dysphagia
Follicular lesions
-
26
28
M
Classic
Cutaneous
FAN 1/80
27
58
F
28
29
F
Classic
Cutaneous
-
Ovary
Classic
Concomitant
-
-
29
34
30
78
F
Classic
Concomitant
FAN 1/80 Mo
-
Tricophytic tinea
-
M
Amyopathic
Cutaneous
-
-
Fibromyalgia
-
Dysglusia
Bone MTS
-
-
31
27
F
Classic
Muscular
-
-
-
32
50
F
Classic
Cutaneous
FAN 1/1600 Mo
-
Erythroderma by chloroquine -
33
50
F
Classic
Concomitant
FAN+
Cervix
Vasculitis ulcers
Pneumonia.
34
33
M
Classic
Concomitant
FAN 1/400 Mo
-
Lung fibrosis
Pharingeal
35
75
F
Hypomyopathic
Cutaneous
FAN 1/160 Mo
-
-
Overlap
FAN 1/80 Ro+
La+
-
Norwegian scaILD Cutaneous vasculitis Livebies. Died duedo and acral ulcers
to neumothorax
Hypomyopathic
Cutaneous
-
-
-
-
Classic
Concomitant
FAN 1/5120
-
ILD
-
F
Amyopathic
Cutaneous
-
-
-
-
M
Classic
Cutaneous
-
-
-
-
36
40
F
Classic
37
72
F
38
32
F
39
40
40
50
ACL: anticardiolipins. LAA: leukocytoclastic allergic angiitis. FAN: antinuclear antibodies. Mo: mottling pattern. MTS: metastasis. ILD: interstitial lung disease.
No satisfactory results were obtained by corticotherapy or by hydroxychloroquine administration on
skin lesions, and these remained in spite of the muscle involvement improvement. In facial lesions, 0.1
percent topical cream tacrolimus, or 1 percent pimecrolimus were indicated in two cases, with partial
responses.
In one case of juvenile DM with calcinosis it was administrated disodium etidronate, 20 mg/day, with
very good motor response and X-ray control after
three months treatment. Currently, we indicate diltiazem, 10 mg/day, or alendronate.
Patient management was supplemented by kinesiotherapy and muscular rehabilitation, indispensable
against contractures and permanent disability, especially in the childhood/juvenile form and to relieve
dysphagia.
Causes of death were: respiratory failure due to aspiration pneumonia with pharyngeal muscle involvement (2); metastasis of associated malignancy (1);
and two deaths of a cause not related to DM: pancreatitis (1), and traumatic pneumothorax (1).
COMMENT
Figure 3. “Miliary” calcinosis in juvenile DM.
Figure 4. Gottron’s papules.
Dermatomyositis appears with specific skin lesions, taken as diagnostic criteria; in addition, less
frequent lesions related to this condition exist.1,9
These encompass: follicular lesions (Figure 2),
found in two cases located on presternal area and
back, having mucin deposits, perifollicular mononuclear infiltrate, follicular hyperkeratosis, and involvement of the arrector muscle of hair; diffuse
alopecia with squamous lesions,16,36 which had to be
differenciated from adult tinea, psoriasis, anticonvulsant pharmacodermia, and Norwegian scabies.
Therefore, direct mycological examination and culture of these lesions are recommended. They have
also been referred to as psoriasiform scalp lesions
in juvenile DM,16 but were not exclusive to that age
range in our patients. The “punch-biopsy scar” appearance is noteworthy in the photosensitive areas
of poikilodermia, but is rare, and shows nonspecific histopathology. Calcinosis in one case adopted
an uncommon “miliary” appearance in the inner
aspect of the thighs in a juvenile ADM,16 and was
not disabling. In two patients coexisted morphealike lesions with compatible histopathology in the
root of upper limbs. Lip and gingival telangiectasia were found in the physical examination of only
one patient; they have recently been described in
this disease, and the significance is yet unknown.
Cutaneous vasculitis (Figures 5 and 6) was found
in two cases: one with white atrophy-like lesions in
the root of upper limbs, following a linear arrangement with round ulcerations. No anti-phospholipid antibodies were demonstrated. Histopathology
showed leukocytoclastic allergic angiitis, which
healed with general treatment. Adjacent sclerodermal lesions (clinical and histopathology) with
ivory shine and hyperpigmentation were seen. The
other case was an overlap DM with petechial fingertip lesions and moderate acral livedo reticularis and ulcerations on the legs; this myositis was refractary to several immunosuppressor treatments
and responded to mycophenolate mofetil. The lung
instertitial condition remained unaltered, and the
patient died of a non-related cause.
Complications observed were the presence of adult
tinea caused by Trichophyton mentagrophytes,37,38
with relapses and extension to hairless skin after
treating with systemic antifungals, and Norwegian
scabies. The first rare condition may be attributed
to: (1) immunosuppression inherent to the corticoid treatment, or the disease, (2) a race or cosntitution predisposition (it was recently related to AfroAmerican women), or (3) insufficient antifungal
treatment.
Two unusual conditions posed diagnostic difficulties: (a) episodic abdominal distension caused by peritoneal adherences seen in abdominal CAT, attributed to a sequela of probable prior mesenteric vasculitis in a young 29-year-old female patient with
noticeable facial lipoatrophy, and (b) non-tropical
pyomyositis.39,40
Pyomyositis is a muscular staphylococcal abscess,
which may be diagnosed by puncture and culture,
biopsy, ultrasonography and/or muscular NMR.
It appears in tropical countries favored by parasitosis (filaria), malnutricion, and local trauma. It
shows three stages: (1) initial, with mild fever, slight
erythema, and local pain, (2) purulent, with fever, erythema, edema and fluctuation, and (3) septic, with hectic fever and poor general condition.
Treatment requires systemic antibiotics and surgical
drainage of the lesion.
It may pass unnoticed, and myalgia and muscular
weakness may be attributed to DM.
One case treated with statins showed association of
DM with a fibromyalgia-like picture,41 with localizad muscular pain on palpation on upper limbs and
trunk, without weakness or alteration of muscle enzimes, EMG, or NMR in a DM construed as amyopathic, with normal erythrosedimentation rate.
Not observed were: flagellated dermatitis or antisynthetase syndrome.42
Figure 5. Cutaneous vasculitis with round ulcerations coexisting with localized sclerodermal lesions
(arrows).
Figure 6. Cutaneous vasculitis. White atrophy-like lesions on legs.
Two classic DM cases were diagnosed as interstitial lung disease, with
negative Jo-1. Diagnosis was reached by high resolution computed tomography (HRCT), respiratory function testing, and carbon monoxide diffusion, with normal chest X-ray. This indicates that the interstitial
lung disease (ILD) must always be searched for by this method in DM/
PM patients, even if no clinical manifestations appear, chest X-ray is normal, and anti-Jo-1 antibody is negative, and even in ADM, as mentioned
above.14,15,42-46
Association with internal malignancy was observed in 16.6 percent
of the cases (6/36), three breast cases, two cervix cases, and one ovary
case. The periods of time between appearance of malignancy and disease onset were: one year and 4 months (in one case), two years (in
two cases), and simultaneous (in two cases), in accordance with previous reports by other authors, based on Scandinavian and European
case-control studies, where the higher relative risk (5.9 – 7.7) appears
at one year, falls after the second year, but never becomes normal.
extensive erythrodermal erythematous outbreak due
to chloroquine, which subsided with medication
discontinuation.
The cause of death was related to respiratory failure (by aspiration pneumonia with pharyngeal muscle involvement in 2 cases), and associated malignancy (recurrence with breast cancer metastasis in
one case). Lung involvement was precocious, and
has been pointed out as one of the signs of poor
prognosis, when it is persistent and refractory to
corticotherapy.1,3,5,14
CONCLUSIONS
Figure 7. Non-tropical pyomyositis. Erythema and blister on border of erythematous plate of leg
overlying muscle abscess.
Figure 8. Muscle ultrasonography. Notice hypoechoic image of intramuscular abscess.
Therefore, an annual examination is recommended, and upon appearance of any new symptom, within the first three years24,35 (Table 5).
Concomitant onset34 occurred in an asymptomatic cervical “carcinoma
in situ”, found in a routine gynecological examination, which was requested at the dermatomyositis diagnosis; therefore, it may be inferred that the
delay in diagnosis of a hidden malignancy may be responsible for the extended period lapsing between diagnosis of the disease and appearance of
neoplasia.
Ovary cancer26 was diagnosed upon bone metastasis in case 27. The finding of gynecological malignancy exclusively confirms that the type of
malignancy related to the most frequent according to age, gender and race
in each country or geographical region. Of the 6 malignancies, only one
was associated to ADM.33,35
As regards treatment,47,54 a noticeable response was detected in a refractary myositis of an overlap DM to mycophenolate mofetil after several
immunosuppressor treatments (cyclophosphamide, corticoids, plasmapheresis, gammaglobulin IV, methotrexate). The lung condition remained unaltered, secondary effects were noticeable (gastric intolerance),
and death occurred due to a non-related cause. One patient showed an
1. In a population of 40 patients who were from
14 to 75 years old at the time of the initial visit between 1991 and 2007, a F:M ratio of
4.71:1 was found.
2. Uncommon skin lesions were observed: blisters
(two patients), follicular (2), scaly scalp alopecia
(2), miliary calcinosis (1), “punch-biopsy scar”
lesions (3), gingival and lip telangiectasia (1),
and cutaneous vasculitis (2). Complications during the course of this condition included: adult
tinea capitis by Trichophyton mentagrophytes,
Norwegian scabies, “non-tropical” pyomyositis,
and intermittent abdominal distension probably
related to intestinal adherences.
3. Two cutaneous vasculitis were found in the
studied population with white atrophy-like
lesions, and coexistence with adjacent ivory
sclerodermal lesions.
4. ADM amounted to 23 percent (9/40) of the
study population.
5. ADM did not appear any different from the classic form (DM). One of the 6 cases associated to
malignancy appeared in this form, and the remaining 5 were identified among the 36 adult
patients of the classic form. Total prevalence of
malignancies was 16.66 percent in the adult study population.
6. All malignancies were gynecological, probably due to the female dominance, and since it
is the prevailing malignancy in women in our
population.
7. Both patients with interstitial lung disease were
Jo-1 negative.
8. Although a pathogenic role of silicone implants in this disease has been denied,6 one
case had history of mamary silicone implant.
It was an ADM, which evolved after several
years of pulmonary fibrosis and remitted after
corticotherapy.
5.
6.
7.
8.
9.
10.
11.
12.
Figure 9. Intermittent abdominal distension. CAT shows intestinal bridles.
13.
TABLE 5. DERMATOMYOSITIS. ASSOCIATION WITH MALIGNANCIES. PUBLISHED CASE-CONTROL STUDIES.
Reference quote
No. pats. Period
RR o percent neoplasia
T. DM-Ca
DM:2.4 (M) y 3.4 (F)
28
788
20 years
Sweden 1992
PM:1.7 (M) y 1.8 (F)
27
705
12 years
DM: 7.7; PM: 2.1
0-2 years
Scotland 1996
RR: 3
DM: 198 neoplasia
618 DM
Sweden, Denmark,
10 años
PM: 137 neoplasia
29
914 PM
Finland 1997
Ovary, lung, pancreas, stomach, colorectal, lymphoma
38 DM
6 years
31.6% (38% naso-pharingeal) Singapore, 199730-31
539
12 years
RR: 5.9. Lung, ovary, lymphoma 0-1 year
Denmark, 199732
1 ADM
No malignancy
Firenze, 200210
33
DM
19 años
40%
0-1 año
France and Switzerland 200234
7 PM
Buenos Aires 2002 [*]
40
10 years
16.6%. Breast, ovary, cervix 0-2 years
Period: study duration. RR o percent malignancy: relative risk or malignancy prevalence.
T. DM-Ca: time between diagnosis of DM and malignancy. M: male. F: female.
[*]: our case-control study.
9. One patient (overlap syndrome) had, late in the evolution, significant
positive titer of anticardiolipin antibodies, and suffered a transient ischemic stroke.
10. The absence of previous work based on own DM patient series in the
local references is highlighted.
14.
15.
16.
17.
18.
19.
20.
21.
22.
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2148-2155.
Research Article
Epidemiological study of basal cell carcinoma in a
community hospital
Virginia Mariana González1, Santiago Pablo Busso2, Rita Leitner2, Gabriel Casas3, Margarita Larralde4
Abstract
Introduction. Even though basal cell carcinoma (BCC) is the most frequent human neoplasm, there are no precise statistics on this entity. In order to
learn about the epidemiologic characteristics of our population we conducted a prospective, descriptive and transversal study.
Objective. To determine clinical, histopathological and demographic characteristics, and known risk factors of BCC in our population.
Materials and methods. Complete clinical history and histopathologic confirmation were performed for all patients with BCC that consulted the Hospital Aleman Dermatology Department between June 2007 and May 2008.
Results. The sample size consisted of 125 patients and 222 lesions. Sixty eight percent had only one lesion. The ages ranged from 32 to 103 years of
age, with an average of 66 years. Forty one percent were females and 59 percent were males, with a male:female ratio 1.4:1. Ninety three percent of
patients had phototypes II and III, with intense recreational sun exposure and severe photodamage. Thirty four percent had personal history of skin
cancer. The distribution of lesions was as follows: 46 percent in head and neck, 27 percent in trunk, and 17 percent in limbs. The superficial form was
the most frequent clinical type seen in trunk and limbs. The infiltrative growth histopathological variant prevailed in head, neck and limbs (41 percent), and the superficial variant prevailed in trunk (54 percent).
Conclusion. In the studied population, the more affected age range was 60 to 69 years, with higher prevalence in male patients, except for those
younger than 40 years. A high percentage of patients had a personal history of skin cancer, and showed multiple simultaneous lesions. Most patients
were of phototypes II and III, with a high degree of photodamage and of intense intermittent sun exposure (73 percent). Nevertheless, only 20 percent used sun exposure protection measures. Unlike what has been published, we found a lower percentage of head and neck involvement (46 percent), and a higher number of aggressive clinical and histopathological forms. Finally, we stressed the importance of carrying out epidemiological studies as the one hereby presented, which provide relevant data about our population, taking into account that no prospective studies have been recently published (Dermatol Argent 2009; 15(1):37-43).
Key words: basal cell carcinoma, skin cancer, epidemiology.
Introduction
1. Fellowship in Oncology Dermatology.
2. Staff Physician of the Dermatology Department.
3. Medical Dermatopathologist.
4. Head of the Dermatology Department.
Hospital Alemán of Buenos Aires. Argentine Republic.
Correspondence
Virginia Mariana González: [email protected]
The term non-melanoma skin cancer (NMSC) is commonly
used with reference to basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). BCC is the most frequent malignant neoplasm in the Caucasian population and accounts for
80-85 percent of all skin cancers. Risk factors for the development of this pathology include those related to the host, and
those related to environmental factors.
In the last few decades, BCC, more than SCC, has undergone a sustained increase of incidence,1,2 including young populations.3 Among other factors, this is due to changes in the sun
exposure habits of certain population groups, and to depletion
of the atmospheric ozone level. Since BCC incidence increases with age, greater life expectancy, along with a majority of elderly people in the population, are yet other factors involved in
the growing number of cases, which shall continue to increase
in the next few decades.
In spite of this worldwide increase in cases, true incidence of
BCC is difficult to establish, because no exact regional and glo-
18 | V. M. González, S. P. Busso, R. Leitner, G. Casas, M. Larralde
TABLE 1. DISTRIBUTION BY AGE GROUP.
Age
n
TABLE 2. R.G. GLOGAU’S CLASSIFICATION OF PHOTOAGING.
percent
Up to 39 years
5
4
40-49 years
14
11.20
50-59 years
19
15.20
60-69 years
38
30.40
70-79 years
23
18.40
80 years or more
26
20.80
bal statistical records exist. This relates to the difficulty in systematically recording a high frequency pathology, which requires
great resource availability to be carried out.
As in most parts of the world, there is no national register of
BCC in this country, although hospital records have been published recently,5 mostly retrospective and based on histopathological data. This work was brought about by the need of
beginning to know the epidemiological characteristics of our
population.
Objective. To estimate frequency distribution of known clinical and histopathological characteristics and risk factor of basal
cell epithelioma in our population.
No clinical keratoses; no wrinkling; without/minimal
discoloration.
Early actinic keratoses; yellowish discoloration; early
Grade II or moderate
wrinkling; parallel smile lines.
Actinic keratoses; obvious yellowish discoloration; telGrade III or advanced
angiectasia; wrinkling while at rest.
Multiple actinic keratoses w/wo skin cancer; severe disGrade IV or severe
coloration and telangiectasia; actinic, gravitational or
dynamic wrinkling.
Grade I or mild
A total of 125 adult patients of both sexes were included.
The study was performed with approval of the Hospital Ethics
Committee.
Statistical analysis. Data was entered in a database (Exceltype), and then analyzed using a Pentium 4, 2.4 Ghz microprocessor and an Epi Info version 6.04 statistical package.
Adequate descriptive statistics were determined for each variable according to their measurement and distribution scale. Where necessary, 95 percent confidence interval, binomial,
and Chi square estimation calculations were performed (with
statistically significant p < 0.05).
Results
Materials and methods
Design. A prospective, observational, descriptive and crosssectional study on BCC was conducted.
Study population. The study was performed among BCC patients of the Dermatology Department of Hospital Alemán
of Buenos Aires, Argentina, during one year, between June
2007 and May 2008. Of the 243 BCC patients observed in
that period of time, included were those with complete clinical and epidemiological data, and incisional and/or excisional histopathological study was performed and assessed by
dermopathologists.
Excluded from this study were BCC patients assessed and treated in other Departments of the hospital, and those individuals
without complete data.
Clinical records were obtained in a form designed to such
effect, specifying gender, age, eye and hair color, phototype (according to Fitzpatrick’s classification), history of UVR exposure, photoprotection, photoaging (according to Glogau’s classification), and sunburns. Exposure to carcinogenic chemicals
such as hydrocarbons, arsenic, and tobacco, personal and family history of skin cancer and other malignant neoplasias, the
presence of immunosuppresion and genodermatosis with skin
oncogenic potential were also considered.
As regards patient lesions, number, body location, size, evolution time, clinical form (according to the Argentine
Dermatology Society [Sociedad Argentina de Dermatología,
SAD] Consensus),4 the presence or absence of pigmentation
and ulceration, and histopathological variant were taken into
account (WHO classification 2006).
Population characteristics
The sample comprised 125 patients, in whom 222 basal cell
carcinomas were diagnosed. The number of tumors per patient ranged from 1 to 16, with an average of 1.76, similar in
males (1.79) and females (1.74). Sixty-nine percent (n=86) of
patients showed only one lesion, while 26.4 percent (n=33)
showed 2 to 4 tumors, 4 percent (n=5) 5 to 9, and 1 percent
(n=1), more than 10 simultaneous lesions.
A significant dominance was found in males (M), representing
59.2 percent (n=74), compared to 40.8 percent (n=51) females (F), with a male/female ratio of 1.4 / 1 (p=0.04).
At the time of diagnosis, patient ages ranged between 32 and
103 years, averaging 66 years (64 in females, and 67 in males).
Highest prevalence (30.4 per cent) was found in the age range
between 60 and 69 years. Noteworthy, 20.8 percent of patients
were 80 years or older. The 5 patients younger than 40 years
were females (Table 1).
All patients were caucasians, with phototypes (according to
Fitzpatrick’s classification) I to IV. The highest percentage (52
percent) belonged to phototype II, with 65 patients, and III
(40.8 percent) with 51 patients. A total of 5.6 percent of patients were phototype I (n=7), and 1.6 percent (n=2) of phototype IV.
There were no statistically significant differences (p=0.92) between the number of patients with light-colored eyes (49.6 percent) and dark-colored eyes (50.4 percent). Identical figures appeared with regard to hair color.
With reference to sun exposure habits, 72.8 percent (n=91)
of patients (95% CI: 64.9-81) had high recreational exposure
Epidemiological study of basal cell carcinoma in a community hospital | 19
120
TABLE 3. CLINICAL FORMS FOUND, AND DISTRIBUTION BY GENDER.
Global
Males
Females
(n=222 tumors)
(n=133 tumors)
(n=89 tumors)
Clinical forms
n (percent)
n (percent)
n (percent)
Superficial
70 (31.6)
40 (30)
30 (33.7)
Nodular
53 (23.8)
33 (25)
20 (22.4)
Morphocic
55 (24.77)
35 (26)
20 (22.4)
Papular
29 (13)
16 (12)
13 (14.6)
Ulcerated
11 (5)
7 (5)
4 (5)
Fibroepithelial of
2 (0.9)
0 (0)
2 (2.24)
Pinkus
Keloidal
1 (0.45)
1 (0.75)
0 (0)
Cutaneous horn
1 (0.45)
1 (0.75)
0 (0)
Number of tumors
100
80
60
40
20
0
Head and neck
Trunk
Limbs
Chart 1. Distribution by body site.
(intense intermittent-type). Only 4.8 percent (n=6) of patients
were exposed daily, for occupational reasons.
No significant use of artificial tanning devices was found in
97.6 percent (n=122) of patients, except in 3 cases (2.4 percent) (95% CI: 0.5-6.9), or phototherapy in 99 percent
(n=124) of the cases (95% CI: 0.01-4.4).
A significant percentage of patients (58.4 percent; n=73) referred to a history of severe childhood and adolescence sunburn ,
where 41.6 (p<0.0001) did not.
No topical photoprotection was used in 87.2 percent
(n=109) of patients, which is data of great statistical significance (p<0.0001). That is to say that only 20 percent of patients
with previous skin cancer were currently using photoprotective measures.
Glogau’s classification was used to assess photodamage (Table
2). Significant photodamage was found in 96 percent of the cases: 44 percent (n=55) of patients showed grade III of photoaging; 28 percent (n=35), grade II; 12 percent grade I; and 12
percent grade IV (p<0.0001).
With respect to other known BCC risk factors, frequent ocupational contact with hydrocarbons was only found in 4.8 percent (n=6) of the patients (95% CI: 1.76-10.17), immunosuppression in 8 percent (95% CI: 3.88-14.23), and no patient
showed signs of arsenicism or genodermatosis with cutaneous
oncogenic potential (Gorlin’s syndrome, etc.) (95% CI: 0-2.9).
Radiotherapy had been done in the involved area several years
before in 3 cases as treatment for acnes, larynx cancer, and vascular malformation, respectively.
Only 4.8 percent (n=6) of patients referred significant or longterm tobacco smoking (95% CI: 1.76-10.17).
Of the 125 patients, 43 (34.4 percent) had previous history
of skin cancer (95% CI: 26.1-46.4), of whom 58 percent had
BCC exclusively. In these 43 patients there were 30 BCC, 9
SCC, 5 melanomas, and 4 epitheliomas of lineage unknown to
the patient.
In 12.8 percent of the patients (n=16) there were extracutaneous neoplasias, without significant dominance of any type
thereof.
Familial history of skin cancer was only recovered in 13 patients (10.4 percent). Of these, 5 were melanomas, 2 were
NCC, and the rest were non-specified epitheliomas.
No statistically significant differences were found between genders in any of the variables analyzed before.
Lesion characteristics
Evolution time of carcinoma was less than 1 year in 46 percent
(n=103), from 1 to 5 years in 42 percent (n=93), and from 10
to 20 years or more in 2 percent (n=4). This data was unknown
to the patient in 10 percent of the cases.
As regards body location (Chart 1), significant (p<0.0001)
dominance was found in head and neck, with 46.3 percent
(n=103), and the most involved area was the forehead (26 percent), followed by the cheeks (18.4 percent) and the nose (16.5
percent). Of these 103 cases, 60 (58 percent) were male, and 43
(42 percent) were female.
In 27 percent (n=81) lesions appeared on the trunk, with 49
percent on the back, and 47 percent on anterior thorax. Only
2 lesions appeared on the abdomen and 1 in the axilla. In this
location, 49 lesions (60 percent) were on male patients, and 32
(40 percent) on female patients. Seventeen percent (n=38) appeared on the limbs. Of these, 58 percent involved lower limbs
(with 77 percent dominance of the leg), and 42 percent to upper limbs (with equal dominance of shoulder and forearm in
37.5 percent). In limbs, 24 lesions (63 percent) were on male
patients and 14 (36 percent) on female patients.
Tumor size was in 44 percent (n=98) of the cases 1 to 9 mm,
10 to 19 mm in 48.6 percent (n=108), 2 to 5 cm in 6.75 percent (n=15), and larger than 5 cm in 0.45 percent (n=1).
Average size was 10 mm; largest size was found on the ulcerated clinical form (5 cm) (Figure 1).
The 4 most frequent clinical forms (93 percent) were: superficial, found in 70 patients (31.6 percent), morphocic (sclerosing) in 55 patients (24.7 percent), nodular in 53 cases (23.8
percent) and papular in 29 (13 percent). If the papular variant
was included in the nodular form, this clinical presentation was
the most frequent (37 percent) (Figure 2).
Figure 1. Ulcerated clinical form: 5 cm lesion located on the back of an elderly patient.
Figure 2. Nodular lesion located on the forehead: this clinical form, taken together with the papular
form, was the most frequent in our case-control study, and particularly in the head and neck area.
The rest of the clinical variants found were: ulcerated, terebrating, fibroepithelioma of Pinkus, cutaneous horn, and one keloidal case. There were no
statistically significant difference between males
and females (p=0.948) (Table 3). Pigmentation was
found in 22.9 percent of the cases (95% CI: 17.629.1), similarly to ulceration, which was found in
22.5 percent of lesions (95% CI: 17.2-28.6).
As regards body location (Table 4): the most frequent clinical forms in head and neck were: morpheaform in 33 cases (32 percent) (Figure 3), nodular in 30 cases (29 percent) and papular in 25
cases (24 percent), with no statistical dominance (p=0.06), or by specific body area (forehead,
nose, etc.).
In contrast, in trunk there was significant dominance of the superficial form (p<0.0001) (Figure 4),
representing 49.3 percent of the cases (n=46), followed by nodular in 22 percent (n=16), and morphocic in 18.5 percent (n=5). Also found in trunk
were 2 papular variants, 1 keloidal, and 1 fibroepithelioma of Pinkus (axilla).
Also dominant in limbs was the superficial form
(p=0.05) in 44,7 percent (n=17), followed by nodular in 21 percent and morpheaform in 18.4 percent.
The patient with greatest number of lesions (16) was
a 44-year-old female, and 2 of her BCC were fibroepithelial tumor of Pinkus (one in axilla and one in
suprapopliteal region). The histological variants
found in the 222 BCCs are shown in Table 5. The
three subtypes found in greater numbers were infiltrative in 41.4 percent, followed by superficial, and
nodular in 27.4 percent, respectively.
Variants found most frequently by body site were:
in head and neck, infiltrative (cord-like) in 56.3 percent (n=58); in trunk, superficial in 54.3 percent
(n=44); and in limbs infiltrating variant in 39.4 percent (n=15) followed by superficial in 34.2 percent
(n=13). This predominance resulted statistically significant (p<0.0001).
As regards therapeutics applied on the 222 BCCs,
15 lesions were treated by photodynamic therapy, 2
by cryosurgery, 2 by imiquimod, and the rest (91.4
percent) by surgical excision.
Discussion
Figure 3. Morphocic clinical form: highly frequent in head and neck.
Incidence of BCC varies widely according to geographic area and race involved.6,7 It is higher close to the equator and in caucasian populations that
migrated to such latitudes, such as Australia and the
Southwestern United States. In the latter, estimated
incidence of BCC for 2008 was 1 million new ca-
ses,8 and the incidence rate by race in males-females
is 31-19.9 per 100,000 Caucasian inhabitants, 4.43.3 in Indians, and 5.8-5,9 in Hispanes.9 Incidence
in Europe ranges from 22 to 87 per 100,000 inhabitants, according to the country.10 Highest rate is
found in Australia, affecting 1 to 2 percent of the
population.11,12
One of the major ethiologic factors of developing
BCC is intense intermittent exposure to UVR, as
continuous exposure (occupational) is for SCC.6,13,14
Genetic susceptibility also plays a role in BCC development. A series of mutations and gene polymorphisms have been described in this pathology. Among them can be found those of melanocortin receptor 1 (MC1R),15 p53,16 Patched (PTCH)
gen,17 RAS, and others.
Although most worldwide cancer statistics exclude
NMSC, as of the last decade some countries have
created registers based on histopathological electronic databases. It is believed that there is an undereporting of 25-30 percent of tumors, because the system only requires registration of the first tumor for
each patient, thus underestimating incidence of simultaneous or successive lesions of the same person
(patient and not case incidence is recorded), which
is frequent in these skin cancers.10,18,19 Also relevant
to this underecording is the fact that occasionally
suspicious lesions are destroyed without histological
confirmation, and many elderly patients do not seek
medical care for these neoplasias.
The purpose of this work was to achieve a better understanding of BCC features in our setting.
Although the number of observed patients during
the year of study was limited, since it is prospective
work, some relevant findings were obtained.
Our study showed a slight male dominance, with a
1.4:1 M:F ratio, similar to the usually referred,20 as
well as 66 years as average age at the time of diagnosis.10,21 Since the Hospital has a significant elderly population, a remarkable percentage of tumors in patients of 80 years old or more was found.
Although the number of cases is too low to attain
statistical significance, the 5 patients under 40
years were female, which is consistent with recent
publications.3,22,23
As usually found in BCC epidemiology, male gender, trunk location, superficial clinical form, and old
age are predictors of multiple BCC.10,24,25 In our series, of the 6 patients with five or more lesions, 5
were male, with an average age of 64 years.
All patients in our study were Caucasians, and most
(93 percent) of phototypes II and III. Although the
presence of light colored hair and eyes usually indi-
Figure 4. Superficial variant: it represents the most common clinical form in trunk and limbs.
TABLE 4. BODY LOCATION OF THE 222 DIAGNOSED BCCS.
Head and neck
Clinical forms found
n (percent)
Superficial
7 (6.8)
Nodular
30 (29)
Morphocic
33 (32)
Papular
25 (24)
Ulcerated
7 (6)
Fibroepithelial of Pinkus
0 (0)
Keloidal
0 (0)
Cutaneous horn
1 (1)
Total of tumors
103
Trunk
n (percent)
46 (49.3)
22 (16)
15 (18.5)
2 (2.4)
0 (0)
1 (1.2)
1 (1.2)
0 (0)
81
Limbs
n (percent)
17 (44.7)
8 (21)
7 (18.4)
1 (2.6)
4 (10.5)
1 (2.6)
0 (0)
0 (0)
38
TABLE 5. DISTRIBUTION VARIATION OF HISTOPATHOLOGICAL FORMS FOUND PER BODY SITE.
Global
Head and neck
Trunk
Limbs
Histologic subtype
n (percent)
n (percent)
n (percent)
n (percent)
Superficial
61 (27.4)
4 (3.8)
44 (54.3)
13 (34.2)
Nodular ()
61 (27.4)
38 (36.8)
14 (17.2)
9 (23.6)
Infiltrative (cord-like)
92 (41.4)
58 (56.3)
19 (23.4)
15 (39.4)
Micronodular
1 (0.45)
1 (0.9)
0 (0)
0 (0)
Fibroepithelial of Pinkus
2 (0.9)
0 (0)
1 (1.2)
1 (2.6)
Adenoid
2 (0.9)
1 (0.9)
1 (1.2)
0 (0)
Keloidal
1 (0.45)
0 (0)
1 (1.2)
0 (0)
Basosquamous
1 (0.45)
0 (0)
1 (1.2)
0 (0)
Keratinizing
1 (0.45)
1 (0.9)
0 (0)
0 (0)
cate BCC development risk factors,13,26 in our patients such factors did
not demonstrate statistical significance.
Most patients had a history of sunburns and high exposure to natural sun
for recreation purposes all their lives, but not to artificial UVR sources for
therapeutic or cosmetic purposes (PUVA, tanning beds, etc.). Also observed was high grade of photodamage, with multiple sun keratoses which, as
acknowledged, increase risk of BCC.27 However, the use of photoprotective measures was minor, even after diagnosis of previous skin tumor, which
should alert us about the need for better education on this matter.
History of previous skin cancer was significant (with 95% CI up
to 46 percent) and most previous tumors were BCC, thus strengthening the concept that a BCC patient has between 30 and 70
percent probability of having others a posteriori.28,12 No significant relationship was found with extracutaneous neoplasias.
Also no relationship was found in our series with other known
BCC risk factors or with smoking, which is not an independent risk factor for BCC except in young patients, as referred
by some authors.22,29
Most individuals had only one lesion. However, we found some
with a remarkable number of simultaneous BCC, with no
known predisposing pathology. Tumor size was less than 2 cm
in 93 percent of patients. Evolution time was less than 5 years
in 88 percent.
Consistent with the literature, the most frequently involved
body area in our patients was the head, but in contrast to the
statistics,4 the percentage was lesser than the usually mentioned
80 percent,25 and the most common area was the forehead, instead of the nose.
The second most frequent location was the trunk, in a percentage higher than the 15 percent mentioned in the literature. In
this area, lesions were predominant in the back and the anterior thorax. As regards limbs, the upper limbs were more involved. The number of lesions found in abdomen, thighs, hands,
and feet was insignificant.
In international statistics on Caucasian populations, the most
common clinical form of BCC is nodular,30 representing about
60 percent of the total. Globally, our study showed a lower incidence of nodular/papular variant (37 percent), which was
predominant, as usual, in the head and neck.
The superficial variant appeared in a greater number of cases
than described in the literature (of 15 percent), and prevailed
in trunk and limbs, as usual.
We also observed a very high percentage of morphocic , up to
24.7 percent, and resulted more frequently in the head and neck.
On the back we found a tumor of the clinical-pathological variant known as keloidal, recently described in the literature,
and of which only 4 cases were published.
Pigmentation of the lesion, of 22 percent in our series, varies in
different populations. In Caucasians, about 6 percent,31 while
in Asians it amounts to 69 percent.21
With reference to histopathological patterns, in contrast to the
literature, in our population we found infiltrative growth (cordlike and micronodular ) as the most frequent histological variant.
This subtype was dominant in the head and neck, in contrast to
usual publications of nodular variant as most frequent.
The superficial variant predominated in the trunk, and infiltrative and superficial variants in the limbs.
growing, with an increasing involvement of older and younger patients, with a great number of successive or simultaneous lesions, and thus greater morbidity and higher health
costs. These findings, added to the dominance of more aggressive clinical and histopathological forms, and the low level of patient photoprotection should motivate us to work
more strongly on the matter.
Finally, we highlight the importance of carrying out epidemiological work such as the one submitted and providing relevant
data on our population, taking into account the lack of recently
published prospective studies.
Acknowledgements
To Dr. Vicente C. Castiglia, for his collaboration in the statistical analysis of this work.
Conflicts of interests
The Oncology Dermatology Fellowship is sponsored by
Fundación Pablo Cassará.
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Original Article
Unilateral nevoid telangiectasia.
Report of four cases
Mariana Arias1, Romina González1, Roberto Retamar1, María Carolina López Santoro2, Mariana Demarchi1,
María Cristina Kien3, Edgardo Chouela4
Abstract
Unilateral nevoid telangiectasia is an uncommon congenital or acquired condition characterized by small, unilateral vascular dilations in a linear, segmentary or metameric distribution, usually located on the face and cervical areas, although they may also be found in other locations.
We report four female patients between 22 and 49 years old, who share clinical and histological features of unilateral nevoid telangiectasia. One of
the cases showed association with secondary biliary cirrhosis, and another patient had flares during pregnancies (Dermatol Argent 2009;15(1):44-48).
Key words: unilateral nevoid telangiectasia, telangiectases.
Introduction
Unilateral nevoid telangiectasia (UNT) is a dermatosis characterized by the presence of multiple linear telangiectasias of arborizing aspect, without central vessel, non-confluent, and unilateral in distribution. Preferably, it appears on the head, but
may also be located on trunk, limbs, and even one side of the
body.
It may be congenital, or more frequently acquired, and in the
latter case it usually associates with physiological or pathological states of hypoestrogenism. It predominates in females, and
in the fertile years of the life.
Diagnosis of this entity is eminently clinical, since the histopathology is not pathognomonic.
No therapeutic implementation is indispensable, but several alternatives are available for the cases where improvement is required, from a cosmetic point of view.
We present four female patients, where UNT diagnosis was
reached based on complete physical skin examination and
supplementary studies. This entity was briefly reviewed.
1. Dermatologist.
2. Chief of Residents.
3. Dermatopatologist.
4. Named Professor of Dermatology UBA.
Dermatology Unit, Hospital General de Agudos “Dr. Cosme Argerich”.
Chouela Dermatology Center.
Correspondence
Mariana Arias: Av. Belgrano 372, (1876) Bernal, Buenos Aires Province, Argentine Republic. Ph.: 15-5416-9947 | E-mail: [email protected]
Clinical cases
Case 1
A 33-year-old female, without a relevant pathological history,
who consulted for lip dryness of about two years evolution.
The physical examination showed scaling of the lower lip semimucosa compatible with exfoliative cheilitis. When examining the perioral skin, segmentary distribution telangiectasias
were identified in that area, on the right half of the nose, the
right malar area, and the right retroauricular area (Figure 1).
Unilateral nevoid telangiectasia. Report of four cases | 25
She also showed similar lesions on the back of the
right hand.
With presumptive clinical diagnosis of UNT, histopathological examination was performed of the lesions, which resulted in vascular dilation without
endothelial proliferation in papilar and intermediate dermis; these findings are compatible with this
entity. In addition, routine laboratory tests were requested, with liver function tests, thyroid profile,
and dosage of estrogens and progesterone, with values within normal ranges.
The patient was cosmetically concerned, and
treatment was started. Two sessions of intense pulsed light were applied (filter: 550 nm; fluency: 42 J;
spot: 8 × 35 mm, triple shots: T3.5 msec D10 msec)
and CO2 laser 1 watt on some punctual lesions, with
moderate improvement after the 2 sessions.
Case 2
A 22-year-old female, without a relevant pathological history, consulted for the presence of facial lesions. She referred gradual appearance of lesions
between 13 and 15 years of age, and subsequent
stabilization.
The physical examination showed segmentary distribution telangiectasias on the right half of the face
with nose, malar and lip dominance (Figure 2).
With presumptive clinical diagnosis of UNT, a skin
biopsy was performed and resulted compatible with
this dermatosis.
Supplementary studies (laboratory routine, thyroid
profile, dosage of estrogens and progesterone) gave
results within normal ranges.
Case 3
A 28-year-old female, 20-week pregnant was hospitalizad in the Obstetrics Department of our
hospital due to extramembranous pregnancy.
Interconsultation was requested due to lesions distributed on the left side of the face, chest, and upper limb. She referred that they had appeared during
adolescence and showed exacerbations in pregnancies, and no other relevant history.
The physical examination showed segmentary distribution telangiectasias involving the whole face, left
chest area, and homolateral upper limb (Figure 3).
The histological study was compatible with UNT
(Figure 4). Laboratory routine and thyroid profiles
were reported within normal ranges.
Figure 1. Case 1. Telangiectasias located on the right side of the nose.
Figure 2. Case 2. Telangiectasias on the right half of the face.
esophageal varices. Complete evaluation showed segmentary distribution
telangiectasias located on the right side of the neck, of 6 years evolution
(Figure 5).
With presumptive clinical diagnosis of UNT, a punch biopsy was performed, resulting in ectasia and vascular congestion compatible with this dermatosis. Routine laboratory tests resulted in alterations of liver function
tests: TB 3.9 mg/dl; DB 3 mg/dl; ALP 985 U/l (NV 50-250); GGT 349
U/l (NV 7-50); GOT 138 U/l (NV 0-38); GPT 86 U/l (NV 0-41); and
the rest, including thyroid profile, within normal ranges.
Discussion
Case 4
A 49-year-old female presented with personal history of psoriasis, secondary biliary cirrhosis and
UNT was described initially by Blaschko in 1899, but only in 1970 had
Selmanowitz coined the current name.
26 | M. Arias, R. González, R. Retamar, M. C. López Santoro, M. Demarchi, M. C. Kien, E. Chouela
Figure 3. Case 3. Multiple telangiectasias on the chest area and left upper limb.
Figure 4. Case 3. Dilated vessels without endothelial proliferation in dermis (H-E).
It may be congenital or, more frequently, acquired
during lifetime. Congenital cases are rare and occur during or after the perinatal period; they appear
more commonly in males.1,2 The acquired forms
are much more frequent, and prefer females during the fertile period of life, but may develop at any
age. They usually relate to states of physiologic or
pathologic hyperestrogenism (Table 1). Mentioned
among the physiological causes of hyperestrogenism
are puberty, use of contraceptives, and pregnancy.3,4 In our first three patients, the disease onset occurred during puberty; the third patient additionally referred lesion exacerbation during pregnancies.
The other 2 had not yet been pregnant. Mentioned
among the pathological causes are alcohol or infectious hepatopathy (HCV, HBV), and primary
or metastatic liver tumors.1,5-7 Our fourth patient
showed association with secondary biliary cirrhosis.
The literature includes reports of UNT associated
with hyperthyroidism,8 while other cases showed no
associated abnormalities.9,10
The etiology is not yet well established, but some research reports increased levels of estrogen and/or
progesterone receptors in the involved skin of some
patients. Other hypothesis indicate abnormalities of
these receptors, and that circulating estrogens may
stimulate production of telangiectasias.2,11-13 Kreft et
al.14 propose subclinical function defects of the cutaneous microvasculature. Some authors believe that
in some cases the entity may be related to mosaicisms due to somatic mutations of cell populations
during embrionary development, and that in situations with hyperestrogenism the cutaneous lesions
may become visible; but the high levels of estrogen
should not be the primary cause of the disease.1
Clinically, the disease is characterized by the presence of arborizing and non-confluent telangiectasias, without central vessel. They are unilateral, and
their distribution may be linear, segmentary or metameric. Preferably, they appear on the head and
neck, but are also found in other body areas, and
even on one half of the body. Dermatomas C3 to D1
are the most commonly involved sites.2,6,15-17 Some
authors noticed that, more than metameric, the distribution follows Blaschko’s lines, a situation which
may be related to cell migration during embrionary
development.2
TABLE 1. CAUSES OF HYPERESTROGENISM.
Physiological
Pathological
Puberty
Alcoholic hepatopathy
Contraceptives
Infectious hepatopathy (HCV, HBV)
Pregnancy
Primitive and metastatic liver tumors
Unilateral nevoid telangiectasia. Report of four cases | 27
TABLE 2. UNT DIFFERENTIAL DIAGNOSIS.6,13,18,19
Simple stellate angioma: scarce in number or isolated, not adopting metameric distribution. If numerous, a liver disorder must be suspected.
Hutchinson’s angioma serpiginosum: predominant in women
(90%), it appears in childhood. Lesions are punctiform and aggregate
with serpiginous disposition. Slightly papulous surface. Preferred location on pelvic girdle, and progressive growth.
Familial hemorrhagic telangiectasia, or Rendu-Osler-Weber
syndrome: hereditary, early manifestation by recurrent epistaxis. Location of telangiectasias is perinasal and peribuccal areas. Associated
to internal organ involvement.
Generalized essential telangiectasia: diffuse form, more frequent in lower limbs, may also appear coincident with pregnancy
or puberty. Predominant in females. Generally linear telangiectasias.
Persisting eruptive macular telangiectasia: form of cutaneous mastocytosis associated with arborizing disposition telangiectasias and erythematous or hyperpigmented macules, accompanied
by itching.
We understand that the therapy, merely cosmetic,
represents a challenge. We report our experience with intense pulsed light associated with CO2
laser.
References
Figure 5. Case 4. Telangiectasias on the right half of the neck.
Lesions are asymptomatic, and without mucosal or systemic involvement.
The evolution is benign, and in most cases the course is chronic and persistent. Some cases of spontaneous post-partum regressions have been reported. Histopathology is not characteristic, and is usually not necessary.
It may show dilated vessels in papillary and intermediate dermis, without
endothelial proliferation.6,17
Possible differential diagnosis (Table 2) are Hutchinson’s angioma serpinginosum, familial hemorrhagic telangiectasia or Rendu-Osler-Weber syndrome, generalizad essential telangiectasia, persistent eruptive macular telangiectasia, and simple stellate angioma.6,13,18,19
Therapeutic alternatives for this merely cosmetic disorder include electrocoagulation, radiofrequency, cryosurgery, or CO2 laser, argon,
Nd:YAG, dye laser, or intense pulsed light.5,6,20,21 Intense pulsed light is
one of the most often indicated therapeutic methods for telangiectasias,
together with pulsed dye laser; laser Nd:YAG may be indicated in the
case of greater vessels. We prefer the association with CO2 laser, because we noticed greater response in combining methods, and without adverse effects or definite sequelae. No treatment was applied in the last
three patients.
Conclusion
The interest of this presentation is to communicate four cases of this rare
entity, and remark the importance of a complete clinical examination of
patients’ skin, which may lead us to diagnosis of disorders which are not
the reason of consultation.
1.
Karakas M, Durdu M, Sönmezoglu S, Akman A, et al. Unilateral nevoid telangiectasia. J Dermatol 2004; 31:109-112.
2. Sardana K, Sarkar R, Basu S, Sharma R, et al. Unilateral nevoid
telangiectasia syndrome. J Dermatol 2001; 28:453-454.
3. Tok J, Berberian BJ, Sulica VI. Unilateral nevoid telangiectasia syndrome. Cutis 1994; 53:53-54.
4. Woollons A, Darkey CR. Unilateral naevoid telangiectasia
syndrome in pregnancy. Clin Exp Dermatol 1996; 21:459460.
5. Cabrera H, García S. Nevos vasculares. In: Cabrera H, García
S. Nevos. Buenos Aires: Editorial Actualizaciones Médicas
S.R.L.; 1998. pp. 113-114.
6. Coronell S, Soljancic C, Ruiz Berguerie J, Cohen Sabban E y
cols. Telangiectasia unilateral nevoide. Presentación de un
caso. Dermatol Argent 2003; 5:285-288.
7. Hynes LR, Shenefelt PD. Unilateral nevoid telangiectasia:
Ocurrence in two patients with hepatitis C. J Am Acad Dermatol 1997; 36:819-822.
8. Kavak A, Kutluay L. Unilateral Nevoid Telangiectasia and Hyperthyroidism: A new association or coincidence? J Dermatol. 2004;31:411-414.
9. Karabudak O, Dogan B, Taskapan O, Harmanyeri Y. Acquired unilateral nevoid telangiectasia syndrome. J Dermatol
2006; 33:825–826.
10. Taskapan O, Harmanyeri Y. Acquired unilateral nevoid telangiectasia syndrome. J Am Acad Dermatol 1998; 39:138-139.
11. Sánchez Cornejo-Mir J, Ortega Resina M, Camacho Martínez F. Síndrome de la telangiectasia nevoide unilateral. Estudio de receptores cutáneos estrogénicos. Med Cut Iber
Lat Am 1984; 12:469-475.
12. Wilkin JK. Unilateral nevoid telangiectasia: three new cases
and the role of estrogen. Arch Dermatol 1977; 113:486-488.
28 | M. Arias, R. González, R. Retamar, M. C. López Santoro, M. Demarchi, M. C. Kien, E. Chouela
13. Woscoff A, Bermejo I, Wagner A, Jaimovich C y cols. Telangiectasia nevoide unilateral (Estudio de receptores estrogénicos). Arch Argent Dermatol 1987; 37:21-26.
14. Kreft B, Marsch WC, Wohlrab J. Unilateral nevoid telangiectasia syndrome. Dermatology 2004; 209:215-217.
15. Rodrígues Martínez MA, Lacaz Martins E, Camargo Paschoal LH. Telangiectasia nevoide unilateral. Relato de un caso y revisión de la literatura.
Med Cutan Iber Lat Am 2001; 29:169-172.
16. Estève E, Georgescu V, Kalis B. A case for diagnosis: unilateral nevoid telangiectasia. Ann Dermatol Venereol 1997; 124:407-408.
17. Marrero Calvo MD, Rodríguez Pichardo A. Lesiones telangiectásicas de
distribución uniforme. Med Cut Iber Lat Am 2000; 28:62-64.
18. de Gálvez Aranda MV, Herrera Ceballos E. Casos para el diagnóstico. Lesiones eritematosas de aparición en la pubertad. Piel 2001; 16:37-38.
19. Trüeb RM, Burg G. Unilateral “nevoid” spider nevi. Vasa 1993; 22:82-85.
20. Sánchez Regaña M, Fortaleza FJ, Creus L y cols. Telangiectasia nevoide unilateral: tratamiento con laser CO2. Actas Dermosifiliogr 1994;
85:378-380.
21. Sharma VK, Khandpur S. Unilateral nevoid telangiectasia - response to
pulsed dye laser. Inter J Dermatol 2006; 45:960-964.
Original Article
HTLV-1 - associated infective dermatitis in an adult
Liliana Olivares1, Gisela D’Atri2, Claudia Martinetti3, Luciana Ciccia4, Olga Forero5, Javier Anaya6
Abstract
Infective dermatitis is a form of chronic, relapsing eczema described as a specific dermatosis associated with HTLV-1 infection.
It mainly affects children, and only exceptionally adults; thus, few of the latter cases have been published.
We present a case of a 42-year-old woman with generalized eczema of 23 years of evolution, with repeated cutaneous infections exacerbating the dermatosis, and relapses after antibiotic treatment discontinuation.
Diagnosis of HTLV-1 and virus-associated infective dermatitis is reached with the patient hospitalized, after ruling out adult T-cell leukemialymphoma. Antibiotic treatment is prescribed, with good response (Dermatol Argent 2009; 15(1):49-53).
Key words: infective dermatitis, HTLV-1.
Introduction
1. Head of Dermatology Department.
2. Medical Resident Instructor.
3. Attending Physician, 3rd year, Superior Course for Specialists in Dermatology.
4. Attending Physician, 2nd year, Superior Course for Specialists in Dermatology.
5. Staff Physician.
6. Medical Pathologist.
Dermatology Department. Hospital “F. J. Muñiz”. Buenos Aires. Argentine Republic.
Correspondence
Liliana M. Olivares: Arroyo 873 10º (1007), Autonomous City of Buenos Aires, Argentine
Republic. Ph: 4327-1606. Fax: 4813-2958 | E-mail: [email protected]
The HTLV-1 virus is the first human retrovirus wherein
oncogenic potential was demonstrated. Infection occurs
worldwide, with an estimate of about 20 million infected
people, but only 5% develop some pathology.
Various diseases have been associated to HTLV-1 infection.
The first one to be identified was adult T-cell leukemialymphoma (ATLL), confirmed by demonstration of monoclonal integration of proviral DNA to the neoplastic cell
genoma. Subsequently, a type of spastic myelopathy known
as tropical spastic paraparesis (TSP) was identified, generally considered an expression of an infection acquired in
adult life.1
In the late,2 a severe type of eczema known as infective dermatitis (ID) was recognized as a HTLV-1-infection specific
dermatosis, usually a marker of early infection (since it appears in children). However, cases of childhood TSP have
been published, as well as of ID in adults,3 and both pathologies may appear associated in the same patient.4
This report would be the first national adult case of ID.
Clinical case
A 42-year-old female patient from Paraguay.
Personal history: Exclusive sexual partner of same origin,
living together for 7 years (from 18 to 25 years of age).
Current disease: She appears at the physician’s office owing
to the presence of a 23-year-evolution dermatosis, characterized by generalized eczema and poor response to steroid
30 | L. Olivares, G. D’Atri, C. Martinetti, L. Ciccia, O. Forero, J. Anaya
and antihistamine treatment. Repeated skin infections exacerbate her dermatosis, with recurrences after discontinuation of antibiotic treatment.
Physical examination. Diffuse, scaling, and
exudative eczema almost completely involving
the integument. On the cephalic pole, involvement of the scalp covered by furfuraceous scaling, discrete alopecia of eyebrow tails, external
ear duct exudate with yellowwiish crusts (Figure
1) and retroauricular fissured and exudating intertrigo (Figure 2). On the anterior trunk, multiple erythematous milliar papules aggregated in sectors (Figure 3). On the back, marked
skin infiltration whereon punctiform erosions.
Lichenification of axillary fold, antecubital and
popliteal fossae (Figure 4). In lower limbs, extended erosive-crusted surfaces alternating with
small and irregular hyperpigmented maculae as
sequeale, and marked cutaneous infiltration at
knee level (Figure 5). The dermatologic picture is associated with intense itching, fever, and
generalized lymphadenopathies (tough-elastic,
painless, not adhered at deep levels).
Figure 1. Scalp involvement and yellowish crusts crusting in external ear canal.
Laboratory tests:
• Routine laboratory tests: eosinophilia (21.9 percent). Orther tests within normal values/limits.
• IgE Dosage: >1000 IU.
• Electrophoretic proteinogram: polyclonal hyper-gammaglobulinemia.
• Serology for HAV, HBV, HCV, EBV, HIV: (–).
• Bacteriological test: skin biopsy culture: (+) for
methicillin-sensible S. aureus.
• Skin biopsy: spongiotic dermatitis with eosinophilia (Figure 6).
Owing to the torpid and long evolution of dermatosis, studies are done to rule out an associated lymphoproliferative process:
• HTLV-1 serology, ELISA and Western Blot:
reactive.
• HTLV-1 PCR (skin biopsy): reactive.
• CD4/CD8 ratio: 3.3 (normal value: 2).
• Neck/chest/abdomen and pelvis CT: no abnormality discovered (NAD).
• Peripheral blood smear: eosinophilia, remaining
tests NAD.
• Axillary/inguinal lymph node biopsy: follicular
hyperplasia.
• Axillary lymph node flow cytometry and bone
marrow aspiration: NAD. After ruling out a
lymphoma, an HTLV-1-associated infective
dermatitis diagnosis is suggested.
Figure 2. Fissured retroauricular intertrigo.
Evolution: parallel course to recurrent infections. The underlying
pathology is exacerbated with each infection, and improves with
treatment.
Treatment: antibiotic for infectious recurrences, antihistamines, topic
emollients-corticoids, and thalidomide 100 mg/d.
HTLV-1 - associated infective dermatitis in an adult | 31
Comments
Figure 3. Multiple erythematous miliary papules.
Figure 4. Lichenification of popliteal areas.
HTLV-1 is a cosmopolitan virus, but with higher
prevalence in areas such as Asia (especially Japan),
Africa, the Caribbean islands, and South America.
In the latter, the country with the higher absolute
number of infected individuals is probably Brazil,
in its northern area.5 Cases have also been detected in Paraguay, Colombia, Chile, Peru, Bolivia,
and in Argentina, especially in the nortwestern
provinces (as opposed to HTLV-2, whose seroprevalence is higher in the northeastern provinces).
Seroprevalence in blood banks in Jujuy is 1 percent,
with high prevalence of TSP.6
This led to the passing of a provincial act in the 90’s,
requiring virus tests in the provincial blood banks.
Prevalence in the general population associated with
HIV is 8 to 13 percent and higher in intravenous
drug addicts.
As with other retroviruses, transmission route may
be: a) by sexual contact, with higher prevalence in
sex workers (2.8 to 5.7 percent); b) by transfusion
(intravenous-drug addiction), and c) vertical (transplacentary, through birth canal, and especially by
breastfeeding). The longer breastfeeding time and
the larger maternal viral burden, the higher probability of transmission.7
Once infection occurs, the virus is incorporated to
the host cell DNA as a provirus and may remain
in latent status or start replicating; a multifunctional viral protein, known as TAX, plays a major role
in the physiopathogenicity of infection. This viral capacity to incorporate itself to the cell genome
enables it to acquire or transduct genetic material
and activate or inactivate cell genes that are essential
to the mechanisms of carcinogenesis.8 In addition,
there may be a cytotoxic effect on CD8 cells, releasing cytokines and immunoglobulins with nervous
system effects such as progressive and irreversible
demyelinization. There is seemingly a contribution
to cell immunity deficit with polyclonal immunoglobulin production and activation of the proinflammatory cytokines such as IL-1, IL-6, and TNF-α.
In addition, however, it is likely that other factors inherent to the host are required for disease development (immunogenetic factors). It has been suggested that the presence of certain HLA-haplotypes
would increase susceptibility to HTLV-1 infection (association with HLA DRB1 and DQB1 was
found in members of infected families).9
Diagnosis is by ELISA and Western Blot serology (the latter is confirmatory and enables HTLV-1
and HTLV-2 differentiation). HTLV-I identifica-
32 | L. Olivares, G. D’Atri, C. Martinetti, L. Ciccia, O. Forero, J. Anaya
tion requires the presence of antibodies to p24, p19,
rgp46-1, and rgp21 proteins.10 High titers of antibodies would relate to higher probability of developing
a disease (prognosis value). Diagnosis is supplemented by PCR in blood, cerebrospinal fluid, or tissue
samples (skin, lymph nodes), which is especially useful for indeterminate serology.9
Quantitative PCR enables viral burden variation detection at different infective stages; a relation between PCR and risk of developing ATLL, TSP or ID
is suggested.11
An interesting aspect of this virus is its skin-tropism.12 Infection prevalence is higher in patients
with a dermatosis. The virus has been identified by
PCR in the skin of seropositive patients, even in the
absence of skin lesions (43 percent); postulating that
this finding could have a predictive value.13
Infective dermatitis was first described in 1966 by R.
Sweet in a group of Jamaican children; it is a special
type of chronic and relapsing eczema.14 Twenty-four
years later, La Granade et al.2 recognize a clear association between this new entity and the human lymphotropic retrovirus (HTLV-1).
ID affects mostly children, with shedding, exudating
features as distinctive traits, and persisting pyogenic
infections. Preferred locations are scalp, folds (retroauricular, axillar, perineal), anterior nares, neck,
and umbilicus,3,9 and is associated with mild to moderate itching, and adenopathies. Occasionally, it is
associated to blepharoconjunctivitis. Staphylococcus
aureus and/or -hemolytic Streptococcus is often re-
Figure 6. Spongiotic dermatitis with eosinophilia
Figure 5. Erosive crusty surfaces, and marked skin infiltration.
covered in skin cultures,7 (94 percent of cases), and recurrences usually appear after discontinuation of antibiotics. Histopathological examination
studies of ID are nonspecific and reveal acanthosis with mild to mode-
HTLV-1 - associated infective dermatitis in an adult | 33
TABLE 1. INFECTIVE DERMATITIS DIAGNOSIS CRITERIA. LAGRENADE.2
Major criteria
• Eczema of scalp, axillae, groin, external ear, retroauricular area, eyelids, perinasal
skin and/or neck.
• Chronic watery nasal discharge without other signs of rhinitis and/or crusting of
anterior nares.
• Chronic relapsing dermatitis with prompt response to appropriate antibiotic
treatment but prompt recurrence upon discontinuation of antimicrobials.
• Onset typically in early childhood.
• HTLV-1 seropositivity.
Minor citeria
• Positive skin or anterior nares cultures for S. aureus and S. pyogenes.
• Fine, generalized papular rash.
• Generalized lymphoadenopathies.
• Elevated ESR.
• IgD and IgE hypergammaglobulinemia.
• Elevated CD4 and CD8, and CD4/CD8 ratio.
rate spongiosis, and occasionally collections of neutrophiles
are described in stratum corneum. Dermal lichenoid, or perivascular and perianexial lymphocyte infiltrate may be found.3
Lymphocyte epidermotropism, with or without atypical lymphocyte collection and dermal lymphocyte aggregations, may
be seen in a small number of cases.
Immunohistochemistry reveals greater CD8 and CD57 positivity.15 These morphological findings, together with CD7 negativity (mature T lymphocytes), are very similar to those found
in early stages of ATLL. This leads some researchers to suggest
that ID is an early stage of ATLL.9
It is suggested that ID could be a marker of more severe associated pathologies, such as ATLL and TSP.3,7,9,10
ID diagnosis is eminently clinical; differential diagnosis is with
atopic dermatitis and seborrheic dermatitis. Major and minor
criteria are proposed. Four of five major criteria are necessary;
and the first, second, and fifth are mandatory (Table 1). Our
patient showed three major criteria (first, third, and fifth), and
all minor criteria. Although ID is a childhood disease, 2 adult
cases have been published.3 Dermatosis development occurred
in adulthood in our patient, and the presence of HTLV-1 virus
was determined in blood and by PCR in skin biopsy.
In regard to the second major criterion, our case did not show
rhinorrhea or crusting in anterior nares. However, a series of 15
patients where the absence of this sign did not invalidate diagnosis was recently published. The authors suggest that this criterion may be deemed transient, and thus not mandatory.7
In conclusion, we believe it to be of interest to publish this first
case in Argentina of an adult patient with unusual presentation
of ID associated with HTLV-1 infection.
HTLV-1 infection is an emerging virosis with marked skin tropism, whose understanding should be further explored in the
dermatological field.
References
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2.
3.
4.
5.
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13.
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Primo JRL, Brites C, de Oliveira Mª de FSP, et al. Infective dermatitis and
human T lymphotrophic virus type 1-associated myelopathy/tropical
spastic paraparesis in childhood and adolescence. Clin Infect Dis 2005;
41:535-541.
La Grenade L, Manns A, Fletcher V, et al. Clinical, pathologic and immunologic features of human T lymphotrophic virus type 1-associated infective dermatitis in children. Arch Dermatol 1998; 134:439-444.
Bittencourt AL, Oliveira M de F, Ferraz N, et al. Adult onset infective dermatitis associated with HTLV-1.Clinical and immunopathological aspects of
two cases. Eur J Dermatol 2006; 16:62-66.
Farre L, de Oliveira Mª de FSP, Primo JRL, et al. Early sequential development of infective dermatitis, human T cell lymphotrophic virus type
1-associated myelopathy and adult T cell leukemia/lymphoma. Clin Infect Dis 2008; 46:440-442.
Nobre V, Guedes ACM, Proietti F, et al. Increased prevalence of human T
cell lymphotropic virus type 1 in patients attending a brazilian dermatology clinic. Intervirology 2007; 50:316-318.
Muchnik GR, Bouzas MB. HTLV-1 en Sudamérica en la PET/HAM: la paraparesia espástica tropical-mielopatía asociada con HTLV-1 de Zaninovic V, de Castro CM. Conciencias-Universidad del Valle-Fundación MAR.
Editores 1998, Bogotá, Colombia.
de Oliveira Mª de FSP, Brites C, Ferraz N, et al. Infective dermatitis associated with the human T- lymphotrophic virus type 1 in Salvador, Bahia,
Brazil. Clin Infect Dis 2005; 40:e90-e96.
McLaughlin-Drubin ME, Munger K. Viruses associated with human cancer. BBA (Biochimica et Biophysica Acta) 2008; 1782:127-150.
Nobre V, Guedes ACM, Proietti F, et al. Lesöes dermatológicas em pacientes infectados pelo vírus linfotrópico humano de células T do tipo 1
(HTLV-1). Rev Soc Bras Med Trop 2005; 38:43-52.
Pérez LC, Villarroel JB, Reyes AJ y cols. Eritrodermia exfoliativa y dermatitis infecciosa en un lactante infectado por el virus linfotrópico humano-1 (HTLV-1). Rev Chil Infect 2007; 24:142-148.
Galeno H, Ramírez E, Mora J, Ojeda M, et al. Títulos de anticuerpos anti
HTLVI en individuos infectados seropositivos. Rev Méd Chile 1994;
122:1004-7.
Nobre V, Guedes ACM, Martins ML, et al. Dermatological findings in 3 generations of a family with a high prevalence of human T cell lymphotrophic virus type 1 infection in Brazil. Clin Infect Dis 2006; 43:1257-1263.
Goncalves DU, Guedes AC, De Freitas AB, et al. Dermatologic lesions in
asymptomatic blood donors seropositive for human T cell lymphotropic virus type-1. Am J Trop Med Hyg 2003; 68:562-565.
LaGrenade L, Hanchard B, Fletcher V, et al. Infective dermatitis of Jamaican
children: a marker for HTLV-1 infection. Lancet 1990; 336(8727):1345-1353.
Bittencourt AL, Oliveira M de F, Brites C, et al. Histopathological and
immunohistochemical studies of infective dermatitis associated with
HTLV1. Eur J Dermatol 2005; 15:26-30.
Original Article
Verrucous melanoma: differences and similarities
between primary and secondary varieties
Daniel Feinsilber1, Nora Kogan2, Olga Matilde Rosati3, Cristina Corbella4, Roberto Schröh5, Ignacio Calb6
Abstract
Verrucous melanoma (VM) is an extremely rare variety that may develop on any clinical type of melanoma (secondary VM), or be a primary type. This
implies differences and similarities. From January 1991 to September 2007 we studied 526 patients who developed 545 melanomas, and found 4 (0.7
percent) primary VM and 6 (0.9 percent) secondary VM. Both affect men and women equally. Mean age of patients of primary type was 37.7 years,
with the head as main site of location. Mean age of patients of secondary type was 40.1 years, most often located on limbs.
Primary VM is an exophytic tumor that has a better prognosis if detected in in situ or microinvasion stage, and requires less aggressive treatment. Diagnosis is difficult because it mimics seborrheic keratosis or pigmented verrucous nevi (Dermatol Argent 2009; 15(2):106-110).
Key words: primary and secondary verrucous melanoma.
Introduction
1. Staff Physician. Head of Oncodermatology and Dermatology Surgery Section of the
Dermatology Department, Hospital “J. M. Ramos Mejía”. Authorized Teacher UBA.
2. Staff Physician. Adjunct Teacher UBA.
3. Attending Physician.
4. Staff Physician, Pathology Department.
5. Staff Physician. Head of Dermopathology Section. Authorized Teacher UBA.
6. Head of Pathology Department, Hospital Piñeiro.
Correspondence
Daniel Feinsilber: Av. Entre Ríos 655 2º B, (1080) Autonomous City of Buenos Aires,
Argentine | Republic. Ph. 4381-9159 | [email protected]
Verrucous melanoma (VM) is an extremely rare variety that
may develop on any conventional clinical type of melanoma
(lentigo maligna melanoma, LMM; superficial spreading melanoma, SSM; nodular melanoma, NM; acral lentiginous melanoma, ALM) or be a primary type, that is, totally de novo.
This implies differences and similarities in clinical, pathological, evolutive, and therapeutic aspects, because when appearing
on a part of any of the various clinical forms of melanoma (secondary VM) it has no incidence on prognosis, which is essentially related to the Clark level and the Breslow thickness detected in the exo-endophytic invasion. In contrast, in the de novo
variety it is generally an exophytic tumor diagnosed in in situ or
at microinvasion stages, with a more favorable prognosis and
a less aggressive therapeutic. In the latter case, difficulties arise
with diagnosis, since they mimic seborrheic keratosis and pigmented verrucous nevi, mainly located on legs and cheeks; this
location is typical in young women with phototypes IV or V.
Therefore, early diagnosis is of utmost importance, with a 95 to
100 percent healing probability. The purpose of this work is to
establish differences and similarities between primary and secondary verrucous MM on the above mentioned aspects.
In the Dermatology Department Oncology Section of
Hospital Ramos Mejía we conducted a retrospective study of
all malignant melanoma (MM) cases studied between January
1991 and September 2007. Included were 526 patients who
Verrucous melanoma: differences and similarities between primary and secondary varieties | 35
developed 545 melanomas, whereof 4 (0.7 percent)
were primary or de novo VM (Table 1), and 6 (0.9
percent) were secondary VM (Table 2). These patients with histopathological diagnosis of VM were
evaluated according to gender, age, lesion location,
clinical aspects, histoprognosis factors, therapeutic
behavior, and evolution.
Results
In this case-control study we observed that both de
novo and secondary VM equally affect male and female. In the former, age range was 17 to 58 years,
with a mean of 37.7 years, while in the latter, age
range was 16 to 72 years with a mean of 40.1 years.
De novo VM was located on the head, cheek and
ear in two cases, and the other two appeared one
on the back and the other on an upper limb (arm).
Secondary VM was distinctive for the limb location
in the four cases.
Evolution time at consultation was from 3 months
to 3 years (mean 17.7 months) in de novo VM, and
from 6 months to 2 years (meand 14.3 months) in
secondary VM.
Follow-up time after surgical treatment was from 3
to 16 years in de novo VM, with 75 percent survival,
while in secondary VM it was from 2 to 8 years with
100 percent survival. In the first group, the patient
with late diagnosis of the lesion (>3 years of evolution) (case 2) died with 3 years survival after surgical treatment. In the secondary VM group, followup could not be performed in one patient, because
he returned to his country of origin (case 8).
Of the verrucous melanomas, both de novo and secondary, 50 percent developed on a congenital me-
Figure 1. Female, aged 43, cheek, 2 years’ evolution. Clinical diagnosis: seborrheic keratosis. Histopathological diagnosis: verrucous MM, level I.
lanocytic nevus as verified by reference of the patient and/or third parties,
previous photos, or histologically.
Comments
In 1967, Clark1 mentions four clinical forms of melanoma, that is: superficial spreading melanoma (SSM), lentigo maligna melanoma (LMM), verrucous melanoma (VM) and nodular melanoma (NM). In this revision,
he identifies the dificulties of histologic diagnosis of VM, and refers a higher frequency of VM developing on SSM, without differences of gender,
and with a mean age of 55 years. Two years later, Clark points out that
TABLE 1. DE NOVO VERRUCOUS MELANOMA.
Case
Sex
Age
Location
Presumptive diagnosis Histopatologic diagnosis - level - thickness
1
M
17
Ear
CMN
VM - II - 2.6 mm (Figures 2 and 3)
2
M
58
Back
SSM
VM - III - 1.5 mm
3
F
43
Cheek (Figure 1) SK
VM - I - in situ
4
F
33
Arm
CMN
VM - I - in situ
CMN: congenital melanocytic nevus. SSM: superficial spreading melanoma. SK: seborrheic keratosis. VM: verrucous melanoma.
Evolution time
8 months
> 3 years
2 years
3 month
Follow-up
4 years
† 3 years
3 years
16 years
TABLE 2. SECONDARY VERRUCOUS MELANOMA.
Case
Sex
Age
Location
Presumptive diagnosis Histopatologic diagnosis - level- thickness
Evolution time
5
M
53
Leg
SSM
SSM - III - 1.47 mm
6 months
6
F
35
Leg
SSM
SSM - III - 1.31 mm
2 years
7
F
16
Foot
ALM
ALM - V - 8 mm Neurotropism
2 years
8
M
72
Foot
ALM (Figure 4)
ALM - IV - 2.6 mm (Figure 5)
8 months
9
F
38
Back
MN
NM-IV - 5.5 mm
1 years
10
M
27
Neck (Figure 6) SSM CMN
SSM-II - 0.73 mm (Figure 7)
1 years
SSM: superficial spreading melanoma. ALM: acrolentiginous melanoma. NM: nodular melanoma. CMN: congenital melanocytic nevus.
Follow-up
3 years
4 years
4 years
2 years
8 years
36 | D. Feinsilber, N. Kogan, O. M. Rosati, C. Corbella, R. Schröh, I. Calb
any melanoma, except nodular, may develop verrucous parts, thus deleting VM from the classification,
and including acral lentiginous melanoma (ALM).
In 1968 Abulafia and Grinspan2 report as “atypical
melanoacanthoma” what later should be known as
verrucous melanoma. These authors mention the verrucous and pigmented feature of lesions, which appear mainly on the head (face and scalp) of both sexes and may be diagnosed as pigmented seborrheic
keratosis, pigmented basal cell carcinoma, or pigmented nevus. They report two female cases aged 60
and 69 with lesions of verrucous aspect located on
the skin of upper lip and cheek measuring 15 and 10
mm in diameter, respectively, and clinically diagnosed the first as seborrheic keratosis and the second
with differential diagnosis of melanoma, seborrheic
keratosis, and basal cell carcinoma. Histologically,
both lesions were characterized by being acanthomatous, hyperkeratotic, and papillomatous circumscribed hyperplasia, with the presence of atypical melanocytes, which in the first case only involved epidermis, thus being an in situ VM. The second case
the lesion invaded the papillar dermis, thus referring to a Clark level II microinvasive VM. In 1980,
Schwartz et al.3 published two cases of SSM with verrucous areas, and insisted on providing identity to
this clinical variant; they referred that the Breslow
thickness of VM depends in part on the extent of
epidermal acanthosis and papillomatosis. In 1982,
Kuehl-Petzoldt et al.4 differentiated for the first
time the clinical forms of melanomas with verrucous areas from de novo verrucous melanoma, which
they called in sensu strictu (ISSVM). These authors
examined 1108 melanomas, whereof 101 were verrucous. Of these, 35 percent were SSM, 28 percent
were ISSVM, 25 percent were NM, 6 percent were
LMM, 3 percent were non-classified, 2 percent were
ALM, and 1 percent was in situ. In sensu strictu VM
is clinically described as uniformly brown or black
lesions, generally on limbs and not ulcerated, which
histologically do not show Pagetoid pattern of neoplastic cells in epidermis, with dermoepidermal
nests and solitary atypical melanocyte hyperplasia
in the basal layer of epidermis. They found a slightly
better prognosis for verrucous melanomas in general, but deemed such difference as non-significant.
In 1988, Steiner et al.5 reported five cases of MM (4
SSM and 1 LMM) with verrucous areas, stressing
the importance of differential diagnosis with verrucous pigmentary lesions such as seborrheic keratosis. These authors stated that VM is clinically characterized by having a hyperkeratotic verrucous surface with horny plugs, dark and relatively uniform
Figure 2. Hyperkeratosis, papillomatosis, junctural activity, hypertrophy of hair follicular infundibulum
(H-E 40×).
Figure 3. Spitzoid atypical melanocytes with prominent nucleoli and mitosis in the deep area of the lesion. VM, level II, thickness 2.6 mm (H-E 400×).
pigmentation, sharp demarcation with moderately irregular borders, and
firm and fleshy consistence. They established that the histopathological
features are: epidermal hyperplasia with crest extension and telangiectasias in the extended dermal papillae, orthohyperkeratosis with irregular
parakeratosis, abundant melanic pigment and atypical fragmented melanocytes in the stratum corneum, focal hypergranulosis, atypical melanocytes proliferating in the basal layer and through the epidermis, fusiform or epithelioid cells and inflammatory infiltrate in bands with numerous melanophages. These authors suggest that the discrepancy between
Breslow thickness and Clark level is caused by the marked epidermal hyperplasia and the hyperkeratosis; therefore, tumors that appear clinically
advanced show moderate thickness.
In 1991 Abulafia et al.6 refer again to atypical melanoacanthoma as a
fifth MM variety with clinical aspect similar to seborrheic keratosis
Verrucous melanoma: differences and similarities between primary and secondary varieties | 37
Figure 4. Male, 72 years old. Pigmented tumor, exophytic, verrucous, black, with vegetating 4 × 4 cm surface, of 8 months evolution, on lateral-medial aspect of left foot.
In 1993, Blessing et al.7 reported 20 cases of VM representing 3.2 percent of the total of melanomas
seen between 1970 and 1991. But in contrast to
the above authors, they were found more frequently
in males, with an average age of 57 years and located mainly on the back and the thighs. In over 50
percent, prior clinical diagnosis was benign lesions
such as verrucous nevus, papilloma and seborrheic
keratosis.
In 1994, Buezo et al.8 reported two cases of LMM
with verrucous areas, emphasizing that clinical similarities with verrucous benign lesions make early
diagnosis of MM difficult.
In 1997, Herrera Sánchez et al.9 reported a female
case with leg VM of several years evolution and clinically not suggesting a melanoma diagnosis. They
reviewed 207 MM and found only one case of VM
(0.4 percent).
VM is deemed a MM variety and not a clinical form in the 2000 Australian Guidelines,10
and in Argentina it was defined in the Melanoma
Consensus of the Argentine Dermatology Society
[Consenso sobre Melanoma de la Sociedad Argentina
de Dermatología] in 1998 (updated in 2003).11
Conclusion
Figure 5. ALM with verrucous parts, Clark level IV, 2.6 mm thick; dominant cell type: epithelioid; moderate TIL, low mitotic index, nuclear degree II. Free surgical margins. Centinel node: negative (H-E 100×).
or melanocytic verrucous nevus, and with acanthomatous hypertrophy histopathology of pilosebaceous infundibulum associated with
atypical melanocyte proliferation. These authors report that this
atypical melanoacanthoma is what Kuehnl-Petzoldt called “in sensu stricto” VM, and must be considered a primitive verrucous melanoma. They studied 37 cases of atypical melanoacanthoma or VM,
whereof 29 (78.4 percent) were de novo and 8 (21.6 percent) showed
development of this verrucous aspect in the other clinical forms of
MM. They stated that the former have an incidence of 2 to 3 percent, and the prognosis should be less severe than the rest of MM
varieties, due to the extended intraepithelial growth. They observed
that de novo VM dominates in females and appears most frequently
in lower limbs.
VM is a MM variant, whose development in a part
of a previous melanoma does not affect the prognosis. We believe that the de novo VM shows a noninvasive growth,4 which is slower than secondary VM.
De novo VM is an exophytic tumor, generally with
more favorable prognosis when diagnosed in the in
situ or microinvasion stages; the most important
histoprognosis factor is the Clark level, thus requiring a less aggressive surgical therapeutic.
It is found in young adults; in our cases, the mean
age (37.7 years) was lower than the one found in the
literature.1-3,7 It is located mainly on the head and
the limbs.
Diagnosis is difficult because they mimic seborrheic
keratosis and pigmented verrucous nevi; biopsy and
histopathological control must be done of seborrheic keratosis with an unusual aspect, fast growth,
and in young females with phototypes IV and V.
Early diagnosis is important, and cure probability
ranges between 95 and 100 percent.
The treatment of choice is surgical, with lateral 5 to
10 mm resection margins, while it is the in situ or
microinvasive stage, including superior or the whole hypodermis; the treatment shall be adjusted to the
invasive vertical growth according to conventional
guidelines provided for melanoma.
38 | D. Feinsilber, N. Kogan, O. M. Rosati, C. Corbella, R. Schröh, I. Calb
References
1.
Figure 6. Male, aged 27, neck with surface congenital nevus from birth.
Figure 7. SSM with verrucous areas developed on small superficial congential nevus (Zitelli’s nevus), level
II, thickness 0.73 mm. Dominant cell type: epithelioid; moderate TIL, low IM, GN II (H-E 100×).
Clark WH Jr. A Classification of malignant melanoma in
man correlated with histogenesis and biologic behavior.
In: Montagna W. Advances in Biology of the Skin. Elmsford,
NY: Pergamon Press Inc; 1967, vol 8: The Pigmentary System, pp. 621-647.
2. Abulafia J, Grinspan D. Melanoacantoma atípico. Medicina
Cutánea 1968; 2:125-130.
3. Schwartz RA, Hill WE, Hansen RC, Fleishman JS. Verrucous Malignant Melanoma. J Dermatol Surg Oncol 1980;
6:719724.
4. Kuehnl-Petzoldt Ch, Berger H, Wiebelt H. Verrucous-Keratotic variations of Malignant Melanoma. Am J Dermatopathol
1982; 4:403-410.
5. Steiner A, Konrad K, Pehamberger H, Wolff K. Verrucous Malignant Melanoma. Arch Dermatol 1988; 124:1534-1537.
6. Abulafia J, Grinspan D, Calb IL, Montes LF. Melanoacantoma atípico. Una 5ta variedad clínico-patológica del
Melanoma Maligno. Arch Argent Dermat 1991; 41:103159.
7. Blessing K, Evans AT, Al-Nafussi A. Verrucous naevoid and
keratotic malignant melanoma: a clinico-pathological study of 20 cases. Histopathology 1993; 23:453-458.
8. Buezo GF, Peñas PF, Fraga Fernández J, Aragües Montañes
M. Melanoma Verrucoso. Actas Dermosifiliogr 1994; 85:
6971.
9. Herrera Sánchez M, Peña Payero ML, Del Cerro Heredero M,
Rueda Gómez-Calcerrada M y cols. Melanoma Verrugoso.
Actas Dermosifiliogr 1997; 88:348-352.
10. Pautas para el Manejo del Melanoma Cutáneo. Australian
Cancer Network, 1997. Spanish Edition, 1997. Ed. Archivos Argentinos de Dermatología. Buenos Aires. Original in
English: Guidelines for the Management of Cutaneous Melanoma. Ed. W. McCarthy, AM. The Stone Press, 1997. Sydney, Australia.
11. Stengel FM, Cabo H, Cabrera HN, Casas JG, Feinsilber D y
cols. Consenso Sobre Melanoma Cutáneo. Sociedad Argentina de Dermatología, Buenos Aires, 1998 (Updating 2003).
Original Article
Multiple miliary osteoma of the face.
Three cases treated with carbon dioxide laser
Roberto Adrián Retamar1, María Inés Hernández2, Viviana Battista2, Débora Kaplan2, Graciela Giavino2, María Cristina Kien3,
Graciela Pellerano4, Edgardo Néstor Chouela5
Abstract
We describe three multiple miliary osteoma of the face (MMOF) patients with and without a history of acne prior to the appearance of lesions. They
were treated with carbon dioxide (CO2) laser with good cosmetic results. MMOF constitute a rare variant of osteoma cutis, described almost exclusively in women with history of acne vulgaris.
The objective of the work is to show the usefulness of CO2 laser in the treatment of MMOF and its cosmetic results. Through our experience, we consider that CO2 laser is a therapeutic option for this condition of difficult approach (Dermatol Argent 2009; 15(2):111-116).
Key words: osteoma cutis, acne, multiple miliary osteomas, carbon dioxide laser.
Introduction
1. Physician, Specialist in Dermatology. Coordinator, 3rd year of Specialist Course.
2. Physician, Specialist in Dermatology.
3. Head of Dermatopatology Unit. Name Professor of Dermatology. University of
Buenos Aires.
4. Head of Dermatology Unit, Hospital General de Agudos “Dr. Cosme Argerich”.
5. Named Professor of Dermatology. UBA.
Hospital General de Agudos “Dr. Cosme Argerich” and Chouela Dermatology and
Aesthetics Center. Autonomous City of Buenos Aires.
Correspondence
Roberto Adrián Retamar: Baigorria 3432, (1417) Autonomous City of Buenos Aires,
Argentine Republic | Phone: 4362-3670 | [email protected]
Multiple miliary osteoma of the face (MMOF) represents a rare
variant of osteoma cutis (OC), in most cases affecting young or
middle-aged women with a history of acne vulgaris. OC may
be classified as primary or secondary, according to the absence
or the presence of preexisting lesions, mainly severe acne, nevi,
collagen disorders, scars, and basal cell epithelioma, among
others. Primary lesions may be associated with Albright’s syndrome, and then be classified as MMOF, isolated osteoma, widespread osteoma, and congenital platelike osteoma.
We report three patients with MMOF treated with CO2 laser and subsequent lesion curettage. The result was cosmetically acceptable, with minimum scarring of the treated areas and
without pigmentation changes after 2 to 10 months follow-up.
Multiple treatments have been reported for this conditions,
such as topical tretinoin, dermabrasion, simple surgical excision, and erbium:YAG laser. Only one paper in international literature reports very good cosmetic results in treating MMOF
with CO2 laser. Our experience provided good results, comparable with previous reports, which lead us to believe that the
applied procedure may be a treatment of choice for this rare
condition of difficult therapeutic approach.
Clinical cases (Table 1)
Case 1
A 62-year-old female patient consulting about the presence of multiple 1.5-3 mm-diameter whitish formations, hard
40 | R. A. Retamar, M. I. Hernández, V. Battista, D. Kaplan, G. Giavino, M. C. Kien, G. Pellerano, E. N. Chouela
TABLE 1.
Data
Sex
Current age
Age at onset
History of acne
Location
Case 1
F
62
52
(-)
Cheeks
Case 2
F
74
25
(cannot remember)
Cheeks
Case 3
F
32
20
(+)
Cheeks
in consistency, covered by normal skin, asymptomatic, located on both cheeks, of a10-year evolution (Figure 1). She referred no acne or previous lesions, and had previously been studied for
thrombocytopenia and treated with methylprednisone. A biopsy was performed for a presumptive
diagnosis of OC, resulting in mature bone spicles
with internal bone marrow tissue located in deep
dermis and subcutaneous cellular tissue, thus confirming diagnosis (Figure 2). Laboratory studies
(blood cell count, liver function test, renal profile, calcium and phosphorus dosage in blood and
urine, proteinogram, and ESR) were within normal ranges.
Case 2
A 74-year-old female patient consulting about whitish 1 to 5 mm-diameter lesions, hard in consistency, asymptomatic, on both cheeks. She referred their
presence since the age of about 25, and a history of
various unsuccessful acne treatments (Figure 3). She
did not recall having acne in her youth. Her personal history included hypertension treated with enalaprile 10 mg/day. Presumptive diagnosis of OC was
confirmed by biopsy. Routine blood tests, and calcium and phosphorus dosages in blood and urine
were normal.
Figure 1. Patient 1. Pre-treatment MMOF lesions on left cheek.
Case 3
A 32-year-old female patient consulting about multiple whitish 2-mm-diameter lesions and 15 mmdiameter plates hard in consistency, asymptomatic,
on both cheeks, of a 12-year evolution (Figure 4).
She referred that she had received antibiotic and topical treatment for acne since the age of 20, without
other health problems. Biopsy confirmed OC diagnosis. Blood and urine tests were normal.
Treatment and evolution
CO2 laser treatment was started after obtaining informed consent from the patients. Topical anesthesia with 5 percent lidocaine and 3 percent prilocaine was used in occlusive ointment 2 hours before treatment. Continuous CO2 laser at 1 to 2 watts
was applied until the osteoma could be visualized
Figure 2. Histopathology showing mature bone formation on reticular dermis.
Multiple miliary osteoma of the face. Three cases treated with carbon dioxide laser | 41
(Figure 5). Then, the osteoma was excised with a curette (Figure 6). A fusidic acid cream was indicated
for curing twice a day.
The procedure was well tolerated by the patients,
with appearance of crusts on the treatment site 7
days later, and resolution with minimal scar after 2
months, without pigmentation changes (Figure 7).
Discussion
Figure 3. Patient 2, pre-treatment. Multiple indurated acne-like lesions on cheeks.
The skin may be the target organ of a rare phenomenon: the formation of extraosseous bone (heterotopic ossification), known as osteoma cutis (OC).1
This process may be classified as primary (neoplastic) or secondary (metaplastic) according to the absence or the presence of preexisting cutaneous lesions
(Table 2).
Primary variant may appear in two forms: associated
with Albright’s hereditary osteodystrophia (pseudo-hypoparathyroidism and pseudo-pseudo-hypoparathyroidism), or without such association, as an
essential differentiation in determining the patient’s
prognosis.2,3 If the association is not present, OC
may be subclassified in four clinical forms: multiple
miliary osteoma of the face (MMOF), isolated osteoma, widespread osteoma, and congenital platelike osteoma.4
MMOF like those described in our patients occur as
multiple papules, 1 to 4 mm in diameter, whitish or
bluish, firm in consistency, and asymptomatic. Most
frequent location is on the face,5-7 although other
areas such as the upper part of the trunk have been
described.8,9 Lesions of similar characteristics occur
on isolated10 and widespread11 osteoma (which may
be larger), while congenital platelike osteomas are
TABLE 2. CLASSIFICATION OF OSTEOMA CUTIS (OC).
•
•
Primary OC
OC secondary to
Figure 4. Patient 3, pre-treatment. Variable size MMOF covered by erythematous skin.
•
•
•
•
•
•
•
•
•
•
•
Associated with Albright’s hereditary
osteodystrophy
Not associated with Albright’s hereditary
osteodystrophy:
º MMOF
º Isolated
º Widespread
º Platelike
Severe acne
Nevi
Scleroderma
Dermatomyositis
Basal cell epithelioma
Scars
Venous stasis
Epithelioma of Malherbe
Systemic lupus erythematosus
Histiocytoma
Late syphilis lesions
42 | R. A. Retamar, M. I. Hernández, V. Battista, D. Kaplan, G. Giavino, M. C. Kien, G. Pellerano, E. N. Chouela
characterized by subcutaneous masses hard in consistency, of a few to several centimetres in diameter, covered by normal or erythematous skin, present
since birth or occurring in the first two years of age,
preferably located on scalp.12,13
Secondary or metaplastic OC is a dominant presentation form. Most frequent development occurs
as a sequel of severe acne (in which case they are
described in the literature as secondary MMOF),
and less frequently they appear subsequent to trauma, nevi, scleroderma, dermatomyositis, lupus, basal cell epithelioma, scars, venous stasis, epithelioma
of Malherbe, histiocytoma, and late syphilis lesions,
among others.7,10,14
In regard to etiopathogenesis, the extraskeletal
bone formation mechanism has not yet been elucidated, as well as the higher prevalence in women of this phenomenon. Multiple explanatory
theories coexist; some authors suggest that the
bone may arise from pluripotential mesenquimal cells in embrionary nests, and differentiate
into osteoblasts, but the triggering event is unknown.2 Long time inflammation (such as in severe
acne) may be a triggering factor of such differentiation.5 Other authors have speculated about the
skin fibroblasts being able to differentiate into osteoblast cells.7,15 Oikarinen et al., found by in situ
hybridization of fibroblasts surrounding an OC a
messenger RNA of type I collagen (Col-I) in higher levels than appropriate to normal skin. This
increase may indicate active deposit of Col-I representing the most important collagen present in bone. By the same technique, these cells
showed an increase in osteonectin, a calcium binding glycoprotein involved in bone formation,
which may suggest a coordinate regulation between collagen and osteonectin. In the same study, immunohistochemistry techniques determined the increase in pro-collagen III and tenascin in close relation with OC lesions, with both
elements present during the processes of wound
healing and epidermal regeneration, respectively.
Thus, the bone formation may possibly be parallel
to the wound healing process (when active formation of connective tissue occurs), taking into account its frequent development in acne scars or
secondary to inflammatory processes.15
Histopathologically, it is characterized by
showing true bone located in superficial and deep
dermis. It appears as concentric, lamellar mature bone, with a central bone marrow cavity.16
Ultrastructure shows macrocalcification areas
comprising lamellar bone with Haversian canals
Figure 5. Osteoma extraction with CO2 laser and curettage.
Figure 6. Bone concretions, 1 to 2 mm in diameter.
containing osteocytes and osteoblasts, and microcalcification areas located near the calcified plate consisting of osteoid tissue harbouring
osteoblast-like cells.16
X-ray difraction studies confirm that the main component of OC is hydroxyapatite cristals.14
MMOF have no malignant transformation potential; however, affected patients require treatment to prevent the appearance of new lesions,
as well as to remove the existing ones. Preventive treatments with disodium etidronate have been reported, with minimal results.3,8 Long-term
Multiple miliary osteoma of the face. Three cases treated with carbon dioxide laser | 43
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
Figure 7. Patient 1, post-treatment. Minimal scars are seen, without pigmentation changes.
topical tretinoin in various concentrations (0.025-0.05 percent) proved to
be a non-invasive treatment resulting in parcial improvement by transepidermal elimination of the OC lesions.17,18 Oral isotretinoin also showed
a limited effect.19 Different surgical techniques have been used to remove skin osteoma, including the “microincision” technique (with needle
or scalpel) and subsequent curettage, and escision preceded by dermabrasion.19,20-22 Treatments with erbium:YAG laser have also been described, with excellent cosmetic results;23,24 these authors highlight the ablative properties of this laser, which may cause less thermal injury than CO2
laser. The work of Baginski et al. (on which we based our work) describes
OC treatment with CO2 laser assisted by curettage with results similar to
ours, although they mention residual hypopigmentation not observed in
our patients.7
We conclude that CO2 laser therapy may become the treatment of choice
for this condition of difficult therapeutic approach.
References
1.
2.
3.
Lever WF, Schaumburg-Lever G. Histopathology of the skin. Sixth edition. Philadelphia, Pa: Lippincott; 1983: 660-666.
Goeteyn V, De Potter CR, Naeyaert JM. Osteoma cutis in Pseudohypoparathyroidism.
Dermatology 1999; 198:209-211.
Sethuraman G, Malhotra AK, Khaitan BK, Kumar R, et al. Osteoma cutis in pseudohypoparathyroidism. Clin Exp Dermatol 2006; 31:225-227.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
Mast AM, Hansen R. Multiple papules on the elbows. Congenital osteoma cutis. Arch Dermatol 1997; 133:777-780.
Levell NJ, Lawrence CM. Multiple papules on the face.
Multiple milliary osteoma cutis. Arch Dermatol 1994;
130:370,373-374.
Lo Scocco G, Di Lernia V, Bisighini G. Multiple miliary osteoma of the face. Clin Exp Dermatol 1997; 22:152-153.
Baginski DJ, Arpey CJ. Management of multiple miliary osteoma cutis. Dermatol Surg 1999; 25:233-235.
Gfesser M, Worret WI, Hein R, Ring J. Multiple primary osteoma cutis. Arch Dermatol 1998;134:641-643.
Goldminz D, Greemberg RD. Multiple miliary osteoma cutis. J Am Acad Dermatol 1991; 24:878-881.
Katz M, Weinrauch L. Primary Osteoma Cutis. Cutis 1985; 36: 477.
Nakamura S, Imai T, Nakayama K, Onda S. Primary osteoma
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Cohen PR, Tschen JA, Schulze KE, Martinelli PT, et al. Dermal plaques of the face and scalp. Platelike osteoma cutis.
Arch Dermatol 2007;143:109-114.
Tresserra L, Tresserra F, Grases PJ, Badosa J, et al. Congenital
plate-like osteoma cutis of the forehead: an atypical presentation form. J Craniomaxillofac Surg 1998;26:102-106.
Basler RS, Taylor WB, Peacor DR. Postacne Osteoma Cutis. XRay diffraction analysis. Arch Dermatol 1974;110:113-114.
Oikarinen A, Tuomi ML, Kallionen M, Sandberg M, et al. A
study of bone formation in osteoma cutis employing biochemical, histochemical and in situ hybridization techniques. Acta Derm Venereol 1992; 72:172-174.
Cottoni F, Dell’Orbo C, Quacci D, Tedde G. Primary osteoma
cutis. Clinical, morphological, and ultrastructural study. Am
J Dermatopathol 1993; 15:77-81.
Cohen AD, Chetov T, Cagnano E, et al. Treatment of multiple
miliary osteoma cutis of the face with local application of
tretinoin (all-trans-retinoic acid): a case report and review
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primary closure. J Am Acad Dermatol 2001; 44:96-99.
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138:371-372.
Research Article
Cutaneous metastasis of internal carcinomas, our
experience in 94 cases
Rubén Azcune1, María Gabriela Spelta2. Julieta Moya3, María Laura Lado Jurjo4, María Inés Fontana2, Ana M. Barbarulo2,
Silvina Gavazza2, Mariana Barrera2, Stella Maris Ortega4, Sofía Martínez4, Silvia Vanzulli5, Eduardo Zeitlin5
Aarón Kaminsky Award 2008
Abstract
Cutaneous metastasis is a neoplasia involving the dermis and/or hypodermal tissue with no contiguity with the primary tumor.
Materials and methods: A retrospective and descriptive study was conducted on all patients with diagnosis of cutaneous metastasis consulting the
POBA Dermatology Department between 1993 and 2008. Features taken into account were: primary tumor, gender, age, location, clinical aspect, number of lesions, lapse between primary tumor detection and appearance of metastasis, and survival time after diagnosis of metastasis. The diagnosis was
confirmed histopathologically in all patients.
Objectives: To calculate incidence; to identify clinical variants; to determine the cases where metastases preceded the primary tumor, and were the sign
that led to diagnosis; and to compare the results with international and national statistics.
Results: A total of 94 patients with diagnosis of cutaneous metastasis were studied: in 65 patients, the primary tumor was in breast, 9 in lung, 3 in kidney, 3 in stomach, 2 in colon, 2 in ovary, 2 in bladder, and 1 case in rectum, parotid gland, liver, esophagus, and osteosarcoma, respectively. In the remaining 3 patients, metastasis preceded diagnosis of the primitive tumor. Most of the cutaneous metastases involved women (76 percent), with breast cancer as first cause. In men, amounting to 24 percent of the patients, most frequent was lung metastasis, followed by kidney and stomach. Most affected
age group ranged from 50 to 70 years. Most frequent location was chest and abdomen. Rare locations were palm of hand, fingers and toes. Survival was
less than 2 years after detection of metastasis.
Conclusions: Our findings are similar to the published data. In our case material we emphasize: rare locations: palm of hand, fingers, and toes; glans
metastasis of osteosarcoma not found in the literature; clinical variants not described (granuloma annulare-like, pagetoid, and eczematous (Dermatol Argent 2009; 15(2):117-124).
Key words: cutaneous metastasis, primary cancer, clinical variants.
Introduction
2. Staff Physician, Dermatology Department.
3. Resident, Dermatology Department.
4. Attending Physician, Dermatology Specialist Course.
5. Staff Physician, Pathology Department.
Dermatology Department, Policlínico Bancario, Autonomous City of Buenos Aires.
Correspondence
Ruben Azcune: J. L. Cantilo 1720, (1676) Santos Lugares, Autonomous City of Buenos
Aires, Argentine Republic | [email protected]
Metastasis [Greek meta (after, beyond), and stasis (stop, stagnate)]1 is any neoplastic lesion arising from another noncontiguous neoplasia.
By cutaneous metastasis, we mean a neoplastic lesion involving
dermis and/or subcutaneous cell tissue not contiguous to the
primary tumor.
It must be differentiated from direct extension, that is the neoplastic lesion produced directly by the primary tumor mass;²
thus, direct propagation occurs by contiguity of implantation,
and is not a metastasis.
For disemination, a metastasis requires a lymphatic pathway
and/or a hematogenous pathway.
By the lymphatic pathway, the neoplastic cells reach the skin
directly (through the thoracic duct-subclavian vein-general
circulation, with subsequent cutaneous permeation; or by retrograde via, due to obstruction of the lymphatic lumen by
the tumor embolus, and subsequent centrifugal deviation to
the skin.³
Cutaneous metastasis of internal carcinomas, our experience in 94 cases | 45
By the hematogenous pathway, the tumor may disseminate
through venous vessels to the left heart cavity; it is less frequent
by arterial pathway, not only due to the arterial wall structure,
but also due to the higher intraluminal pressure.4-6
The mechanism to produce a cutaneous metastasis comprises
several steps or stages:5-7
1. Detachment of primary tumor.
2. Invasion and intravasation of the neoplastic cell within the
vessel.
3. Passage through the blood and/or the lymphatic circulatory system.
4. Stoppage (stasis) in a receptor bed vessel.
5. Extravasation through the vessel wall, and invasion of the
receptor tissue bed.
6. Proliferation in the tissue.
Cutaneous metastases of internal neoplasias have a 0.8 to 8 percent incidence.8 They may be a tumor sign in advanced states,
or the first clinical manifestation of an unknown visceral neoplasia. We stress the importance of the dermatologist in the
diagnosis of an unknown primary tumor through cutaneous
metastasis.
Classic clinical forms of metastases are divided in: early, erysipeloid or inflammatory, and telangiectatic; and late, nodular
and cuirass.
The atypical clinical variants include bullous, sclerodermiform, cicatricial, umbilical, dysmetabolic papula-like, zosteriform, and alopecic variants.9
Objectives
• To calculate incidence of cutaneous metastases.
• To identify clinical variants.
• To determine proportion of cases wherein metastasis preceded the primary tumor and was the sign that led to diagnosis.
• To compare data and results with international and national statistics.
·
·
lapse between primary tumor detection and appearance
of metastasis
survival after diagnosis of metastasis
• Diagnosis were confirmed by histopatological and immunohistochemical studies for orientation on probable triggering tumor in patients with unknown primitive tumor.
Results
A total of 94 patients with diagnosis of cutaneous metastasis
were studied: in 65 patients the primary tumor was in breast,
9 in lung, 3 in kidney, 3 in stomach, 2 in colon, 2 in ovary, 2 in
bladder, and 1 case in rectum, parotide gland, liver, esophagus,
and osteosarcoma, respectively.
In the remaining 3 cases, metastasis preceded the primitive
tumor.
Most affected age group ranged from 50 to 70 years.
Predominant primary tumor appeared in breast (70 percent of
the cases), followed in frequency by lung cancer (10 percent)
(Chart 1).
Average lapse between primary tumor and metastasis ranged
from 2 and 5 years (Chart 2).
Of the cutaneous metastases, 76 percent were in female patients, and breast cancer was the first cause in women, with 65
patients (94 percent of the cases). Following in frequency are
ovary in 2 cases, and lung, rectum, and bladder in 1 case. In males (24 percent of the cases) most frequent was lung metastasis with 8 cases (37 percent). Following in frequency are kidney
and stomach with 3 cases each, colon with 2 cases, bladder, parotid gland, liver, esophagus, and osteosarcoma with one case
each. Described in detail are age, location, number of lesions
and clinical variant in the 2 dominant tumors: breast cancer
and lung cancer.
The 65 breast cancer metastasis cases appeared in females, and
the age of 76 percent of patients ranged from 50 to 80 (Chart 3).
Breast 70%
Lung 10%
Unknown 3%
Stomach 3%
A retrospective and descriptive study was conducted on all patients with diagnosis of cutaneous metastasis of internal carcinoma consulting the Dermatology Department of Policlínico
Bancario in the period 1993-2008.
Kidney 3%
Bladder 2%
Ovary 2%
Colon 2%
• We analyzed:
· triggering primitive tumor
· gender
· age
· location
· clinical aspect
· number of metastasis
Osteosarcoma 1%
Esophagus 1%
Liver 1%
Parotid gland 1%
Rectum 1%
Chart 1. Primary tumor.
46 | R. Azcune, M. G. Spelta, J. Moya, M. L. Lado Jurjo, M. I. Fontana, A. M. Barbarulo, S. Gavazza, M. Barrera, S. M. Ortega, S. Martínez, S. Vanzulli, E. Zeitlin
20
30
Number of cases
Number of cases
25
20
15
15
10
10
5
5
0
0
'1
'2
'3
'4
'5
>5
unknown
31-40
41-50
Chart 2. Lapse between primary tumor and metastasis.
TABLE OF VALUES FROM CHART 3.
31 to 40 years
41 to 50 years
51 to 60 years
61 to 70 years
71 to 80 years
81 to 90 years
Dysmetabolic papule 1%
Pagetoid 1%
Annular 1%
Eczematoid 3%
Sclerodermiform 3%
Alopecic 3%
Herpetiform 3%
Bullous 3%
Telangiectatic 4%
Cuirass 10%
Erysipeloid 14%
Nodular 54%
VALUES OF CHART 4.
Nodular
Erysipeloid
Cuirass
Telangiectatic
Bullous
Herpetiform
Alopecic
Dysmetabolic papule
Sclerodermiform
Annular
Eczematous
Pagetoid
39 cases
10 cases
7 cases
3 cases
2 cases
2 cases
2 cases
1 case
2 cases
1 case
2 cases
1 case
71-80
81-90
Chart 3. Breast cancer metastasis. Incidence per age.
9 cases
11 cases
23 cases
19 cases
28 cases
7 cases
3 cases
Chart 4. Breast cancer metastases. Clinical features.
61-70
Age
Time in years
TABLE OF VALUES FROM CHART 2.
Up to 1 year
Up to 2 years
Up to 3 years
Up to 4 years
Up to 5 years
More than 5 years
Unknown
51-60
2 cases
8 cases
15 cases
14 cases
20 cases
6 cases
Single presentation form was found in 42 cases, and multiple
lesions in 25 patients.
Lesions were located in mammay area in 34 cases, chest 18,
back 10, arm 6, presternal 6, ribs 5, flank 5, axilla 5, scalp 3, clavicular area 1, pubis 1, leg 1 and neck, 1 case.
In 56 percent of cases, lesions involved the mammary (34 cases)
and the chest (18) area. The age was divided in decades, with a
dominance ranging from 50 to 80 years (76 percent) (Chart 3).
Predominant clinical variant was nodular, with 39 cases corresponding to 54 percent of the total. The rest of variants are described in Chart 4, with predominance of erysipeloid (10 cases). Variants not described in the literature are: eczematous,
pagetoid, or granuloma annulare-like.
In some patients two clinical forms appeared simultaneously or
during the course of the disease. Cases 17 and 18 combined nodular and erysipeloid variants, case 55 combined nodular and
telangiectatic variants, case 28 combined erysipeloid form and
two years later nodular and telangiectatic forms, case 65 combined nodular clinic form and herpetiform some years later. Lung
cancer metastasis amounted to 9, 8 of which were in males.
The age of onset was: 41 to 50 years 1 case, 51 to 60 years 3 cases, 61 to 70 years 4 cases, 71 to 80 years 1 case, maintaining
dominance in males between 50 and 70 years.
Single clinical forms were seen in 6 cases, and multiple in 3
cases. Their locations were: scalp 4 cases as predominant site,
back 2, face 2, toe, shoulderblade area, neck and arm 1 case.
The nodular form was the most frequent clinical variant (70
percent of the cases). Other variants were in plaque, alopecic
and telangiectatic.
Follow-up was completed in 88 cases, 75 patients
evolved to death: 39 patients died in the first year
(52 percent of the cases) and 16 patients in the second year (21 percent of the cases).
Discussion
Most frequent was breast cancer metastasis, with
76 percent of the total of cases and 94 percent
for females. In males, predominant primary tumor was in lung, with 37 percent of the patients.
These figures are similar to those found in the
literature.1,7,10
In contrast, colon cancer metastasis stated as second in frequency both in females and males was
displaced by those originated in ovary and stomach,
respectively.1,10
Time lapsed between primary tumor diagnosis and
metastasis detection was from 2 to 5 years.
The age group wherein most cases were recorded
was between 50 and 70 years. Data is consistent
with the literature.1-3,9
All primitive tumors were described by other
authors, except osteosarcoma.11-16
Multiple metastases are defined as lesions found in
various body sites. Taking into account this concept,
42 cases were found as single variant and 25 with
multiple lesions in breast cancer metastasis; 6 patients with single lesions and 3 with multiple lesions
in lung cancer metastasis.
Reviewed data indicate higher incidence in multiple lesions, because they do not take into account
the above described concept, and consider that multiple metastases occur when there is more than one
lesion.3,7,17
Most frequent location of breast cancer metastasis
was on chest and breast, with 56 percent of the total
cases. Following in frequency are the back and the
scalp.
Lung cancer metastases were located on scalp in 34
percent of patients.
Among the rare locations we highlight: one breast
cancer metastasis located on a leg, one lung cancer metastasis located on a toe18,19 (Figure 1), a lesion on palm of the hand (Figure 2) with origin in
a renal carcinoma, and two lesions located on a foot
sole and thumb tip with origin in a liver carcinoma
(Figure 3).
Of the clinical variants of breast cancer metastasis we point out the nodular form as the most frequent, followed by the erysipeloid form. The two
cases with herpetiform clinical features had breast
cancer as primary tumor and were preceded by an
Figure 1. Lung cancer metastasis located on a toe.
Figure 2. Renal carcinoma metastasis in palm of the hand.
Figure 3. Metastasis located on thumb tip originated from a liver carcinoma.
Figure 4. Bullous clinical appearance of a breast adenocarcinoma metastasis.
Figure 5. Pagetoid or bowenoid variant of a breast adenocarcinoma metastasis.
Figure 6. In cuirass breast carcinoma metastasis.
hemorragic and ulcerated type aggressive herpes
zoster, and then metastatic nodes appeared on it
in linear distribution.20-23
As rare variants, 2 cases are mentioned with bullous
clinical presentation 24 (Figure 4). We point out variants not described in the literature: pagetoid or
bowenoid (Figure 5); eczematous, where lesions
were seated on the mastectomy scar and extended to
the breast and arm of the other side; and granuloma
annular-like, which clinical features were found reported as “annulare centrifugum type”.25
The clinical in cuirass variant, described in patients with years of survival to the primary tumor,
generally begins with nodular forms that with
time converge as a cuirass.26-29
Of the 7 cases with this metastasis variant stands
out a female patient showing lesions extended on
all the chest and abdomen (Figure 6).
We do not consider sclerodermiform and in cuirass as synonyms.
The alopecic forms were only found on scalp.30,31
Patients with nodular forms evolved to the cuirass
form.32
The number of clinical variants was greater than
the 65 cases found, because some patients showed
2 clinical forms simultaneously or during the disease evolution.
Primary tumors causing metastasis in the umbilical area were stomach, colon and ovary, in data
consistent with the literature.33-36
Rectum adenocarcinoma metastasis appeared as
an inflammatory plaque located in abdomen, in
a similar way to uterus or stomach metastasis.16,37
Noteworthy was the extention of a metastatic lesion in a patient with primary bladder tumor of
erysipeloid type involving abdomen, flank and
both thighs.38
Parotid gland cutaneous metastasis are rare.39 The
case shown in the case material appeared as an extensive infiltrated hemorragic plaque in cuirass
involving left side of the face, ear, neck and chest,
whereon multiple nodes developed (Figure 7).
Esophagus carcinoma metastasis involved the
floor of the mouth; the tumoral mass extended forward and behind the lower incisives40,41
(Figure 8).
We reported one case of penis metastasis of an osteosarcoma. Lesions of nodular aspect were distributed on the gland (Figure 9). Cutaneous osteosarcoma metastases are exceptional, and no genital location has been published so far.
In 3 patients, the cutaneous metastasis led to
diagnosis of unknown primary tumor. Diagnosis
of lung cancer was reached through a scalp lesion;
and in the two other cases, metastases on chest
and axilla came from a breast cancer.
Different theories have been suggested to explain
the affinity of metastasis for scalp. Perhaps it occurs because it is a nonmobile, highly irrigated
area.2,3,7,42-44
Of the 94 cases, 11 were located on scalp, with
alopecic and nodular clinical forms; 5 cases had a
lung primary tumor, 3 a breast tumor, 2 a kidney
tumor, and one case a bladder tumor.
Histological study of the lesions may lead to the
diagnosis of the primary tumor: the adenocarcinoma is related to breast, lung, digestive tract and
ovary neoplasias. In the case of an epidermoid
carcinoma, it may be in lung, esophagus and oral
cavity. If it is a undifferentiated or anaplastic tumor, it may be in lung or breast.46,47
Diagnosis presumption is confirmed by immunohistochemical techniques45 (Table 1).
Follow-up was completed in 88 cases, 75 patients
evolved to death: 52 percent of patients died in
the first year, and 21 percent died in the second
year. These facts correlated with the data found
in the literature, since 73 percent of patients
died in the 2 years subsequent to the metastasis
diagnosis.3,29,48
Conclusions
Our findings are similar to those found in the reviewed
literature:
• Higher incidence of cutaneous metastasis in females.
• Predominant primary tumor:
· Females: breast cancer
· Males: lung cancer
• Most affected age group: between 50 and 70
years.
• Most frequent location: on chest
Figure 7. Parotid gland adenocarcinoma metastasis.
• Survival less than 2 years after diagnosis of metastasis.
In our case material, we highlight:
• Rare locations: palm of the hand, fingers and toes.
• One location, not found in the literature, glans metastasis of osteosarcoma
TABLE 1. IMMUNOHISTOCHEMISTRY FOR DETECTION OF UNKNOWN PRIMARY TUMOR.
Vim
CK 7
CK 20
CA 15.3
CA 19.9
Renal CA 125 Hep. CEA
TTF-1 Alpha fp Thyroglobulin
Breast duct cancer
+
+
-/+
-/+
+
Colon adenocarcinoma
+
+
+
-/+
+
Pancreas adenocarcinoma
+
+
+
+
-/+
+
Renal carcinoma
+
-/+
+
+
+
Serous ovary cancer
+
+
+
Mucinous ovary cancer
+
+
+
+
+
+
Liver carcinoma
-/+
+
+
Thyroid cancer
+
+
+
+
+
-/+
+
+
Lung adenocarcinoma
-/+
+
+
+
+
+
Vim: vimentin. CK: citokeratin. TTF-1: Thyroid transcription factor. Alpha fp: alpha fetoprotein. Renal: anti-renal cancer cell Ab (clone 66-4C2). Hep: anti-hepatocyte Ab (clone OCH 1E5).
• Not described clinical variants: granuloma annulare-like, pagetoid and eczematous.
• The importance of a dermatologist in diagnosis
of unknown primary tumor through cutaneous
metastasis.
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45. Zeitlin E, Kordich M del C. Propuesta para el abordaje del cáncer de primario desconocido. HD 2006; 4:117-122.
46. Schwartz R. Histopathologic aspects of cutaneous metastatic disease. J
47. Sariya D, Ruth K, Addams- McDonnell R, Cusack C, et al. Clinicopathologic correlation of cutaneous metastases: experience from a cancer center. Arch Dermatol 2007; 143:613-620.
48. Aparicio S, Moreno M, Diez E, Romero N, et al. Metástasis cutáneas de
carcinomas internos. Revisión de nuestros casos de 1993-1999. Actas
Dermatosifiliogr 2000; 91:327-331.
Research Article
Reactional leprosy
Liliana M. Olivares1, Graciela E. A. Pizzariello2, Gisela D’Atri3, Alfonsina Martínez4, Cecilia Casas4, M. Belén Jalo4,
Guadalupe Rodríguez Prados4
Abstract
Background. Reactional leprosy is a clinical modality of acute or subacute presentation with local or systemic involvement as the expression of an
inmmune disorder, which appears in the evolutive course of the disease. It may occur in about 30 percent of multibacillary patients (MB): lepromatous and dimorphic or borderline (borderline lepromatous, BL: borderline, BB, borderline tuberculoid, BT). The lack of local published papers on clinical and epidemiological characteristics of reactional episodes (RE) are one of the reasons of this research.
Objetives. To estimate prevalence of RE of leprosy, globally and in each clinical form, identifying them as initial consultation cause, during treatment
and/or during follow-up; to characterize clinical polymorphism; and to assess deficiencies/disabilities and therapeutic difficulties (thalidomide- and
corticosteroid-dependence).
Design. Retrospective, descriptive of series of cases.
Material and methods. From a total of 276 patients who started leprosy treatment from January 1995 to December 2006, those developing RE (110
patients) were selected and analyzed. Statistical methods used included: prevalence, 95% confidence intervals (95% CI).
Results. Overall RE prevalence: 39.85 percent (110/276). RE prevalence in different clinical forms: lepromatous leprosy (LL) 58.11 percent (86/148);
borderline leprosy 22.86% (24/105): BL 29.1 percent, BB 37.5 percent, BT 33.3 percent; tuberculoid leprosy (TT): 0%. Onset of RE: first consultation 32.72
percent (36/110), during treatment: 52.72 percent (58/110), first RE in post-treatment follow-up: 14.5 percent (16/110). Clinical presentation of type
I RE: upgrading 83.3 percent (20/24), downgrading 20.83 percent (5/24). Clinical presentation of type II RE: erythema nodosum (EN) 94.19 percent
(81/86), acute neuritis 20.93 percent (18/86), erythema multiforme 13.95 percent (12/86), arthritis 12.79 percent (11/86), orchitis 8.14 percent (7/86),
Lucio reaction 3.49 percent (3/86), uveitis 2.33 percent (2/86), splenitis 2.33 percent (2/86). Disabilities and sequelae: 30 percent (33/110) of patients.
Therapeutic difficulties: thalidomide-dependence: 54.21 percent (45/83) and costicosteroid-dependence: 15 percent (9/60).
Conclusions. Most frequent RE was erythema nodosum leprosum (ENL). Thalidomide-dependence was confirmed in over half of these patients (Dermatol Argent 2009; 15(2):125-130).
Key words: leprosy, reactional episodes, thalidomide-dependence.
Introduction
1.
2.
3.
4.
Head of Dermatology Unit, Hospital de Infecciosas “F. J. Muñiz”.
Head of Medicine Division, Hospital de Infecciosas “F. J. Muñiz”.
Medical Chief of Residents, Hospital de Infecciosas “F. J. Muñiz”.
Attending Physician, Hospital de Infecciosas “F. J. Muñiz”. Aut. City of Buenos Aires.
Correspondence
Liliana M. Olivares: Arroyo 873 10º, (1007) Autonomous City of Buenos Aires,
Argentine Republic | E-mail: [email protected]
Reactional leprosy constitutes a clinical modality of acute
or subacute presentation, local or general, as an expression of
complex and diverse immune phenomena occurring during the
chronic course of the disease. The reactional episode (RE) may
appear before, during or after treatment, and may cause important complications and/or lead to severe disability sequelae.1
The local literature does not include works reflecting RE prevalence or RE clinical and epidemiological characteristics of the
leprosy patients in Argentina. This information may be of great
use to assess requirements and to design therapeutic strategies
implemented at national level. The fact that our hospital is a reference center for infectious pathologies, mostly for a population from Great Buenos Aires (57.32 percent), is another motivating reason of special interest for our research, since it represents a significant sample of what may happen in our city, and
also in the province of Buenos Aires.
The purpose is to estimate RE prevalence; to identify incidence as first consultation cause, during treatment and/or during post-treatment follow-up; to characterize clinical po-
Reactional leprosy | 53
I
TT 3.26%
5.07%
58
60
58%
BL
7.61%
52.72%
110 Patients
50
BB
14.13%
LL
53.62%
40
36
30
32.72%
20
16
14.54%
10
BT
16.3%
0
During treatment
Follow-up period
Chart 4. Identification at the time of RE appearance
20
20
Number of patients
Chart 1. Percentage of leprous patients according to the clinical classification. Hospital “F.
J. Muñiz”, years 1996 to 2005.
Table of values from Chart 1.
Clinical form
Number
Percentage
LL
148
53.62
BT
45
16.30
BB
39
14.13
BL
21
7.61
TT
14
5.07
I
9
3.26
276
100.00
Cause of first consultation
15
10
5
5
0
Upgrading
4
Downgrading
EN
Type I RE
RE
39.85%
110 patients
Chart 5. RE in borderline patients.
100
without RE
60.15%
166 patients
81
Number of patients
80
Chart 2. Global prevalence of RE in 276 patients.
150
86-148
Number of patients
30
7-24
9-24
8-24
BB
BL
BT
0
LL
18
BORDERLINE
12
EN
AN
EM
11
AR
7
OR
3
2
LR
UV
Chart 6. Type II RE.
22%
60
0
40
0
24-105
90
60
20
58%
120
Type II RE
BORDERLINE
Chart 3. Prevalence of RE in each clinical form.
TT
Table of values in Chart 6.
Diagnosis
E.N.L.
Acute neuritis
E. M.
Arthritis
Orchitis
Lucio reaction
Uveitis
Number
81
18
12
11
7
3
2
Percentage
94.19
20.93
13.95
12.79
8.14
3.49
2.33
54 | L. M. Olivares, G. E. A. Pizzariello, G. D’Atri, A. Martínez, C. Casas, M. B. Jalo, G. Rodríguez Prados
lymorphism; and to assess deficiencies/disabilities and therapeutic difficulties (thalidomide/
corticosteroid-dependence).
Therefore, we conducted an observational-descriptive, retrospective study of series of cases encompassing
10 years (1996-2005), on the reactional leprosy population of the Leprosy Section of Hospital “F. J. Muñiz”.
From the revision work 2 of 276 patients from the
Dermatology Department of Hospital Muñiz
with clinical, baciloscopy, and histopathologic diagnosis of leprosy, between January 1996
and December 2005 (Chart 1), those developing reactional episodes were exclusively selected and analyzed. Statistical methods used included: prevalence and 95 percent confidence intervals (95% CI).
Only a small percentage, 16.11 percent (4 of 24), also developed type II
RE with characteristics of erythema nodosum (EN) (95% CI: 1.7-31.5
percent) (Chart 5).
Clinical modalities of type I RE
It encompasses a broad scope of symptoms, both in the upgrading
and the downgrading form. In the upgrading episode, preexisting lesions turn erythematous-edematous and infiltrative with appearance
of new urticated elements, mainly with eyelid, neck and the external
ear involvement (Figure 1).
Facial edematous lesions confer some patients a remarkable likeness to lepro-
Results
Global RE prevalence
Of the total of 276 patients, 39.85 percent (110/276)
developed RE at some time of the disease evolution,
(95% CI: 34.03-45.57 percent) (Chart 2).
RE prevalence in each clinical form
RE appeared at some time of the evolution of the lepromatous leprosy patients (LL), 58.11 percent (86 of
148) (95% CI: 50.16-60 percent), as well as 22.86 percent of borderline patients (24 of 105), 95% CI: 14.8330.8 percent, with similar RE distribution in each borderline subgroup. None of the tuberculoid leprosy patients included in the study showed RE (Chart 3).
Identification of time of RE occurrence
In one third of the 110 patients who developed RE,
it was the initial cause of consulting (36 of 110 patients), that is, 32.72 percent (95% CI: 24.02-41.42
percent). RE developed for the first time during the
follow-up in 14.54 percent (16 of 110) of the patients (95% CI: 7.91-21.08 percent). In the remaining patients (58 of 110), the first RE appeared during treatment, 52.72 percent (CI95%: 43-61.8 percent) (Chart 4).
RE in borderline patients
Type 1 RE was found in 22.86 percent (24 of
105) of borderline leprosy patients (BT, BB, BL)
(95% CI: 14.83-30.89 percent). In most of them,
83.3 percent (20 of 24), type I RE upgraded during treatment (95% CI: 68.4-98.2 percent).
Figure 1. Type I RE manifestations three months after starting treatment.
Figure 2. Leonine and pseudoleonine fascies.
matous leprosy leonine fascies (Figure 2). Patients not exposed to treatment
or with discontinuous treatments may develop downgrading RE. In this case,
lesions locate similarly to upgrading RE, but with less erythema and edema
(Figure 3).
Figure 3. Downgrading reactional episode.
RE in lepromatous patients
Clinical modalities of type II RE
Almost all lepromatous patients with RE had EN
(81 of 86), 94.19 percent; and the remaining clinical modalities of type II RE in a lesser percentage. In
each patient, the REs appeared in isolated, simultaneous, successive and/or recurrent form (Chart 6).
Second RE in frequence was neuritis, 20.93 percent,
with most severe sequelae in the borderline group
(Figure 4).
Erythema multiforme (EM) and arthritis were
found with similar frequency in about 10 percent of
the cases. Lucio reaction represented 3.49 percent of
the cases (3 of 86 patients); it usually starts with irregular purplish maculae that follows vascular courses
and evolves to cutaneous infarcts with geographical
borders evoking disseminated intravascular coagulation. After of necrotic tissue, stellate ulcers appear
(Figure 5). Less frequent are After of orchitis, uveitis and splenitis (2 cases).
Disabilities and sequelae
According to the WHO definition, 30 percent (33
of 110) of patients had disability/deficiency, with
sequelae such as: chronically ulcerated feet, trophic
ulcers, ulnar claw, wrist-drop, stepagge, amputations
(Figure 6).
Therapeutic difficulties
Of the 83 patients (79 LL, 4 BL) receiving thalidomide, 54.22 percent (45 of 83) showed thalidomide-dependence (95% CI: 43.5-64.9 percent). Dependence
means impossibility to discontinue a minimal drug
dose to maintan the patient free from RE.
Of the 60 patients (36 LL and 24 borderline) receiving corticosteroids, about 15 percent (9/60)
showed corticosteroid-dependence (95% CI: 6.324.2 percent). In these cases, outbreaks were continuous and led to complications related to chronic
corticosteroid therapy, without preventing severe disability sequelae.
Discussion
Figure 4. Peripheral facial paralysis in a BB patient.
A distinctive feature of RE, as an expression of immune phenomenon, is the heterogeneity of the immune response: not all leprous patients have RE, and
only some have recurrent RE. The situation may occur in about 30 percent3 of multibacillary patients
(MB): lepromatous and borderline (BL, BB, BT).
In this study, of the 276 patients that started multidrug therapy (MDT), about 40 percent had RE
56 | L. M. Olivares, G. E. A. Pizzariello, G. D’Atri, A. Martínez, C. Casas, M. B. Jalo, G. Rodríguez Prados
Figure 5. Lucio reaction.
Figure 6. Sequelae/disability in corticosteroid-dependent patient.
at some time of evolution, more frequently in lepromatous patients.
Occasionally, it may cause delay in disease diagnosis at first consultation. We found it in more than 30 percent of our patients, in contrast
to other case-control studies that mention an incidence of 17 percent.4
Noteworthy, 14.5 percent of patients showed first RE post-treatment.
Borderline RE had a similar distribution in each
subgroup (BL, BB, BT), and upgrading RE was
most frequent. Some patients showed successive
downgrading and upgrading episodes, and ENL was
also found in 4 of them.
As regards type II RE, ENL was found most frequently (94.19 percent) among our patients, alone
or associated with other reactions such as neuritis,
erythema multiforme, arthritis, orchitis, Lucio reaction, uveitis, etc.
In our case-control study, the severity of RE depended on systemic repercussions (2 patients with splenitis), profusion of cutaneous lesions, clinical modality (EM, Lucio reaction) and/or simultaneous
reactions.
As regards RE tratment, both thalidomide for ENL
and prednisone were the first drugs of choice for our
patients.
Thalidomide has been an extensively used drug by
latinamerican leprologists, with excellent results and
good tolerance. However, this use has raised controversy in other international settings, such as the
United States, where the FDA only authorized the use for EN
in 1998.5,6 Development of thalidomide-dependence was established in our study in 54.22 percent (45 of 83) of the dosed patients. This finding, frequently seen in practice, is seldom
mentioned in the treated literature.7,8 It is hypothesized that
these patients may have genetic predisposition to “reacting”,
thus needing a minimal dose of thalidomide to keep levels of
TNF-α sufficiently low to prevent triggering a RE.9
Corticosteroid-dependence, with its unwanted effects, did not
reach a significant value.
rapeutic strategies, in order to adequately prevent and control
the possible harmful sequelae of reactive leprosy.
References
1.
2.
3.
4.
Conclusions
• About 40 percent of patients with leprosy developed RE.
• 58 percent of lepromatous patients had RE.
• 22% of borderline patients had RE, with similar distribution in the different subgroups.
• RE was initial consulting cause in 32 percent of the patients; less than 15 percent showed it for the first time during the follow-up period.
• ENL was the most frequent RE
• Thalidomide-dependence was confirmed in more than 54
percent of ENL patients.
It must be noticed that treatments were effective, although insufficient to prevent severe disability sequelae. The present fndings should be considered in the programming of future the-
5.
6.
7.
8.
9.
Olivares LM. Lepra reaccional. Dermatol Argent 2004; 10:94-101.
Olivares LM, Carabajal MT, Jaled M, Iriarte A, Anaya A. Estudio retrospectivo a 10 años (1996-2005) de enfermos con lepra - Hospital F. J. Muñiz.
Dermatol Argent 2006; 12:280-285.
Lockwood DNJ, Sujai S. Leprosy: Too complex a disease for a simple elimination paradigm. Bull World Health Organ 2005; 83:33,230-235.
Gomes Guerra J, Oliveira Pennal G, Miranda de Castro LC, Turchi Martelli
CM, et al. Erythema nodosum leprosum case series report: clinical profile, immunological basis and treatment implementedin health services.
Rev Soc Bras Med Trop 2004; 37:384-390.
Teo SK, Colburn WA, Tracewell WG, Kook KA, et al. Clinical pharmacokinetics of thalidomide. Clin Pharmacokinet 2004; 43:311-327.
Lockwood D, Bryceson A. The return of thalidomide: new uses and renewed concerns-Replay. Commentaries. Lepr Rev 2003; 74:290294.
Villahermosa LG, Fajardo TT Jr., Abalos RM, Balagon MV, et al. A randomized, double-blind, double-dummy, controlled dose comparison of thalidomide for treatment of erythema nodosum leprosum. Am J Trop Med
Hyg 2005; 72:518-526.
Carsalade GY, Achirafi A, Flageul B. Pentoxifylline in the treatment of
erythema nodosum leprosum. Results of an open study. Acta Leprol
2003; 12:117-122.
Oliveira Penna G, Martelli CM, Stefani MM, Macedo VO, et al. Talidomida
no tratamento do eritema nodoso hansênico: revisao sistemática dos
ensaios clínicos e perspectivas de novas investigacoes. An Bras Dermatol 2005; 80:511-522.
Research Articles
Cutaneous manifestations of acromegaly
Myriam Dahbar1, Karina Danilowicz2, Marcos Malavela2, Dolores Velásquez1, Miguel Allevato3, Hugo Cabrera4, Oscar D. Bruno5
Abstract
Acromegaly is a rare syndrome, usually with insidious manifestations. Cutaneous changes are precocious. The dermatologist may be the first to suspect this early diagnosis and thus prevent the high morbidity of this disorder. The present paper describes dermatological findings in acromegaly
(Dermatol Argent 2009; 15(3):186-190).
Key words: acromegaly, cutaneous manifestacions.
Introduction
Acromegaly is a syndrome resulting from an excess of growth
hormone or somatotropin (GH), whose biological activity is
mediated by insulin-like growth factor 1 (IGF-1). Most cases
are secondary to a GH-secreting pituitary adenoma. Diagnosis
is usually delayed, and 60 percent of the cases show disease remission; therefore, the tissues are usually exposed to excessive
growth hormone for a long period of time. The most common
clinical manifestations are hypertension, diabetes, hypertriglyceridemia, and cardiomyopathy.1 The cutaneous manifestations
include skin thickening and increase of eccrine, apocrine, and
sebaceous gland secretion. Hypertrichosis and/or hirsutism
may be found in the early phase, and hair rarefaction and miniaturization may appear in the late phase.2 Onychodystrophy
is described as ungual alteration.3
In rare cases, the acromegaly may be associated with multiple
endocrine neoplasia type I, McCune-Albright syndrome, and
Carney’s syndrome.1
1. Medical Dermatologists, Hospital de Clínicas “José de San Martín”.
2. Medical Endocrinologists, Hospital de Clínicas “José de San Martín”.
3. Head of Division, Hospital de Clínicas “José de San Martín”.
4. Named Consulting Professor, Universidad de Buenos Aires, UBA.
5. Named Consulting Professor, Universidad de Buenos Aires, UBA.
Dermatology and Endocrinology Divisions, Hospital de Clínicas “José de San Martín”.
Autonomous City of Buenos Aires. Argentine Republic.
Correspondence
Myriam Dahbar: Av. Santa Fe 1622 3º B - (1060) Autonomous City of Buenos Aires. Argentine Republic. Phone: 4812-4288 | E-mail: [email protected]
Objectives
To describe dermatologic manifestations of acromegalic patients and the behavior of some signs and symptoms with
treatment.
Population and sample
The study included 19 patients from Hospital de Clínicas “José
de San Martín” consulting at the Endocrinology Division and
subsequently referred to the Dermatology Division of the same
hospital (patients were always assessed by the same medical
dermatologist). Diagnosis of acromegaly was reached by clinical evaluation and biochemical abnormalities (loss of GH sup-
Cutaneous manifestations of acromegaly | 59
pression in the oral glucose tolerance test, and/or increase of IGF-1).
A prospective, observational, and transversal study was conducted between January 2006 and
September 2006).
Study variables
Data were obtained from ambulatory consulting
patients and analyzed taking into account the following study variables:
• Age: in years
• Gender: male - female
• Most common dermatologic manifestations, such
as acromegaloid facies; increased size of hands
and feet; increased size of the nose, external
ear and lower lip; the presence of macroglossia,
prognathism, onychodystrophy, acanthosis nigricans, soft fibromas or acrochordons, eruptive seborrheic keratoses. Reference of oily skin or
hyperhidrosis was also assessed.
• Behavior of some signs and symptoms after
treatment. The definition of “cured and/or with
controlled acromegaly” included those patients
with normal serum IGF-1 concentracion according to age and gender, and “active” were the patients without normal serum IGF-1 concentracion according to age and gender.4,5
Figure 1. Acromegaloid facies.
Processing and statistical analysis
Data were entered into a database (Excel-type) and
then analyzed with a Pentium III microprocessor
and the Epi Info version 6.00 statistical package.
Frequency distribution and percentage to total cases
were established for categorical variables.
Results
The study included 19 patients (11 female y 8 male)
between 25 and 87 years of age, averaging 52.6 ±
17.8. The dermatologist carried out a thorough dermatologic clinical examination.
Of these 19 patients, 8 are cured, 7 are controlled,
and 4 are active. “Cured” patients were surgically
treated; “controlled” patients were subjected to transeptosphenoidal surgery with partial adenoma removal and/or radiotherapy plus octreotide for disease persistence (Table 1).
All patients showed increased size of hand and feet,
independently of the acromegaly status. Only 15 (79
percent; 95 percent confidence interval [95% CI]:
54.4-93.9) had increase size of the nose, 4 (21 percent; 95% CI: 6.1-45.6) had increased size of external ear, and 4 (21 percent; 95% CI: 6.1-45.6) had
Figure 2. Acneiform lesions.
60 | M. Dahbar, K. Danilowicz, M. Malavela, D. Velásquez, M. Allevato, H. Cabrera, O. D. Bruno
increased size of lower lip. Just 4 showed macroglossia (21 percent; 95% CI: 6.1-45.6) and 5 showed prognathism (26 percent; 95% CI: 9.1-51.2). Fifteen patients had oily skin (79 percent; 95% CI: 54.4-93.9). All showed partial post-treatment
improvement (data reported by patients). Acneiform lesions
are uncommon; they appeared in 2 of our patients (11 percent;
95% CI: 1.3-33.1), whereof 1 remains active and the other is
controlled.
Only 8 of 19 patients (42 percent; 95% CI: 20.3-66.5) had soft
fibromas, 1 (5 percent; 95% CI: 0.1-26) had hypertrichosis,
and 1 (5 percent; 95% CI: 0.126) had eruptive seborrheic keratoses, with no association to neoplasias.
Seven (37 percent; 95% CI: 12.6-56.6) had toenail onychodystrophy (onycholysis and ungular plate thickening). Seven of
the 19 (37 percent; 95% CI: 16.3-61.6) referred history of hyperhidrosis at the time of the acromegaly diagnosis. All referred
disappearance of the symptom, even in the active remaining patient, where serum GH concentration decreased from 88.7 ng/
ml at onset to 13 ng/ml.
Acanthosis nigricans was found in 2 patients (11 percent; 95%
CI: 1.3-26) currently cured. Patients referred decrease in hyperpigmentation without complete post-treatment regression
of the acanthosis.
Comment
The incidence of acromegaly is estimated in 3-4 cases per million population per year.1 Occurrence is most frequent in
middle-aged patients, with an average of 40 years in males and
45 years in females.1 Average age of our patients was 52.6 ±
17.8 years.
Growth hormone (GH) stimulates production of insulin-like
growth factor (IGF-1), which binds to the IGI-1 receptor and
leads to the growth and differentiation of several skin cell lines
such as keratinocytes, fibroblasts, and hair unit cells.1
Clinical aspects
The most common general complications of growth hormone
(GH) excess are hypertension, diabetes mellitus, hypertriglyceridemia, and cardiomyopathy,1 with a 2-4 times higher mortality than in the general population.6
Skin involvement was described in 1899 by Steinberg.1 Skin
changes have been considered a classic finding in acromegaly.1
However, few published reports related to skin manifestations
of this disease were found.1,3,7 Progression of the condition is
characteristically slow and insidious; thus, the diagnosis is tardive. Skin changes may remain stationary or decrease when the
disease activity diminishes.1,7
Cutaneous manifestations in acromegaly (Table 2)
One of the earliest signs is an edematous and doughy feeling
most noticeable in face, palms and soles.3 Patients have acromegaloid facies consisting of prominent frontal area, hypertelorism, eyelid edema, increased size of the nose and the external ear, prognathism, and macroglossia. In the studied population, 15 (79 percent) had increased size of the nose, 4 (21 percent) had increased size of the external ear, and 4 (21 percent)
had increased size of the lower lip. Only 4 (21 percent) showed
macroglossia, and 5 (19 percent) had prognathism.
Patients usually have oily skin with dilated pores; but, interestingly, acne is only rarely found.7 In this aspect, we noticed that
15/19 (79 percent) patients had oily skin at assessment and all
referred partial improvement with the indicated treatments.
Two of the 15 patients (11 percent) with oily skin had acneiform lesions. Hyperhidrosis, usually with bromhidrosis, is important and is found in 50-88 percent of the cases.7 Analysis
of our patients showed that only 7 of 19 (37 percent) had hyperhidrosis of hands and feet at diagnosis (data referred by the
patients). It was not present at the time of the clinical dermatology examination and the patients referred regression of the
symptom at onset of treatment. Although one of the patients
remained active, noteworthy after two pituitary surgeries with
partial tumor excision, radiotherapy and current treatment
with octreotide LAR, the patient reduced serum GH concentration. Hypothetically, improvement of hyperhidrosis may be
caused by improvement of acromegaly, even though it is not yet
controlled. Some skin changes, such as hyperhidrosis, improve
readily when the disease activity is controlled. This finding was
reported in our patients and correlated in the literature.3
Soft fibromas or acrochordons are a common finding in up to
45 percent of acromegaly patients.8 They were found in 42 perTABLE 1.
19 patients were included (11 female and 8 male)
Age range
Cured
Controlled
Active
25 to 87 years
8 (42.10 percent)
7 (36.80 percent)
4 (21.10 percent)
TABLE 2. CUTANEOUS MANIFESTATIONS OF ACROMEGALY PATIENTS.
n
Prevalence
95% CI
Increased size of hands and feet
19
100%
82.4-100
Increased size of the nose
15
79%
54.4-93.9
Oily skin
15
79%
54.4-93.9
Soft Fibromas
8
42%
20.3-66.5
Hyperhidrosis
7
37%
16.3-61.6
Onychodystrophy
6
32%
12.6-56.6
Prognathism
5
26%
9.1-51.2
Increased size of external ear
4
21%
6.1-45.6
Increased size of lower lip
4
21%
6.1-45.6
Macroglossia
4
21%
6.1-45.6
Acneiform lesions
2
11%
1.3-33.1
Acanthosis nigricans
2
11%
1.3-33.1
Eruptive seborrheic keratoses
1
5%
0.1-26
Hypertrichosis
1
5%
0.1-26
Cutaneous manifestations of acromegaly | 61
Figure 3. Eruptive seborrheic keratoses.
Figure 4. Hypertrichosis.
cent of patients in our case material (8 of 19), a finding similar to the literature.8 Soft fibromas also occur in the general population in patients with
diabetes mellitus, dyslipidemia, and other metabolic disorders appearing
in acromegaly.8,9 The search of colonic polyps is recommended if multiple
soft fibromas are found.10
Acanthosis nigricans occurs in 10 percent of the cases, in the literature.3
It appeared in 11 percent of our patients, who referred decreased hyperpigmentation after starting treatment, without complete regression of
acanthosis (data reported by the patients). Hyperpigmentation, especially
on photoexposed areas, is probably caused by an increase of melanocytestimulating hormone; these findings are not specific, and are also seen in
other metabolic disorders, as mentioned above.
Hypertrichosis and/or hirsutism are detected in the early phase, and hair
rarefaction and miniaturization tend to appear in the tardive phase (hirsutism and hyperhidrosis may be caused by a higher level of free testosterone).3 Hypertrichosis was found in one woman (5 percent) of the 19 patients (cured).
In patients with acromegaly, nails show onychodystrophy.3 Prevalence in
our patients was 32 percent. The main cause of this sign is secondary to
trauma. Patients without onychodystrophy had most likely made appropriate shoeware adaptations as the size of the feet increased.
None of our patients showed cutis verticis gyrata, a finding described in
the literature.11 In addition, 2/19 patients (5 percent) showed trichilem-
mal and eruptive cysts with a similar frequency to
the general population. Only one patient (5 percent) showed sudden appearance of multiple seborrheic keratoses not associated with neoplasia.3
Conclusion
Some cutaneous manifestations may remain stationary with treatment and not regress (as occurs with
acromegaloid facies, increase in size of hands and
feet, soft fibromas, hypertrichosis, seborrheic keratoses), while others may decrease partially (such
as oily skin and acanthosis nigricans). Above all, it
must be remembered that skin alterations are precocious and that hyperhidrosis is an activity marker that may lead to diagnosis of the disease and
thus reduce morbility and mortality; therefore, the
dermatologist’s observation and clinical suspicion
are essential.
Acknowledgement
To Dr. Castiglia, for her contribution of statistical
data.
62 | M. Dahbar, K. Danilowicz, M. Malavela, D. Velásquez, M. Allevato, H. Cabrera, O. D. Bruno
References
1.
2.
3.
4.
5.
Centurión S, Schwartz R. Cutaneous signs of acromegaly. Int J Dermatol
2002; 41:631-634.
Feingold KR, Elias PM. Endocrine-Skin interactions. J Am Acad Dermatol
1987; 17:921-940.
Zanini M, Oshiro Rodrigues R, Camargo Paschoal l, Paschoal Macedo F, et
al. Aspectos dermatológicos de acromegalia. Ann Bras Dermatol 2004;
79:491-494.
Clemmons DR, Van Wyk JJ, Ridgway EC, Kliman B, et al. Evaluation of acromegaly by radioimmunoassay of somatomedin-C. N Engl J Med 1979;
301:1138-1142.
Freda PU, Post KD, Powell JS, Wardlaw SL. Evaluation of disease status with
sensitive measures of growth hormone secretion in 60 postoperative patients with acromegaly. J Clin Endocrinol Metab 1998; 83:38083816.
6.
Rajasoorya C, Holdaway IM, Wrightson P, Scott DJ. et al. Determinants of
clinical outcome and survival in acromegaly. Clin Endocrinol 1994; 4:95102.
7. Ben-Shlomo A, Melmed S. Skin manifestations in acromegaly. Clin Dermatol 2006; 24:256-259.
8. Tyrell JB, Wilson CB. Pituitary syndromes. In: Friesen SR, editor. Surgical
Endocrinology Clinical Syndromes. Philadelphia: J.B. Lippincott. 1978:
304-324.
9. Crook MA. Skin tags and the atherogenic lipid profile. J Clin Pathol 2000;
53:873-874.
10. Leavitt J, Klein I, Kendricks F, Gavaler J, et al. Skin tags: a cutaneous marker for colonic polyps. Ann Intern Med 1983; 98:928-930.
11. Tiberio C, Lozano G, Blaustein A, Storani ME. Cutis verticis gyrata secundario a acromegalia. Dermatol Argent 2001; 7:343-345.
Original Article
Pyoderma gangrenosum associated with ulcerative
colitis treated with infliximab
Daniela Malieni1, Ana C. Torre2, M. Carolina Baztán3, Carolina Anselmi3, Ricardo Galimberti4
Abstract
Pyoderma gangrenosum is an uncommon destructive and inflammatory skin disease of the neutrophilic dermatosis group. Of unknown etiology, it is
possibly an immunological disorder. Infliximab is an anti-tumor necrosis factor alpha monoclonal antibody. We report 3 patients with ulcerative colitis and recalcitrant pyoderma gangrenosum not responsive to conventional therapies and treated with infliximab with favorable results. Seemingly, infliximab is an effective and well tolerated drug for the treatment of pyoderma gangrenosum associated with ulcerative colitis (Dermatol Argent
2009; 15(3):191-195).
Key words: anti-tumor necrosis factor alpha, inflammatory bowel disease, infliximab, pyoderma gangrenosum, ulcerative colitis.
Introduction
1. Associate Physician.
2. Chief of Residents.
3. Fourth Year Resident.
4. Head of the Dermatology Department.
Hospital Italiano of Buenos Aires, Dermatology Department. Autonomous City of Buenos Aires, Argentine Republic.
Correspondence
Ricardo Galimberti. Hospital Italiano de Buenos Aires, Servicio de Dermatología. Gascón 450, Autonomous City of Buenos Aires, Argentine Republic |
[email protected]
Pyoderma gangrenosum (PG) is an uncommon and destructive inflammatory disease of the neutrophilic dermatosis group.1
This dermatosis may appear without other underlying disorders,
or be associated with a systemic disease (17 to 74 percent).2 It
has been related to multiple entities, especially with inflammatory bowel disease (IBD), rheumatoid arthritis (RA), and
immunoglobulin A monoclonal gammopathy.3 Association of
PG and ulcerative colitis (UC) is uncommon; prevalence ranges between 0.6 percent and 15 percent.1 Clinically, it is characterized by the presence of nodules or sterile pustules progressing to painful ulcers with elevated crenated, erythematous and
purplish borders, and an oozing necrotic base. Lesions are typically isolated. The ulcerated form is the most frequent clinical variant, and is generally associated with IBD, RA, and monoclonal gammopathy. Other less frequent forms are the pustulous variant usually related to IBD, the bullous form associated with myeloproliferative diseases, and the vegetating variety,
usually idiopathic.4 The most frequent location of lesions is the
legs.3 The etiology of PG is unknown. Although some immune
regulation alterations have been reported, a specific pattern has
not yet been detected.1 The treatment of this disease is based
on the use of immunosuppresive drugs. Systemic corticosteroids and cyclosporine are described in the literature as first choice drugs. However, numerous pharmaceutical drugs have been
used for remission (azathioprine, cyclophosphamide, dapsone,
thalidomide, etc.).2,5
Infliximab is an anti-tumor necrosis factor alpha monoclonal
antibody (TNF-α). Since it is effective for the treatment of va-
64 | D. Malieni, A. C. Torre, M. C. Baztán, C. Anselmi, R. Galimberti
Figure 1. Ulcer, 15 × 8 cm in diameter, with undermined erythemato-purplish borders and necrotic base
on the external area of the lower third of the right leg.
Figure 2. Ulcer on the external area of the lower third of the right leg after the third infliximab infusion.
rious inflammatory pathologies involving multiple cytokines, its use in
treating PG has been considered. Several retrospective studies and series
of cases suggest that this monoclonal antibody may induce the cure of PG
in IBD patients.6-9 Three patients with UC and PG treated with infliximab with favorable results are reported here in below.
Clinical cases
Case 1
A 41-year-old female patient with PG of an 11 years’ evolution and episodes of parcial remission in response to treatment with systemic corticosteroids and cyclosporine. Ten years after diagnosis of dermatosis she
presented episodes of bloody diarrhea. Thus a videocolonoscopy (VCC)
and a colon biopsy were performed, enabling a UCdiagnosis; sulfazalazine treatment was instituted (4 g/day). Two months later, a 10 cm diame-
ter oval and painful blister with hemorrhagic content appeared, eventually evolving to a 15 × 8 cm
diameter ulcer with undermined erythematous purplish borders and necrotic base, on the external area
of the lower third of the left leg (Figure 1). A biopsy of the lesion was obtained and the histopathologic study revealed epidermal hyperplasia with severe spongiosis on the ulcer border, and a dense polymorphonuclear inflammatory infiltrate extending to
the deep dermis. Upon diagnosis of PG, treatment
with cyclosporine 3.33 mg/kg/day was started with
little improvement, and prednisone was added to a
maximum dosage of 120 mg/day. No response was
detected, and infliximab treatment was decided on a
5 mg/kg EV dosage on weeks 0, 2, and 6. Previously,
supplementary tests were performed, without evidence of alterations (Table 1). Patient referred pain
alleviation 24 hours after the first infusion, and decrease of perilesional erythema was observed after
second infusion. Nineteen days after treatment onset, the ulcer was superinfectd with methicillin-resistant Staphylococcus aureus, and treated with vancomycin and trimethoprim-sulfamethoxazole, with
good response. After 4 months, the ulcer showed
complete reepithelization. Currently, control continues without relapses (Figure 2).
Case 2
A 34-year-old male patient with PG of a 10 years’
evolution showing partial improvement with corticosteroid and dapsone treatment. At followup, he showed liver enzyme alterations; thus, liver biopsy and cholangioresonance were performed. Diagnosis was primary sclerosing cholangitis,
and treatment with ursodeoxycholic acid was started. Subsequently, bloody diarrhea appeared and
thus VCC with intestinal biopsy was performed, resulting in UC diagnosis. Three years earlier he developed two painful oval, 6 cm diameter ulcers with
erythematous undermined borders and hemorrhagic base on the inner area of both legs (Figure 3).
Biopsy was obtained and histologic study showed
neutrophilic exocytosis, fibrinoleukocytic exudate, and polymorphonuclear inflammatory infiltrate throughout the dermis. Diagnosis of PG was established taking into account the clinical examination and the histologic data. Given the association
of the three conditions, it is decided to begin with
infliximab treatment. Supplementary studies were
carried out before the first infusion, revealing anemia, abnormalities of liver tests (due to cholestasis)
and positive PPD with normal chest X-ray, therefore 8-weeks isoniazid treatment was indicated be-
Pyoderma gangrenosum associated with ulcerative colitis treated with infliximab | 65
TABLE 1. PREVIOUS STUDIES TO INFLIXIMAB TREATMENT.
• PPD 2 UT.
• Blood cell count with leukocyte formula and platelet count.
• Serum level of total and fractionated bilirubin, glutamic oxalacetic transaminase, glutamic pyruvic transaminase, leukocyte alkaline phosphatase, total cholesterol, prothrombin time, albuminemia, total proteins.
• Serum ionogram.
• Fasting glycemia.
• Serum urea and creatinine.
• Antinuclear factor.
• Complete urinanalysis.
• Electrocardiogram.
• Chest X-ray.
TABLE 2. INFLIXIMAB PREPARATION AND INFUSION METHOD.
1. Calculation of total dosage to be infused (5 mg/kg/dose).
2. Careful dilution of total dose in 250 ml of 9% sodium chloride,
without stirring the vessel, mixing with gentle movements.
3. Continuous intravenous infusion (with infusion pump) for 2 hours.
4. Control of vital signs every 30 minutes for the total infusion time
and the 2 subsequent hours.
Figure 3. Painful oval ulcers, 6 cm in diameter, with erythematous undermined borders and hemorrhagic base on inner area of the leg.
fore the infliximab treatment. The patient received
intravenous infliximab on weeks 0, 2, 6 (Table 2).
After the first infusion, the patient referred an important decrease in pain and diarrhea. After the second infusion, the ulcers reduced in size, and after
the third infusion, the ulcer showed almost complete reepithelization (Figure 4). Since a small ulcer on the right leg persisted, a fourth infusion was
administered.
Case 3
A 39-year-old female patient with UC history of a
5 years’ evolution treated with mesalazine and meprednisone. She consulted due to fever and a recent
painful lesion on right ankle. Simultaneously, she
started with bloody diarrhea and was hospitalized.
Examination showed an oval, 5 cm diameter painful ulcer with purplish undermined borders and necrotic base on the external area of the right ankle
(Figure 5). Biopsy was obtained for histologic study
resulting in diagnosis of PG. Topical cures with meprednisone 1 mg/kg/day and azathioprine 100 mg/
day were started. After four weeks, the ulcer increased in size and the pain worsened, so treatment with
infliximab was decided. Studies listed in Table 1
were requested, and the results were all within normal parameters. Intravenous infliximab treatment
was instituted on weeks 0, 4, 8. After the first infusion, the patient referred pain alleviation. After
the second infusion, the lesion and the perilesional
erythema reduced in size (Figure 6). Two weeks after the second infusion, the patient was hospitalized
Figure 4. Ulcers on the inner area of the leg after the second infliximab infusion.
for pneumonia by Streptococcus viridans, thus receiving piperacillin-tazobactam treatment resulting in rapid clinical improvement. Two months
after the third infliximab infusion the lesion showed complete reepithelization. No new lesions appeared in 2 years follow-up.
Comments
PG is a rare, inflammatory, and destructive disease. Treatment is still challenging. Both high dosage corticosteroids and cyclosporine have shown
maximum efficacy in managing this disease. They may be used alone or
combined with other immunosuppresive drugs (azathioprine, cyclophosphamide, etc.). However, patients receiving such associations have a
higher risk of adverse effects, and the efficacy is controversial.2,10
TNF-α is a proinflammatory cytokine that induces other cytokine synthesis and release, and contributes in recruiting inflammatory cells in the skin
by increasing adhesion molecule expression. TNF-α inhibition may reduce inflammatory response. Currently, two biological agents exist with
66 | D. Malieni, A. C. Torre, M. C. Baztán, C. Anselmi, R. Galimberti
Figure 5. Painful oval ulcer, 5 cm in diameter, with purplish and undermined borders and necrotic base
on the external area of the right ankle.
se where infliximab showed effectiveness. FDA has
not authorized this use in spite of the satisfactory results in plaque psoriasis and psoriatic arthritis.4,15,16
As from 2000, several studies have been submitted
on the use of infliximab in treating PG associated
with IBD and evidencing satisfactory results.6,17,18
Infliximab was administered to our patients on weeks 0, 2, and 6, as described in published works on
CD and PG treatment.6,15 We wish to point out that
in our three reported patients the treatment with infliximab was chosen because of the presence of recalcitrant PG. A net alleviation of pain was detected
24 hours after first infusion, thus markedly improving quality of life of all patients. Throughout the
treatment a gradual reduction of inflammatory signs
in the lesion was found, together with the appearance of granulation tissue gradually covering the base
of the ulcers. Infliximab has been well tolerated by
our patients, with few adverse effects. Although the
literature describes acute and delayed hypersensibility reactions, we did not find them in these cases.
At the onset of infliximab treatment, the physician
in charge must be aware of the possibility of reactivating latent infections. Tuberculosis is the main
condition to be taken into account in our setting.
Thus, mandatory studies to be performed before
treatment include PPD and chest X-ray. Other adverse effects that may appear with the use of this biological agent are optic neuritis, seizures and demyelinizing diseases. The fact that the chronic use of infliximab may increase the incidence of lymphoproliferative disorders is still unknown. According to our
experience, the use of infliximab in treating PG associated with IBD is efficacious in controlling symptoms and inducing clinical remissions of lesions and
the gastrointestinal condition. It may be adequate
for the recalcitrant form of the cutaneous disease, refractary to other treatments.
References
Figure 6. Ulcer on the external area of the right ankle after the second infliximab infusion.
1.
action mechanism consisting in TNF-α inhibition: ethanercept and infliximab. The former is a soluble TNF-α and TNF-β transporting protein.11 The latter agent is an anti-TNF-α monoclonal antibody comprising a constant human fraction and a murine variable fraction that bind to
TNF-α with higher affinity and specificity. It acts by neutralizing TNF-α
soluble and transmembrane forms. In vitro, it has been proved that infliximab induces TNF-α expressing cell lysis through an antibody- or complement-mediated cytotoxicity mechanism.12 In 1998, the Food and Drug
Administration (FDA) authorized its use for treatment of Crohn’s disease (CD).6,13 In 1999, its use was licenced together with methotrexate for
refractary RA management.14 Psoriasis was the first dermatologic disea-
2.
3.
4.
Wolff K, Stingl G. Pioderma Gangrenoso. In: Freedberg I, Eisen A, Wolff K, Austen K, et al. Fitzpatrick, Dermatología en
Medicina General. Buenosw Aires: Edit. Médica Panamericana; 2005:1088-1096.
Wollina U. Clinical management of pyoderma gangrenosum. Am J Clin Dermatol 2002; 3:49-58.
Mlika RB, Riahi I, Fenniche S, Mokni M, et al. Pyoderma gangrenosum: a report of 21 cases. Int J Dermatol 2002; 41:6568.
Ogilvie ALJ, Antoni C, Dechant C, Manger B, et al. Treatment
of psoriatic arthritis with antitumor necrosis factor-a; antibody clears skin lesions of psoriasis resistant to treatment
with methotrexate. Br J Dermatol 2001; 144:587-589.
Pyoderma gangrenosum associated with ulcerative colitis treated with infliximab | 67
5.
Sheldon DG, Sawchuk LL, Kozarek RA, Thirlby RC. Twenty cases of peristomal pyoderma gangrenosum: diagnostic implications and management. Arch Surg 2000;135:564-569.
6. Ljung T, Staun M, Grove O, Fausa O, et al. Pyoderma gangrenosum associated with Crohn disease: eff ect of TNF-α; blockade with infliximab.
Scand J Gastroenterol 2002; 37:1108-1110.
7. Triantafillidis JK, Cheracakis P, Sklavaina M, Apostolopoulou K. Favorable
response to infliximab treatment in a patient with active Crohn disease
and pyoderma gangrenosum. Scand J Gastroenterol 2002; 37:863-865.
8. Grange F, Djilali-Bouzina F, Weiss AM, Polette A, et al. Corticosteroid-Resistant Pyoderma gangrenosum Associated with Crohn’s Disease: Rapid
Cure with Infliximab. Dermatology 2002; 205:278-280.
9. Batres LA, Mamula P, Baldassano RN. Resolution of severe peristomal
pyoderma gangrenosum with infliximab in a child with Crohn’s disease.
J Pediatr Gastroenterol Nutr 2002; 34:558-560.
10. Blitz NM, Rudikoff D. Pyoderma Gangrenosum. Mt Sinai J Med
2001;68:286-297.
11. Mease PJ, Goffe BS, Metz J, VanderStoep A, et al. Etanercept in the
treatment of psoriatic arthritis and psoriasis: a randomised trial. Lancet
2000; 356:385-390.
12. Scallon BJ, Moore MA, Trinh H, Khight DM, et al. Chimeric anti TNF-α monoclonal antibody cA2 binds recombinant transmembrane TNF-α; and
activates immune effector functions. Cytokine 1995; 7:251-259.
13. Zaccagna A, Bertone A, Puiatti P, Picciotto F. Anti-tumor necrosis factor alpha
monoclonal antibody (infliximab) for the treatment of Pyoderma Gangrenosum associated with Crohn´s disease. Eur J Dermatol 2003; 13:258-260.
14. Maini RN, St Clair EW, Breedveld F, Furst D, et al. Infliximab (chimeric anti-tumor necrosis factor monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet 1999; 354:1932-1939.
15. Tan MH, Gordon M, Lebwohl O, George J, et al. Improvement of pyoderma gangrenosum and psoriasis associated with Crohn’s disease with
anti-tumor necrosis factor a monoclonal antibody. Arch Dermatol 2001;
137:930-933.
16. Krueger JG. The immunologic basis for the treatment of psoriasis with
new biologic agents. J Am Acad Dermatol 2002; 46:1-23.
17. Botros N, Pickover L, Das KM. Image of the Month. Pyoderma gangrenosum caused by ulcerative colitis. Gastroenterology 2000; 118:250.
18. Crowson AN, Magro C, Mihm MC Jr. Pyoderma Gangrenosum: a review.
J Cutan Pathol 2003; 30:97-107.
Original Article
HLA patients with an association of familial lupuspsoriasis
Baltazar Ángel Paniagua1, María Estela Fiad2, Alicia Sylvina Quenardelle3, Manuel Fernando Giménez4,
Patricia María Fabiana Motta5 y Alicia María Habegger de Sorrentino6
Abstract
Lupus and psoriasis are autoimmune diseases of multifactorial etiology, with involvement of genetic and non-genetic factors. The most widely studied genetic factor is Human Leukocyte Antigen (HLA) or Major Histocompatibility Complex in the chromosome 6 region.
We report HLA from three generations of patients in the same family with different forms of cutaneous lupus, two of which are associated with psoriasis, and compared the results with seven healthy members of the same family. No HLA found conferred greater susceptibility or protection related
to these diseases. (Dermatol Argent 2009; 15(3):196-189).
Key words: HLA, genetic association, lupus, psoriasis.
Introduction
1. Attending Physician, 5th year.
2. Head of Practical Applications of the Dermatology Course, Universidad Nacional del
Nordeste.
3. Attendant Instructor of Dermatology.
4. Named Professor of the Dermatology Course, Universidad Nacional del Nordeste,
and Head of Attendant Teaching and Research, “Manuel María Giménez” Dermatology Center.
5. Physician of the Histocompatibility Department.
6. Head of the Histocompatibility Department, Hospital “Julio C. Perrando”. Resistencia.
Province of Chaco. Argentine Republic.
Correspondence
Baltazar Angel Paniagua: Pasaje Bertaca 870, Resistencia, Chaco, Argentine Republic.
Phone: 03722689337 | e-mail: [email protected]
Lupus is an autoimmune disease appearing in 2.6 of 100,000 inhabitants, with recognized genetic predisposition.1 The clinical
spectrum is variable, from cutaneous forms such as discoid lupus
erythematosus (DLE) to systemic forms such as systemic lupus
erythematosus (SLE), rapidly progressive and with multiorganic
involvement, associated with HLA-DR2 and -DR3.2-3
Psoriasis is a chronic inflammatory disease affecting 1 to 3 percent of the world’s population.1 It has a genetic basis, immune
pathogeny and receives the influence of multiple factors determining from mild forms to isolated erythematosquamous
plaques, and to a generalized erythrodermal variant with joint
involvement in some cases.
Only one locus has been confirmed for susceptibility to psoriasis
(PSORS1), located on the major histocompatibility complex (MHC)
on chromosome 6.4 Multiple HLA alleles have been associated with
psoriasis: HLA-A1, -A2, -B13, -B17, -Cw6, -DR7, and -DQ.5
The purpose of this work is to analyze genotypes and phenotypes of patients with associated cutaneous lupus and psoriasis suggesting susceptibility of suffering these conditions versus
healthy individuals within the same family, and to compare results with the current literature.
Clinical cases
Case 1
A 61-year-old male patient, who started 30 years ago with erythematous plaques with well-demarcated edges and follicular atrophy located on the external ear and face (Figure 1).
HLA patients with an association of familial lupus-psoriasis | 69
Histopathology: Dermal lymphocyte infiltrate
with perivascular and periadnexial dominance was
found.
Diagnosis compatible with DLE.
Laboratory: Antinuclear factor (ANF) and antiDNA antibody: negative.
Treatment: He was treated with hydroxychloroquine 6 mg/kg/day and photoprotection, which was
irregularly complied with.
Evolution: For the last three years, he has had erythematosquamous plaques on scalp and elbows
(Figure 2) accompanied by hand arthralgia.
A new histopathological examination results in
thick lamellar parakeratosis and psoriasiform acanthosis enclosing Munro’s microabscesses.
Diagnosis compatible with psoriasis.
Laboratory: Rheumatoid factor (RF): negative,
ANF and anti-DNA: negative.
X-ray of hands: Proximal phalangeal osteolysis.
Treated with metothrexate (MTX) 15 mg/week
and folic acid, with good response.
Genetic typification:
HLA haplotype:
A* 01-B* 1517-DRB1*13 -DQB1* 0604
A* 23-B* 1503/ 1554 -DRB* 11-DQB1*0301,0309,0313
Case 2
A 24-year-old male patient. Physical examination
showed infiltrated erythematous plaques with cribiform scar on both preauricular regions of a three
years’ evolution (Figures 3 and 4).
Histopathology: Lymphocyte infiltrate in all dermal thickness, as well as perivascular, periadnexial,
interstitial and diffuse.
Diagnosis compatible with lupus tumidus.
Laboratory: ANF and anti-DNA antibody:
negative.
Treatment: Hydroxychloroquine 6 mg/kg/d and
photoprotection, with good response.
HLA haplotype:
A* 01-B* 1517-DRB1*13 -DQB1* 0604
A* 31-B* 3543-DRB* 04 -DQB1*0302
Case 3
A 14-year-old female patient, starting two years ago
with sharply demarcated erythematous plaques and
cribiform scar located on cheeks and nose (Figure
5). Erythematosquamous plaques appear on the interscapular area (Figure 6).
Histopathology (cheek): Hyperkeratosis, suprabasal area granulosis. Thickened and undulating connective basal membrane.
Figure 1. Case 1. Erythematosquamous plaques on forehead and follicular atrophy located on cheeks and nose.
Figure 2. Case 1. Erythematosquamous plaques on elbow.
Diagnosis compatible with (DLE).
Histopathology (interscapular area): parakeratosis with spongiform
pustule of Kogoj, acanthosis by epidermal extension of epidermal creases
interdigitating with dermal papillae.
Diagnosis compatible with psoriasis.
Laboratory: ANF and anti-DNA negative.
Treatment: Hydroxychloroquine 6 mg/kg/d and sun protection.
HLA haplotype:
A* 32B* 18 -DRB1* 04 -DQB1* 0302
A* 31-B* 3543-DRB* 04 -DQB1*0302
Comment
Psoriasis and lupus are two very important genetically based diseases of
multifactorial ethiology. Various genes may be involved, and environmental factors play an essential role in the development of such diseases.
Familial association is found in some cases.
Scarce literature exists on lupus-psoriasis association, especially in cutaneous
lupus. In the review we found that around the middle of the twentieth cen-
70 | B. Á. Paniagua, M. E. Fiad, A. S. Quenardelle, M. F. Giménez, P. M. Fabiana Motta, A. M. Habegger de Sorrentino
A*1 B*1517 DRB1*013 DQB1*0604
A*23 B*1503 DRB1*011 DQB1*0301
A*1 B*1517 DRB1*013 DQB1*0604
A*31 B*3543 DRB1*04 DQB1*0302
A*23 B*5002 DR*15 DQB1*0602
A*31 B*3543 DRB1*04 DQB1*0302
A*1 B*1517 DRB1*013 DQB1*0604
A*23 B*5002 DRB1*015 DQB1*0602
A*31 B*3543 DRB1*04 DQB1*0302
A*23 B*1503 DRB1*011 DQB1*0301
A*31 B*3543 DRB1*04 DQB1*302
A*1 B*1517 DRB1*013 DQB1*604
Figure 3. Case 2. Infiltrative erythematous plaques with cribiform scar on left preauricular area.
A*1 B*1517 DRB1*013 DQB1*0604
A*23 B*5002 DRB1*015 DQB1*0602
A*31 B*3543 DRB1*04 DQB1*0302
A*1 B*1517 DRB1*013 DQB1*0604
A*29 B*15 DRB1*03 DQB1*0201
A*32 B*18 DRB1*04 DQB1*0302
Healthy individuals
Sick individuals
A*31 B*3543 DRB1*04 DQB1*0302
A*32 B*18 DRB1*04 DQB1*0302
Chart 1. Familial genetic typification scheme of three generations.
Figure 4. Case 2. Infiltrative erythematous plaques with cribiform scar on right preauricular area.
tury, clinical observation studies were first published; then, with the development of new knowledge, associations with HLA in chromosom 6 were reported, and genes resistant to both entities have been found in recent years.
The first series on the occurrence of this association in four members of
one family was published in 1962: 2 had psoriasis, 1 had DLE, and 1 had
pityriasis rubra pilaris.6
In another study from 1964, 520 SLE cases were analysed: 0.6 percent
were associated with psoriasis.7
In 1980, 27 patients with lupus and psoriasis were studied, where of 4 relatives had history of psoriasis and 2 of lupus.1
In 1984, Hays et al. added 4 patients with SLE and psoriasis, but who
were not consanguineous; and finally in 2003, Astudillo et al. reported 3
cases of patients with SLE and psoriasis.8-9
In 1993, an increase in the relative risk of developing SLE was described in
91 patients with HLA-B8, -DR3, -DQ6 and -C4A.10
In 1996, it was noticed in 124 psoriasis patients that the
A2,B13,Cw6,DR7,DQA1*0201 and A1,B17,Cw6,DR7,DQA1*0201 association carried higher risk of having the disease.5
Psoriasis was associated after 1999 to chromosome 1 and then to chromosomes 4, 5, 6, 9, 17, 19, and 20.4,11-16
The most studied region is the major histocompatibility complex on chromosome 6, with highest susceptibility to psoriasis.4
In chromosome 5, a cytokine suggests susceptibility
not only to psoriasis, but also to Crohn’s disease and
rheumatoid arthritis.13
Locus 20p13 predisposes to psoriasis independently
from chromosome 6, and also from other inflammatory diseases such as asthma and atopic dermatitis.4
After 2001, lupus was associated with chromosome
1 and in successive reports, with chromosomes 2, 3,
4, 10, 13, 16, 18, and 20.17-21
At first, there was a dominance of clinical communications attempting to associate phenotypical variants with filiation data.
Initial genetic studies heralded the discovery of the
responsible genes, and thus the definite cure of such
pathologies.
But this was not true, the inheritance pattern is
still uncertain. However, great advances have been
achieved in prognosis and treatment through small
contributions like ours.
In reviewing the literature, we have not found a
study on cutaneous lupus and psoriasis in three successive generations of the same family.
In reference to HLA performed on our patients,
none showed association with susceptibility to or
protection against the development of these diseases, in comparison to consanguineous healthy
individuals.
HLA patients with an association of familial lupus-psoriasis | 71
5.
6.
7.
8.
9.
10.
Figure 5. Case 3. Erythematous plaques with sharply defined edges and cribiform scar located on cheeks and nose.
11.
12.
13.
14.
15.
16.
Figure 6. Case 3. Erythematosquamous plaques on interscapular area, some with light center.
17.
This probably suggests that HLA may not be the main factor involved in
the development of these diseases, and it is likely that others genes in this
or other chromosomes are responsible. This could motivate the development of future research.
18.
References
19.
1.
2.
3.
4.
Millns J, Muller S. The Coexistence of Psoriasis and Lupus Erythematosus. Arch Dermatol 1980; 116:658-663.
Eroglu G, Kohler P. Familial systemic lupus erythematosus: the role of genetic and environmental factors. Annals of the Rheumatic Diseases 2002; 61:29-31.
Rood M, Van Krugten M, Zanelli E, Van Der Linden M, et al. TNF-308A and HLA- DR3
alleles contribute independently to susceptibility to systemic lupus erythematosus.
Arthritis & Rheumatism 1999; 43:129-134.
Lesueur F, Lefèvre C, Has C, Guilloud-Bataille M, et al. Confirmation of psoriasis Susceptibility loci on chromosome 6p21 and 20p13 in French families. J Invest Dermatol 2007; 127:1403-1409.
20.
21.
Ikäheimo I, Silvennoinen-Kassinen S, Karvonen J, Järvinen
T, et al. Immunogenetic profile of psoriasis vulgaris: Association with haplotypes A2,B13,Cw6,DR7,DQA1*0201 and
A1,B17,Cw6,DR7,DQA1*0201. Arch Dermatol Res 1996;
288:63-67.
Lerner M, Braverman I. Psoriasis, Lupus Erythematosus, and
Pityriasis Rubra Pilaris. Arch Dermatol 1962; 85:109-110.
Dubois E, Tuffanelli D. Clinical Manifestations of Systemic
Lupus Erythematosus JAMA 1964;190:104-111.
Hays S, Camisa C, Luzar M. The coexistence systemic lupus
erythematosus and Psoriasis. J Am Acad Dermatol 1984;
10:619-622.
Astudillo L, Sailer L, Barreiro M, Dahan S, et al. Psoriasis and
systemic Lupus erythematosus: a rare association with specific therapeutic problems. Ann Med Interne 2003;154:3-6.
Goldstein R, Sengar D. Comparative studies of the major
histocompatibility complex in French Canadian and nonFrench Canadian Caucasians with systemic lupus erythematosus. Arthritis Rheum 1993;36: 1121-1127.
Capon F, Novelli G, Semprini S, Clementi M, et al. Searching
for psoriasis susceptibility genes in Italy: genome scan and
evidence for a new locus on chromosome 1. J Invest Dermatol 1999; 112:32-35.
Sagoo G, Tazi-Ahnini R, Barker J, Elder J, et al. Meta-analysis of genome- wide studies of psoriasis susceptibility reveals linkage to chromosome 6p21and 4q28-q31 in Caucasian and Chinese Hans population. J Invest Dermatol 2004;
122:1401-1405.
Friberg C, Björck K, Nilsson S, Inerot A, et al. Analysis of chromosome 5q31-32 and psoriasis: confirmation of a susceptibility locus but no association with SNPs within SLC22A4
and SLC22A5. J Invest Dermatol 2006; 126:998-1002.
Sun L, Li W, Yang S, Fan X, et al. Evidence for a novel psoriasis susceptibility locus at 9q33-9q34 in Chinese Hans. J Invest Dermatol 2007; 127:1140-1144.
Speckman R, Wright Daw J, Helms C, Duan S, et al. Hum
Genet 2003; 112:34-41.
Hensen P, Windemuth C, Hüffmeier U, Rüschendorf F, et al.
Association scan of the novel psoriasis susceptibility region
on chromosome 19:evidence for both susceptible and protective loci. Exp Dermatol 2003; 12:490-496.
Chen J, Wang C, Lu S, Chou Y, et al. Association of apoptosisrelated Microsatellite polymorphisms on chromosome 1q
in Taiwanese systemic lupus erythematosus patients. Clin
Exp Immunol 2006;143: 281-287.
Cantor R, Yuan J, Napier S, Kono N, et al. Systemic lupus erythematosus genome scan: support for linkage at 1q23, 2q33,
16q12-13, and 17q21-23 and novel evidence at 3p24, 10q2324,
13q32 and 18q22-23. Arthritis Rheum 2004; 50:3203-3210.
Xing C, Gray-McGuire C, Kelly J, Garriot P, et al. Genetic linkage of systemic lupus erythematosus to 13q32 in African
American families with affected male members. Hum Genet. 2005; 118:309-321.
Johansson C, Kritjánsdottir H, Gröndal G, Steinsson K, et al.
Characterization of a susceptibility locus for SLE, SLEB5, on
chromosome 4p14-13. Scand J Immunol 2006; 64:308-313.
Gaffney P, Langefeld C, Graham R, Ortmann W, et al. Finemapping chromosome 20 in 230 systemic lupus erythematosus sib pair and multiplex families: evidence for genetic epistasis with chromosome 16q12. Am J Genet 2006;
78:747-758.
Original Article
Subcutaneous fat necrosis of the newborn, report
of five cases
Margarita Larralde1, María Eugenia Abad2, Cristina Corbella3, Carina Andrea Ferrari4, Romina Plafnik4
Abstract
Subcutaneous fat necrosis of the newborn (SCFN) is a rare, self-healing condition affecting full-term or post-term newborns within the first weeks
of life. Although the etiology is unknown, this disorder is associated with neonatal hypoxia, hypothermia, obsteric trauma, anemia, thrombocytopenia, gestational diabetes, pre-eclampsia and maternal exposure to use of cocaine or calcium channel blockers during pregnancy. Hypercalcemia is the most serious although rare complication and may occur up to six months after the skin lesions appear. We report five patients with diagnosis of subcutaneous fat necrosis of the newborn detected during 2001-2008. All patients had history of perinatal hypoxia, four of the pregnancies presented with hypertension and no child had complications (Dermatol Argent 2009;15(3):200-204).
Key words: subcutaneous fat necrosis, hypercalcemia, newborn.
ABREVIATURAS
SCFN : subcutaneous fat necrosis of the newborn
Introduction
Subcutaneous fat necrosis of the newborn (SCFN) is a rare disorder affecting full-term or post-term newborns in the first
weeks of life.1-4 Clinical features include nodules or indurated
erythematous plaques. The most frequent location is the trunk,
cheeks and lower limbs. The evolution is favorable, generally
self-healing in the first months of life.
Although the etiology is not completely clarified yet, it has
been associated with various risk factors:
1. Head of the Dermatology Department, Hospital Alemán. Head of the Pediatric
Dermatology Department, Hospital “JM Ramos Mejía”. Buenos Aires, Argentine.
2. Pediatric Dermatology Department, Hospital “JM Ramos Mejía”. Dermatology Department, Hospital Alemán. Buenos Aires, Argentine.
3. Pathology Department, Hospital “JM Ramos Mejía”. Buenos Aires, Argentine.
4. Pediatric Dermatology Department, Hospital Ramos Mejía. Buenos Aires, Argentine.
Correspondence
Margarita Larralde: Acevedo 1070, (1828) Banfield, Prov. of Buenos Aires, Argentine Republic |
Phone: 4823-0919 / 4242-3066 | Fax: 4202-6068 | [email protected]
• Neonatal factors: neonatal hypoxia,4 hypothermia,2local
trauma,3,5 anemia3 and thrombocytopenia.4
• Maternal factors: gestational diabetes, pre-eclampsia during pregnancy. Recently, smoking and familiar history of
thrombosis were described as risk factors.4
Normal adipose tissue contains mainly triglycerides, especially
palmitic, stearic, and oleic acids, in a variable ratio, depending
on whether it is adult or neonatal fat tissue. The inversion of
the index oleic/palmitic that normally occurs in the newborn
due to the higher proportion of saturated to insaturated fatty
acids determines a higher melting point and a lower solidification point of the adipose tissue. These features of neonatal fat
Subcutaneous fat necrosis of the newborn, report of five cases | 73
imply a higher tendency to crystallization when exposed to risk factors.6
We evaluated five patients with clinical and/or
histopathological diagnosis of SCFN detected in
2001-2008.
The objective of this work is to describe risk factors,
clinical presentation, and evolution of our patients.
Clinical cases
We describe five patients with diagnosis of SCFN
(Table 1)
Case 1
A 28-day-old female newborn; developed at 25 days
of life, a firm nodule on the neck.
Perinatal history: Full term birth weight appropriate for gestational age, vaginal delivery, controlled
pregnancy, abruptio placentae, cigarette-smoking
mother. She stayed hospitalized for 7 days for birth
asphyxia requiring halo oxygenotherapy (72 hours)
and luminotherapy for 4 days. Laboratory tests were
within normal ranges. Lesions regressed at 45 days
of life.
Histopathological: areas of subcutaneous tissue
necrosis with inflammatory cells and giant cells.
Remaining adipocytes show fusiform spaces with
radially arranged needle shaped clefts. Diagnosis:
SCFN.
Case 2
A 19-day-old male patient; at 4 days of life he
showed indurated, erythematous plaques with
painful skin colored nodules located in the upper
back area, left arm and left cheek. Perinatal history: ful term neonate, birth weight was 4.060,
born by cesarean section; controlled pregnan-
cy; maternal hypertension; thick, meconial amniotic fluid; and fetal
bradycardia. During the perinatal period, he developed hypoglycemia,
hypothermia, moderate pulmonary hypertension, and mild hypertrophy of left ventricle; other laboratory tests were within normal ranges.
Histopathology: No significant epidermal or dermal alterations were
observed; adipocyte necrosis with septum breakdown and the presence of discrete lymphohistiocytic inflammatory infiltrate were found in
the fragment corresponding to subcutaneous tissue. Remaining adipocytes showed fusiform spaces with radiated layout. Diagnosis: SCFN.
Case 3
A 4-day-old boy showed an indurated erythematous plaque located on
trunk and right upper limb, which appeared at 2 days of age. Perinatal
history: Full term, birth weight 4.330, born by cesarean section, controlled pregnancy, gestational hypertension. Was reffered to neonatal
unit care for transient respiratory distress requiring oxygen for 24 hours.
Laboratory tests were within normal ranges.
Figure 1. Patient 2. Erythematous plaque on left cheek.
TABLE 1. FILIATION DATA AND PERSONAL MATERNAL AND NEONATAL HISTORY.
Patient 1
Patient 2
Gender
Female
Male
Patient 3
Male
Patient 4
Male
Patient 5
Female
4 days
32 days
18 days
Age
28 days
19 days
Age at Onset
Delivery
Pregnancy history
25 days
Vaginal
Abruptio placentae
4 days
2 days
24 days
15 days
Cesarean section
Cesarean section
Cesarean section
Cesarean section
Gestational pre-eclampsia Gestational pre-eclampsia Gestational pre-eclampsia None
Perinatal history
40 weeks
Weight 3.950
Perinatal asphyxia
41 weeks
Weight 4.060
Meconial amniotic fluid.
Hypoglycemia, hypothermia, pulmonary hypertension, left ventricle hypertrophy.
Full term
Perinatal asphyxia
Weight 4.330
Seizures.
Transient respiratory distress Admitted for bronchiolitis
at 28 days of age.
42 weeks
Weight 2.740
Respiratory distress.
Halo for 48 hours.
Age of lesion disappearance
45 days of age
Unknown
Unknown
60 days of age
60 days of age
74 | M. Larralde, M. E. Abad, C. Corbella, C. A. Ferrari, R. Plafnik
Histopathology: areas of subcutaneous tissue with adipocyte necrosis and septa rupture.
Remaining adipocytes showed fusiform spaces
with radiated layout. Mild lymphohistiocytic infiltrate. Diagnosis: SCFN.
Case 5
An 18-day-old female patient; she showed erythematous and indurated plaques located on trunk
and left cheek, appearing at 15 days of age. Perinatal
history: Posterm (42 weeks of gestation),birth
weight was 2.740 g, born by cesarean section, controlled pregnancy. She stayed hospitalized for transient respiratory distress for 48 hours. Laboratory
tests were within normal ranges. Lesions disapeared within the second month of life. The parents
refused to perform skin biopsy.
Discussion
Figure 2. Patient 3. Erythematous plaque on right upper limb.
Figure 3. Patient 4. Indurated plaque with superficial telangiectasia on left upper limb.
Histopathology: areas of subcutaneous cell tissue necrosis with mild inflammatory infiltrate and giant cells. Remaining adipocytes showed needle-shaped clefts. Diagnosis: SCFN.
Case 4
A 32-day-old male patient; he showed an indurated plaque of hard, stony
consistency, 2 x 2 cm in diameter, with superficial telangiectasia, surrounded by a whitish halo, located on the medial aspect of the left arm, appearing at 24 days of life. Perinatal history: full term neonate with adequate
weight for gestational age born by cesarean section after a controlled pregnancy with maternal hypertension. He stayed hospitalized for 14 days for
perinatal asphyxia requiring halo oxygen therapy. He was readmitted at 28
days of age for bronchiolitis. Laboratory tests were within normal ranges.
Lesions resolved at about two months of age.
Risk factors, clinical manifestations, complications, and outcome of five SCFN patients were
assessed in this work.
SCFN is a rare disorder occurring in Full term or
post term neonates.
Four of the five patients studied were full term
babies, 3 with adequate weight and one large for
gestational age; the remaining patient was a post
term girl with adequate weight for gestional age.
Although the etiology of this disorder is unknown, it was associated with perinatal hypoxia,4,7
aspiration of meconial amniotic fluid, hypothermia,7 local trauma,4,5 and anemia.3 In our series,
all patients showed perinatal hypoxia, one patient
presented meconium aspiration, and another
hypothermia. Although trauma has been described as a triggering factor for this disorder, a higher incidence has been reported in children born
by cesarean section than by vaginal delivery. Four
of the 5 patients were born by cesarean section.
With reference to maternal risk factors, the following are described: gestacional diabetes gestational hypertension, exposure of cocaine or calcium channel, use of blockers during pregnancy,
and cigarette-smoking.4 In our series, 3 mothers
had gestational hypertension, one mother was a
smoker, but none had gestional diabetes or used
toxic substances.
Clinically, SCFN is characterized by multiple
nodules or indurated erythematous plaques in
trunk, buttocks, limbs, thighs, and cheeks. Some
lesions may contain calcium, as in patient 1. The
presence of calcifications justifies the use of sim-
Subcutaneous fat necrosis of the newborn, report of five cases | 75
ple X-rays for study purposes. Lesions typically
develop in the first 6 weeks of age,1 and may appear from the first 7 days to12 months of life, like
in our patients. In most cases, lesions are spontaneously self-limiting in 2 to 4 weeks with no atrophy or residual scar.6 All our cases resolved in the
first 2 months of age (about 20 days after onset).
In some cases, lesions may be very painful and require opioid management.2
Hypercalcemia is the most severe but infrequent
complication developed by these patients. It has
been described in about 25% of the cases, generally in the presence of more extended lesions.7-12
Mechanisms involved in hypercalcemia include increase in prostaglandin E, alteration of parathormone homeostasis and aberrant levels of
vitamin D.1 Hypercalcemia may appear up to 6
months after lesion onset, therefore all newborns
must be adequately monitored in this period of
time.9 Treatments described for this complication include: adequate rehydration, loop diuretics, prednisolone, and etidronate. 2,10 If hypercalcemia occurs, extracuataneous calcification foci
must be searched for at renal, myocardial, and hepatic level. Platelet and lipid levels must also be
monitored. Thrombocytopenia is an early systemic complication of unknown origin.4,9 A relationship with history of familial dyslipemia exists
in SCFN children. Hypertriglyceridemia may develop after skin lesions appear and resolve subsequent to their regression.4 None of our patients
had these complications.
Histologically, normal epidermis and dermis is noted, with mixed inflammatory infiltrate and abundant histiocytes. Hypodermis shows adipocyte
necrosis with multinucleated giant cells forming
needle-shaped cleft granulomas in radial layout.8
Biopsy confirmed diagnosis in 4 of our patients.
Main differential diagnoses are rhabdomyosarcoma, myofibromatosis, infantile hemangioma,
neurofibromas and escleredema neonatorum.12,13
Although clinical presentation of these lesions
and general condition involvement of the newborn are very different, image diagnosis methods
(ultrasonography, computerized axial tomography, and nuclear magnetic resonance),13 and finally biopsy may be resorted to in order to attain
certainty diagnosis.
In conclusion, we wish to highlight that our case
series reflects what is published in the literature.
It is important to understand the associated risk
factors and complications in order to reach adequate diagnosis and follow-up.
Figure 4. Patient 5. Erythematous and indurated plaque on the back.
Figure 5. Histology: Adipocyte necrosis with granuloma formation (H-E 100×).
76 | M. Larralde, M. E. Abad, C. Corbella, C. A. Ferrari, R. Plafnik
References
1.
2.
3.
4.
5.
6.
Burden AD, Krafchik BR. Subcutaneous fat necrosis of the newborn: a review of 11 cases. Pediatr Dermatol 1999;16:384-387.
Wiadrowski TP, Marshman G. Subcutaneous fat necrosis of the newborn
following hypothermia and complicated by pain and hypercalcaemia.
Australas J Dermatol 2001; 42:207-210.
Varan B, Gürakan B, Ozbek N, Emir S. Subcutaneous fat necrosis of the
newborn associated with anemia. Pediatr Dermatol 1999;16:381383.
Mahé E, Girszyn N, Hadj-Rabia S, Bodemer C, et al. Subcutaneous fat necrosis of the newborn: a systematic evaluation of risk factors, clinical manifestations, complications and outcome of 16 children. Br J Dermatol
2007; 156:709-715.
Diamantis S, Bastek T, Groben P, Morrell D. Subcutaneous fat necrosis in
a newborn following icebag application for treatment of supraventricular tachycardia. J Perinatol 2006; 26:518-520.
Karochristou K, Siahanidou T, Kakourou-Tsivitanidou T, Stefanaki K, et al.
Subcutaneous fat necrosis associated with severe hypocalcaemia in a
neonate. J Perinatol 2006; 26:64-66.
7.
8.
9.
10.
11.
12.
13.
Zaulyanov LL, Jacob SE, Elgart GW, Schachner L. Subcutaneous fat necrosis of the newborn and hyperferritinemia. Pediatr Dermatol 2007;24:93.
Dawe SA, Edwards R, Williams JS, Higgins E. Painful skin induration in a
neonate. Clin Exp Dermatol 2005; 30:607-608.
Tran JT, Sheth AP. Complications of subcutaneous fat necrosis of the newborn: a case report and review of the literature. Pediatr Dermatol 2003;
20:257-261.
Alos N, Eugène D, Fillion M, Powell J., et al. Pamidronate: Treatment for
severe hypercalcemia in neonatal subcutaneous fat necrosis. Horm Res
2006; 65:289-294.
Borgia F, De Pasquale L, Cacace C, Meo P, et al. Subcutaneous fat necrosis
of the newborn: be aware of hypercalcaemia. Pediatr Child Health 2006;
42:316-318.
Srinath G, Cohen M. Imaging findings in subcutaneous fat necrosis in a
newborn. Pediatr Radiol 2006;36:361-363.
Tajirian A, Ross R, Zeikus P, Robinson-Bostom L. Subcutaneous fat necrosis of the newborn with eosinophilic granules. J Cutan Pathol 2007;
34:588-590.
Research Article
Cutaneous manifestations in alcoholic patients.
Relation with cirrhosis
Yamila Murga1, Viviana Parra2, Angeles Aredes3, Milvia Alasino1, Alfredo Torres4, Laura Santolín4, Susana Salomón5, José Carena6
Abstract
Introduction. Prevalence of alcoholism in Hospital Lagomaggiore is high (15 percent of discharges. Detection of such abuse skin markers is essential for early treatment and limitation of negative consequences.
Objectives. To identify cutaneous manifestations in hospitalized alcoholic patients and to carry out a comparative analysis of those with and without liver cirrhosis.
Methods. The study included 69 alcoholic patients accepted in the Internal Medicine Department in a 7-month period. They were assessed by a clinical physician and a dermatologist.
Results. From the total of 69 patients, 42 percent had liver cirrhosis. Average age was 58.2, and 89.8 percent were males. All patients had some skin
lesion. The most common were telangiectasias, xeroderma, tinea pedis, palmar erythema, cherry hemangioma, spider nevus, jaundice, among others. The most frequent mouth lesion was gingivitis, followed by candidiasis. We also found hypotrichosis, female pubic hair distribution, and onychomycosis. Comparative analysis of cirrhotic and non-cirrhotic patients showed significant differences (p<0.05). The most common lesions in the first
group of patients were: jaundice, palmar erythema, purpuric lesions, tinea pedis, hyperpigmentation, spider nevus, female pubic hair distribution,
and watch-glass deformity in nails.
Conclusions. All alcoholic patients showed some type of skin lesion, and those with liver cirrhosis most frequently had: jaundice, palmar erythema,
purpuric lesions, tinea pedis, hyperpigmentation, spider nevus, female pubic hair distribution, and watch-glass nails (p<0.05). Identification of this
type of lesion may suggest the presence of liver cirrhosis through cutaneous examination (Dermatol Argent 2009; 15(4):255-259).
Key words: alcohol cutaneous manifestations, liver cirrhosis, alcoholism.
Introduction
1.
2.
3.
4.
5.
6.
Attending Physician of the Dermatology Department.
Head of the Dermatology Department, Hospital “L. Lagomaggiore”.
Fellow. School of Medicine, Universidad Nacional de Cuyo. Mendoza.
Internal Medicine Resident, Hospital “L. Lagomaggiore”.
Staff Physician of the Intermal Medicine Department, Hospital “L. Lagomaggiore”.
Head of the Internal Medicine Department, Hospital “L. Lagomaggiore”. Mendoza,
Argentine.
Correspondence
Yamila Murga: Sarmiento 975, (5501) Godoy Cruz, Mendoza, Argentine Republic |
[email protected]
There are about 2.5 million alcoholics in Argentina, representing about 7 percent of the population. Thereof, 125,000 are alcohol-dependent (85 percent males and 15 percent females).1
Use and abuse of alcohol generates multiple medical and social
problems, mainly: liver cirrhosis (associated with high morbidity and mortality in marginal urban areas), hepatitis, pancreatitis, cancer, and nutrition deficiencies.2
The skin is an extensive and readily accesible organ for any
physician, and alcohol abuse may produce various skin
manifestations.3
The present study was conducted taking into account the high
prevalence of alcoholism in our setting (15 percent of discharges) and that recognition of alcohol abuse cutaneous markers
may enable early identification and treatment, and thus limit
the negative consequences associated with this habit.
The purpose of this work is to establish cutaneous manifestations of alcoholic patients hospitalized in the Internal
Medicine Department of Hospital “L. Lagomaggiore”, and
to conduct a comparative analysis between patients with and
without liver cirrhosis.
78 | Y. Murga, V. Parra, A. Aredes, M. Alasino, A. Torres, L. Santolín, S. Salomón, J. Carena
A protocolized, descriptive, observational and crosssectional study was conducted. It included all patients with diagnosis of alcohol abuse admitted in
the Internal Medicine Department from February
to September 2008. They were assessed by a clinical
physician and a dermatologist.
Central tendency and dispersion measurements,
Fisher’s exact test, chi2, and Student’s t test were used
for statistical analysis. Significance criterion was stated for an alpha error lesser than 5 percent.
tients referred itching, and 29 percent had photosensitivity. Less frequent were purpuric lesions (26.1 percent), pellagra and hypopigmentation, each 18.8 percent, and finally skin neoplasias in 4.3 percent of the
cases. Hair and nails were assessed in 57 patients, where hair alterations
appeared in 82.60 percent (95% CI: 71.59-90.68), with 84.2 percent
hypotrichosis (95% CI: 72.13-92.52) and 61.4 percent female pattern
hair distribution (95% CI: 47.57-74.00). 82.6 percent (95% CI: 71.5990.68) had ungular lesions; the most common ones were onychomycosis
(73.7 percent) and Terry’s nails (49.1 percent) (Figure 3). Watch-glass
deformity in nails was also found (15.8 percent).
The most frequent mouth lesion was gingivitis (80.7 percent; 95%
CI: 68.09-89.95) (Figure 4), seconded by candidiasis (38.6 percent;
Results
Sixty nine alcoholic patients were included, of
which 42 percent had liver cirrhosis. Mean age ±
standard deviation [SD] was 58.2 ± 16.22 years.
Of these, 89.8 percent were males. Average daily alcohol intake ± SD was 2.13 ± 1.50 liters, and wine
was the most common beverage. 54 percent of patients were currently drinkers. Mean hospital stay ±
SD was 18.5 ± 24.08 days. Infections were the main
hospitalization cause (44.9 percent) followed by upper digestive bleeding (14.5 percent), uncontrolled
cirrhosis (11.6 percent), and acute alcohol intake
(5.8 percent).
All patients studied had coexisting morbidity, whereof mainly detected were smoking and anemia
(66.7 percent and 56.5 percent, respectively), followed by chronic obstructive pulmonary disease
(36.2 percent), hypertension (23.2 percent), diabetes mellitus (18.8 percent), heart failure (15.9 percent), chronic renal failure (13.1 percent), and neoplasias (11.6 percent). In addition, simultaneous use
of illegal drugs such as marihuana, cocaine, among
others, was assessed, and it was found that 11.6 percent of patients usually consumed some of the above mentioned.
Some type of cutaneous lesion was found in 100
percent of the patients, most frequently: telangiectasias (72.5 percent; 95 percent confidence interval [95% CI]: 60.38-82.54) (Figure 1), xeroderma (65.2 percent; 95% CI: 52.79-76.29), tinea pedis (63.8 percent; 95% CI: 51.31-75.00),
palmar erythema (59.4 percent; 95% CI: 46.9271.09) (Figure 2), cherry hemangioma (56.5 percent; 95% CI: 44.04-68.42), spider nevus (50.7
percent) and jaundice (49.3 percent). Also observed were hyperpigmentation (43.5 percent) mainly
on photoexposed areas (face, V neckline, dorsum
of hands, forearms, legs and dorsum of feet), and
facial erythema (36.2 percent). 34.8 percent of pa-
Figure 1. Jaundice, spider nevus, telangiectasias and purpura.
Figure 2. Palmar erythema.
Cutaneous manifestations in alcoholic patients. Relation with cirrhosis | 79
95% CI: 26.00-52.43) (Figure 5); angular cheilitis was less frequent (15.8 percent) (Table 1).
Comparative analysis of patients with and without
liver cirrhosis showed significant differences in
skin, hair, and nails. In skin, jaundice (75.86 percent vs. 30 percent), palmar erythema (82.7 percent vs. 42.5 percent), purpuric lesions (44.82
percent vs. 12.5 percent), as well as tinea pedis
(79.31 percent vs. 47.5 percent), hyperpigmentation (62.06 percent vs. 30 percent) and spider nevus (65.5 percent vs. 40 percent) were significantly
more frequent in cirrhotic than non-cirrhotic patients (p<0.05). Likewise, watch-glass deformity in
nails (25.92 percent vs. 6.66 percent), and female
pattern hair distribution (85.18 percent vs. 40 percent) were more frequent in the first group of patients (p<0.05) (Table 2).
Comments
Alcoholic beverage consumption is part of our culture, increased by its
low cost and social acceptance. In addition, the beneficial cardiovascular
effects of moderate alcohol consumption have stimulated it.3,4
Several questionnaires are used for alcoholism diagnosis (CAGE,
Audit, Malt), as well as analytical parameters (GGT, ASAT, ALAT,
MCV) and physical signs/symptoms (parotid hypertrophy, gynecomastia, anorexia, tremor, memory disorders).3 Skin lesions may be
specific of alcohol abuse (telangiectasias, liver palm, flushing, Terry’s
nails, red lunula, hyperpigmentation), a consequence of alcohol-induced diseases (pellagra, porphyria cutanea tarda, infections, pancreatitis), or primary cutaneous manifestations exacerbated by alcohol abuse, such as psoriasis and rosacea.5 The obtained data show that all alcoholic patients had some type of skin lesion. Most frequent among
them were vascular lesions such as telangiectasia, cherry hemangioma, and spider nevus, consistent with the literature.3,5,6 These lesions
TABLE 1. SKIN, MUCOSA, AND ADNEXAL LESIONS.
Skin
N
%
69
100
Telangiectasias
50
72.5
Xeroderma
45
65.2
Infections
44
63.8
Palmar erythema
41
59.4
Cherry hemangioma
39
56.5
Spider nevus
35
50.7
Jaundice
34
49.3
Hyperpigmentation
30
43.5
Facial erythema
25
36.2
Itching
24
34.8
Photosensitivity
20
29
Purpuric lesions
18
26.1
Pellagra
13
18.8
Hypopigmentation
13
18.8
Neoplasias
3
4.3
Hair
57
82.60
Hypotrichosis
48
84.2
Hair distribution
35
61.4
Hypertrichosis
5
8.8
57
82.60
Onychomycosis
42
73.7
Terry’s nails
28
49.1
Watch-glass deformity
9
15.8
Nails
Mouth
57
82.60
Gingivitis
46
80.7
Candidiasis
22
38.6
Angular cheilitis
9
15.8
Figure 3. Watch-glass deformity in nails.
Figure 4. Gingivitis.
80 | Y. Murga, V. Parra, A. Aredes, M. Alasino, A. Torres, L. Santolín, S. Salomón, J. Carena
are produced by peripheral vasodilation induced by ethanol plus a direct central vasomotor effect, as well as the existence of estrogen metabolism alterations.3,5 An additional vascular lesion associated with alcohol abuse, and mainly present in liver cirrhosis patients, is palmar
erythema or liver palm. It appears as localized erythema of the thenar and mainly the hypothenar eminence, or as hot erythema of the
whole palm surface. It is also found in pregnancy and leukemia, and
may appear as a familial trait without underlying disease. It has been
associated with estrogen metabolism alterations caused by liver disease. However, since it may also develop in patients without liver disease
or with chronic inflammatory diseases, the pathogenesis of the vascular abnormality is still unknown. In our case, palmar erythema showed
statistically significant differences between patients with (82.75 percent) and without (42.5 percent) liver cirrhosis, p = 0.007.
Another frequent lesion in our series was xeroderma (65.2 percent)
which may mainly be related to nutrition deficits, among other causes. It is commonly known that alcohol abusing persons have higher
incidence of skin infections due to cell-based and humoral immunosuppression, nutrition deficiencies, and a higher incidence of trauma. About 30-35 percent of alcoholics have superficial fungal infections (tinea pedis, onychomycosis, pitiriasis versicolor).3,5 In our study, said percentage is doubled, with 63.8 percent of tinea pedis and
73.7 percent of onychomycosis. Some long-term alcohol liver disease patients, mainly cirrhotics, have hyperpigmentation of unknown
origin. Ultrastructure studies have shown melanin excess inside giant
melanosomas in epidermal cells of alcoholic patients. We found hyperpigmentation in 43.5 percent of patients, mainly located on photoexposed areas such as facial area, V-neckline, dorsum of the hands,
forearms, legs and dorsum of feet, as well as palm and finger folds.
When comparing such manifestation in patients with (62.06 percent)
vs. without (30 percent) liver cirrhosis, we noted significant differences, p = 0.0079. There appear oral mucosa changes in people consu-
ming alcohol; however, none is specific, and relate, among other factors, to oral cavity hygiene
deficit.
Nails in alcoholics may show a great range of alterations, or be completely normal. Most ungular changes are nonspecific. The most typical lesion is “Terry’s
nails” found in about 80 percent of cirrhotic patients.3,5 One or several nails may be affected, and clinically appear with white proximal two third of the
TABLE 2. COMPARISON OF SKIN, MUCOSA, AND ADNEXAL LESIONS IN PATIENTS WITH AND WITHOUT LIVER CIRRHOSIS.
With
cirrhosis
Without
cirrhosis
N
%
N
%
29
100
40
100
Spider nevus
19
65.51
16
40
0.03
Cherry hemangioma
20
68.96
19
47.5
0.07
Facial erythema
10
34.48
15
37.5
0.07
Palmar erythema
24
82.75
17
42.5
0.0007
Telangiectasias
24
82.75
27
67.5
0.154
Jaundice
22
75.86
12
30
0.00016
Itching
11
37.93
13
32.5
0.64
Hyperpigmentation
18
62.06
12
30
0.0079
Hypopigmentation
3
10.34
10
25
0.12
Purpuric lesions
13
44.82
5
12.5
0.0025
Photosensitivity
10
34.48
10
25
0.391
Pellagra
8
27.58
5
12.5
0.113
Xeroderma
22
75.86
23
57.5
0.113
Infections
23
79.31
19
47.5
0.0075
Neoplasias
3
10.34
0
27
93.1
30
75
Hypertrichosis
2
7.4
3
10
0.729
Hypotrichosis
23
85.18
25
83.33
0.848
Female hair distribution
23
85.18
12
40
0.00046
28
96.55
29
72.5
Terry’s nails
14
51.85
14
46.66
0.695
Watch-glass deformity
7
25.92
2
6.66
0.046
Onychomycosis
22
81.48
20
66.66
0.2
27
93.1
30
75
Angular cheilitis
4
14.81
5
16.66
0.848
Gingivitis
22
81.48
24
80
0.887
Candidiasis
12
44.44
10
33.33
0.389
Skin
Hair
Nails
Mouth
Figure 5. Candidiasis.
p
Cutaneous manifestations in alcoholic patients. Relation with cirrhosis | 81
nail, and pink distal one third of the nail. This alteration may result from reduced capillary blood flow to the ungular bed caused
by excessive growth of connective tissue. “Watch-glass deformity” in nails may appear in 10-15 percent of cirrhotic patients. The
pathogenesis is unclear, but has been related to peripheral blood
flow increase with finger arteriovenous anastomosis dilation and
increase of ungular bed connective tissue.
In contrast with the above mentioned, in our study Terry’s nails
appeared in a similar percentage in cirrhotic (51.8 percent) and
non-cirrhotic (46.7 percent) patients, but watch-glass deformity in nails showed a statistically significant difference in patients with and without cirrhosis (p = 0.046).
Finally, we found that 84.2 percent of patients had hypotrichosis, and 61.4 percent had pubic hair changes with female distribution. This last finding showed statistically significant differences between patients with (85.18 percent) vs. without (40
percent) cirrhosis. Both are clinical manifestations of hyperstrogenism caused by alcoholic liver disease.
In conclusion, 100 percent of hospitalized patients with history of alcohol abuse had skin lesions, most frequently: telangiectasias, xeroderma, tinea pedis, palmar erythema, cherry
hemangioma, spider nevus, and jaundice. The most common
mouth lesions were gingivitis and then candidiasis; and hair
and nails showed hypotrichosis, female hair distribution and
onychomycosis.
In alcoholics with liver cirrhosis, the most significant lesions
were: jaundice, palmar erythema, purpuric lesions, hyperpigmentation and spider nevus, as well as female hair distribution,
watch-glass deformity in nails, and tinea pedis (p<0.05). These
signs and symptoms must be taken into account for early diagnosis of liver cirrhosis in alcoholic patients.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
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15.
16.
Comisión Nacional sobre Alcoholismo, 1999. Health I.G. Consultora Periodística (http://www.info-medica.wdc.com.ar).
Chou S, Grant B, Dawson D. Medical consequences of alcohol consumption. Alcohol Clin Exp Res 1996; 20:1423-1429.
Molina Bermejo M, Reyes Fernández N. Manifestaciones cutáneas y consumo de alcohol. FMC 2004; 11:183-191.
San Molina L. ¿Tiene el alcohol algún efecto beneficioso? Med Clin 1996;
107:655-659.
Smith K, Fenske N. Cutaneous manifestations of alcohol abuse. J Am
Acad Dermatol 2000; 43:1-16.
Fantóbal A, Amaro P. Manifestaciones cutáneas de las enfermedades gastrointestinales. Gastr Latinoam 2005; 16:39-57.
Disotuar I, Martínez Jiménez A, Aguilar Medina J, González Rodríguez M.
Pesquisaje de Alcoholismo en un Área de Salud. Rev Cubana Med Gen
Integr 2001; 17:62-67.
Guardia Serecigni J, Jiménez-Arriero M, Pacual P, Flórez G, Contel M.
Alcoholismo:Guías clínicas basadas en la evidencia científica. Socidrogalcohol 2007, 2nd edition.
Martín Centeno A, Rojano Capilla P. Conceptos y anamnesis del consumo de alcohol en la consulta de atención primaria. Medicina General
2000; 29:975-962.
Almocacid C, Gil L. Alcoholismo en atención primaria. In: http://www.
udomtyc.org/descarga/sesiones/2003y4/Alcoholismo.pdf. Accessed
December 12, 2008.
Higgins EM, du Vivier AW. Alcohol abuse and treatment resistance in skin
disease. J Am Acad Dermatol 1994; 30:1048.
Higgins EM, du Vivier AW. Alcohol and the skin. Alcohol 1992; 27:595602.
Sarkany I. The skin-liver connection. Clin Exp Dermatol 1988; 13:152-159.
Shellow WVR. The skin in alcoholism. Int J Dermatol 1983; 22:506-510.
Woeber k. The skin in diagnosis of alcoholism. Ann N Y Acad Sci 1975;
252:292-295.
Burton JL, Kirby J. Pigmentation and biliary cirrhosis. Lancet 1975; 1:458459.
Research Article
Mucous membrane pemphigoid:
our 14 years’ experience
María del Pilar Beruschi1, Mónica Bolatti2, Sandra Marinescu3, Claudia Ardissone4, Laura López4, Jorge O. Zárate5,
Eduardo Zeitlin6, Ana Kaminsky7, Elina Dancziger8
Abstract
Introduction. Mucous membrane pemphigoid includes a group of subepithelial immunobullous diseases mainly affecting mucous membranes and
occasionally the skin. Evolution is chronic and progressive, leading to cicatricial sequelae, which produce morbidity, disability, and sometimes death.
Objective: To describe epidemiological and clinical aspects, and the evolution of mucous and cutaneous lesions in our patients.
Materials and methods. The retrospective, observational, and descriptive study included 41 patients with confirmed mucous membrane pemphigoid diagnosis consulting the Dermatology Department between 1994 and 2008. Ocular involvement was graded using the Foster staging system.
Each patient received systemic and local treatment.
Results. Thirty nine patients had only ocular involvement and 2 patients had ocular, oral and cutaneous disease, with female predominance of the
disease. Mean age was 60 years, 46.34 percent had history of severe ocular injury, 17.07 percent had used topical glaucoma medications, and 80.48
percent consulted for chronic conjunctivitis. In 60.96 percent of the cases, diagnosis was confirmed in advanced stages of ocular disease. 62.41 percent of patients had over 5 years evolution before diagnosis. Cutaneous and oral lesions responded to therapy in less than 2 months. Ocular lesions
remission according to stage was as follows: stage I, 83.33 percent; stage II, 40 percent; and stage III, 30.43 percent. No immunosuppressive treatment
was given in stage IV. No improvement was achieved in terminal ocular disease patients.
Conclusion. Ocular involvement is prognostic. Diagnosis was made in advanced stages of ocular disease. Remission was achieved only with early
treatment. (Dermatol Argent 2009; 15(4):260-266).
Key words: Mucous membrane pemphigoid, cicatricial pemphigoid..
Introduction
1. Staff Physician of Dermatology Department. Hospital General de Agudos “C. Durand”.
2. Staff Physician of Oculoplasty Department. Hospital de Oftalmología “P. Lagleyze”.
3. Emergency Physician. Hospital “P. Lagleyze”.
4. Dermatologist.
5. Director of Ophtalmology and Visual Research Laboratory. Pathology Department,
UBA.
6. Head of Pathology Department. Hospital “C. Durand”.
7. Named Professor of Dermatology.
8. Head of Dermatology Department. Hospital “C. Durand”. Hospital General de Agudos “C. Durand”. Autonomous City of Buenos Aires, Argentine Republic.
Correspondence
María del Pilar Beruschi. Corrientes 486. (CP 1640) Martínez, Buenos Aires, Argentine
Republic | [email protected]
Mucous membrane pemphigoid comprises a group of subepithelial immunobullous diseases mainly affecting mucous
membranes and secondly the skin. Evolution occurs by recurrent outbreaks characterized by the appearance of blisters, erosions, and marked scarring.1
Most frequent location is oral mucosa, followed by conjunctiva, skin, pharynx, external genitals, nasal mucosa, larynx, anus,
and esophagus. Cicatricial sequelae are an important cause of
morbidity and disability; if involving larynx or esophagus, they
may lead to death.2
This work comprises 14 years’ observation experience of this
infrequent pathology.
Objectives
To describe epidemiological aspects (age, gender distribution, history of ocular injury or use of eye drops for glaucoma
treatment), clinical aspects (consultation cause, evolution time
from symptoms onset to diagnosis, stage of ocular disease), and
the evolution of mucocutaneous lesions in our patients.
Design
Retrospective, observational, descriptive.
Mucous membrane pemphigoid: our 14 years’ experience | 83
The study included 41 patients with confirmed diagnosis of mucous membrane pemphigoid, who appeared at the Dermatology Department of our
Hospital between June 1994 and June 2008. A clinical examination of skin and mucous membranes
was performed in all patients. Ocular involvement
was assessed by the ophtalmologist and classified according to the Foster staging system, which describes four stages:
•
•
•
•
Stage I: subconjunctival fibrosis (Figure 1).
Stage II: shortening of inferior fornix (Figure 2).
Stage III: symblepharon (Figure 3).
Stage IV: ankyloblepharon (Figure 4).3
Diagnosis was confirmed by conjunctival (in patients with only ocular involvement) or skin biopsy.
Samples were analyzed with hematoxilin-eosin stain
and direct immunofluorescence in all cases (Figures
7 and 8).1
All patients received systemic and local
treatment. Systemic treatment included: dapsone, methylprednisone, cyclophosphamide,
azathioprine, metothrexate, cyclosporine, colchicine and antibiotics. Local treatment consisted of tear substitutes, antibiotics, corticosteroids, and cyclosporine.
Stage IV patients received no immunosuppressive
treatment, only ocular lubricants and antibiotics for
the treatment of infectious complications.
Average patient follow-up was 38 months, with a 1
to 97-month range. Ocular disease remission was
construed as the absence of inflammatory activity
(white eye). Skin lesion remission consisted in complete blister epithelization and the absence of new
lesions.
Results
Of the 41 patients included in the study, 26 were female and 15 were male.
Female:male ratio was 1.7:1.
Average age at diagnosis was 60 years, with a 32 to
82-year range.
Nineteen patients (46.34 percent) had history of severe ocular injury. Most frequently recorded trauma
background was surgery (10 patients), followed by
trauma (6 patients), Stevens-Johnson’s syndrome (3
patients), severe conjunctivitis (2 patients), ophtalmic zoster (1 patient), contact with metal dust (1
patient).
Figure 1. Stage I. Subconjuncival fibrosis (arrow).
Figure 2. Stage II. Arrow indicates inferior fornix shortening.
Three patients had association of different traumatic events.
Seven of the 41 patients (17.07 percent) referred use of eyedrops for
treatment of glaucoma. All 41 patients had conjunctival mucosa involvement; 39 patients had only ocular involvement, and 2 patients had conjunctival, oral and cutaneous involvement (Figures 5 and 6) (Table 1).
Chronic conjunctivitis was the most frequent consultation cause in 33 patients (80.48 percent); 5 (12.19 percent) consulted for dry eye. The 2 patients with skin lesions (4.87 percent) consulted first at the Dermatology
Department, where diagnosis was confirmed. One patient (2.43 percent)
consulted for epiphora.
In 41.46 percent of patients, diagnosis was set 10 years after symptom onset (Table 2).
In 25 patients (60.96 percent), diagnosis was confirmed in advanced stages of ocular disease (Chart 1).
When female and male populations were analyzed separately, we found
that half of females had diagnosis in stages I and II, while 79.99 percent of
men had diagnosis in stages III and IV (Chart 2 y 3).
84 | M. del P. Beruschi, M. Bolatti, S. Marinescu, C. Ardissone, L. López, J. O. Zárate, E. Zeitlin, A. Kaminsky, E. Dancziger
S IV
4.87%
SI
14.67%
S II
24.39%
S III
56.09%
Chart 1. Ocular disease stage (S) at diagnosis (n = 41).
S IV
4%
Figure 3. Stage III. Symblepharon (arrow).
SI
23%
S III
46%
S II
27%
Chart 2. Ocular disease stage (S) in female (n = 26).
S I 0%
Figure 4: Stage IV. Ankyloblepharon. Arrows mark fusion of tarsal conjunctiva and bulbar conjunctiva, and corneal clouding.
In the 2 patients with cutaneous and oral lesions, remission was achieved
in skin and oral mucosa 2 month after onset of treatment. Remission of
ocular disease occurred only in 16 patients (39.02 percent).
Remission occurred in 83.33 percent of the cases in stage I; this percentage decreased when therapy was started in more advanced stages (Table 3).
Of the 9 patients remitting in stages I and II, 7 remained in this condition
between 3 months and 2 years after treatment discontinuation.
All remitting patients in stage III required continuing support medication.
Two patients progressed from stage II to III due to early medication
discontinuation.
Two patients progressed from stage III to IV, one due to irregular
treatment compliance and the other due to lack of response.
S IV
7%
S II
20%
S III
73%
Chart 3. Ocular disease stage (S) in males (n = 15). S I 0%
TABLE 1. CASE-CONTROL STUDY.
Case Gender Age
Location
OI
ET
OS F-up Evolution
1
F
69
Ocular
29y
III
38m
R
2
F
57
Ocular
40y
III
60m
I
3
F
58
Ocular
10y
III
64m
R
4
F
59
Ocular
6m
II
97m
R
5
F
56
Ocular
8y
I
92m
R
6
F
56
Ocular
C
30y
III
60m
R
7
F
58
Ocular
T+ Sx
35y
II
67m
R
8
F
45
Ocular
2y
I
48m
R
9
F
73
Ocular
S
2y
I
48m
R
10
F
72
Ocular
T
18y
III
72m
R
11
F
63
Ocular
S
10y
II
2m
R
12
F
67
Ocular
T+ Sx
15y
III
55m
NA
13
F
34
Ocular
SSJ
30y
III
90m
R
14
F
72
Ocular
Sx
6y
III
22m
I
15
F
68
Ocular
2y
I
19m
R
16
F
55
Ocular
15y
IV
16m
17
F
89
Ocular
5y
III
60m
NA
18
F
51
Ocular
2y
I
77m
R
19
F
82
Ocular
Sx
2y
II
3m
I
20
F
83
Ocular
2y
II
1m
NA
21
F
77
Ocular
12y
III
2m
R
22
F
64
Ocular
10y
II
43m
P
23
F
60
Ocular
T+Sx+C
7y
II
16m
NA
24
F
32
Ocular
9y
III
1m
NA
25
F
32
Ocular
Sx
3m
I
3m
NA
26
F
56
Ocular
HZ
5y
III
12m
NA
27
M
45
Ocular
4y
III
6m
NA
28
M
55
Ocular
MD
1y
II
39m
I
29
M
55
Ocular
T
4y
III
89m
P
30
M
70
Ocular
20y
II
36m
P
31
M
67
Ocular
5y
III
39m
I
32
M
54
Ocular
10y
III
42m
I
33
M
74
Ocular
4y
III
33m
I
34
M
64
Ocular-skin-oral
2y
III
16m
R
35
M
79
Ocular
Sx
3y
II
81m
R
36
M
34
Ocular
SSJ
22y
IV
18m
37
M
64
Ocular
T
30y
III
6m
I
38
M
45
Ocular-skin-oral
6y
III
72m
39
M
41
Ocular
SSJ
30y
III
5m
NA
40
M
80
Ocular
Sx
4y
III
7m
I
41
M
76
Ocular
6y
III
27m
I
ET: evolution time before diagnosis. OS: ocular disease stage. y: years. m: months. F-up: followup. OI: ocular injury. C: conjunctivitis. T: trauma. Sx: surgery. SSJ: Stevens-Johnson syndrome. HZ:
herpes zoster. MD: metal dust. R: remission. I: improvement. P: progression. NA: non-assessable.
Nine of the total patients were not assessed due to control failure or
treatment discontinuation (Table 3).
Discussion
Mucous membrane pemphigoid is a rare disease of unknown incidence
and prevalence. An incidence between 1:12,000 and 1:40,000 is estimated, although subdiagnosis is suspected, especially in early stages of the
disease.4,5 Some cases have been described in children, but the usual age
TABLE 2. EVOLUTION TIME BEFORE DIAGNOSIS.
< 6 months
1 (2.43 %)
6 months – 2 years
2 (4.87 %)
2 years to 5 years
12 (29.96 %)
5 years – 10 years
9 (21.5 %)
> 10 years
17 (41.6 %)
TABLE 3. OCULAR INVOLVEMENT EVOLUTION.
S
III
S I (n=6)
S II (n=10)
S IV (n=2)
(n=23)
Remission
5
4
7
0
Inflammato0
2
8
0
ry activity
Progression 0
2
2
2
Non-assess1
2
6
0
able
Remission
83.33%
40%
30.43%
0%
percentage
at diagnosis is from 60 to 80 years.6,9 A female dominance is observed, with a 1.5-2.2:1 ratio matching
our case material.9,10
Etiopathogenesis is unclear, but as in all autoimmune diseases, both genetic and environmental factors
are probably included.11
The presence of HLA-DR4 allele may increase risk
of ocular disease.12,13 Prevalence of HLA-DQB1
0301 allele was described in patients with only ocular disease, but was later found associated with all locations of the disease.14,15 This allele may be related
to production of IgG against basement membrane
antigens. A relation between this allele and severity
of the disease is also suggested.15
The condition is characterized by production of immunoglobulin G (IgG) autoantibodies targeting different molecules present in the basement membrane area, such as 180-kDa bullous pemphigoid antigen (BPAg 180), b4 integrin, and laminin V.16–23
Although the role of environmental factors is still
unclear, it is believed that antibodies produced
against infectious agents or drugs may cross-react
with basement membrane antigens (molecular mimetism). Exposure of conjunctival epithelium antigens caused by severe ocular injury (surgeries, trauma, burns, Stevens-Johnson syndrome, and others)
may favor their processing by immune system
cells.24-26
Many drugs are also described, especially eyedrops indicated for treatment of glaucoma, as mucous membrane pemphigoid triggering factors.27-32
We found both types of background in our case
material.
The disease involves mainly mucosae. Locations are,
in order of frequency: oral mucosa (85 percent),
conjunctiva (64 percent), skin (24 percent), pharynx
Figure 5. Skin involvement: general bullous eruption.
Figure 6. Oral mucosa erosions.
(19 percent), external genitals (17 percent), nasal mucosa (15 percent),
larynx (8 percent), anus (4 percent), an esophagus (4 percent).2,9
Oral involvement usually appears as desquamative gingivitis and mucosal
erosions.10
Response to treatment is usually favorable, and may occur with local
therapy.1
Conjunctiva may be the only location of disease,
as occurred with most of our patients.3,33,34 It starts
with a chronic conjunctivitis developing in outbreaks.35,36 In time, conjunctival fibrosis with fornix
shortening and production of symblepharon occurs.
Eyelids fuse and conjunctival sacs obliterate in late
stages (ankyloblepharon).3,33,36 Fibrosis also obliterates channels, tear glands and Meibomian glands,
with alterations of the tear layer. Tarsal conjunctiva scarring causes trichiasis and entropion, which as
the dry eye cause corneal damage with pannus formation, ulceration, posterior clouding of the cornea,
and blindness.33,35,36
All these alterations were evidenced in our case
material.
Skin lesions are rarely predominant. Two types of
skin lesions are described. The first is a general bullous eruption similar to bullous pemphigoid.2,3,37,38
The second form is located in head and neck
(Brunsting-Perry), and consists of occasionally itching erythematous base blisters that heal with atrophy and may leave cicatricial alopecia if the scalp is
involved.39-41
A vegetating form is also described.42
Marked clinical and immunologic variability exists
among patients. Four main groups are described,
probably related to different target antigens. One
group refers to only ocular disease, with IgG antibodies targeted against b4 integrin, or IgA antibodies against a 45-kDa antigen.18,43 The second group
consists of patients with mucocutaneous lesions and
IgG and IgA against BPAg 180.20
The cicatricial phenotype differs from bullous pemphigoid, probably because the antibodies recognize
different antigen molecule epitopes more deeply located in the basement membrane.
Only oral variety refers to a group of IgG against
BPAg 180.44
The fourth group includes patients with multiple
mucosal and no skin involvement.11
A last group of patients with anti-laminin V antibodies is described, which may be associated with
neoplasias.21,22,45,46
Currently, mucous membrane pemphigoid is understood as a set of syndromes characterized by having autoantibodies with different specificities, and
not as one single entity.1,2,11
Clinical differential diagnosis include: bullous pemphigoid, epidermolysis bullosa acquisita, linear
IgA dermatosis, bullous lupus, and paraneoplastic
pemphigus.2,11
Drug-induced ocular pseudo-pemphigoid must
References
1.
2.
3.
4.
5.
6.
7.
8.
Figure 7. Subepidermal blister (H-E).
9.
10.
11.
12.
13.
14.
Figure 8. DIF of conjunctiva. Lineal IgG deposit on basement membrane.
also be ruled out, as well as other causes of non-immunological cicatricial
conjunctivitis.47,48
Ocular disease was dominant in our case material, because most of our patients came from an ophtalmology hospital.
Epidemiological, clinical and evolution aspects coincided with data published in the available literature.
In all cases, ocular involvement marked prognosis of disease. Early stage
therapy allowed a higher remission percentage.
In advanced stages, disease complications complications (dry eye, infections, corneal abrasion caused by eyelashes) generate a permanent inflammatory stimulus that contributes to disease activity perpetuation, thus
hindering remission.49,50
Since it is a disabling and occasionally fatal disease, we wish to highlight
the need for an early diagnosis in order to implement timely therapy and
multidisciplinary approaches, thus preventing or delaying irreversible sequelae occurrence.
15.
16.
17.
18.
Chan LS, Ahmed AR, Anhalt GJ, Bernauer W, et al. The First
International Consensus on Mucous Membrane Pepmphigoid: definition, diagnostic criteria, pathogenic factors, medical treatment and prognostic indicators. Arch Dermatol
2002; 138:370-379.
Fleming TE, Korman NJ. Cicatricial pemphigoid. J Am Acad
Dermatol 2000; 43:571-591.
Foster CS. Cicatricial pemphigoid. Trans Am Ophthalmol
1986; 84:527-663.
Mondino BJ, Stuart IB. Ocular cicatricial pemphigoid.
Ophthalmology 1981; 88:95-100.
Nguyen QD, Foster CS. Cicatricial pemphigoid: diagnosis
and treatment. Int J Ophthalmol Clin 1996; 36:41-60.
Jolliffe DS, Sim-Davis D. Cicatricial pemphigoid in a young
girl. Clin Exp Dermatol 1977; 2:281-284.
Rogers M, Painter D. Cicatricial pemphigoid in a 4-year-old
child. Aust J Dermatol 1981; 22:21-23.
Rosenbaum MM, Esterly NB, Greenwald MJ, Gerson CR.
Cicatricial pemphigoid in a 6-year-old child: report of a
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19. Chan RY, Bhol K, Tesavihul N, Letko E, et al. The role of antibody to human ß4 integrin in conjunctival basement membrane separation: possible in vitro model for ocular cicatricial pemphigoid. Invest Ophthalmol
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20. Ogama N, Setterfield JF, Powell AM, Sakuma-Oyama Y, et al. Bullous pemphigoid Antigen II (BP 180) and its soluble extracellular domains are the
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22. Nousari HC, Rencic A, Hsu R, Yancey KB, et al. Antiepiligrin cicatricial pemphigoid
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23. Leverkus M, Schmidt E, Lazarova Z, Bröcker EB, et al. Antiepiligrin cicatricial pemphigoid. Arch Dermatol 1999; 135:1091-1098.
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25. Nayar H, Wojnarowska F, Venning V, Taylor CJ. Association of autoimmunity and cicatricial pemphigoid: is there an immunogenetic basis? J Am
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26. Chan LS, Soong HK, Foster CS, Hammerberg C, et al. Ocular cicatricial
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27. Vassileva S. Drug induced pemphigoid: bullous and cicatricial. Clin Dermatol 1998; 16:379-387.
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pemphigoid affecting the conjunctiva: light and electron microscopic
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32. Van Joost T, Faber WR, Manuel HR. Drug induced anogenital cicatricial
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Original Article
Periorificial dermatitis in children
Margarita Larralde1, Maria Eugenia Abad2, Paula Luna3, Romina Plafnik4, Betina Pagotto4
Abstract
Periorificial dermatitis is a recurrent papulopustular eruption located in perioral, perinasal, or periocular regions, and seldom in vulvar area.
It has been described in association with the use of topical or inhaled corticosteroids, moisturizing creams, fluoride toothpastes, topical
antibiotics, sun blockers, among other agents.
Objective: To describe clinical presentation, association with the use of topical or inhaled corticosteroids, and treatment in patients with
periorificial dermatitis.
Material and Method: Descriptive, retrospective study at the Pediatric Dermatology Section of Hospital Ramos Mejía.
Results: A total of 48 patients with diagnosis of periorificial dermatitis were evaluated between 1986 and 2008. Sixty percent of the cases were female. Average age was 8.4 years. Most frequent location was perioral (41.7 percent), followed by perioral and perinasal location
(25 percent). Only 4 patients had perivulvar lesions, 3 of them without previous use of corticosteroids. Use of topical or inhaled corticosteroids was observed in 66.6 percent of patients for an average period of 2 years. Most cases received metronidazole and erythromycin as
topical, systemic, or combined treatment.
Conclusion: Higher incidence of periorificial dermatitis was observed in association with the use of topical and inhaled corticosteroids. Inhaled corticosteroids were associated with perioral and perinasal locations. Perivulvar location was not associated with the use of corticosteroids. Lesions appeared earlier with the use of topical corticosteroids. (Dermatol Argent 2009; 15(4):267-271).
Key words: periorificial dermatitis, perioral dermatitis, steroids.
Introduction
1. Head of the Dermatology Department, Hospital Alemán. Buenos Aires, Argentine. Head
of Pediatric Dermatology Section, Hospital “JM Ramos Mejía”, Buenos Aires, Argentine.
2. Physician of the Pediatric Dermatology Section, Hospital “JM Ramos Mejía”. Physician of
the Dermatology Department, Hospital Alemán.
3. Physician of the Dermatology Department of the Police Medical Complex “Churruca-Visca”, Buenos Aires, Argentine. Physician of the Superior Course of Pediatric Dermatology.
Pediatric Dermatology Section, Hospital “JM Ramos Mejía”, Buenos Aires, Argentine.
4. Physician of the Superior Course of Pediatric Dermatology. Pediatric Dermatology Section,
Hospital “JM Ramos Mejía”, Buenos Aires, Argentine.
Correspondence
Betina Pagotto: Charcas 3028 Piso 6to D, (1485) Autonomous City of Buenos Aires, Argentine Republic | [email protected]
Periorificial dermatitis (PD), also known as perioral dermatitis, is a relatively frequent dermatosis of increasing incidence in recent years. Although more common in adults
and in females, it may also appear in childhood, mainy in
prepuberal age.1 It is characterized by the presence of papules and pustules over an erythematous base, of periorificial
distribution with tendency to be confluent, and they may be
pruriginous.1,2
Etiopathogenesis is ill-defined; its course is benign and
mostly limited, without involvement of the patient’s general
condition. Suitable treatment is topic or systemic antibiotics, and discontinuation of the triggering factor.
In this study, we describe PD clinical and epidemiological
features in our pediatric population.
Materials and method
A descriptive, retrospective, transversal section study
was conducted in the Pediatric Dermatology Section of
Hospital Ramos Mejía. Clinical records were reviewed from
year 1986 to 2008. All patients from 0 to 18 years old having
typical periorificial dermatitis, with the presence of papules
90 | M. Larralde, M. E. Abad, P. Luna, R. Plafnik, B. Pagot
or pustules located on perioral, perinasal, periocular, or vulvar areas were included whereas patients with diagnosis of contact dermatitis, atopic
dermatitis, perianal, acne y rosacea were excleded.
Inclusion criteria were met by 52 patients. Before
data analysis, 4 patients with insufficient clinical
record data were excluded. In the remaining 48
patients, age, gender, lesion distribution, history
of topic or inhaled corticosteroid use, lapse of lesion appearance after using corticosteroids, and
treatment data were collected.
TABLE 1. LESION DISTRIBUTION.
Lesion location
Perioral
Periocular
Perinasal
Perioral + perinasal
Perioral + periocular
Perioral + perivulvar
Perioral + perinasal + periocular
Perioral + periocular + perivulvar
Patients
20 (41.7%)
2 (4.2%)
1 (2.1%)
12 (25%)
5 (10.4%)
3 (6.2%)
4 (8.3%)
1 (2.1%)
Results
Included in the study were 48 patients with diagnosis of periorificial dermatitis, whereof 29 (60
percent) were female, and 19 (40 percent) were
male.
PD age range was from 10 months to 16 years,
with a mean of 8.4 years. Clinical distribution of
lesions is summarized in Table 1. Most frequent
location was perioral with 41.7 percent, followed
by perioral + perinasal in 25 percent of the cases
(Figure 1). Four patients had vulvar involvement
(Figure 2 A) associated with perioral (Figure 2
B) and periocular location.
In 32 patients (66.6 percent) there was history
of corticosteroid use: 21 patients (43.7 percent)
used inhaled corticosteroids and 11 (22.9 percent) used topical corticosteroids (hydrocortisone, betamethasone, momethasone). In 33.4 percent of patients there was no PD triggering factor.
In patients using inhaled corticosteroids, dominant lesion location was perioral (n = 13) and perioral + perinasal (n = 5).
No dominant location was found in patients
using topic corticosteroids.
Four (8.3 percent) patients showed perivulvar
lesions, always associated with other locations.
Three of them had no history of prior corticosteroid use.
Lapse between onset of corticosteroid use and appearance of lesions ranged from 7 days to 4 years,
with a mean of 2 years. In patients using inhaled corticosteroids, lesions appeared in an average period of 18 months, while in patients using
topical corticosteroids the average period was 3
months. PD was treated with 0.75 percent topical metronidazole in 16 patients (33.3 percent),
topical erythromycin in 15 (31.3 percent), oral
erythromycin in 6 (12.5 percent), combined topical and oral erythromycin in 4 (8.3 percent), oral
erythromycin with 0.75 percent topical metroni-
Figure 1. Perinasal and perioral lesions.
dazole in 3 (6.2 percent), oral clarithromycin in 2 (4,2 percent), topical clindamycin in 1 (2.1 percent) and pimecrolimus in 1 patient (2.1
percent). Average systemic antibiotic therapy was 3 weeks.
Discussion
Periorificial dermatitis was first described in 1970 by Gianotti, and
since then several terms have been used to refer to this disease, such as
Gianotti-type perioral dermatitis, granulomatous periorificial dermatitis, and Afro-Caribbean facial eruption of the childhood.2,3
Periorificial dermatitis in children | 91
Figure 2 A. Perivulvar location.
Figure 2 B. Perioral location associated with perivulvar location.
The occurrence is higher in females, as shown in our
study, where 60 percent of the patients were women.
Age at presentation varies; between different reports; some studies show a higher incidence in
children under 5 years.2,4 In our results, mean presentation age was 8.4 years.
Clinically, PF appears with erythematous papules, papulopustules or papulovesicles, frequently
with diffuse erythema, and may cause itching or
burning sensation.2,5 Blepharitis and conjunctivitis have occasionally been reported as associated manifestations.3 Most frequent location is
perioral (Figures 3 and 4), with a clear zone immediately around the vermilion border of the
lips, but it may also involve perinasal, periocular (Figure 5), and less frequently the perivulvar
area.1,2 Sometimes, the eruption may extend to
cheeks, forehead, neck and chest, however, this is
not a sign of poor disease evolution or systemic
involvement.3,6
Etiopathogenesis is ill-defined; various triggering
factors, both endogenous and exogenous have
been suggested, of which we may point out infectious causes (Candida, Demodex), oral contraceptives, topical antibiotics, fluoride toothpaste,
amalgam mercury, UVB radiation and corticosteroids (oral, topical and inhaled); the latter are the
most frequent cause of periorificial dermatitis in
children and adolescents.1,2,7
Topical corticosteroids of various potencies (low,
medium, and high) may produce PD, as well as
other adverse effects such as atrophy, telangiectasias, striae, rosacea, steroid induced acne, hypopigmentation, and hypertrichosis.8 In our study, 66.6 percent of patients had history of corticosteroid use. In the group of patients using inhaled corticosteroids, lesions were mainly located on the perioral area, followed by perioral
plus perinasal; this may be related to the use of
nebulizing chambers or masks. We also observed
that lesions appeared earlier after using topical
corticosteroids.
Corticosteroids play an important role in the disease etiopathogenesis; use of topical corticosteroids may transiently relieve clinical manifestations,
but these tend to relapse after medication discontinuation, being more severe in many cases.9
Diagnosis is based on clinical features and lesions
distribution. Histopathologic findings are nonspecific; there is presence of lymphohistiocytic infiltrate located about hair follicles, dermal granulomatous inflammation and occasionally perifollicular abscesses.1
92 | M. Larralde, M. E. Abad, P. Luna, R. Plafnik, B. Pagot
Figure 3. Perioral lesions.
Figure 4. Perioral lesions.
Other therapeutic options with good results were topical
pimecrolimus and adapalene.10-12
Although PD is a disease with good prognosis, early diagnosis and adequate treatment are necessary to improve symptoms and cosmetic involvement, and to prevent relapses.
Some studies have shown that PD occurred not only due to
the use of corticosteroids, but to the device used for dispensing the drug.13
We consider important to highlight the well-documented
association between use of inhaled corticosteroids in asthma management and the development of PD; thus it is very
important to inform parents and patients using this type of
medication, in order to optimize the effects of the drug and
reduce complications.14
References
1.
Figure 5. Periocular and perinatal location.
2.
Typical appearence of periorificial dermatitis enables differentiation from other dermatosis such as rosacea, contact
dermatitis, acne, seborrheic dermatitis, lip-licking cheilitis,
xanthoma and papular sarcoidosis.1
In reference to treatment, in our setting the most used topical antibiotic was metronidazole (33.3 percent) followed by
erythromycin (31.3 percent), and the most used oral antibiotic was erythromycin (12.5 percent).
A suggested strategy was initial use of topical metronidazole for 2 weeks and, according to the evolution, addition
of oral erythromycin. Treatment duration was usually 4-6
weeks.2
3.
4.
5.
6.
7.
Hafeez Z. Perioral dermatitis: an update. Int J Dermatol. 2003; 42:514517.
Nguyen V, Eichenfield L. Periorificial dermatitis in children and adolescents. J Am Acad Dermatol 2006; 55:781-785.
Urbatsch AJ, Frieden I, Williams ML, Elewski BE, et al. Extrafacial and generalized granulomatous periorificial dermatitis. Arch Dermatol 2002;
138:1354-1358.
Kuflik JH, Janniger CK, Piela Z. Perioral dermatitis: an acneiform eruption.
Cutis. 2001; 67:21-22.
Weber K, Thurmayr R. Critical appraisal of reports on the treatment of
perioral dermatitis. Dermatology. 2005; 210:300-307.
Boeck K, Abeck D, Werfel S, Ring J. Perioral dermatitis in children- clinical presentation, pathogenesis- related factors and response to topical
metronidazole. Dermatology. 1997; 195:235-238.
Guarneri F, Marini H. An unusual case of perioral dermatitis: possible
pathogenic role of neurogenic inflammation. J Eur Acad Dermatol Venereol. 2007; 21:410-412.
Periorificial dermatitis in children | 93
8.
Hengge UR, Ruizcka T, Schwartz RA, Cork MJ. Adverse effects of topical
glucocorticosteroids. J Am Acad Dermatol. 2006; 54:1-15.
9. Manders SM, Lucky AW. Perioral dermatitis in childhood. J Am Acad Dermatol. 1992; 27:688-692.
10. Oppel T, Pavicic T, Kamann S, Brautigam M, et al. Pimecrolimus cream
(1%) efficacy in perioral dermatitis - results of a randomized, doubleblind, vehicle-controlled study in 40 patients. J Eur Acad Dermatol Venereol. 2007; 21:1175-1180.
11. Rodríguez-Martín M, Sáez-Rodríguez M, Carnerero-Rodríguez A, Rodrí-
guez-García F, et al. Treatment of perioral dermatitis with topical pimecrolimus. J Am Acad Dermatol. 2007; 56:529-530.
12. Jansen T. Perioral dermatitis successfully treated with topical adapalene.
J Eur Acad Dermatol Venereol. 2002; 16:175-177.
13. Dubus JC, Marguet C, Deschildre A, Mely L, et al. Local side-effects of inhaled corticosteroids in asthmatic children: influence of drug, dose, age,
and device. Allergy. 2001; 56:944-948.
14. Poulos GA, Brodell RT. Perioral dermatitis associated with an inhaled corticosteroid. Arch Dermatol. 2007; 143:1460.
Original Article
Rare tumors of difficult initial diagnosis
María Inés Sanz1, Daniel Feinsilber2, Cristina Corbella3, Roberto Schröh3, Mercedes Lidia Hassan4.
Abstract
Five rare tumors of difficult initial diagnosis are reported. In each case, several differential diagnoses were suggested and many supplementary exams were
necessary. These 5 patients were studied at our hospital in a six-month period, with final diagnoses of skin and soft tissue angiosarcoma, peripheral primitive
neuroectodermal tumor, plasmablastic lymphoma, amelanotic and desmoplastic polipoid melanoma, and nodular vulvar melanoma (Dermatol Argent 2009;
15(4):272-277).
Key words: angiosarcoma, primitive neuroectodermal tumor, plasmablastic lymphoma, desmoplastic melanoma, vulvar melanoma.
Introduction
Five cases of rare tumors of difficult initial diagnosis are reported. Many supplementary exams were necessary in order to rule
out other possible diagnoses and decide on a suitable therapeutic approach.
Clinical cases
1.
2.
3.
4.
Dermatologist, chief Residents.
Staff Dematologist.
Dermatopathologists.
Professor Head of Dermatology Division.
All authors belong to the Dermatology Course and Division, Hospital General de Agudos “J.M. Ramos Mejía”. Autonomous City of Buenos Aires, Argentine.
Correspondence
María Inés Sanz: Av. Callao 942 Piso 1º Autonomous City of Buenos Aires, Argentine Republic | [email protected]
Case 1
A 52-year-old male patient, with a previously unremarkable
medical history, consulted on February 2008 for a 7-month
evolution tumor on right shoulder. He had noticed an increase
in tumor size in the preceding month with functional disability of right upper limb.
Physical examination of anterior shoulder area evidenced a 7 ×
7 cm subcutaneous tumor lesion, hard to elastic in consistency, painful on palpation, covered by apparently normal skin,
with telangiectasias on lower half (Figure 1). No lymphadenopathies were identified.
Soft tissue ultrasonography evidenced a heterogeneous
hypoechoic formation of solid appearance with poorly defined borders and calcifications within it. Shoulder magnetic nuclear resonance image (MRI) was performed and shows an extending 65 × 40 × 45 mm lesion on the anterior area with heterogeneous signal in T1 and T2 and hypointensive focal areas,
attached to the coracoid process. Deltoid and pectoralis major
muscles covered the surface of the lesion. No axillary lymphadenopathies were found.
The suggested differential diagnoses were leiomiosarcoma, angiosarcoma, dermatofibrosarcoma protuberans and myxoid
metastasis of melanoma.1
Rare tumors of difficult initial diagnosis | 95
Losange biopsy reported vascular neoplasia with
retiform hemangioendothelioma features. The patient was subjected to surgery, with complete excision of the tumor lesion and dissection of pectoralis major and minor, subscapularis, and part of
deltoid muscles, and the clavicle. Histopathology
of the specimen reported vascular neoplasia with
morphological and immunohistochemical characteristics (positive Factor VIII and CD34, slightly
positive Ki-67) of skin and soft tissue angiosarcoma, alternating with differentiated hemangiolymphangiomatous and other poorly differentiated
areas separating soft tissues (Figure 2). There was
no underlying bone involvement. Resection margins were scarce.
Chest, abdomen and pelvis computed axial tomography (CAT) did not evidence systemic involvement. The patient started radiotherapy and chemotherapy with doxorubicin and dacarbazine, but
discontinued treatment after the second cycle. He
consulted again 8 months after diagnosis for the
presence of a 3-mm painful tumor mass on surgical site. He is currently undergoing a restaging
program.
Case 2
An 82-year-old male patient consulted on July 2008
for a 4-month evolution tumor on the right foot.
Physical examination evidenced on the internal malleolar area a 5-cm purplish tumor of lobated surface, soft in consistency, friable, with superficial serosanguineous crust, slightly painful at palpation
(Figure 3). Additionally, a right inguinal lymphadenopathy was found. Probable differential diagnoses were angiosarcoma, Merkel-cell carcinoma, and
B-cell cutaneous lymphoma.
Losange biopsy reported blue-cell dermo-hypodermal tumor with morphology and immuhistochemistry suggesting peripheral neuroectodermal tumor. Routine laboratory test, dosage of 24-hour urine catecholamines, and chest and pelvis CAT were
requested, with results within normal limits. Right
foot MRI evidenced a 49-mm heterogeneous nodular formation in medial compartment involving subcutaneous cell tissue and contacting in depth with
posterior tibial, flexor digitorum and flexor hallucis
tendons. Needle aspiration punction was performed
on palpable inguinal lymphadenopathy related to a
reactive node.
After an interdisciplinary consultation with the
Traumatology Department, it was decided to perform right infrapatellar amputation -due to the
functional deficit of the foot which may result
from simple excision of the tumor– and inguinal lymphadenectomy.
Histopathology of the samples reported blue-cell dermo-hypodermal
neoplasia consistent with primitive peripheral neuroectodermal tumor
(Figure 4). Immunohistochemistry was positive for S100, neuron-specific enolase, vimentin and synaptophysin, and negative for CK20, ACL,
Melan-A, HMB 45, and CD99. Neoplastic cells was found in the inguinal lymph node.
After surgery, the patient developed a rapidly growing, painful, stony hard right inguinal mass; thus, a superficial and deep inguinal lymphadenectomy was performed, with evidence of lym-
Figure 1. Subcutaneous tumor, 7 × 7 cm, on right shoulder.
Figure 2. Incomplete and anastomosed blood and lymphatic vascular structures.
96 | M. I. Sanz, D. Feinsilber, C. Corbella, R. Schröh, M. L. Hassan
ph node involvement. A new CAT was performed three months after diagnosis, where images consis×tent with lung metastasis were identified. Currently, the patient undergoes a palliative radiotherapy and chemotherapy plan.
Case 3
A 61-year-old male patient, with no known history
of pathologies consulted on July 2008 for a 7-month
evolution purplish erythematous plaque on his left
leg.
Physical examination evidenced a 7 × 13 cm purplish erythematous plaque with atrophic center on
anterior aspect of the leg. When the patient undressed, multiple small wine red plaques were identified on abdomen, back, neck, thighs and palate.
An asymptomatic 6 × 3 cm ulcerated exophytic tumor lesion with sanious base and raised erythematous borders was identified on the right lateral area
of the hard palate, infiltrating the upper dental arch
(Figure 5). No lymphadenopathy was identified.
Clinically, we suspected an HIV-positive patient
with epidermal Kaposi’s sarcoma; thus, differential diagnoses suggested for the oral lesion included plasmablastic lymphoma, squamous cell carcinoma, ulcerated Kaposi’s sarcoma, CD30+ anaplastic T-cell lymphoma and deep mycosis. Numerous
supplementary tests were performed, whereof the
relevant ones were:
• Positive HIV serology (CD4: 135, viral burden:
178,644).
• Direct and culture of palate biopsy for AFB and
fungi: negative.
• Serologies: Positive EBV and HHV-8; negative
HCV, HBV and HTLV I/II.
• Helical CAT of facial bones, chest, abdomen,
and pelvis: thickening of mucosa and moderate
resorption of the right side maxillar sinus floor.
Rest with no abnormalities discovered.
Biopsy of the leg plaque was consistent with Kaposi’s
sarcoma. Biopsy of the palate lesion was performed, reporting CD138+ plasmablastic lymphoma,
MUM1+, Ki-67+; negative CD3, CD20, and bcl6 (Dr. Narbaitz, Academia Nacional de Medicina)
(Figure 6). In situ hybridization for EBERs was positive. Bone marrow biopsy reported 20 percent interstitial lymphocyte infiltration, with the presence of CD138+ plasma cells in 5 percent of the
population.
The patient started antiretroviral therapy and
EPOCH protocol chemotherapy (etoposide, vin-
Figure 3. Erythematous purplish, lobated tumor, soft in consistency, and friable.
Figure 4. Cells with irregular hyperchromatic nuclei, with scarse cytoplasm; Homer-Wright pseudorosettes.
cristine, cyclophosphamide, doxorubicin, and prednisone) as continuous
infusion for 6 cycles. Noticeable improvement of the tumor lesion was
evidenced after the first cycle.
Case 4
An 87-year-old female phototype II patient consulted on March 2008 for
a painful 5-month evolution tumor on her left leg. She produced a biopsy performed 1 month before reporting “micro-lobated and chorded malignant fibrohistiocytic proliferation (negative for cytokeratins and melanocytic markers)”.
On posterointernal aspect of left leg, she had a tumor consisting of
three erythematous, bright and erosive surfaced lobes hard-to-elastic
areas, 7.3 mm thick, predominance of fusiform cell
type, high mitotic rate. Immunohistochemistry was
positive for S100 and vimentin, and partially positive for HMB45 and melan-A. Supplementary tests
were within normal ranges.
Taking into account the age of the patient, no adjuvant treatment was instituted. No relapses occurred
in 8-months follow-up.
Figure 5. Ulcerated exophytic palate tumor.
Case 5
A 46-year-old female phototype IV patient consulted on May 2008 for a 2-month evolution vulvar tumor. Physical examination evidenced a 12 ×
9 mm polypoid tumor lesion on left labium minus
(Figure 8). Ipsilateral inguinal lymphadenopathy
was identified.
Suggested presumptive diagnoses were amelanotic melanoma, squamous cell carcinoma,11 fibrosclerosing botryomycoma and adnexal carcinoma. Histopathology (punch) reported invasive nodal melanoma not less than 1.5 mm thick. Rapid
growth and development of peripheral pigmented
area with central ulceration was noted few days after hospitalization. Appropriate supplementary tests
were within normal limits, and excision of left labium minus and inguinal lymphadenectomy were
performed. The former evidenced invasive ulcerated
4.2 mm thick lymph node melanoma, epithelioid
cell type, high mitotic rate, and free margins. Lymph
node biopsy showed microscopic metastases. The
patient currently undergoes the third cycle of dacarbazine and interferon chemotherapy.
Comments
Figure 6. Proliferation of atypical cells with broad cytoplasm and eccentric nuclei.
in consistency, seated on a 15 × 10 cm indurated erythematous plaque (Figure 7). No lymphadenopathies were identified.
Suggested clinical differential diagnoses were amelanotic melanoma, dermatofibrosarcoma protuberans, cutaneous metastasis, B-cell cutaneous
lymphoma, and basal cell carcinoma.
Three punch biopsies were performed, two from the lobes and one
from the indurated plaque, which resulted in: lobated and ulcerated neoplasia; epithelioid sectors in both lobes; verticillated fusocellular sector (smaller lobe); intraepidermal activity (erythematous plaque).
Immunohistochemistry was positive for S100 and vimentin; HMB45 and
melan-A were positive in plaque only. Surgical excision with 3 cm safety margin and sentinel lymph node biopsy were decided, the latter reporting reactive lymphadenitis. Histopathology of the specimen was consistent with ulcerated and amelanotic polypoid melanoma with desmoplasia
The five tumors studied have low incidence in
everyday dermatology practice.
Angiosarcomas account for only 1-2 percent of all
sarcomas;2,3 they are highly malignant, with a tendency to recur locally and highly metastazising.3 In
our case, it is important to highlight the unusual location and that although the incisional biopsy was
consistent with retiform hemangioendothelioma
–a low-grade angiosarcoma of benign evolution–4
complete lesion excision demonstrated the presence of an aggressive tumor with radically different
prognosis.
Peripheral primitive neuroectodermal tumor
(pNET) is a rare small round cell-malignant tumor
seated on soft tissues, bone and solid organs in children. Incidence has not been estimated in adult patients due to its extremely low frequency.5
Plasmablastic lymphoma is a recently described
98 | M. I. Sanz, D. Feinsilber, C. Corbella, R. Schröh, M. L. Hassan
Figure 7. Tumor constituted by three erythematous lobes seated on an indurated plaque.
(1997) non-Hodgkin’s B-lymphoma predominantly
affecting HIV-positive individuals, with notorious
preference for the oral cavity.6,7 There are only 151
cases published in the literature.8
Desmoplastic melanoma is a rare melanoma variant
characterized by the presence of fusiform melanocytes in a dense fibrous stroma. As in our case, it appears in older ages, compared to conventional melanoma, it usually develops on photoexposed areas
of the head and neck, and tends to relapse locally.9
Compared to a conventional melanoma of equal
thickness, prognosis seems to be better, with lesser incidence of lymph node metastasis. However,
diagnosis is often delayed.9,10 In our case, we wish
to point out the presence of a tumor in the shape of
three lobes seated on an indurated plaque, with different histological aspect in each sector.
Although of low incidence, vulvar melanoma is the
second most frequent invasive cancer of this area, after squamous carcinoma, accounting for 5-10 percent of vulvar neoplasias and 1.3-2.3 percent of female melanomas.12 At our Department, of a total
of 552 melanoma patients, only 6 vulvar locations
were found (1.08 percent). Relevant to the reported patient was a history of gynecologic control 3
months before consultation, wherein no alteration
was informed.
We wish to highlight the difficult initial diagnosis of
these entities, which required numerous supplementary tests, and the request of interdisciplinary consulting in order to rule out other relevant differential diagnoses and define therapeutic approaches.
Likewise, it is appropriate to highlight the identification of these rare neoplasias at our Department in
a less than 6 month-period of time.
Acknowledgement
To Drs. Adriana Flores, Diego Parodi, Carolina
Escobar Correa, Lucrecia Costa, Amalia Gamallo,
Luciana Cabral Campana, José Luis Lemme, Ana
Clara Acosta, attending, resident, and fellowship
physicians of our Department, whose valuable collaboration made this work possible.
References
1.
2.
3.
Figure 8. Polypoid tumoral lesion on left labium minus.
Hassan ML, Zeballos E, Schroh R, Arra A. Componente
mixoide en metástasis de melanoma. Rev Argent Dermatol. 1995; 76:155-159.
Mark RJ, Poen JC, Tran LM. Angiosarcoma: a report of 67 patients and a review of the literature. Cancer. 1996; 77:24002406.
Marini MA, Casas JG, Baldrich MA. Angiosarcoma de la piel
de la cabeza. Arch Argent Dermatol. 2003; 53:207-212.
4.
5.
6.
7.
Calonje E, Fletcher C, Wilson-Jones E, Rosai J. Retiform hemangioendothelioma. A distinctive form of low-grade angiosarcoma delineated
in a serie of 15 cases. Am J Surg Pathol. 1994; 18:115-125.
Banerjee SS, Agbamu DA, Eyden BP, Harris M. Clinicopathological characteristics of peripheral primitive neuroectodermal tumour of skin and
subcutaneous tissue. Histopathology. 1997; 31:355-366.
Flaitz CM, Nichols CM, Walling DM, Hicks MJ. Plasmablastic lymphoma:
an HIV-associated entity with primary oral manifestations. Oral Oncol.
2002; 38:96-102.
Castillo J, Pantanowitz L, Dezube BJ. HIV-associated plasmablastic lymphoma: Lessons learned from 112 published cases. Am J Haematol. 2008;
83:804-809.
8.
Riedel DJ, Gonzalez-Cuyar LF, Zhao XF. Plasmablastic lymphoma of the
oral cavity: a rapidly progressive lymphoma associated with HIV infection. Lancet Infect Dis. 2008; 8:261-267.
9. Hawkins WG, Busam KJ, Ben-Porat L. Desmoplastic melanoma: a pathologically and clinically distinct form of cutaneous melanoma. Ann Surg
Oncol. 2005; 12:207-213.
10. de Almeida LS, Resquena L, Rüten A. Desmoplastic malignant melanoma: a clinicopathologic analysis of 113 cases. Am J Dermatopathol. 2008; 30:207-215.
11. Wetcher M, Gruber S, Haefner H. Vulvar melanoma: a report of 20 cases
and review of the literature. J Am Acad Dermatol 2004; 50:554-562.
12. Raspagliesi F, Ditto A, Paladino D. Prognostic indicators in melanoma of
the vulva. Ann Surg Oncol. 2000; 10:738-742.
Research Article
Susceptibility of different mouse strains to
Leishmania amazonensis infection
María Alejandra Falú1, María Fernanda García Bustos2, Cecilia María Parodi Ramoneda3, Ema Molina de Raspi4, Rubén Marino
Cardozo5, Rubén Cimino6, José Fernando Gil7, Jorge Leonardo Vasvari8, Miguel Angel Basombrío9
Winner work: Research Grant Prize - SAD 2007
Abstract
Background. In the most studied mouse model produced by Leishmania major, association was found between Th1 and Th2 immune responses,
and resistant (C57BL/6) and susceptible (BALB/c) strains, respectively. This dichotomy is not observed in models developed with other Leishmania
species. Therefore, advancing in the study of experimental models involving dominant species in our region represents an important challenge. The
purpose was to reproduce the disease in different mouse strains after infection with L. amazonensis.
Methods. To study the effect of the mice strain variable on susceptibility for L. amazonensis infection, a constant parasite inoculum was applied to
the studied strains. Response to infection was characterized in C57BL/6, BALB/c, and Swiss strains by measuring lesions, estimating parasite load and
histological analysis. Serum antibodies and cytokines were determinated by ELISA. Statistical analysis: ANOVA test.
Results. BALB/c showed maximum susceptibility to infection, Swiss demonstrated an intermediate phenotype, and C57BL/6 was the less susceptible strain. We obtained murine models reproducing different clinical forms comparable to human disease.
Conclusions. The results will be useful to extrapolate the conclusions of future therapeutic and prophylactic analysis in experimental models to human pathology (Dermatol Argent 2009; 15(5):334-339).
Key words: L. mexicana, animal models, mice.
Introduction
1. Dermatology Specialist and Public Health Specialist. Chief of practical applications,
Anatomy and Physiology Course, Universidad Nacional de Salta School of Health
Sciences.
2. Surgeon. Type II Doctorate Fellowship, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). Experimental Pathology Institute, Universidad Nacional
de Salta School of Health Sciences. Chief of practical applications, Anatomy and
Physiology Course, Universidad Nacional de Salta School of Health Sciences.
3. Doctor in Virology. CONICET Post-Doctoral Fellowship. Experimental Pathology Institute. Universidad Nacional de Salta School of Health Sciences.
4. Pathologist. Adjunct Professor of Pathophysiology, Universidad Nacional de Salta
School of Health Sciences.
5. Bachelor in Biology. Experimental Pathology Institute, Universidad Nacional de Salta School of Health Sciences.
6. Bachelor in Biology. Public Health Specialist. Biological Chemistry and Molecular
Biology Course, Universidad Nacional de Salta School of Natural Sciences.
7. Bachelor in Biology. Type I Doctorate Fellowship, CONICET. Biological Chemistry
and Molecular Biology Course, Universidad Nacional de Salta School of Natural Sciences.
8. Dermatology Specialist.
9. Doctor in Medicine. Principal Investigator, CONICET. Experimental Pathology Institute. Universidad Nacional de Salta School of Health Sciences.
Correspondence
María Alejandra Falú: Alazán 10, (4400) Altos de San Lorenzo, Salta, Argentine Republic
| [email protected]
Leishmania genus protozoan parasites cause a broad spectrum
of diseases known as leishmaniasis. In our setting, L. braziliensis is the main etiological agent of American tegumentary leishmaniasis (ATL), but not the only one: L. amazonensis and L.
guyanensis have also been described as circulating species in the
province of Salta.1-3
Murine models of cutaneous leishmaniasis (CL) are valuable
tools to study different disease-related mechanisms. The broad
variety of Leishmania species causing human ATL, combined
with host immune mechanisms, produce a great spectrum of
clinical, histopathological, and immunopathological manifestations, as well as different therapeutic responses to conventional drugs. The most studied murine model is produced by L.
major, where specific mouse strains are more resistant to infection (C57BL/6) and others are more susceptible (BALB/c). In
this model, there is correlation between a Th1 type cell-mediated immune response profile predominant in the more resistant strains and a Th2 type profile in the more susceptible strains.4-6 This dichotomy is not identified in other models developed with other Leishmania species. For example, models infected by L. braziliensis prove that both BALB/c and C57BL/6
strains may heal spontaneously.7 In the case of experimental in-
Susceptibility of different mouse strains to Leishmania amazonensis infection | 101
fection by the L. mexicana complex strains, such as
L. amazonensis, no relation is found between resistance and susceptibility with predominant Th1 or
Th2 responses. However, the observations obtained
from different groups do not always coincide, thus
indicating different degrees of susceptibility and resistance between the mentioned mouse strains.8-10 In
addition, human CL caused by L. major is usually
bening, producing a localized skin lesion eventually healing spontaneously and promotes life-long immunity against reinfection. In contrast, the disease
caused by L. amazonensis is characterized by chronicity, latency and tendency to develop metastatic foci
in nasal mucosa.11
Murine models may reflect clinical and histopathological features similar to those appearing in human
infection. Therefore, and due to the controversies
found in different studies on this matter, it is highly
relevant to move forward in the study of experimental models with dominant species in our setting.
Our objective was to reproduce the disease in different mouse strains, in order to demonstrate different
susceptibility to infection by L. amazonensis, the circulating species in the Province of Salta.
Design. In order to recognize the effect of the mouse strain variable upon susceptibility to L. amazonensis infection, a consistent parasite inoculum was
applied to the mice of each studied strain sample.
Population. Two 4-months-old male inbred
(BALB/c and C57BL/6) and one outbred (Swiss)
mouse strains were used.
Sample. Each experimental group consisted of 6
mice, and 6 non-infected mice of each strain were
used as controls.
Parasite culture, subcutaneous inoculation, and
measeurement of lesions. Parasites of a L. amazonensis strain (Biomedicine Institute, Universidad
Central de Venezuela), Ministry of Health and
Social Development, Caracas, Venezuela) were
kept by serial passages on BALB/c mice right
footpad (RFP). Isolation was performed by inoculating the RFP homogenate in modified
USMARU medium (blood-base agar as solid
phase containing 15 percent of defibrinated and
hemolyzed rabbit blood, and 1 percent glucose
saline). First through eighth passages were used.
Parasites were harvested during the exponential
phase, after 3 days culture (at room temperature,
in the dark) and washed (sterile phosphate-buffered saline [PBS] 1´, pH=7.2 with 100 IU/ml pe-
Figure 1. Normal BALB/c mouse footpad skin. Aspect of epidermis and dermis is visualized, with numerous sweat glands. Part of muscle tissue underlies dermis (H-E, ×10).
nicillin/streptomycin). Parasites as promastigotes in the exponential
phase were resuspended in PBS at a 2 × 107/ml concentration. A 50
μl volume containing 106 parasites was subcutaneously inoculated in
the RFP of each experimental animal. Progressive swelling (granuloma) caused by the infectious inoculum was assessed from day 7 to day
78 post-infection by measuring both mouse hind footpads with a special sub-millimeter caliper and computing the difference (delta, Δ).
Spleen parasite load estimate: splenic index. It was calculated by spleen
weight/body weight ratio. The presence of amastigotes was assesed by stained spleen histology sections (May-Grünwald-Giemsa).
Histology. It was performed 11 weeks post-infection. Primary infection
sites (RFP) were removed, fixed with 10 percent formaldehyde, processed (after 12-24 hours) and included in paraffin. Sections 5 μm thick were
stained with hematoxylin-eosin.
Protein Leishmania parasite homogenate. Promastigote forms of L.
amazonensis were cultured at 25°C in LITHSP culture medium containing 20 percent fetal bovine serum, penicillin (100 IU/ml) and streptomycin (100 g/ml). Parasites were concentrated by centrifugation,
10 minutes at 5000 rpm. Pellet was treated with 0.1 percent PBS-BSA
(phosphate saline buffer - bovine serum albumin), three times. Soluble
fraction extract was obtained by pellet lysis using lysis buffer (50 mM Tris
base pH=8, 1 mM EDTA, 1 mM 0.1 percent phenylmethyl sulfonyl fluoride [PMSF] Triton ×100), with sucrose addition (final concentration 10
percent). The parasite lysate was centrifuged 20000 ×g for 60 minutes at
4°C. An aliquote was separated from the supernatant (soluble homogenate) for quantification by the Bradford method.12 Supernatant was preserved at –20ºC until used.13
Enzyme-Linked Immunosorbent Assay (ELISA). Two mg L. amazonensis protein homogenate per well (in polystyrene plates) were used.
For plate adhesion, antigens were diluted in sodium carbonate buffer (pH=9.6) and incubated at 4°C (12 hrs). Blockade was done with
PBS-5 percent low fat milk (1 hour, room temperature). Serum was
added diluted 1/25 in PBS-1 percent milk for 1 hour (room temperature). All samples were analyzed in duplicate. Secondary mouse anti-
102 | M. A. Falú, M. F. García Bustos, C. M. Parodi Ramoneda, E. Molina de Raspi, R. Marino Cardozo, R. Cimino, J. Fernando Gil, J. L. Vasvari, M. Á. Basombrío
Results
Swelling comparison on different post-infection days.
Significant differences (p < 0.0001; ANOVA for iterated samples) were found between the different studied strains. BALB/c
strain mice showed mean swelling significantly larger in diameter than C57BL/6 and Swiss strains (Chart 1). This difference
started to be significant as from day 49 post-infection, and extended to the end of study (day 78 post-infection). In contrast,
the progressive swelling developed by C57BL/6 and Swiss strains was similar throughout the analyzed period of time.
Comparison of splenic index (SI). Splenic index was used as
disease progression indicator, and thus of the degree of infection susceptibility. Significant differences (p < 0.0001) between average SI of the different studied groups was demonstrated by ANOVA test in analyzing the various groups of experimentally infected mice and their respective control groups
8.58
6.44
Swelling (mm)
body (total biotin marked anti-IgG, SIGMA) was used diluted 1:2500, incubating plates for 30 minutes. After washing 3 times (0.1 percent PBS-Tween), 1:2000 diluted conjugate was added for 30 minutes. Ortho-phenylene diamine (OPD) was used as chromogen and 30 percent H2O2
(SIGMA) as substrate diluted in citrate buffer (pH=5.3).
After 30 minutes incubation at room temperature and
the dark, the reaction was stopped with 2M sulfuric acid.
Microplates were read at 490 nm.14-16
Determination of serum pro-inflamammatory and regulatory cytokines. Serum from the different experimental
groups were obtained on days 15, 22, and 80 post-infection
and kept at –20ºC until used. Dosage of IFN-γ (15-2000
pg/ml), IL-12 (15-2000 pg/ml) and IL-4 (4-500 pg/ml) in
said samples was done by commercial enzyme-immunoassay
(ELISA), following manufacturer’s instructions (ebioscience, San Diego, U.S.A.).
Statistical analysis. Progressive footpad swelling was analyzed by variance analysis (ANOVA) for iterated measurements, including statistical significance for treatment effect
(strain) and swelling progress (time), as well as interaction
of both. A comparison of means by orthogonal contrasts
was performed to determine the time when swelling differed according to strain. Splenic index and strain factor serology data were compared by one-way analysis of variance (ANOVA). It was fixed at α = 0.05 for all inferences, and
the null equality hypothesis was rejectd below that value; in
such case, Tukey’s mean comparison test was used (α = 0.05)
to check where differences were concentrated. Distributive
data normality was verified by the Shapiro-Wilk test.
4.29
2.15
0.00
25
36
Balb/C
64
42
49 60
Days post-infection
C57b
70
78
Swiss
Chart 1. RFP swelling progression in time in each strain of L. amazonensis infected mice.
(healthy mice). However, by using Tukey’s test, this difference was only found in the BALB/c strain infected mouse group
in relation to the remaining animals (C57BL/6 and Swissinfected experimental groups, and healthy controls of the three
strains; see Table 1). On the other hand, in coincidence with
these results, the BALB/c-infected mouse group was the only
showing presence of amastigotes in spleen, although in small
amounts.
Spleen and primary infection site histopathology. In the
BALB/c group, RFP showed wide skin ulceration, abscess formation and chronic moderately exacerbated inflammatory infiltrate invading the dermis, with abundant parasite-filled macrophages (Figures 1 to 6; Figure 1 is a microphotography of
normal skin as comparison). The spleen had abundant chronic
inflammatory reaction foci, and a moderate number of amastigotes. In the Swiss group, RFP showed skin abscess formation with Leishmania in a large amount, while spleen showed
macrophages with few parasites. In contrast, in the C57BL/6
group, RFP showed granuloma with few or no amastigotes.
The spleen of these mice showed macrophages with little or no
Leishmania.
Comparison of serology data. This analysis demonstrated that
average optical density values (OD) were significantly different
(p = 0.029) between some of the three studied mouse strains.
The Tukey’s test determined that average OD found in Swiss
strain mice was significantly higher than C57BL/6, while average OD of BALB/c did not express comparative differences.
All control group mice showed negative results (Chart 2).
Serum proinflammatory and regulatory cytokines. In all
analyzed cases and time periods, the obtained results were below the used technique detection range.
TABLE I. AVERAGE SPLENIC INDEX VALUES (MEAN ± STANDARD ERROR) FOUND IN DIFFERENT MOUSE STRAINS (INFECTED BY L. AMAZONENSIS AND NOT INFECTED).
Swiss
Swiss (control)
C57BL/6
C57BL/6 (control)
BALB/c
BALB/c (control)
p
2.51a ± 0.24
3.02a ± 0.26
2.66a ± 0.10
2.45a ± 0.11
7.34b ± 1.42
2.67a ± 0.19
< 0.0001
Letras distintas indican diferencias significativas de acuerdo con la prueba de Tukey (alfa = 0,05).
Comments
a
Figure 2. BALB/c mouse footpad skin inoculated with L. amazonensis and eutanized 11 weeks post-infection. Chronic inflammatory infiltrate is identified in dermis, with signs of vasculitis (H-E, ×10).
0.83
a
Optical density
Histopathological findings correlate with clinical
findings, with reference to lesion site swelling degree
and determined splenic indexes. In infected BALB/c
mice we found massive inflammatory reaction and
great amount of parasites in RFP, clinically correlated with large and progressive swelling. In spleen, we
also identified massive inflammatory reaction with
moderate number of parasites, consistent with the
higher splenic index found in comparison with the
other studied strains. These data indicate a remarkable L. amazonensis infection susceptibility of the
BALB/c strain. In analyzing the Swiss strain results,
we also found inflammation and a large number of
parasites in RFP, consistent with progressive evolution of lesions,a but less intense than the BALB/c
strain. In addition, Swiss mice spleen contains scarce
Leishmania, correlating with a lower splenic index.
Finally, the C57BL/6 group shows few parasites in
RFP and spleen, regressing swelling, and a low splenic index. These clinical and histological findings in
the C57BL/6 strain are consistent with a lower susceptibility to L. amazonensis infection.
On the other hand, in different studies carried out
by infection by different Leishmania species in humans and experimental mouse models, an increase
in total IgG levels may correlate not only to protection failure, but may also contribute to disease progression, while titration reduction may be associated
with improvement or effective treatment.17,18 The
critical role of circulating antibodies in the pathogenesis was also identified in L. amazonensis infection.19 In this work, serology results support clinical
findings, since the two strains with disease progression (Swiss and BALB/c) have higher average OD
values than C57BL/6 sera. Even though these differences are statistically significant in the Swiss strain,
this trend also appears in BALB/c. With reference
to Th1 and Th2-type serum cytokine production levels in the suggested model, they may result too low
for detection with the technique used (serum detection), not only in early, but also in extended infection periods of time.
In conclusion, by characterizing infection in each
mouse strain, we obtained murine models with
different degrees of resistance and susceptibility to L. amazonensis infection. In turn, these models reproduced different clinical forms which are
0.62
ab
0.41
b
0.21
0.00
Swiss
Balb/C
C57b
Chart 2. Average OD values (± standard error) found in different L. amazonensis inoculated mouse strains. Different letters indicate significant differences according to Tukey’s test (alfa = 0,05).
Although RFP swelling progression in Swiss does not show significant differences with C57BL/6, the curve trend differs, as seen in Chart 1: progression trend
in Swiss, and regression trend in C57BL/6. This might have been significantly expressed in a later analysis.
104 | M. A. Falú, M. F. García Bustos, C. M. Parodi Ramoneda, E. Molina de Raspi, R. Marino Cardozo, R. Cimino, J. Fernando Gil, J. L. Vasvari, M. Á. Basombrío
Figure 3. Zoom-amplified view of a segment of right lower part in Figure
2, observing dermal and pertiarteriolar inflammatory infiltrate with greater detail.
Figure 4. BALB/c mouse footpad skin, inoculated with L. amazonensis and eutanized 11 weeks post-infection. Chronic dermal inflammatory infiltrate is seen in this section, with a large number of Leishmania
amastigotes. Circle: subepidermal focus with macrophages loaded with amastigotes (H-E, ×40).
Figure 5. Zoom-amplified view of the Figure 4 segment enclosed in a circle. Macrophages loaded with Leishmania are identified with greater detail.
Figure 6. Subepidermally located L. amazonensis amastigotes in BALB/c infected mouse footpad (red
arrows). Morphology is clearly visualized, especially nucleus and kinetoplast (green arrows) (H-E,
×100).
comparable to human disease. These results shall be useful
to explore in depth host mechanisms capable of regulating
infection response, and to extrapolate subsequent therapeutic and prophilactic assays in experimental animals to human pathology.
9.
10.
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2000; 191:1063-1068.
Research Article
María Marcela Lustia1, Paula Carolina Luna2, Mabel Jimena Nocito3, María Jimena Soutelo4, M. Laura Castellanos Posse5,
Carolina Marchesi6, Nadia Guadalupe Cañadas5, Romina Garuti5, Miguel Ángel Mazzini7
Abstract
Introduction. Psoriasis is a chronic immune-mediated inflammatory disease that affects skin, nails, and joints. Its incidence varies from 2 to 4 percent. Advances in knowledge have led us to understand its systemic inflammatory feature. Various studies demonstrated an increased association
with some comorbidities such as insulin resistance, obesity, blood hypertension, and dyslipidemias, as well as a higher incidence of neoplasias and
autoimmune diseases.
Objective. To analyze if the described comorbidities are present in our Hospital patients.
Materials and methods. We retrospectically reviewed clinical records of 120 patients followed at the Psoriasis Section of Hospital Churruca, taking into
account gender, age, evolution time, personal and family history, previous treatments, and laboratory tests.
Results. Out of 120 patients, there were 44 females and 76 males, with ages ranging from 6 to 87 years (mean: 46.5 years). Of these, 54.5 percent of
females and 48.6 percent of males had arthralgias. With regard to laboratory tests, 71 patients had some type of carbohydrate metabolism alteration,
of whom only 12 patients had history of diabetes. In 92 patients there was at least one type of lipid metabolism alteration (increased total cholesterol: 56 patients; reduced HDL: 58 patients; increased LDL: 45 patients; increased triglycerides: 40 patients), and 12 patients had alterations of all lipid
fraction tests.
Conclusions. An integrated approach of the psoriasis patient is essential; thus the dermatologist must know the potential comorbidities in order to
enable an early detection and eventual referral to a specialist for adequate treatment (Dermatol Argent 2009; 15(5):340-343).
Key words: psoriasis, comorbidities, metabolic syndrome.
Introduction
1. Dermatologist, staff physician in charge of Psoriasis Section.
2. Dermatologist, staff physician.
3. Dermatologist, head of residents.
4. Endocrinologist, staff physician.
5. Residents.
6. Attending physician, course of Dermatology Specialist.
Dermatology Department, Endocrinology Department. Police Medical Complex “Churruca Visca”. Autonomous City of Buenos Aires, Argentine.
Correspondence
María Marcela Lustia: Av. Belgrano 3436 8º “A”, (1210) Autonomous City of Buenos Aires, Argentine Republic | [email protected] | dermatologiachurruca@gmail.
com
Psoriasis is a chronic and multisystemic inflammatory disease
mainly affecting skin and joints.1
Recently it has been demonstrated that psoriasis patients have
an increased risk of having cardiovascular disease and metabolic syndrome, among other disorders.
Diverse physiopathogenic hypothesis relating these two diseases include the responsibility of Th1 lymphocytes that release
mediators such as TNF-alpha, interferon, and interleukines-1
and 6 in skin and vessel wall tissue inflammation, thus favoring
atherosclerosis and carrying the risk of future coronary events.
The presence of increased visceral fat, construed as alteration
of the waist-hip ratio, one of the metabolic syndrome criteria,
would be an important source of TNF-alpha responsible for
inflammation.
The understanding of this causal relationship induces the evaluation of psoriasis patients from an integral point of view, as a
patient with a higher cardiovascular risk. The estimation of laboratory alteration percentages and the impact of such diseases on the life of our patients will enable us to compare with
estimated risks in papers published in literature, and develop
primary and secondary preventive strategies when treating patients with psoriasis.
Psoriasis: comorbidities in our community | 107
Objectives
To analyze if the above described comorbidities associated with
psoriasis appear in patients consulting the Psoriasis Section of
our Hospital.
A retrospective and observational study was performed, taking into account data from clinical records of 120 patients
followed at the Psoriasis Section of Hospital Churruca in
Buenos Aires.
Assessed were: gender, age, disease evolution time, familial
history of psoriasis, personal history, previous treatments, as
well as laboratory tests including: glycemia, insulinemia, lipid
profile, thyroid function.
Results
Of the 120 patients, 44 were females and 76 were males, with
ages ranging from 6 to 87 years, and a mean of 46.5 years.
Arthralgia appeared in 54.5 percent of females and 48.6 percent of males.
With regard to laboratory results, 71 (59 percent) patients had
some type of carbohydrate metabolism alteration (diabetes, altered fasting glycemia, glucose intolerance), whereof only 12
had previous diagnosis of diabetes. With reference to lipid metabolism disorders, 92 patients had at least one type of alteration, 56 had increased total cholesterol, 58 had reduced HDL,
45 had increased LDL, 40 had increased triglycerides, and 12
patients had alterations in all lipid fractions (total cholesterol,
HDL, LDL, and triglycerides).
Diagnosis of arterial blood hypertension was established in 38
of the 120 patients.
With reference to thyroid disease, 20 patients had hypothyroidism. Thyroid autoimmunity was found in 38 patients (32 percent), 28 males and 10 females, that is 41 percent of females
and 26 percent of males. Four patients had hyperthyroidism.
Discussion
Before the 1980’s it was believed that psoriasis was caused
by a keratinocyte proliferation alteration with secondary inflammatory infiltrate, but today psoriasis is considered a multisystemic inflammatory disease mainly affecting in skin and
joints.1,2
It affects both sexes equally, with an incidence of 2 to 3 percent
of the world’s population. It appears in a bimodal pattern, with
a first peak at 16-22 years (type 1 psoriasis) and a second peak
at 57-60 years (type 2 psoriasis). Mean age is 33 years.
Incidence is higher in first and second degree relatives than
in the general population. About 30 percent of psoriasis patients refer at least one affected relative. At least nine chro-
mosomic loci associated to psoriasis (known as PSORS 1 to
9) have been recognized.3,4 Between 35 and 50 percent of patients with a familial disease have PSOR 1 alteration; it appears clinically as psoriasis vulgaris in 90 percent of patients.3
The deep impact of psoriasis on the quality of life has been acknowledged, and it has been considered one of the most psychologically and socially disabling skin diseases, comparable
to patients with diseases such as cancer, arthritis, hypertension, cardiac disease, and diabetes.5-7
In recent years, particular importance has been given to comorbidities frequently associated to psoriasis, such as various
degrees of insulin resistance, arterial hypertension, dyslipidemia, and obesity; in turn favoring cardiovascular diseases.
We found that more than half of the group of patients studied
had some type of carbohydrate metabolism alteration (71 patients [59 percent], but only 12 patients were known diabetics [10 percent]). Altered postprandial glycemia is important, because of the higher association of cardiovascular complications related to high results 2 hours after ingestion.
At least four theories try to explain this higher incidence. Th e
first one assigns a critical role to genetic factors, since psoriasis diabetes, and lipid metabolism disorders have identified genetic loci, which are shared in some cases.9 In the second place, a fundamental role is assigned to chronic inflammation, similarly to other autoimmune diseases, such as rheumatoid arthritis, where coronary risk factors are also increased. Th1 lymphocytes release mediators such as TNF-α, INF,
and IL-1 and -6, responsible for skin and vessel wall tissue inflammation, thus favoring atherosclerosis. On the other hand,
the presence of increased visceral fat is an important source
of TNF-α, a fundamental cytokine in psoriasis.10 In the third
place, we found that psoriasis patients have a greater predisposition to environmental coronary risk factors such as sedentary lifestyle, smoking, and alcoholism. And last, the use
of drugs potentially increase the risk, such as methotrexate, a
known homocysteinemia producer, cyclosporin in relation to
AHT and retinoids with hyperlipidemia. The cause of such
greater association may not be just one of these factors, but
the combination of several of them.
The metabolic syndrome, as a global metabolism disorder
and the stage previous to diabetes, has been defined as a set
of clinical features deriving in insulin resistance. It may include various combinations of lipid and glucose disorders, obesity and hypertension. No consensus exists about clinical and
laboratory criteria defining a patient as a metabolic syndrome carrier, but it is generally admitted that this carrier state
represents the association of cardiovascular risk factors with
a pathophysiology related to insulin resistance, obesity and
type 2 diabetes.
In 1998, WHO suggested the following definition:9
Insulin resistance, construed as glucose intolerance, diabetes, or
HOMA alterations (insulin/glucose ratio), plus two of the following criteria:
108 | M. M. Lustia, P. C. Luna, M. J. Nocito, M. J. Soutelo, M. L. Castellanos Posse, C. Marchesi, N. G. Cañadas, R. Garuti, M. Á. Mazzini
•
•
•
•
Arterial hypertension.
Dyslipidemia
Central or general obesity
Microalbuminuria.
Patients with moderate to severe psoriasis, who have a more relevant inflammation, may constitute the group of greater risk,
with increased mortality rate in severe cases.3,11
The increased inflammatory mediators in these doseases have
pleiotropic effects on various processes such as angiogenesis,
adipogenesis, lipid metabolism, immune cell traffic, and epidermal proliferation.12
Gisondi et al. found that, taking into account all metabolic syndrome features, only hypertriglyceridemia and abdominal obesity were significantly relevant in psoriatic versus non-psoriatic
patients.
Some epidemiologic studies also indicate that psoriasis per se
may be an independent cardiovascular mortality risk factor,
but variables such as obesity and smoking were controlled, no
arterial hypertension risk increase was found.10,13
Different lipid metabolism abnormalities appeared in our
patient population: 56 patients showed decreased HDL, 40
had increased triglycerides, and 45 had increased LDL.
HDL decrease is intimately related to insulin activity reduction, which determines adipocyte free fatty acid
secretion.
Consequently, the liver produces more VLDL from triglycerides, which are exchanged by HDL and LDL cholesterol esters and generate HDL particles rich in triglycerides, which
are substrate of the hepatic lipase; in turn, this enzyme reduces the size of the HDLs, thus increasing kidney clearance and leading to its reduction in blood. Likewise triclyceriderich LDLs are hydrolyzed by the endothelial lipase to smaller
and denser LDL, which confers a higher cardiovascular risk
to this group of patients.
The acknowledgement of potentially associated comorbidities enables us to perform primary prevention, and in that sense, working with multidisciplinary teams trained on these systemic psoriasis associations is essential (by the same specialist or
referring the patient to a general physician.
From the above, we may conclude that a high percentage of our
study population has laboratory abnormalities falling within
the scope of a metabolic syndrome, or predisposing to its
development.
The high percentage of thyroid abnormalities found during the
study must be highlighted, particularly in the male population.
Although a male dominance exists in psoriasis, the number of
patients with thyroid disorders exceeds the general male population. This phenomenon may be possibly explained by both
psoriasis and thyroiditis being autoimmune diseases, in relation
to associations demonstrated in several published studies.
This study represents the initial step of an integral clinical follow-up of psoriatic patients. The acknowledgement of laboratory abnormality percentages in our population, together with
weight, arterial blood tension, and habit assessment may enable
us to modify cardiovascular risk factors, which if left unattended, may negatively affect the health and the quality of life of
our patients.
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Conclusions
Several studies demonstrate that psoriasis is related to an increased risk of having diabetes, insulin resistance, dyslipidemia,
and consequently, a higher risk of cardiovascular events. On
the other hand, the association of psoriasis and thyroid disorders has not been so extensively studied.
11.
12.
13.
Menter A, Gottlieb A, Feldman SR, Van Voorhees AS, et al. Guidelines of
care for the management of psoriasis and psoriatic arthritis. Section 1.
Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad Dermatol 2008; 58:826-850.
Chouela E. Patogénesis de la psoriasis. Dermatol Argent 1998; 4:203-217.
Mease PJ, Menter MA. Quality-of-life issues in psoriasis and psoriatic arthritis: Outcome measures and therapies from a dermatological perspective. J Am Acad Dermatol 2006; 54:685-704.
Christophers E. Genotyping Psoriasis. J Invest Dermatol 2003; 120:XVII.
Pellerano G, Buonsante Fieghelstein ME. Psoriasis. Comorbilidades. Asociaciones. Dermatol Argent 2009; 1:18-25. Langley RG, Krueger GG, Griffith CE. Psoriasis: epidemiology, clinical features, and quality of life. Ann Rheum Dis 2005; 64(Suppl II):ii18-ii25.
Fortune DG, Richards HL, Griffiths CE. Psychologic factors in psoriasis:
consequences, mechanisms, and interventions. Dermatol Clin 2005;
23:681-694.
Kimball AB, Gladman D, Gelfand JM, Gordon K, et al. National Psoriasis
Foundation clinical consensus on psoriasis comorbidities and recommendations for screening. J Am Acad Dermatol 2008; 58:1031-1042.
Kaye JA, Li L, Jick SS. Incidence of risk factors for myocardial infarction
and other vascular diseases in patients with psoriasis. Br J Dermatol 2008;
159:895-902.
Mallbris L, Granath F, Hamsten A, Ståhle M. Psoriasis is associated with lipid abnormalities at the onset of skin disease. J Am Acad Dermatol 2006;
54:614-621.
Puchulu F. Síndrome Metabólico. http://www.montpellier.com.ar/separatas/sepSindromemetabEndocrinD.zip
Azfar RS, Gelfand JM. Psoriasis and metabolic disease: epidemiology and
pathophysiology. Curr Opin Rheumatol 2008; 20:416-422.
Neimann AL, Shin DB, Wang X, Mangalis DJ, et al. Prevalence of cardiovascular risk factors in patients with psoriasis. J Am Acad Drmatol 2006;
55:829-835.
Original Article
Vulvar squamous cell carcinoma. Presentation of
28 patients
V. Parra1, F. Flores2, C. Sánchez de Giménez3, P. Daguerre4, V. García Llaver2, F. Galdeano2, N. Driban5
Abstract
Introduction. Vulvar squamous cell carcinoma constitutes from 1 to 4 percent of all female cancers, and is placed fourth among female genital tract
neoplasias.
Objectives. To determine the incidence of vulvar squamous cell carcinoma and identify degree of invasion.
Material and methods. An observational retrospective study was conducted on patients consulting for vulvar pathologies in a period of 4 years and
8 months. The study included 28 patients with clinical and histopathologic diagnosis of vulvar squamous cell carcinoma.
Results. From the total of patients assessed in our hospital office, 6.17 percent (28) had squamous cell carcinoma. The average age was 62.5 years. Of
the 28 patients, 64.28 percent (18) had invasive squamous cell carcinoma, and 35.7 percent (10) had vulvar intradermal neoplasia (VIN), where 4 developed from lichen sclerosus, 3 from epithelial dysplasia (differentiated VIN) and 3 from a bowenoid papulosis (usual VIN) diagnosis. All patients referred itching as dominant sign, and 60 percent of patients were smokers.
Conclusions. 28 cases of vulvar epidermoid carcinoma were studied, whereof 64.2 percent were invasive and 35.7 percent were VIN. Of the latter, 70
percent were differentiated VIN and 30 percent were usual VIN. This case material enabled us to learn about the incidence of squamous cell carcinoma in our setting, and to differentiate degrees of invasion and pathogenic factors (Dermatol Argent 2009; 15(5):344-349).
Key words: squamous cell carcinoma, vulvar intraepidermal neoplasia, vulvar carcinoma.
Introduction
Vulvar squamous cell carcinoma constitutes from 1 to 4 percent of female patient cancers, and is placed fourth within female genital neoplasias.1,2
According to clinical, pathological, and ethiological presentation, it is classified into two main categories (Chart
1):3,4
1. Head of Dermatology Department, Hospital “Luis Lagomaggiore”. Adjunct professor of the Dermatology Department.
2. Attending physicians of the Dermatology Department, Hospital “Luis Lagomaggiore”.
3. Staff Physician of the Gynecology Department, Hospital “Luis Lagomaggiore”.
4. Staff Physician of the Gynecology Department. Adjunct professor of the Gynecology Department, Universidad Nacional de Cuyo.
5. Named Professor of the Dermatology Department, Universidad Nacional de Cuyo.
Mendoza, Argentine Republic.
Correspondence
Viviana Parra: Guayaquil 115, (5519) Dorrego, Mendoza, Argentine Republic |
Ph.: 0261-4315618 | [email protected]
1. Vulvar intradermal neoplasia (VIN) or in situ carcinoma.
1.1. Usual or classic VIN (associated to HPV infection).
1.2. Differentiated VIN (associated with lichen sclerosus
and epithelial dysplasias).
1.3. Non-classified VIN.
2. Invasive carcinoma.
Usual VIN refers to human papilloma virus infection, especially serotypes 16 and 18, and less frequently serotypes 31,
33, 35, and 39. It appears in young women, and the incidence increases according to the age at onset of sexual intercourse, the number of sexual partners, smoking, and the
use of immunosuppressive drugs.5-10 Differenciated VIN appears in older women associated with lichen sclerosis in 15
to 40 percent of the cases.
110 | V. Parra, F. Flores, C. Sánchez de Giménez, P. Daguerre, V. García Llaver, F. Galdeano, N. Driban
Epidermoid
carcinoma
IN SITU
VIN
INVASIVE
USUAL
HPV
DIFFERENTIATED
NON-HPV
BOWEN‘S DISEASE
BOWENOID PAPULOSIS
LEUKOPLASIA
LICHEN SCLEROSUS
Chart 1. Classification of vulvar squamous carcinoma.
Invasive carcinoma penetrates the basement membrane, and it is classified
into four stages according to FIGO staging (International Federation of
Gynecology and Obstetrics).
Objectives
1.
2.
3.
4.
5.
To determine incidence of vulvar squamous carcinoma in our setting.
To detect average age and predominant signs and symptoms.
To obtain objective clinical and pathological invasion degree of lesions.
To identify dominant risk factors.
To determine types of therapy performed.
Material and methods (Chart 2)
A retrospective, observational study was performed, including 454 patients from the vulvar pathology consulting office of Hospital “Luis
Lagomaggiore” between January 2003 and August 2008. It must be
454 PATIENTS
28 EPIDERMOID CARCINOMA (6.17%)
18 INVASIVE (64.28%)
10 VIN (35.7%)
7 VINd 3 VINu
Chart 2. Material and methods.
highlighted that dermatologists and gynecologists
work jointly in this consulting office, which receives
referred patients exclusively; therefore, consulting
patients present themselves with pathologies not resolved at primary health centers.
The study enrolled 28 patients with clinical and
pathological diagnosis of vulvar squamous cell carcinoma. Clinical record and pathological and iconographic data archives were reviewed.
Results
Between January 2003 and August 2008, 454 patients of a 15 to 90-years age range consulted our office (mean 51.5 years). Diagnosis of squamous cell carcinoma was established in 28 patients, constituting
6.17 percent of our population. From the total of genital carcinomas, vulvar squamous cell carcinoma appeared in 5 percent of genital tract tumors, preceded
by cervical, endometrium, and ovary carcinomas.
Average age of squamous cell carcinoma incidence, including epitelial neoplasia and invasive carcinoma, was 62.5 years with the following age distribution: 20 to 30 years: 10.7 percent, 31 to 40 years:
7.14 percent, 41 to 50 years: 3.57 percent, 51 to 60
years: 22 percent, 61 to 70 years: 22 percent, 71 to
80 years: 19 percent, and 81 to 90 years: 15 percent.
From the 28 squamous cell carcinomas, 18 invasive
carcinomas (64.28 percent) (Figures 1, 2, and 3),
and 10 VIN (35.7 percent) (Figures 4 and 5) were
detected.
Vulvar squamous cell carcinoma. Presentation of 28 patients | 111
TABLE 1. LESION STAGING.
STAGE
N
%
S0
10
35.7%
S1
2
7.14%
S2
8
28.5%
S3
4
14.2%
S4
4
14.2%
Predominant symptom was itching in 85.7 percent of the cases, followed by pain in 42.8 percent of the cases. Most outstanding signs were
tumor in 32 percent, and bleeding in 40 percent.
Location coincided with the one described in
the literature: dominant in labia (57 percent),
followed by diffuse involvement forms (28 percent), clitoris (10.7 percent), and perineum in
one patient (3.57 percent).
Staging at the time of diagnosis was stage II or
higher in 58 percent in invasive carcinomas, and
stage 0 in VIN (Table 1).
Lapse from onset of lesions to consulting was
greater than 8 months in more than 80 percent
of the cases.
From the total of squamous cell neoplasias, 10
patients had diagnosis of VIN (35.7 percent),
four developed from lichen sclerosus, three
from epitelial dysplasia (differentiated VIN),
and three had diagnosis of bowenoid papulosis
(usual VIN).
Topic treatment with imiquimod cream was
used in 3 patients (10.7 percent), partial resection in 7 (25 percent), simple vulvectomy in 4
(14.2 percent), radical vulvectomy plus lymphadenectomy in 10 patients (35.7 percent), and palliative in 4 (14.2 percent).
Smoking was reported in 60 percent of the
patients.
Discussion
According to statistics, vulvar squamous carcinoma accounts for 1 to 4 percent of female tumors.
Incidence shows an exponential progressive increase
related to human papilloma virus infection, especially associated to serotypes 16, 18, 31, and 33.8
Predisposing factors are mainly age at onset of sexual
intercourse, number of partners, the presence of accuminated condiloma, immunosuppression, lichen
sclerosus, bad hygiene, and smoking.9,10
The number of vulvar squamous carcinomas (5 percent of genital tract carcinomas) found at Hospital
Figure 1. Epidermoid carcinoma on lichen sclerosus.
“Luis Lagomaggiore” exceeds the percentage referred to in the literature,
probably because it is a province reference center with higher number of
patients with rare pathologies.1,2
Average age of detected incidence was 62.5 years, which is expected to decrease with time, due to the exponential increase of human papilloma virus infection mainly affecting young women.
Lesion location and dominant signs and symptoms coincide with those
published in the international literature; noteworthy is the delayed patient consultation, with higher incidence of lesions in stage II or higher.11
Therapy varied according to type of lesion and degree of invasion.12-14
In the cases of usual type of intraepidermal vulvar neoplasia (bowenoid papulosis), imiquimod therapy was instituted three times a week
for 14 or 16 weeks, with good response.15,16 Differentiated VIN lesions, both from lichen sclerosus and severe epitelial dysplasia, were
mainly treated by local resection, except where lesions were clinically
multicentric, which were more extensively excised by surgery (simple
vulvectomy).17,18
112 | V. Parra, F. Flores, C. Sánchez de Giménez, P. Daguerre, V. García Llaver, F. Galdeano, N. Driban
With time, the trend is to reduce the size of vulvar excisions, because they cause great morbidity
without survival improvement. Radical vulvectomy
has been replaced by broad local excision with at
least 1 cm margins; it was found that in T1 (size lesion < 2 cm) there were no increase in recurrences,
and statistical data is lacking in T2 (size tumor > 2
cm) or higher.
Montones et al. found 50 percent recurrences with
less than 8 mm margins, while De Hullu reported 0
percent recurrences with larger than 8 mm margins,
and 22.5 percent with less than 8 mm margins.18
Current standard therapy is broad local excision
with 2 cm margins and unilateral or bilateral inguinofemoral lymphadenectomy by the triple incision technique (preferably preserving fascia lata
and saphenous vein) after detecting sentinel lymph
node.19-23
The purpose of this work was to determine vulvar
carcinoma incidence in our setting; noteworthy is
the delayed patient consultation, probably due to
lack of information.
Highlighted is the need of intensifying vulvar carcinoma prevention through extended information
diffusion, both among the general population and
health personnel, because only the thorough examination of the vulvar area, and the joint work of dermatologists and gynecologists may enable early detection of pre-neoplastic and neoplastic lesions.
Figure 2. Epidermoid carcinoma on clitoris.
References
1.
2.
3.
4.
5.
6.
7.
Wagner W, Prott FJ, Weissmann J, Niewöhner-Desbordes
U, Ostkamp K, Alfrink M. Vulvar carcinoma: a retrospective
analysis of 80 patients. Arch Gynecol Obstet 1999; 262:99104.
van de Nieuwenhof HP, van der Avoort IA, de Hullu JA. Review of squamous premalignant vulvar lesions. Crit Rev Oncol Hematol 2008; 68:131-156.
Sideri M, Jones RW, Wilkinson EJ, Preti M, et al. Squamous
vulvar intraepithelial neoplasia: 2004 modified terminology, ISSVD Vulvar Oncology Subcommittee. J Reprod Med.
2005; 50:807-810.
Bergeron C. New histological terminology of vulvar intraepithelial neoplasia. Gynecol Obstet Fertil 2008; 36:74-78.
Jones RW, Rowan DM, Stewart AW. Vulvar intraepithelial
neoplasia: aspects of the natural history and outcome in
405 women. Obstet Gynecol 2005; 106:1319-1326.
van Seters M, ten Kate FJ, van Beurden M. In the absence
of (early) invasive carcinoma, vulvar intraepithelial neoplasia associated with lichen sclerosus is mainly of undifferentiated type: new insights in histology and aetiology. J Clin
Pathol 2007; 60:504-509.
Leroy JL, Vinatier D, Collier F, Thomas P. Diagnosis of vulvar
intraepithelial neoplasias (VIN). Gynecol Obstet Fertil 2008;
36:190-199.
Figure 3. Invasive epidermoid carcinoma.
Vulvar squamous cell carcinoma. Presentation of 28 patients | 113
9.
10.
11.
12.
13.
14.
15.
Figure 4. Multicentric VIN.
16.
17.
18.
19.
20.
21.
22.
23.
Figure 5. VIN on lichen sclerosus.
8.
Hillemanns P, Wang X. Integration of HPV-16 and HPV18 DNA in vulvar intraepithelial
neoplasia. Gynecol Oncol 2006; 100:276-282.
Wassila S, Leila S, Noureddine H, Sihem H, et al. Prognostic
factors in squamous cell carcinoma of the vulva. About 35
cases Tunis Med 2005; 83:612-616.
Hussain SK, Madeleine MM, Johnson LG. Cervical and vulvar
cancer risk in relation to the joint effects of cigarette smoking and genetic variation in interleukin 2. Cancer Epidemiol Biomarkers Prev 2008; 17:1790-1799.
Preti M, Rouzier R, Mariani L, Wilkinson EJ. Superficially invasive carcinoma of the vulva: diagnosis and treatment. Clin
Obstet Gynecol 2005; 48:862-868.
Masak L, Hudakova G. Comparison of the treatment results
in the vulvar and clitoris squamous cell carcinoma. Neoplasma 1998; 45:377-379.
Chiesa-Vottero A, Dvoretsky PM, Hart WR. Histopathologic
study of thin vulvar squamous cell carcinomas and associated cutaneous lesions: a correlative study of 48 tumors
in 44 patients with analysis of adjacent vulvar intraepithelial neoplasia types and lichen sclerosus. Am J Surg Pathol
2006; 30:310-318.
Bousema MT, Romppanen U, Geiger JM, Baudin M, et al. Acitretin in the treatment of severe Echen sclerosus et atrophicus of the vulvae: a double-blind, placebo-controlled study. J Am Acad Dermatol 1994; 30:225-231.
Moore A, Edwards J, Hopwood J, Hicks D. Imiquimod for
the treatment of genital warts: a quantitative systematic
review. BMC Infectious Diseases 2001; 1:3.
Le T, Hicks W, Menard C, Hopkins L. Preliminary results of
5% imiquimod cream in the primary treatment of vulva
intraepithelial neoplasia grade 2/3. J Obstet Gynecol 2006;
194:377-380.
Rouzier R, Haddad B, Atallah D, Dubois P, Paniel BJ. Surgery
for vulvar cancer. Clin Obstet Gynecol. 2005; 48:869-878. van der Avoort IA, Shirango H, Hoevenaars BM, Grefte JM,
et al. Vulvar squamous cell carcinoma is a multifactorial disease following two separate and independent pathways.
Int J Gynecol Pathol 2006; 25:22-29.
Balega J, Van Trappen PO. The sentinel node in gynaecological malignancies. Cancer Imaging 2006; 28;6:7-15.
Wydra D, Sawicki S, Emerich J, Romanowicz G. Evaluation
of sentinel node detection in vulvar cancer. Nucl Med Rev
Cent East Eur 2005; 8:128-130.
Douay-Hauser N, Akerman G, Tulpin L, et al. Sentinel node
biopsy in vulvar cancer. Bull Cancer 2008; 95:701-706.
Johann S, Klaeser B, Krause T, Mueller MD. Comparison of
outcome and recurrence-free survival after sentinel lymph
node biopsy and lymphadenectomy in vulvar cancer. Gynecol Oncol 2008; 110:324-328.
Beriwal S, Heron DE, Kim H, King G, et al. Intensity-modulated radiotherapy for the treatment of vulvar carcinoma:
a comparative dosimetric study with early clinical outcome. Int J Radiat Oncol Biol Phys 2006; 64:1395-1400.
Original Article
Hydroa vacciniforme-like cutaneous T/NK-cell
lymphoma, nasal type
Mabel Dacal1, Eduardo Formentini2, Ada Vaccarezza1, Antonio Arra3, Liliana Gagliardi3
Abstract
Hydroa vacciniforme-like cutaneous T/NK-cell lymphoma is a rare lymphoma mainly affecting Asian and Latin American inndian children. It starts
with swelling, vesicles, crusts, and vacciniform scars of extended evolution. Its severity increases with time and may cause disfigurement, thus physically and psychologically affecting patients.
Generally, these patients have poor prognosis due to late detection of the lymphoma. A 20-year-old female patient with nasal-type NK-cell lymphoma starting with hydroa vacciniform (HV) of poor evolution at the age of 13 years is reported. The authors suggest that patients with atypical HV may
improve with treatment at an early stage (Dermatol Argent 2009; 15(5):350-353).
Key words: T/NK-cell lymphoma, nasal type; hydroa-like cutaneous T/NK-cell lymphoma.
ABREVIATURAS
AFB: acid-fast bacillus.
ALP: alkaline phosphatase.
ANCAs: antineutrophil cytoplasmic antibodies.
Anti-EBNA: anti-Epstein-Barr virus nuclear antigen antibody.
Anti-MPO: antimyeloperoxidase antibody.
Anti-PR3: antiproteinase 3 antibody.
Anti-VCA: anti-Epstein-Barr virus capside antigen antibody.
CAT: computerized axial tomography.
CHOP: cyclophosphamide, doxorubicin, vincristine, and methylprednisone.
EBER: small size EBV nuclear RNA.
EBV: Epstein-Barr virus.
GOT: glutamic-oxalacetic transaminase.
GPT: glutamic-piruvic transaminase.
H-E: hematoxylin-eosin.
HV: hydroa vacciniforme.
LDH: lactic dehydrogenase.
LMP-1: latent membrane protein 1.
NK: natural killer.
Introduction
1. Staff Dermatologist.
3. Pathologist of the Pathology Department. Hospital General de Agudos “Francisco
Santojanni”. Autonomous City of Buenos Aires, Argentine Republic.
Correspondence
Mabel Dacal: Las Heras 1553 PB, (1704) Ramos Mejía, Buenos Aires, Argentine Republic | Ph: (011)4654-8566 | [email protected]
HV-like T-cell cutaneous lymphoma is a rare lymphoma that
mainly affects children and is associated with Epstein-Barr virus (EBV). Patients, almost exclusively from Latin America and
Asia, develop HV-like papulovesiculous lesions associated with
swelling, bullae, ulcers, crusts, and scars involving both areas
exposed and not exposed to solar radiation. We report a HVlike NK lymphoma, nasal type.
Hydroa vacciniforme-like cutaneous T/NK-cell lymphoma, nasal type | 115
Clinical case
A 20-year-old female Bolivian patient residing
in the Province of Buenos Aires since she was 13
years old, without significant inherited-familial
history. Personal history: measles. According to
the patient, it started at the age of 6 years with facial erythema and swelling which increased with
solar exposure and did not totally remit in winter. She consulted at several hospitals and reached HV diagnosis; she was treated with chloroquine and subsequently with methylprednisone. She was admitted at our hospital in July 2007
with left basal pneumonia. Interconsultation with
Dermatology was requested for facial erythema
and swelling with vesicles, erosions, crusts, and
smallpox-like scars affecting both cheeks, the forehead and the chin (Figure 1). There was no relation with solar exposure, and no reference to
hypersensitivity to mosquito bites. With clinical diagnosis of HV, a skin biopsy was performed, which resulted in the presence of epidermal
vesicles containing fibrin and inflammatory cells,
and perivascular inflammatory infiltrate in dermis consistent with HV (Figure 2). Laboratory:
blood cell count within normal limits. ESR 101
mm/h. Liver function tests: GPT 36 U/L, GOT
42 U/L; ALP 334 U/L. Treatment with methylprednisone 8 mg/day was instituted, with improvement of the clinical picture. The patient referred events of chronic sinusitis and hemoptisis,
and we requested facial bone and chest CATs,
which showed mucosa thickening in paranasal
areas and irregularities of mucosa in nasal fossae
and turbinate bone; and bronchial ectasia at lung
basal segments. In October, she presented intense facial swelling and an ulcerated crusty lesion at
left nasal lateral level (Figure 3), which evolved
into perforation of the nasal wall. It was accompanied with fever, rinorrhea and left sinusopathy,
and was treated with levofloxacin 500 mg/day
and methylprednisone 40 mg/day. A new laboratory test showed slight decrease in hematocrit and
neutrophilia. EBV serology: anti-EBNA IgG +;
anti-VCA IgG +; anti-VCA IgM -. ANCAs++.
Anti-PR3 0.1 U (N < 3.5 U). Anti-MPO 7.5 U
(N < 9 U). Sputum AFB: negative. Normal porphyrin test. LDH 822 U/L. Beta 2 microglobulin
6.41 mg/l. The clinical picture worsened and suspecting a diagnosis of HV-like T-cell lymphoma,
biopsy was obtained from the borders of the nasal
ulcer and mucosa, with negative results for lymphoma. Therefore, a surgical biopsy from left side
Figure 1. Involvement of forehead, cheeks, and chin with swelling, erythema, vesicles, crusts, and smallpox-like scars.
Figure 2. Presence of epidermal vesicle and dermal perivascular infiltrate with lymphocyte dominance (H-E).
of nasal septum was obtained and analyzed with H-E, resulting in the
identification of a small-to-medium size monomorphic lymphoid cell
population (Figure 4) involving all the dermis and partly migrating to
epithelium, with the presence of atypical mitosis, angiocentricity, and
areas of necrosis. Immunomarkers: weak intracytoplasmic CD3; positive CD56 (Figure 5); positive TIA-1 (Figure 6), and negative LMP1. She was referred to the Hematology Department with diagnosis
of T/NK lymphoma and treated with a cycle of cyclophosphamide,
doxorubicin, vincristine, and methylprednisone (CHOP), but the patient developed septicemia and died. No autopsy was performed.
116 | M. Dacal, E. Formentini, A. Vaccarezza, A. Arra, L. Gagliardi
Comments
HV is a chronic photosensitive disorder characterized by the presence of recurrent vesicles and necrotic ulcerations which heal with smallpox-like scars,
located on photoexposed areas; starting in childhood, it usually resolves spontaneously during adolescence and does not affect the general condition.1
In 1986, Oono et al.2 reported HV associated with cutaneous lymphoma in a 16-year-old patient, where HV
lesions had appeared at 6 years of age; evolution was
atypical, since lesions were not photoinduced, did not
improve with age and affected general health.
Subsequently, several similar cases were reported,
mostly in Asian and Latin American Indian children.3-5 Recently, some authors suggested that these cases were related to lymphoproliferative processes leading to the development of a cutaneous T-cell
lymphoma.3-8 Chen et al.7 reported in 2002 a case of
CD8+ T-cell cutaneous primary lymphoma with
lesions similar to HV; these authors suggested that
lymphoma may appear with early HV-like lesions, or
develop years after their occurrence. Likewise, Feng
et al.9 report a case of CD8+ T-cell lymphoma in
a 12-year-old girl with hypersensitivity to mosquito bite since her first years of life; and they believed
this hypersensitivity to insect bite was a nonspecific
expression of altered immune response. A HV-like
form associated to Hodgkin’s lymphoma and node
lymphoma has also been described in adults.10,11
The presence of EBV has been mentioned in HV,
HV-like and other lymphoproliferative processes;
this suggests that this virus may trigger such processes in genetically predisposed patients and in a specific environment. Early exposure to EBV may cause immunotolerance of infected cells, allowing their
continuous proliferation. This is possibly caused by
loss or reduced expression of LMP-1 by neoplastic
cells, thus becoming non-detectable by the immune
system. It was also found that EBER (EBV-encoded
small nuclear RNA) becomes more positive as the
disease progresses; thus whether it is the cause or
a consequence of the disease remains uncertain.12
For some authors, this association of virus and lymphoproliferative processes possibly reflects endemic
EBV distribution and may not suffice to justify virus association with lymphoma.13 However, others
believe that EBV infection in a genetically susceptible population would firstly induce hypersensitivity
to mosquito bite and hydroa vacciniforme, and later
progress in a small number of cases to atypical hydroa vacciniforme or centrofacial lymphoma, possibly causing death by hemophagocytic syndrome.14
Figure 3. Ulcerated crusty lesion at the level of the left nasal side.
Figure 4. Small-to-medium-size lymphoid tissue pleomorphic infiltration with atypical mitosis (H-E).
Thus, typical and atypical forms of HV are included in the scope of cutaneous disorders induced by EBV-infected T-cells.15
In relation to the therapeutic approach of atypical HV, some authors suggest maintaining an expectant behavior, and others suggest treatment
with thalidomide, cyclophosphamide, or corticosteroids.4
This case clearly manifested clinical and atypical HV, where the presence of lymphoma could be identified in the nasal septum biopsy specimen,
with positive immunohistochemical markers for NK lymphoma.
Nasal type T/NK lymphoma, formerly known as midline malignant
granuloma, is an aggressive neoplasia that may derive from NK-cells
(CD56+) or T-cells (CD56-); incidence is higher in Asia and Central
and South America, predominantly in young males. It appears as a rapidgrowing destructive centrofacial tumor tending to ulcerate; in addition
to its nasal and oropharyngeal location, the skin is the second site of involvement. By histology it is proved to consist of small to large cells with
pale cytoplasm and irregular nucleus, which constitute a dense infiltrate
in dermis, and occasionally in hypodermis. Immunohistochemistry generally marks positive CD2+, CD56+, CD3-, CD3 citoplasmic +, TIA1+,
Grazima B+, Perforin+, LMP-1+ and EBV usually. Internal organ dis-
Hydroa vacciniforme-like cutaneous T/NK-cell lymphoma, nasal type | 117
References
1.
2.
3.
4.
Figure 5. CD56+ immunomarkers.
5.
6.
7.
8.
9.
10.
Figure 6. TIA-1+ immunomarkers. Angiocentricity is identified.
semination is common, with poorer prognosis. Treatment of nasal T/
NK lymphoma includes cyclophosphamide, doxorubicin, vincristin and
prednisone.16
Conclusions
Evidence exists that the presence of EBV in lymphoproliferative processes is an important factor in etiopathogenesis of such processes, with direct correlation. Thus, when cells were scarce, a spontaneous involution
occurred; while a larger amount of infected cells correlated with development of lymphoma.12 Like other authors, we believe that atypical HV
falls within the scope of lymphoproliferative processes6,9,14 and is a lymphoma from the start. Consequently, we suggest that polychemotherapy treatment is justified in early stages of the cases of extended evolution
affecting general condition and causing intense physical and psychological
suffering due to this disfigurating disease, thus allowing the improvement
of the currently severe prognosis with late treatment of these patients.
We believe this case report is relevant, since no reports of this rare lymphoma have been found in the national literature.
11.
12.
13.
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16.
Hawk JLM, Norris PG, Hönigsmann H. Respuestas anormales a la radiación ultravioleta: idiopáticas, probablemente
inmunes y fotoexacerbadas. In: Fitzpatrick TB, Fritberg IM,
Eisen AZ y cols (eds.). Dermatología en medicina general.
Buenos Aires: Ed. Médica Panamericana; 2005:1448-1449.
Oono T, Arata J, Masuda T, Ohtsuki Y. Coexistence of hydroa vacciniform and malignant lymphoma. Arch Dermatol 1986; 122:1306-1309.
Ibarra-Durán G, Rodríguez-Jurado R, Moguer L, ValenciaMayoral P. Linfoma T cutáneo angiocéntrico en una niña
con hidroa vacciniforme. Dermatol Rev Mex 1991; 35:344348.
Ruiz-Maldonado R, Parrilla FM, Orozco-Covarrubias ML, Ridaura C, et al. Edematous, scarring vasculitic panniculitis: a
new multisystemic disease with malignant potential. J Am
Acad Dermatol 1995; 32:37-44.
Magaña M, Sangüeza P, Gil-Beristain J, Sanchez-Sosa S, et
al. Angiocentric cutaneous T-cell lymphoma of childhood
(hydroa-like lymphoma): A distinctive type of cutaneous Tcell lymphoma. J Am Acad Dermatol 1998; 38:574-579.
Iwatsuki K, Ohtsuka M, Akiba H, Kanebo F. Atypical hydroa vacciniform in childhood: From a smoldering stage
to Epstein-Barr virus-associated lymphoma malignancy. J
Chen HH, Hsiao CH, Chiu C. Hydroa vacciniformes-like primary cutaneous CD8-positive T- cell lymphoma. Br J Dermatol 2002; 147:587-591.
Quero-Hernández A, Sánchez-Navarro LM, Socorro-López
Z, Carrasco-Daza D. Linfoma cutáneo angiocéntrico de células T que semeja hidroa vacciniforme. Bol Med Infant Mex
2005; 62:50-55.
Feng S, Jin P, Zeng X. Hydroa vacciniformes-like primary
cutaneous CD8-positive T-cell lymphoma. Eur J Dermatol
2008;18:364-365.
Stenger GG, Dittrich C, Hönigsmann H, Moser K. Permanent cure of hydra vacciniformes after chemotherapy for
Hogdkin’s disease. Br J Dermatol 1988;119:684-685.
Yoon TY, Kim YG, Kim JW, Kim MK. Nodal maginal zone lymphoma in association with hidroa vacciniforme like papulovesicular eruption, hypersensitivity to mosquito bites and
insect bite-like reaction. Br J Dermatol 2005;153:210-212.
Iwatsuki K, Ohtsuka M, Harada H, Gangwen H, et al. Clinicopathologic manifestations of Epstein-Barr virus associated cutaneous lymphoproliferative disorders. Arch Dermatol 1997;133:1081-1086.
Sangüeza O, Magaña M. Atypical hydroa vacciniforme in
chilhood: From a smoldering stage to Epstein-Barr virusassociated lymphoma malignancy. Reply J Am Acad Dermatol 1999;40:283.
Bravo Puccio F. Nuevas enfermedades dermatológicas inducidas por virus. Diagnóstico 2004;4:176-179.
Itwatsuki K, Satoh M, Yamamoto T Oono T, et al. Pathogenic link between Hydroa vacciniforme and Epstein Barr virus associated hematologic disorders. Arch Dermatol 2006;
142:587-595.
Gallerano VB, Danilo C, Consigli JE, Papa M y cols. Linfoma
angiocéntrico T/NK nasal. Rev Arg Derm 2003;9:290-293.
Research Article
A clinical-epidemiological study
Matías Federico Stringa1, Carla Castro2, Alejandro Daniel Olivera3, Paula Bonavía4, Osvaldo Jorge Stringa5, Raúl Valdez6
Abstract
Introduction. Classification of primary vasculitis is difficult and little is known about prevalence in childhood.
Objective. To determine frequency, epidemiological data and clinical features of primary vasculitis in pediatric patients between May 2000 and May
2008.
Design. Observational, retrospective and descriptive study.
Materials and methods. We reviewed medical record data base of primary vasculitis in pediatric patients of between 0 and 16 years of age that
met the established inclusion criteria.
Results. 47 patients, 29 boys and 18 girls were included. The average presentation age was 4 years (range: 7 months to 13 years). The most frequent
vasculitis was Henoch Schönlein purpura with 33 cases (70 percent), followed by Kawasaki disease with 9 patients (19 percent), acute hemorrhagic
edema of infancy with 3 cases (6 percent) and cutaneous panarteritis nodosa and Churg-Strauss syndrome with 1 case each (2 percent).
Conclusions. Primary vasculitis is rare in childhood. Henoch Schönlein purpura was most frequent in our patients. Kawasaki disease was the vasculitis with highest morbidity. Acute hemorrhagic edema of infancy was less frequent, showed less morbidity and appeared in children under two years
of age. We also identified 2 cases of lower frequency vasculitis such as cutaneous panarteritis nodosa and Churg-Strauss syndrome (Dermatol Argent
2009; 15(6):411-419).
Key words: vasculitis, vasculitides, childhood, children.
1.
2.
3.
4.
5.
6.
Head of Residents.
Head of Pediatric Dermatology Section.
Pediatric Dermatologist.
4º year Medical Resident.
Deputy Head of Dermatology Department.
Head of Dermatology Department.
ABBREVIATIONS
ACR: American College of Rheumatology
AHEI: Acute hemorrhagic edema of infancy
ANCA: Antineutrophil cytoplasmic antibodies
ASTO: Antistreptolysin O antibodies
CPAN: Cutaneous panarteritis nodosa
CSS: Churg-Strauss syndrome
ESPN: European Society of Paediatric Nephrology
EULAR: European League against Rheumatism
HSP: Henoch-Schönlein purpura
ICD-9: Ninth review of the International Classification of Diseases
KD: Kawasaki disease
PAN: Panarteritis nodosa
PReS: Paediatric Rheumatology European Society
TA: Takayasu arteritis
TAA: Temporal artery arteritis
WG: Wegener’s granulomatosis
Hospital Universitario Austral. Buenos Aires, Argentine Republic.
Introduction
Correspondence
Matías Federico Stringa: Hospital Universitario Austral, Avenida Perón 1500. Derqui,
Pilar, Buenos Aires, Argentine Republic |
Ph: 02322-48-2983 | [email protected]
The term vasculitis refers to a broad group of clinically heterogeneous diseases with a common histological substrate, the presence of inflammatory infiltrate in the thickness of the blood
vessel wall.1
Primary vasculitis in children: A clinical-epidemiological study | 119
In idiopathic or primary vasculitis, the triggering event has
not been identified, and secondary vasculitis occurs in relation
to specific factors such as infections, allergic reactions, adverse drug effects, and different neoplasias.2 Primary or idiopathic
forms comprise about 45-55 percent of the cases.3-5 Several
classifications have been suggested in order to unify diagnostic
criteria, quite a difficult goal to achieve, especially because etiologies are unknown, there is overlapping in clinical manifestations of different entities, and defining patognomonic or specific signs are lacking.6-10
In 1993, a group of experts gathered in Chapel-Hill (North
Carolina, U.S.A.) reached consensus about a classification intended to become an international unifying reference, where
10 types of vasculitis are defined.11
Many vasculitis affect both adults and children, for example
Henoch-Schönlein purpura (HSP) and secondary vasculitis.
But some vasculitis, such as Kawasaki disease (KD) and acute hemorrhagic edema of infancy (AHEI), involve children exclusively; others, such as temporal artery arteritis (TAA) do
not affect children; and yet others, such as nodose panarteritis (PAN) or Wegener’s granulomatosis (WG), have different
etiological, clinical and prognosis features in pediatric patients.
In 2006, the European League against Rheumatism (EULAR)
was convened through the vasculitis work group of the
Paediatric Rheumatology European Society (PReS), with the
collaboration of colleagues from the American College of
Rheumatology (ACR) and the European Society of Paediatric
Nephrology (ESPN), with the purpose of establishing vasculitis classification criteria in children: HSP, KD, PAN, WG, and
Takayasu arteritis (TA).12 This consensus did not assess criteria
for Churg-Strauss syndrome (CSS) or AHEI.
Little is known about vasculitis incidence and prevalence at pediatric age, partly due the scanty amount of statistical records.
According to data obtained from some reference centers, the
condition may account for between 1 and 4 percent of pediatric rheumatology consultations.13,14 Skin is a frequently involved organ, either from onset or during the evolution of the disease; however, as far as we know, no statistics on this disease
exist in pediatric dermatology settings in Argentina.
The purpose of our work was to determine frequency, epidemiological features, and clinical findings of primary vasculitis
observed in pediatric patients consulting our hospital between
May 2000 and May 2008.
The design of our work is observational, descriptive and retrospective. It was performed by revision of clinical history medical records of patients with diagnosis of primary vasculitis, according to our hospital data base diagnosis codes (PECTRA
2000 system).
The study period comprised from May 1, 2000 to May 1, 2008.
Inclusion criterion was diagnosis of primary vasculitis in pe-
diatric patients (from birth to 16 years of age). To establish
this diagnosis, we used the criteria from the EULAR/PReS12
consensus for HSP, KD and cutaneous panarteritis nodosa
(CPAN), Chapel-Hill11 diagnostic criteria for CSS, and clinical-epidemiological data appearing with a frequency equal or
higher than 80 percent in a systematic revision of 294 patients
with AHEI diagnosis15 (Table 1).
The studied variables were the frequency of the different types
of vasculitis and distribution by gender and age, generally and
in particular, for each entity: cutaneous involvement, type and
location of lesion, skin biopsy, history of previous infectious
process, treatment and outcome. In addition, the following
particulars were studied for each condition:
HSP: The presence and location of abdominal pain, arthritis or
arthralgia, renal involvement defined by hematuria and/or proteinuria and/or alteration of renal function
KD: The presence of at least 5 days of persisting fever, cervical
lymphadenopathy, coronary arterial involvement detected by
echocardiography, involvement of another organ.
AHEI: General condition of the patient, involvement of
another organ.
CPAN: Titration of antineutrophil cytoplasmic antibodies
(ANCA); previous history of clinical streptococcal infection, or diagnosis by laboratory data (streptest and/or culture and/or increase of antistreptolysin O antibodies (ASTO)
for a normal value <200 IU/ml); involvement of another
organ, myalgia or muscular tenderness; arterial hypertension according to age and gender percentiles, as suggested
by the Argentine Pediatric Society [Sociedad Argentina de
Pediatría]; the presence of mono- or polyneuropathy, and testicular pain or tenderness.
CSS: Personal history of asthma, eosinophilia, mono- or polyneuropathy, fixed pulmonary infiltrates assessed with image
studies (chest X-ray, computarized tomography).
Statistical analysis of 95 percent confidence interval (95% CI)
was done by VCCSTAT 0.12 version beta 2002.
Results
Of the 62 cases referred as pediatric primary vasculitis found
according to the ninth revision codes of the International
Classification of Diseases (ICD-9), 47 patients met the inclusion criteria (Table 2).
Twenty nine cases (62 percent; 95 percent CI: 46-75 percent)
were male and 18 (38 percent; 95 percent CI: 24-53 percent)
were female. Average presentation age was 4 years, with a range
of 7 months to 13 years.
Most frequent vasculitis was HSP with 33 records (70 percent; 95 percent CI: 55-82 percent). Following in frequency
were KD with 9 cases (19 percent; 95 percent CI: 9-33 percent), AHEI with 3 cases (6 percent; 95 percent CI: 1-17 percent), and CPAN and CSS with 1 case (2 percent; 95 percent
CI: 0.1-11 percent) each (Chart 1).
120 | M. F. Stringa, C. Castro, A. D. Olivera, P. Bonavía, O. J. Stringa, R. Valdez
TABLE 1. DIAGNOSTIC CRITERIA.
2% 2%
Henoch-Schönlein purpura12
CSS (1 case)
Palpable purpura in the presence of one of the following criteria:
6%
• Diffuse abdominal pain
CPAN (1 case)
• Skin biopsy with predominant IgA deposit
• Arthritis or arthralgia (acute, any joint)
19%
• Renal involvement (hematuria and/or proteinuria)
AHEI (3 cases)
12
Kawasaki disease
KD (9 cases)
At least 5 days persistent fever, in addition to four of the following criteria:
•
Changes in peripheral extremities or perineal area
•
Polymorphic exanthema
•
Bilateral conjunctival injection
•
Lip and oral cavity changes
•
Cervical lymphadenopathy
70%
HSP (33 cases)
Chart 1. Distribution by included vasculitis types.
In the case of arterial coronary involvement (detected by echocardiography)
and fever, less than 4 criteria suffice (the exact figure is being subject to review).
Cutaneous panarteritis nodosa12
•
Painful nodules and purpuric lesions without systemic involvement
•
Skin biopsy with non-granulomatous necrotizing vasculitis
•
Negative antineutrophil antibodies (ANCA) test
•
Association with Group A β-hemolytic Streptococcus pyogenes
Acute hemorrhagic edema of infancy15
•
Age range 6 to 24 months
•
Good general condition, without systemic involvement, resolution without
sequelae
•
Purpuric target-like lesions
•
Edema of hands and feet
•
Normal platelet count (= 150000/mm3)
Churg-Strauss syndrome11
Four or more of the following criteria:
•
Asthma
•
Skin biopsy with eosinophile extravasation
•
Peripheral neuropathy (mono- or polyneuropathy)
•
Eosinophilia > 10%
•
Sinusitis
•
Non-fixed pulmonary infiltrate in chest X-ray
Henoch-Schönlein purpura (Table 3)
Fourty seven cases of HSP were reported, whereof 33 fulfilled inclusion criteria. Nineteen patients (58 percent) were
male and 14 (42 percent) were female. The average age at
onset was 5 years, with a range of 2 to 12 years. All cases
showed palpable purpura involving lower extremities with
the classic distribution pattern on the buttocks and legs,
and 8 cases also had purpura lesions in upper extremities,
4 in trunk, and 2 in the face (Figures 1 and 2). One patient showed bullous and necrotic lesions. Four patients had
scalp edema, associated with pain in 2 cases. Two patients
had scrotal swelling. Arthritis or arthralgia appeared in 90
percent (30/33): 22/30 in ankles, 10/30 in knees, 5/30 in
hands and wrists, and less involvement in other joints such
as feet, elbows and vertebral area. Abdominal involvement
was present in 57 percent (19/33) of patients, and abdominal pain was the most frequent symptom. In 7 cases, abdo-
TABLE 2. STUDY POPULATION
Vasculitis
n
Average age (range)
HSP
KD
AHEI
CPAN
CSS
33
9
3
1
1
Total
47
5 years (2 - 12 years)
23 months (4 months - 7 years)
13 months (7 - 23 months)
11 years
13 years
4 años (7 months
- 13 years)
TABLE 3. HENOCH-SCHÖNLEIN PURPURA.
HSP
total n = 33
Palpable purpura
33
Arthritis or arthralgia
30
Abdominal pain
19
Renal involvement
8
History of infection
18
History of immunization
3
Hospitalization
12
Corticosterids
11
Gender
Male
Female
19
14
5
4
2
1
1
1
28
19
Percentage
100%
90%
57%
24%
55%
9%
36%
33%
minal ultrasonographies were indicated to address the cause
of this pain; none of them showed evidence of occlusion or
intestinal bleeding. Renal involvement appeared in 24 percent, one had macrogross hematuria, four had microhematuria, and three had proteinuria; none showed functional
impairment. So far, no long-term involvement was detected in this organ. Of the 21 patients with arterial tension records, only 3 had hypertension according to the corresponding percentile;16 all resolved the condition throughout the
disease evolution. Skin biopsies were obtained from 6 patients, and in all cases the histopathological diagnosis was
leukocytoclastic vasculitis. Only two were studied by direct
immunofluorescence, with positive result for type A immunoglobulin deposit.
Eighteen patients (55 percent) had a history of a previous
infection: fourteen had respiratory infection, whereof 3
were pharingitis with isolation of group A -hemolytic
tion. Fifteen patients were studied by Streptest,
with a positive result in 6 cases. Thirty six percent
(12/33) of the patients required hospitalization;
most frequent causes were the need of intravenous treatment, renal involvement follow-up, and
abdominal and joint pain control. The rest were
controlled as outpatients. Eleven patients received systemic meprednisone treatment, the remaining evolved favorably with rest and nonsteroidal
antiinflammatory drugs.
Figures 1 y 2. Henoch-Schönlein purpura: palpable purpura in lower extremities with distribution pattern on the buttocks and legs.
Streptococcus pyogenes in throat swab culture; and 3 patients had pneumonia, two of them with positive IgM for Mycoplasma pneumoniae.
In addition, three patients referred history of recent immunization.
In one patient, Escherichia coli was isolated from an urinary infec-
Kawasaki disease (Table 4)
We identified 10 KD cases, whereof nine fulfilled
inclusion criteria. The average age at onset was 23
months, with a range from 4 months to 7 years.
In regard to gender, there were no significant differences (5 males and 4 females). In all cases, fever occurred for over five days, and infectious cause was ruled out. Six cases (66 percent) had changes in distal extremities, 3 with edema of hand
and feet, one associated with erythema, 2 with
palmoplantar scaling, and another with pain and
erythema on the same location. Only one case had
perineal area scaling. Exanthema was present in
7 patients (78 percent), which was morbilliform
type in 4 children, maculopapulous in 2, and polymorph in 1 (Figure 3). One case showed erythema about the BCG immunization scar. Seven patients (78 percent) had clinical manifestations in
lips and oral mucosa. The most frequent manifestations in lips were erythema and lip fissures,
and vesicles and scaling were also found. Four cases showed enanthema, and two cases showed
erosions of the oral mucosa. Bilateral conjunctival injection in characteristic pericorneal area
was found in 8 cases (89 percent), and cervical
lymphadenopathies were identified. All were assessed by color Doppler echocardiography, and
images showed left coronary artery aneurysms in
6 (66 percent) children, 2 associated with myocardial involvement, and one with pericarditis
also. Additionally, the latter showed subclavian
and humeral dilations. With respect to laboratory
results, at the time of diagnosis all patients had
increased erythrosedimentation rate, 7 had leukocitosis, of which three had thrombocytosis.
All received 2 g/kg/dose intravenous gammaglobulin and 80-100 mg/kg/day acetylsalicilic acid.
Six responded to the first dose, 2 patients needed
a second dose, and one required a third dose. Of
the 6 patients with aneurysms, 4 resolved totally
after the gammaglobulin treatment and 2 showed
improvement without complete resolution of the
arterial dilations by the date of this report. Of
the reversible complications, one patient had arterial hypertension and another had ocular involvement, which resolved by gammaglobulin administration; of the irreversible complications, one
patient showed necrosis of the vasculitis affected
extremity that forced amputation, and intestinal
subocclusion requiring partial colectomy (Figure
4).
Acute hemorrhagic edema of infancy
Three cases of AHEI fulfilled all inclusion criteria. At the time of diagnosis, the ages were 7, 11,
and 23 months. Two were males and one was female. Two had history of an upper respiratory
condition, and one was recently immunized. All
presented good general condition, with purpuric
target-like lesions, ecchymosis dominantly in face
and extremities, and hand and feet edema (Figure
5). Two showed the typical pinna involvement
(Figure 6). Only one had oral mucosa purpura. One case showed small cervical and inguinal
lymphadenopathies. One patient presented fever
at the time of diagnosis, and no child had systemic involvement. Leukocytosis occurred in all
cases, and two had increased erythrosedimentation rate. All patients received acetaminophen
treatment as needed, and evolved with lesion resolution without cutaneous or systemic sequelae.
Cutaneous panarteritis nodosa
One 11-year-old male patient appeared with
diagnosis of CPAN, fulfilling diagnostic criteria for this disease. Clinically, he showed multiple erythematous and painful nodules located in
upper extremities, and other erythemato-purpuric ones on left sole and right ankle, associated
TABLE 4. KAWASAKI DISEASE.
Case
Age
Fever
1
36 m
+
2
12 m
+
3
4
24 m
84 m
+
+
5
12 m
+
Exanthema
Morbilliform
Erythematous
and papulous
Morbilliform
Erythematous
and papulous
with wrist arthralgia, and ankle arthritis (Figure 7). No livedo reticularis or ulcerations were observed. Also no myalgia, systemic arterial
hypertension, neuropathy or testicular tenderness appeared. Dosage of
antineutrophil antibodies was negative. No pharingitis appeared and
streptest and throat culture were negative; however, a high 1250 IU/
ml ASTO titration was detected. Hepatitis B serology was negative.
Skin biopsy confirmed the presence of vasculitis in small dermo-hypodermal vessel and small arteries. The indicated treatment consisted
of rest, nonsteroidal antiinflammatory drugs, meprednisone 60 mg/
day and prophylactic penicillin. The patient had favorable outcome,
without recurrences so far.
Figure 3. Kawasaki disease: maculopapulous exanthema.
Cardiac involvement
-
Distal involvement
Pain, palmoplantarerythema
CI
-
Lips and mucosa
Lip erythema and fissure, perianal scaling
CA
-
LC myocardial aneurysm
Palmoplantar scaling
+
Lip erythema
+
LC aneurysm
Palmoplantar scaling
Edema and erythema of hands and feet
+
+
Lip scaling and fissure, oral erosions
No
+
+
+
Lip erythema enanthema, erosions
+
LC and RC aneurisma
LC and RC aneurysm*
Myocarditis Pericardi+
No
tis Pericardial effusion
7
4m
+
Erythematous
LC coronary aneurysm
Hand and feet edema
Lip erythema Enanthema
8
24 m
+
Polymorph
Hand and feet edema
+
Lip besicles and fissures, enanthema
9
10 m
+
Erythema
LC aneurysm
+
Enanthema
m: months. F+: fever of more than 5 days evolution. CI: conjunctival injection. CA: cervical lymphadenopathies. LC: left coronary. RC: right coronary.
* Association with subclavian and humeral arteries.
6
4m
+
Morbilliform
+
+
Churg-Strauss syndrome
One 13-year-old male patient fulfilled diagnostic
criteria of Churg-Strauss syndrome. Relevant history included recent diagnosis of Klinefelter syndrome and asthma of difficult control. He presented palpable purpuric lesions of lower extremities,
myalgia, and sensitive and motor polyneuropathy
(Figure 8).
Laboratory results included 24 percent eosinophilia (2160/mm3), increased erythrosedimentation rate of 52 mm/h, 1/8192 IU/ml positive rheumatoid factor and 1/160 IU/ml positive ANCA-P. No alterations were found in the
chest and paranasal sinus X-rays. Skin biopsy resulted in small and intermediate vessel leukocytoclastic vasculitis accompanied by eosinophilic infiltration. Direct immunofluorescence was negative. Kidney and peripheral nerve biopsies were
also performed, thus confirming involvement. He
was treated with three pulses of 500 mg/day/dose
metilprednisolone and then 50 mg/day azathioprine for five days, with little response, and pulses of 750 mg/day cyclophosphamide were indicated, with favorable outcome. Currently, no active lesions appear on skin, renal function is normal
and neurological signs have improved noticeably.
Figure 4. Kawasaki disease: right lower extremity necrosis secondary to vasculitis.
Discussion
Vasculitis are rare in childhood. A 2002 British
study shows an estimated global annual incidence of primary vasculitis in children under 17 years
of age of 20.4/100,000, and HSP is most prevalent.17 Although we cannot refer incidence data
in our population, taking into account the average 1400 monthly consultations at our hospital
pediatric Dermatology Section in the 2007-2008
period, and the total of 47 primary vasculitis in
the 8-year period studied, we may infer a low incidence. As in the rest of publications, HSP was the
most frequent vasculitis identified in our population.18 HSP mainly affects the age group ranging
from four to seven years. Fifty percent of cases occur in children under five, and 75 percent in children under ten years of age.19 These data are consistent with our work results.
Fifty five percent of our patients had an infection at the time of diagnosis. The most frequently found etiologic agent was -hemolytic
Streptococcus, as referred in multiple reports.20
It is worth mentioning that we found references of 47 HSP cases in clinical records, but only
33 fulfilled EULAR/PReS diagnostic criteria;
Figure 5. Acute hemorrhagic edema of infancy: purpuric target-like lesions on right upper extremity and
homolateral hand edema.
that is, 30 percent were overdiagnosed. This situation had previously
been seen in other reports on HSP.21 We believe it is caused by the
use of non-thrombocytopenic purpura as sole HSP diagnostic criterion in children, following the criteria suggested by ACR and taken
from the Chapel-Hill classification.10-11,22 This would imply an unnecessary follow-up of patients for the likelihood of renal complication
in HSP patients. Twenty to forty percent of HSP patients have renal symptoms appearing in 90 percent of the cases within one month
Figure 6. Acute hemorrhagic edema of infancy: erythemato-purpuric lesion of left pinna.
Figure 7. Churg-Strauss syndrome: purpuric papules on lower extremities.
of the onset of the disease. Generally, the outcome of patients with
slight hematuria and proteinuria is good, while in less than 5 percent of the cases terminal renal disease occurs after a 10 to 25 years
follow-up. Patients with nephritic or nephrotic syndrome have poorer prognosis. 23-25 We found a similar ratio of patients with renal alterations in our work (24 percent); however, none of our patients had
long-term morbidity, which may be due to a shorter follow-up term
so far.
In reference to KD, data found was similar to
other national and international reports.26-30 Due
to the lack of a specific diagnosis test, the difficulty in differentiating it from other infectious
or bacterial toxin-mediated diseases, and the large number of cutaneous-mucosal manifestations,
the dermatologist has an important role in early
diagnosis of this entity, allowing the institution
of an early treatment and thus preventing cardiac
and other organ sequelae.30-33
Coronary artery aneurysms appeared in 66 percent of our patients, and less frequently, myocarditis and pericarditis. These figures coincide with references in the literature. 34 Using the
Takahashi score,35 half of our patients showed
certain clinical features such as persistent fever, thrombocytosis, less than one year of age
and male gender, which enable prediction of
high risk. A study by Juan et al. reaffirms these factors as cardiac risk predictors and adds delay in diagnosis. 33 All our one-year-old or younger patients (five cases) had cardiac involvement,
one with another organ morbidity. The response of our patients to conventional KD treatment
with intravenous immunoglobulin and aspirin
was very good, with total resolution of coronary
aneurysms in four cases, and partial resolution
in two. None of them received corticosteroids as
associated treatment. 36
Eighty percent of reported AHEI cases occurred
in 6 to 24-month-old children.37 The ages of our
patients were within this range. Also characteristic of AHEI is the good general condition of
the children at the time of diagnosis and the history of a febrile event in 45 percent of the cases.
Involvement disappears without sequelae after 2
to 60 days of evolution, mean 10 days.15,38 Our
three patients also behaved this way. We believe
that not all AHEI cases were reported in our setting, because its frequency is usually three or four
times below HSP, and our case material is much
lower than this reference value.39 Although less
frequent, CPAN and CSS are differential diagnosis which must be considered in pediatric patients with palpable purpura; this work describes
a case of each with classic clinical and histological
manifestations.40-46
In conclusion, although pediatric vasculitis are
rare, the dermatologist’s role is essential to reach
diagnosis, since cutaneous involvement is of
great importance in diagnostic criteria; the presence of palpable purpura is mandatory to define
HSP, and three of the diagnostic criteria are der-
Figure 8. Cutaneous nodose panarteritis: erythemato-purplish nodule on right ankle and left sole.
matologic in KD. However, dermatologists are not always called to
participate in diagnosis and treatment of these patients.
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Research Article
Palmoplantar melanocytic nevi: dermoscopic and
histopathological correlation
Mónica Andrea Barengo1, María Paula Gutiérrez1, Enrique Valente2, Alejandro Ruiz Lascano3
Abstract
Introduction. A nevus is defined as a circumscribed malformation of the teguments, which may be dysembryoplastic or hereditary, temporary or
permanent. Nevi are important given their well-known causal relationship with melanoma, a percentage of which results from preexisting melanocytic nevi. Therefore, it is important to distinguish nevi at risk of undergoing change. Dermoscopy is a non-invasive technique, particularly useful to
distinguish pigmented melanocytic lesions, which may be nevi or melanomas, from pigmented non-melanocytic lesions. Palmoplantar skin exhibits
special dermoscopic features producing peculiar images.
Objectives. To describe acral dermoscopic patterns, their frequency, and dermoscopic and histopathologic correlation of palmoplantar nevi, and to
assess dermoscopic agreement between the researcher and an independent observer.
Material and Methods. Observational, prospective, cross-sectional and analytical study of patients with clinical diagnosis of palmoplantar melanocytic nevi. The study was conducted at Hospital Privado, Córdoba, from May 2006 through April 2007. Studied variables included age, gender, personal history, skin phototype, location, and dermoscopic and histologic patterns. All patients were observed by the researcher and by an independent
observer; dermoscopy and surgery were performed on all nevi.
Results. Eighty three acral melanocytic nevi were detected in 74 skin phototype II patients. Mean age of patients was 32 years. Most frequent dermoscopic pattern was parallel furrow pattern, and most frequent was the compound histologic pattern. Dermoscopic agreement, calculated with Kappa values, was excellent.
Conclusion. The dermoscopic patterns found in our study is consistent with the reviewed literature (Dermatol Argent 2009; 15(6):420-427).
Key words: nevi of the palms and soles, dermoscopy, histopathology.
Introducción
1. Dermatologists. Dermatology Department, Team B.
2. Dermatologist. Dermatology Department, Team B.
3. Head of Dermatology Department. Team B.
Hospital Privado de Córdoba. Cordoba, Argentine Republic.
Correspondence
Mónica Barengo: Poeta Lugones 24 11 F. Córdoba, Rep. Argentina |
[email protected]
A nevus (Latin word meaning mark, sign or signal) is defined
as a circumscribed malformation of teguments, which may be
dysembrioplastic or hereditary, temporary or permanent.
Melanocytic nevi consist of cells from the neural crest, and
are important given their well-known causal relation with
melanoma.1
A percentage of melanomas results from preexisting melanocytic nevi. Therefore, it is important to distinguish nevi
with high risk of modification, a relevant data in preventing
melanoma.2,3
Dermoscopy (also known as dermatoscopy, epiluminiscence
microscopy, incident light microscopy, and skin surface microscopy) is a non-invasive diagnosis technique enabling an in vivo
view of pigmented anatomic structures in epidermis, dermoepidermal junction, and superficial papillary dermis, which are
invisible to the unaided eye.4 This technique is particularly useful to distinguish between melanocytic and non-melanocytic
pigmented lesions; and among the former, between nevus and
melanoma.5
128 | M. A. Barengo, M. P. Gutiérrez, E. Valente, A. Ruiz Lascano
Figure 1. Parallel furrow pattern (dermoscopy).
Figure 2. Lattice-like pattern (dermoscopy).
Figure 3. Fibrillar pattern (dermoscopy).
Figure 4. Globular pattern (dermoscopy).
Dermoscopic techniques are classified into two types: direct technique, where the diagnosis instrument contacts the skin; and
indirect technique, where the diagnosis instrument does not
contact the skin.
The direct technique uses in vivo microscopy, where the device contacting a fluid, either oil, water, or alcohol, is applied to
the patient’s skin; this fluid decrease light reflection, refraction
and difraction. Thus, stratum corneum becomes more translucent and enables a better view of the skin.6 The indirect technique uses in vivo microscopy, where the device does not contact the patient’s skin, that is, there is no need for an immersion
fluid. This procedure uses a polarized light dermatoscope with
crossed polarized lenses allowing a simultaneous view of all the
light waves dispersed on the skin, and the transmission of one
light beam in only one plane.
Volar skin shows specific anatomic features that produce peculiar dermoscopic images. The skin surface appears in a parallel distribution forming dermatoglyphs, where furrows (sulcus
superficialis) and ridges (crista superficialis) may be identified.
This specific distribution appears due to the peculiar interpapillary processes of the volar area formed by the limiting deep ridge (under the dermatoglyph furrow) and the intermediate deep
ridge (under the dermatoglyph ridges) crossed by acrosyringes.7
Saida et al.5,8 described specific dermoscopic features of acral
melanocytic nevi, and classified them as: parallel furrow, latticelike, fibrillar, and atypical pattern.
In addition, these authors established four melanoma-associated dermoscopic patterns: parallel ridge pattern, irregular
diffuse pigmentation in different shades, peripheral irregular
dots and globules, abrupt border cutoff.9 These patterns were
reproduced in Caucasians, in a study carried out by Malvehy
y Puig,10 adding three patterns: globular, homogeneous and
reticular.
Previous studies have reported clinical features of acral melanocytic lesions in Caucasic population. Although the dermoscopic assessment of these lesions has been described, the reviewed
literature does not comprise reports of large series of patients in
our population.
Palmoplantar melanocytic nevi: dermoscopic and histopathological correlation | 129
Figure 5. Homogeneous pattern (dermoscopy).
Figure 7. Mixed pattern (dermoscopy).
This induced the study in our setting (Hospital Privado)
of acral dermoscopic patterns, their occurrence frequency,
dermoscopic and histopathological correlation of palmoplantar nevi related to determination of benign vs. malignant patterns in the analyzed lesions; we also deemed it important to determine the degree of dermoscopic agreement
between a research student and a dermoscopy-trained independent observer, in order to determine the researcher’s training. This enables us to infer that this accessible method
for trained dermatologists may be very useful in differential
diagnosis of benign vs. malignant lesions.
An observational, prospective, cross-sectional, and analytical study was carried out in patients with clinical diagnosis of palmoplantar melanocytic nevi consulting the offices of the Dermatology Department of Hospital Privado
de Córdoba, between May 2006 and April 2007, inclusive.
Included were all patients of both sexes consulting sponta-
Figure 6. Atypical pattern (dermoscopy).
neously or referred with clinical diagnosis of palmoplantar
nevi. Children under 10 years of age were excluded
Studied variables were: age, gender, related personal history,
skin phototype, location, dermoscopic pattern, histologic
pattern.
Every patient with palmoplantar melanocytic nevi was examined by the research physician and a dermoscopy-trained independent observer during the study period of time.
Each nevus was visualized with a dermatoscope (Heine Delta
10 brand, which magnifies the image 10 times), and a double
protocol card was completed based on the above mentioned
variables. Lesions on fingers, palms and soles were included;
but not lesions on dorsal and subungual areas.
Digital images (cámara HP Photosmart R 707 5.1 MP) were
taken before surgical procedure, and then digitalized in order
to review clinical and dermoscopic features of each nevus.
Dermoscopic patterns of palm and sole nevi were categorized
as parallel furrow, lattice-like, fibrillar or filamentous, globular,
homogeneous, atypical, reticular, and parallel ridge pattern, according to the criteria established by Saida et al.8,9 and Malvehy
and Puig.10 In clinical practice we found more than one dermoscopic pattern on the same lesion, therefore classification
according to the above mentioned criteria was impossible; these cases were defined as mixed or combined patterns and were
added to the former classification.
Histopathologic study was performed on all nevi by a dermatopathologist (sole observer) of the Pathology Department of the
same hospital where the study was carried on.
Histologically, nevi were classified as: junctional, compound,
dermal, displastic, blue, congenital, and combined nevus.
Palmoplantar nevi location was identified on: palm, fingers
(hands and feet), interdigital (foot), internal lateral aspect of
foot, external lateral aspect of foot, heel, and sole.
All digitalized lesions were independently examined by the research student and the independent observer, and categorized
according to the predominant pattern.
For analysis, data were expressed as averages, with respective
standard deviations for continuous variables, and as percentages with respective 95 percent confidence interval (95% CI)
for nominal variables. Agreement on dermoscopic diagnosis
was calculated by kappa value. A kappa value of 1.0 indicates
perfect agreement, values above 0.75 are deemed excellent, values of 0.4 and 0.75 are deemed regular to good, and values below 0.4 are deemed poor. Statistical significance level was established at p < 0.05.
Results
50
43
40
26
30
20
10
3
1
0
I
III
II
IV
Chart 1. Distribution according to phototypes.
Seventy four patients were examined, 54 (73 percent) females
and 20 (27 percent) males, average age 32.5 years (25-42.25).
History of non-melanoma skin cancer appeared in 2 (2.7 percent) patients, history of melanoma in 1 (1.4 percent) and no
pathological history in 71 (95.9 percent).
Mainly skin phototype II was found (Chart 1). Of all patients,
61 (82.4 percent) knew about the lesion in that location, and
13 (17.6 percent) were unaware of it.
The study included 83 acral melanocytic nevi in 74 patients,
whereof 79 lesions were excised. Of the total sample, 73 (88
percent) nevi were located on foot and 10 (12 percent), on
hands (Chart 2).
Of the total of patients, 6 (75.9 percent) had only 1 nevus, 16
(19.3 percent) had 2 nevi, and 4 (4.8 percent) patients had 3
nevi. No lesion showed clinical signs of malignancy according
to ABCD rule of dermoscopy (asymmetry, border, color and
differential structures).
We identified the following dermoscopic patterns; the researcher student detected a parallel pattern (Figure 1) in 25 (30.1
percent) lesions, a lattice-like pattern (Figure 2) in 7 (8.4 percent), a fibrillar pattern (Figure 3) in 9 (10.8 percent), a globular pattern (Figure 4) in 6 (7.2 percent), a homogeneous pattern (Figure 5) in 4 (4.8 percent), reticular pattern in 1 (1.2
percent), atypical pattern (Figure 6) in 10 (12.0 percent) and
mixed (Figure 7) in 21 (25.3 percent) lesions.
The independent observer found the following patterns: a parallel pattern in 26 (31.35) lesions, a lattice-like pattern in 7
(8.4 percent), a fibrillar pattern in 9 (10.8 percent), a globular pattern in 8 (9.6 percent), a homogeneous pattern in 4 (4,8
percent), a reticular pattern in 1 (1.2 percent), an atypical pattern in 10 (12.0 percent) and a mixed one in 18 (21.7 percent)
(Table 1 and Chart 3).
The dominant pattern in the different locations was parallel furrow patterns as shown in Table 2 and Chart 4. Seventy nine lesions were excised for histopathology. All lesions were benign.
Most frequent was the compound histological pattern, representing 39 percent of the sample (Chart 5).
Distribution frequency of dermoscopic patterns and histopathological results are shown in Table 3.
Dermoscopic and histological correlation appear in Table 4
and Chart 6.
4
(5%)
2
3
(4%) (2%)
S/D
Heel
5
(6%)
Intergital feet
7
(8%)
Ext. Lat. Asp. foot
40
(48%)
Int. Lat. Asp. foot
9
(11%)
Palms
M and T fingers
13
(16%)
Soles
Chart 2. Distribution according to location.
Mixed
Parallel ridge
25%
Mixed
31%
Parallel furrow
Atypical
Reticular
%
Homogeneous
12%
Globular
8%
Filamentous o fibrilla
5%
1%
7%
11%
Lattice-like
Parallel furrow
Chart 3. Dermoscopic patterns distribution.
Dermoscopic agreement between the researcher and the independent observer was excellent; kappa coefficient calculation
resulted in 0.836, a statistically significant value with p < 0.05.
No lesion showed parallel ridge pattern characteristic of malignancy or other features previously associated with acral melanoma (Chart 7).
TABLE 1A. DERMOSCOPIC PATTERN ACCORDING TO THE RESEARCHER.
TABLE 1B. DERMOSCOPIC PATTERN ACCORDING TO THE OBSERVER.
Dermoscopic pattern
Dermoscopic pattern
Frequency
%
Aggregated %
25
30.1
30.1
Parallel furrow
Parallel furrow
Frequency
%
Aggregated %
26
31.3
31.3
Lattice-like
7
8.4
38.6
Lattice-like
7
8.4
39.8
Filamentous or fibrillar
9
10.8
49.4
9
10.8
50.6
Globular
6
7.2
Globular
8
9.6
60.2
Homogeneous
4
4.8
56.6
Homogeneous
4
4.8
65.1
Reticular
1
1.2
61.4
Reticular
1
1.2
66.3
Atypical
10
12.0
62.7
Atypical
10
12.0
78.3
Mixed
21
25.3
74.7
Mixed
18
21.7
100.0
Total
83
100.0
100.0
Total
83
100.0
TABLE 2. PATRONES DERMATOSCÓPICOS SEGÚN LOCALIZACIÓN.
Hands
Foot
%
Total
16%
7
0
1
1
0
11
1
84
25
30%
1
0
1
10%
14%
0
0
0
0
0
6
0
6
8%
86
7
8%
Filamentous
or fibrillar
0
0
0
0%
0%
1
0
0
0
3
5
0
9
12%
100
9
11%
%
Inter- Internal External
Fingers
Heel
hand
digital lat. asp. lat. asp.
Sole
S/D
Part.
in
foot
29%
Total
Lattice-like
Parallel furrow
Part.
in
hand
40%
%
foot
Subtotal
foot
21
Pattern
SubPalm Fingers total
hand
4
0
4
Globular
0
0
0
0%
0%
0
0
0
1
0
4
1
6
8%
100
6
7%
Homogeneous
0
0
0
0%
0%
2
1
1
0
0
0
0
4
5%
100
4
5%
Reticular
0
1
1
10%
100%
0
0
0
0
0
0
0
0
0%
0
1
1%
Atypical
3
0
3
30%
30%
0
0
2
2
0
3
0
7
10%
70
10
12%
Parallel ridge
0
0
0
0%
0%
0
0
0
0
0
0
0
0
0%
0
0
0%
Mixed
1
0
1
10%
5%
2
3
3
1
0
11
0
20
27%
95
21
25%
Total
9
1
10
100%
12%
12
4
7
5
3
40
2
73
100%
88
83
100%
TABLE 3. CORRELACIÓN DE LOS PATRONES DERMATOSCÓPICOS E HISTOPATOLÓGICOS.
Lesions
Patterns
Excised
Junctional
Compound
Dermal
Congenital
Displastic
Blue
30%
6
11
1
0
1
0
1
4
8%
3
2
0
0
1
0
0
0
0
n = 83
%
n = 79
%
Parallel rrowfu
25
30%
24
Lattice-like
7
8%
6
Filamentous
brillar
or fi
Mixed No nevus
9
11%
9
11%
3
2
1
0
3
0
0
Globular
6
7%
5
6%
0
1
2
0
0
0
1
1
Homogeneous
4
5%
4
5%
0
1
1
0
0
1
1
0
Reticular
1
1%
0
0%
0
0
0
0
0
0
0
0
Atypical
10
12%
10
13%
2
5
0
0
0
0
3
0
Parallel idge r
0
0%
0
0%
0
0
0
0
0
0
0
0
Mixed
21
25%
21
27%
5
9
3
0
1
0
1
2
19
31
8
0
6
1
7
7
Discussion
In Caucasian population, acral melanoma represents 4.5 to 7 percent of melanomas, and prognosis is poorer for Caucasian patients
with acral melanoma, compared to Japanese patients; this may be
attributed to delay in diagnosis. Diagnosis of these lesions by visual
examination may be difficult, even by expert dermatologists.
Therefore, a better way of characterizing acral melanocytic lesions may be very useful. Dermoscopy significatively improves diagnosis accuracy in melanocytic lesions and malignant
melanomas.
Acrally located benign melanocytic lesions commonly found in
the population may be difficult to differentiate clinically from
early acral melanoma. Therefore, Saida et al.11 recommended
40
Mixed
Parallel ridge
Atypical
Reticular
35
30
10
Homogeneous
Globular
Filamentous o fibrillar
Lattice-like
Mixed
Parallel ridge
Atypical
Reticular
8
Homogeneous
Globular
Lattice-like
Parallel furrow
25
Parallel furrow
6
20
4
15
10
2
5
0
0
Fingers
Internal lat. Asp.
Interdigital
Heel
External lat. Asp.
Palm
S/D
Fingers
Sole
Chart 4. Dermoscopic pattern distribution according to location. Left: pattern distribution in foot. Right: pattern distribution in hand.
25
No nevus
7
(9%)
Mixed
7
(9%)
1
(1%)
19
(24%)
Congenital
Mixed
Dermal
Blue
Compound
Displastic
Junctional
Blue
15
Displastic
6
(8%)
0
(0%)
20
No nevus
Congenital
8
(10%)
10
Dermal
31
(39%)
Compound
5
Junctional
0
Parallel
furrow
Filamentous
or fibrillar
Lattice-like
Chart 5. Histological pattern distribution.
excision of any acquired melanocytic lesion larger than 7 mm
in diameter in hairless skin, and additionally described four
dermoscopic patterns for acral melanocytic nevi:
• parallel furrow pattern, wherein pigmentation predominantly follows dermatoglyph furrows;
• lattice-like, where pigmentation follows the furrow, and lineal pigment bands transversely cross from one furrow to
the next;
• fibrillar, consisting of numerous very fine or filamentous lines obliquely or perpendicularly crossing dermatoglyphs
(ridges and furrows);
• atypical, consisting of lesions which cannot be assigned to
the former groups.
Subsequently, three additional patterns were described:10,12
• globular pattern, defined as brown aggregated globules
independent of dermatoglyphs (no presence of parallel
pattern);
Homogeneous
Atypical
Reticular
Globular
Mixed
or combined
Parallel ridge
Chart 6. Correlation of dermoscopic and histological patterns.
TABLE 4. RESEARCHER DERMOSCOPIC PATTERN–OBSERVER DERMOSCOPIC
PATTERN. CONTINGENCY TABLE.
Dermoscopic pattern acc. observer
Dermoscopic
pattern
acc. researcher
Total
Total
1
2
3
4
5
6
7
9
1
24
1
0
0
0
0
0
0
2
1
5
0
0
0
0
0
1
7
3
0
0
8
0
0
0
0
1
9
4
0
0
0
6
0
0
0
0
6
5
0
0
0
0
4
0
0
0
4
6
0
0
0
0
0
1
0
0
1
7
0
0
0
0
0
0
9
1
10
9
1
1
1
2
0
0
1
15
21
26
7
9
8
4
1
10
18
83
25
• homogeneous pattern, light brown pigmentation homogeneously diffusing on the skin surface;
• acral reticulate, consisting of a well-defined light or dark brown
pigmented reticulate, differing from lattice-like pattern in that
lines and distribution are independent of dermatoglyphs.12
30
Observer
Researcher
25
20
15
10
5
0
Parallel furrow
Lattice-like Filamentous or fibrillar Globular
Homogeneous
Reticular
Atypical
Mixed or combined
Chart 7. Dermoscopic agreement between student researcher and trained observer.
More specific identification of benign dermoscopic patterns
should prevent unnecessary palm and sole surgeries;13,14 this led
us to carry out this work, both to understand method suitability and dermoscopic and histologic correlation, and dermoscopic agreement between the in-training and the expert observer.
In this sense, it was very useful to demonstrate that the method,
provided the availability of a device of accessible cost, may reduce morbidity of patients with acral nevi; and method training is relatively simple if taught by an expert.
Dermoscopic aspects of lesions located on hairless skin differ
from those appearing on hairy skin, due to the different epidermal structures in these two anatomic sites.
The dermoscopic classification of acral benign melanocytic lesions proposed by Saida et al.8 has been widely acknowledged
as simple and highly reproducible in clinical practice.
The main purpose of our study was to investigate dermoscopic
features of 83 acral melanocytic nevi in Caucasian population,
their relation with structure, and the degree of agreement between observers.
We found that parallel furrow pattern was the most common dermoscopic pattern (31 percent), where other
authors have found the following ratios: 44 percent, 8 42
percent, 5 42.1 percent 12 and 52.9 percent; 10 followed by
mixed or combined patterns (25 percent), atypical (12
percent), fibrillar (11 percent), lattice-like (8 percent),
globular (7 percent), homogeneous (5 percent) and reticular (1 percent), in coincidence with the Italian population, except a greater frequency of lattice-like pattern presentation in the latter. In comparison with other reports
( Japanese population), we found a lower frequency of all
patterns; this may be attributed to the presence in our study of a high percentage of mixed or combined pattern,
which was not reported by other studies. None of the 83
lesions had the characteristic malignant parallel ridge pattern. A noteworthy finding is the presence of fibrillar pattern in pressure areas such as the sole and the heel, a condi-
tion reported by Altamira et al.12 In our series, the fibrillar
pattern was more frequent in soles than in palms, in coincidence with the reviewed literature.10
With reference to histopathological type, we found the following distribution: firstly, compound nevi (39 percent), followed by junctional nevi (24 percent), dermal nevi (10 percent), combined (9 percent), not nevi (9 percent), and displastic (8 percent). Most frequent histologic pattern was compound nevi; this pattern represents 39 percent of the sample, as found in other studies on Caucasian population.10,12
Noteworthy is the presence of fibrillar pattern associated with
displastic nevus (3 of 6).
Further studies are necessary to clarify the management of lesions with this pattern.
Dermoscopic agreement between the researcher and the independent observer (Table 4) was verified in parallel pattern in
24 of 26 lesions, in lattice-like pattern in 5 of 7 lesions, fibrillar pattern in 8 of 9 lesions, globular pattern in 6 of 6 lesions,
homogeneous pattern in 5 of 5 lesions, reticular pattern in 1 of
1 lesion, atypical pattern in 9 of 10 lesions and mixed pattern
in 15 of 21 lesions. Agreement results were excellent (kappa =
0.836) and statistically significant (p < 0.05).
Conclusion
Dermoscopic patterns found in our study coincide with the literature, except in the mixed or combined pattern concept (defined as the finding of more than one dermoscopic pattern in
one lesion), which was not described in previous reports.
The most frequent dermosopic pattern in our series was parallel furrow pattern, and the histological type found in highest
percentage was compound nevus, in coincidence with the reviewed literature.
Dermoscopic agreement between the researcher student and
the dermoscopy-trained independent observer was excellent.
We highlight the significance of the dermatologist understan-
ding the dermoscopy technique, which may contribute to improve the cost-benefit relation of the surgical excision of plantopalmar melanocytic nevi which dermatologically do not suggest
malignancy. It may be considered an intermediate step between
clinical dermatology and dermopathology; Its use may increase
sensibility and specificity in diagnosis of skin lesions.
We must understand dermoscopy as a new morphological dimension in exploring skin lesions, which allows the adjustment
of in vivo diagnosis, but that this diagnosis accuracy highly depends on the expertise and training of the observer.
References
1.
2.
3.
4.
5.
Cabrera H, García S. Generalidades. Parte I, Nevos. Editorial Actualizaciones Médicas 1998:3-4.
Grichnik JM, Rhodes AR, Sober AJ. Hiperplasias y neoplasias de los melanocitos. In: Freeberg I, Eisen A, Wolf K y cols. Fitzpatrick: Dermatología
en Medicina General. Argentina: Editorial Médica Panamericana; 2005
tomo II: 989-1016.
Kowalczuk AM, Galimberti RL, Vasconcelos M, Cabarcas F y cols. Dermatoscopía de lesiones pigmentadas palmoplantares. Dermatol Argent
2005; 11:169-175.
Braun RP, Rabinovitz HS, Oliviero M, Kopf AW, et al. Dermoscopy of pigmented skin lesions. J Am Acad Dermatol 2005; 52:109-121.
Saida T, Oguchi S, Miyazaki A. Dermoscopy for acral pigmented lesions.
Clin Dermatol 2002; 20:279-285.
6.
7.
8.
9.
10.
11.
12.
13.
14.
Marghoob A, Swindle LD, Moricz CZ, Sánchez Negron FA, et al. Instruments and new technologies for the in vivo diagnosis of melanoma J
Miyazaki A, Saida T, Koga H, Oguchi S, et al. Anatomical and dermoscopic patterns seen in melanocytic nevi on the soles: a retrospective study. J Am Acad Dermatol 2005; 53:230-236.
Saida T, Oguchi S, Ishihara Y. In vivo observation of magnified features of
pigmented lesions on volar skin using video macroscope. Usefulness of
epiluminescence techniques in clinical diagnosis. Arch Dermatol 1995;
131:298-304.
Saida T, Mijazaki A, Oguchi S, Ishihara Y, et al. Significance of dermatoscopic patterns in detecting malignant melanoma on acral volar skin. Arch
Dermatol 2004; 140:1233-1238.
Malvehy J, Puig S. Dermatoscopic patterns of benign volar melanocytic
lesions in patients with atypical mole syndrome. Arch Dermatol 2004;
140:538-544.
Saida T, Yoshida N, Ikegawa S, Ishihara K, et al. Clinical guidelines for the
early detection of plantar malignant melanoma. J Am Acad Dermatol
1990; 23:37-40.
Altamura D, Altobelli E, Micantonio T, Piccolo D, et al. Dermoscopic patterns of acral melanocytic nevi and melanomas in a white population
in Central Italy. Arch Dermatol 2006; 142:1123-1128.
Kuchelmeister C, Schaumburg Lever G, Garbe C. Acral cutaneous melanoma in Caucasians: clinical features, histopathology and prognosis en
112 patients. Br J Dermatol 2000; 143:275-280.
Kukita A, Ishihara K. Clinical features and distribution of malignant melanoma and pigmented nevi on the soles of the feet in Japan. J Invest
Dermatol 1989; 92:210S-213S.
Original Article
Merkel cell carcinoma. Study of five cases
Nadia Guadalupe Cañadas1, Paula Carolina Luna2, Mabel Jimena Nocito3, María Marcela Lustia2, Mauro Damián Etcheverry2,
María Laura Castellanos Posse1, Carolina Marchesi4, Romina Agustina Garuti1, Graciela Carabajal5, Miguel Angel Mazzini6
Abstract
Merkel cell carcinoma (MCC) is a rare malignant tumor, locally aggressive, that tends to metastasize to lymph nodes and distant sites. These cells resemble neuroendocrine cells in ultrastruture and immunohistochemistry. The etiopathology is unknown, but an association with other epithelial tumors has been reported, and recently, virus replication within the tumor was demonstrated. Risk factors are clinically characterized by the acronym:
AEIOU.
We report five MCC patients diagnosed during the last 15 years in our Dermatology Department. We reviewed the literature and analyzed clinical features, treatment, and outcome. Our results coincide with previous publications: we found increased incidence; age and immunosuppression as predisposing factors; association with in situ squamous-cell carcinoma; tumor regression in one patient, and a mortality rate that depends on tumor size
at the time of diagnosis (Dermatol Argent 2009; 15(6):428-433).
Key words: Merkel cell carcinoma, primary cutaneous neuroendrocrine carcinoma.
Introduction
Merkel cell carcinoma (MCC) is a rare primary skin tumor,
highly aggressive both locally and in distant sites. It mainly
affects the cephalic pole. Generally, it appears as a nodular, asymptomatic, rapidly expanding tumor, usually in patients over
50 years of age with photodamage and some type immunosuppression. This article reports five cases of patients with MCC
diagnosed in the last 15 years in our Hospital. Clinical, histological and immunohistochemical features were assessed, as well
as evolution and treatment.
1. Medical Resident.
2. Staff Dermatologist.
3. Dermatologist, Head of Residents.
4. Course attending physician.
5. Dermatopathologist.
6. Dermatologist, Head of Dermatology Department.
“Churruca-Visca” Police Medical Complex. Autonomous City of Buenos Aires, Argentine Republic.
The following work has not received financial support from any entity.
The authors do not have conflict of interests.
This work received the Young Dermatologists Award at the Argentine Dermatology
Congress, Tucumán, August 2008.
Correspondence
Nadia Guadalupe Cañadas: Moldes 2220 5º A. Autonomous City of Buenos Aires, Argentine Republic. Ph.: 011 47857584 | [email protected]
Case series
Case 1
A 64-year-old male patient without relevant medical history,
with skin phototype II and multiple actinic keratoses. He consulted on November 1996 for an asymptomatic round, raised,
and erythematous tumor lesion with central ulceration and peripheral serosansanguineous crusts measuring 2.5 cm in diameter, located on posterosuperior area of left antehelix, of about
one year evolution.
Histologically, the epidermis included an in situ squamous cell
carcinoma (Bowen’s disease) associated with an ill-defined adjacent dermal mass consisting of small, ovoid cells with scanty cytoplasm (Figure 1) expressing cytokeratin 20 in a paranuclear pattern. With electron microscopy, electron-dense
136 | N. G. Cañadas, P. C. Luna, M. J. Nocito, M. M. Lustia, M. D. Etcheverry, M. L. Castellanos Posse, C. Marchesi, R. A. Garuti, G. Carabajal, M. Á. Mazzini
granules were surrounded by an electron-lucid halo
(Figure 1). Diagnosis was MCC.
Treatment. Tumor removal and graft on the resection area.
No local recurrences were identified after 7 years follow up.
Case 2
A 48-year-old female patient without relevant medical history, consulted in May 1998 for an asymptomatic, raised, spherical, brownish erythematous tumor lesion with irregular and ulcerated surface and
defined borders, indurated, of about 3 cm in diameter, located on the medium third of the external aspect of the left leg, of a 5 months’ evolution. Nonpainful hard-to-elastic lymphadenopathies were
identified at homolateral inguinal level.
The histopathological study revealed the presence of
MCC: dermal proliferation of small, undifferentiated, round, and basophilic cells, with dusty chromatin and high mitotic count. These elements expressed cytokeratin 20 in a paranuclear pattern, neurofilaments and synaptophysin.
Supplementary studies showed increase of lactic dehydrogenase (LDH) and erythrosedimentation rate. Abdomen and pelvis computed axial tomography (CAT) showed homolateral inguinal
lymphadenopathies.
Treatment. Complete resection and skin graft were
performed, with subsequent homolateral inguinal
node emptying, and metastases were identified in 2
of the 8 lymph nodes studied. She underwent 4 chemotherapy cycles with cisplatin and etoposide. A
year after ending chemotherapy recurrence arose on
the area adjacent to the graft and subsequent systemic tumor dissemination with lung metastases; she
died shortly after.
Case 3
A 79-year-old female patient with history of low
grade remitting non-Hodgkin lymphoma, type II
diabetes and hypertension in treatment, consulted
in February 2007 for an asymptomatic, warm and
indurated erythematous plaque of a 3 months’ evolution, with a dome-shaped, bright pink tumor lesion with surface telangiectasias, friable, of about 1
centimeter in diameter (Figure 2), located on left
malar area. After a biopsy was performed, antibiotic
treatment was indicated for 7 days, believing it to be
a tumor bacterial superinfection.
Histology showed small dermal cells with scanty
cytoplasm and positive immunohistochemical markers for cytokeratins 7 and 20, AE1AE3, chromo-
Figure 1. Left: (10×) Poorly defined dermal mass. Upper right: (40×) Small ovoid cells with scanty cytoplasm. Lower right: (electron microscopy) Electron-dense granules surrounded by an electron-lucid halo.
granin and synaptophysin, thus establishing diagnosis of MCC. Markers
were negative for CD45 (leukocyte common antigen) and for B and T
lymphoma. The patient showed clinical involution of the lesion (Figure
2). Excision with 2 cm in depth and with 3 cm wide margin was the elected treatment with no histological finding of tumor disease. At present (2
years follow up) the patient shows no sign of recurrence.
Case 4
A 77-year-old male patient with history of arterial hypertension and type
II diabetes consulted in February 2008 for an asymptomatic, nodular, raised erythemato-purplish tumor lesion with hyperpigmented and ulcerated areas covered with serosanguineous crusts of 1 cm in diameter, friable,
located on the forehead, of 3 a months’ evolution (Figure 3). Histology
showed small cell proliferation. Immunohistochemistry resulted positive
for cytokeratin 20, synaptophysin (Figure 4), chromogranin and enolase.
Treatment. Lesion was removed with wide margins, and subsequent radiotherapy was instituted.
He continues with bimonthly controls, which are normal so far.
Case 5
An 89-year-old male patient consulting in April 2008 for an asymptomatic, round, raised tumor lesion with irregular crusty surface and defined
borders, hard in consistency, located on left leg, of 4 months evolution
(Figure 5).
Histopathology reported small dermal cells with scanty cytoplasm.
Immunohistochemistry resulted positive for cytokeratin 20, chromogranin and synaptophysin. This information led to diagnosis of MCC.
Treatment. Surgical treatment was instituted, removing the lesion with 3
cm margins. Quarterly controls have been done since then.
Comments
Merkel cell carcinoma (MCC) is a rare malignant tumor described by
Toker in 1972 as a trabecular carcinoma based on its infiltrating feature.1
Merkel cell carcinoma. Study of five cases | 137
Figure 2. Left: Dome-formed tumor lesion, bright pink in color, with telangiectasias. Right: Spontaneous tumoral resolution.
In Argentina, the first case was described by Magnin
et al., in 1982.2 Its origin is unclear, since although
ultrastructural findings of neurosecretory granules
may lead to Merkel cells, and further to the neural
crest,3 others suggest an origin from epidermal pluripotent stem cell with high degree of differentiation
into diverse phenotypes.4 It seldom behaves as intraepidermal neoplasia.5
Although etiology is controversial, several factors
contribute to its pathogenesis, including sun exposure, malignant epithelial tumors6 psoriasis, arsenic
exposure, chemotherapy immunosuppression,7 HIV,
chronic lymphocytic leukemia,8 transplants and the
presence of another neoplasia.
MCC may be associated with multiple skin tumors,9
mainly squamous cell carcinoma, sharing many risk
factors. Walsh reported 37 percent coexistence with
invasive10 and in situ11 squamous-cell, as in case 1
patient.
Tumor incidence has trebled in the last 15 years
(0.42 per 1,000,000 patients per year).12 The increase in more than 1,000 cases per year in the United
States has recently placed it as the second death-causing primary non-melanoma skin cancer.13 The same
trend appeared in our group of patients, since during
the 15 assessed years, three patients have been diagnosed in the last 18-month period of time.
It is more frequent in patients older than 50 years,
with slight prevalence of women. Photoexposed sites are most often involved: 65 percent of the cases
involve head and neck; 18 percent involve upper extremities, and 13 percent involve lower extremities,
Figure 3. Erythemato-purplish nodular tumor lesion on scalp with serosanguineous crusts.
and less frequently trunk.8 Involvement of other sites, such as vulva, penis,
pharynx, and nasal and oral mucosa, has also been reported.14
Heath et al. described a prospective cohort study of 195 patients in which
most (88 percent) were asymptomatic, rapidly expanding, and red or pink
in color in 56 percent of the cases. Location was related to prior sun exposure in 81 percent of primary tumors, and most patients were older than
50 years old (90 percent). This group created an acronym clinically characterizing these tumors: AEIOU (Asymptomatic; Expanding rapidly;
Immunosuppression; Older than 50 years; UVB-exposed).14
Our five patients showed at least three of the acronym clinical features.
Taking into account epidemiological features,15 the increase in incidence
in the general population and the greater incidence in immunosuppressed
and elderly patients were also observed in our series.
138 | N. G. Cañadas, P. C. Luna, M. J. Nocito, M. M. Lustia, M. D. Etcheverry, M. L. Castellanos Posse, C. Marchesi, R. A. Garuti, G. Carabajal, M. Á. Mazzini
Figure 4. Positive immunohistochemistry for cytokeratin 20, chromogranin and synaptophysin.
Figure 5. Round and indurated tumor with irregular crusty surface on left leg.
Feng et al. stated the hypothesis of a possible viral association, which was
confirmed in 2008 by the detection of a polyomavirus viral transcription
sequences. This virus is known as Merkel cell poliomavirus.16
The mortality rate is 33 percent in 3 years. Survival at 5 years is 75 percent,
59 percent, and 25 percent for localized, regional and distant forms, respectively.13 Localized forms represent 49 percent of the cases.17
Histologically, MCC is characterized by proliferation of monomorphic
cells with a large, round and regular nucleus, fine dispersed internal granular chromatin, multiple eccentric small nucleoli, and a high degree of mitosis. Cytoplasm is scanty and basophilic. Apoptosis is common.
Growth patterns are classified as: a) solid, b) diffuse, and c) trabecular.18
Immunohistochemistry results are positive for paranuclear cytokeratin 20, synaptophysin, chromogranin, specific enolase and neurofilaments, among others.19 These techniques prompt differential diagnosis,
mainly between MCC and cutaneous metastasis of small cell lung carcinoma. Although both tumors are positive for specific enolase and occasionally CD99 expressed in cytoplasm, MCC is negative for cytokeratin
7 (CK7). TTF1 (transcriptional thyroid factor 1) has also been described
as a useful marker to differenciate MCC from small cell lung carcinoma.20
Other entities to be considered in differential diagnosis are: primary cuta-
neous lymphoma, which is negative for cytokeratins
and positive to CD45 leukocyte common antigen
and the corresponding B or T lymphocyte markers;
small cell melanoma (negative for cytokeratins and
positive to protein S-100); and primitive neuroectodermal tumor (negative to cytokeratins and positive
to specific neuronal enolase and CD99, with membrane stain).
Electron microscopy shows small cells with scanty
cytoplasm, electron-dense granules with a characteristic clear halo, and paranuclear intermediate filaments aggregates (cytokeratins).21
Early diagnosis is the best prognosis factor. Poor
prognosis factors are: male gender, associated systemic diseases, location on trunk, head and neck,
young age, local recurrence and location on legs;22
these three last features coincide with patient 2 (
the only patient with fatal outcome in our series).
Histologically, a tumor larger than 5 mm with diffuse expansion pattern, dense lymphocyte infiltrate,
high ki67+ mitosis index, large cell size, and vascular and lymphatic invasion are worst prognosis
markers.18
The described treatments include, firstly surgical excision with 3 cm safety margins and 2 cm in depth,23
and the sentinel lymph node technique.24 Mohs micrographic surgery may be very useful, especially in
cases requiring a good cosmetic outcome, and some
authors report a better local-regional control than
with traditional surgery. Even though radiotherapy
(RT) has resulted in a reduction in the recurrences
and metastases, thus increasing survival,24,25 its use
remains controversial.
A meta-analysis study of 1254 MCC cases published by Garneski et al. compared surgical treatment
associated with RT vs. surgical treatment alone in
a 5 years follow-up. It was concluded that surgical
treatment with RT results in three-fold reduction of
local and regional recurrences.23
Four of five reported cases were low risk tumor stages treated with surgical excision and followed by
the Oncology Department; one case was further
treated with radiotherapy. The only patient requiring chemotherapy had a poor outcome.
Currently, some authors believe that adjuvant chemotherapy as applied in case II is not a treatment of
first choice, because it may increase morbility and
mortality.26
MCC has increased incidence and poorer prognosis in relation to immune function impairment.
It increases by 10 percent in patients with leukemia, solid organ transplant, and/or acquired
immunodeficiency.27
Merkel cell carcinoma. Study of five cases | 139
Noteworthy is the tumoral autoregression in patient 3.
Spontaneous regression of tumors and metastases of tumors
excised by Mohs micrographic surgery have been described.28
The mechanism is unknown,29 but immunity may play a relevant role, and may be used in the near future as a therapeutic
target.30
Conclusion
Although a rare tumor, MCC incidence is rising; thus, it is increasingly important to recognize the clinical, epidemiological and behavioral features of these tumors, as well as learning
about the most adequate therapies and the most recent management guidelines to handle our patients, firstly by suspecting
and establishing an early diagnosis (most important prognosis
factor) and later by indicating the most suitable treatment.
Surgery with safety margins, biopsy of sentinel lymph node,
and radiation therapy are useful in management of MCC
treatment, but cannot always be applied because of patient
comorbidities. A broader understanding of new associations,
such as viral replication and immunity, and the mechanism
of tumor regression may be the therapeutic target in a near
future.
References
1.
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