dermatologia e venereologia

Transcription

GIORNALE ITALIANO DI
DERMATOLOGIA E VENEREOLOGIA
Official Journal of the “Società Italiana di Dermatologia Medica, Chirurgica,
Estetica e delle Malattie Sessualmente Trasmesse (SIDeMaST)”
Honorary Editor
Editor in Chief
Mario PIPPIONE
Andrea PESERICO
Assistant Editors
Dennis LINDER - Nicola PIMPINELLI
Giovanna ZAMBRUNO
Honorary Members and Editorial Committee
M. Bagot (Paris, France) - L. Borradori (Bern, Switzerland) - R. Cerio (London, UK) - K. D. Cooper (Cleveland, USA)
P. M. Elias (San Francisco, USA) - J. Hercogova (Prague, Czech Republic) - F. Kerdel (Miami, USA) - C. Paul (Tolouse, France)
M. R. Pittelkow (Rochester, USA) - J. L. Rees (Edimburgh, UK) - W. Sterry (Berlin, Germany) - E. Tschachler (Vienna, Austria)
Editorial Board
P. Amerio (Chieti) - G. Argenziano (Reggio Emilia) - A. Belloni Fortina (Padova) - N. Cassano (Bari) - A. Costanzo (Roma)
E. Cozzani (Genova) - M. C. Fargnoli (L’Aquila) - I. Neri (Bologna) - P. Quaglino (Torino) - F. Rongioletti (Genova)
F. Sampogna (Roma) - C. Tomasini (Torino) - M. Venturini (Brescia)
SOCIETÀ ITALIANA DI DERMATOLOGIA MEDICA, CHIRURGICA, ESTETICA
E DELLE MALATTIE SESSUALMENTE TRASMESSE (SIDeMaST)
Board of Directors
Andrea Peserico (President) - Federico Bardazzi - Piergiacomo Calzavara-Pinton - Santo Dattola
Pasquale Frascione - Giampiero Girolomoni - Silvano Menni - Aurora Parodi
Ketty Peris - Anna Virgili - Giovanni Fabio Zagni
Managing Editor
Alberto OLIARO
This journal is PEER REVIEWED and is indexed by: EMBASE/Excerpta Medica, Index Medicus/Medline/PubMed, Science Citation Index Expanded
(SCIE, Thomson Reuters - ISI)
The “Giornale Italiano di Dermatologia e Venereologia”, Bi-monthly Journal of Dermatology and Venereology, was founded in 1866 by G.B. Soresina, formerly
“Giornale di Dermatologia e Sifilologia”, “Minerva Dermatologica”, “Giornale Italiano di Dermatologia”, “Il Dermosifilografo”, “Dermatologia”, “Cosmetologia”.
Editorial, business, graphic and advertising address - Edizioni Minerva Medica - Corso Bramante 83-85 - I-10126 Torino (Italy) - Tel. +39 011 678282 - Fax +39 011 674502 E-mail: [email protected] - Web Site: www.minervamedica.it
Typesetting and printed - Edizioni Minerva Medica - Tipografia di Saluzzo - Corso IV Novembre 29-31 - I-12037 Saluzzo (Italy) - Tel. +39 0175 249405 - Fax +39 0175 249407
Annual subscription:
Italy: Individual: Online € 100.00, Print € 105.00, Print+Online € 110.00; Institutional: Print € 140.00, Online (Small € 262.00, Medium € 300.00, Large € 346.00, Extra-Large
€ 362.00), Print+Online (Small € 270.00, Medium € 315.00, Large € 360.00, Extra-Large € 375.00).
European Union: Individual: Online € 175.00, Print € 180.00, Print+Online € 190.00; Institutional: Print € 250.00, Online (Small € 262.00, Medium € 300.00, Large € 346.00, ExtraLarge € 362.00), Print+Online (Small € 270.00, Medium € 315.00, Large € 360.00, Extra-Large € 375.00).
Outside the European Union: Individual: Online € 195.00, Print € 205.00, Print+Online € 215.00; Institutional: Print € 275.00, Online (Small € 280.00, Medium € 315.00, Large
€ 365.00, Extra-Large € 380.00), Print+Online (Small € 290.00, Medium € 330.00, Large € 380.00, Extra-Large € 395.00).
Subscribers: Payment to be made in Italy: a) by check; b) by bank transfer to: Edizioni Minerva Medica, INTESA SANPAOLO Branch no. 18 Torino. IBAN: IT45 K030 6909 2191 0000 0002
917 c) through postal account no. 00279109 in the name of Edizioni Minerva Medica, Corso Bramante 83-85, 10126 Torino; d) by credit card Diners Club International, Master Card, VISA,
American Express. Foreign countries: a) by check; b) by bank transfer to: Edizioni Minerva Medica, INTESA SANPAOLO Branch no. 18 Torino. IBAN: IT45 K030 6909 2191 0000 0002 917;
BIC: BCITITMM c) by credit card Diners Club International, Master Card, VISA, American Express.
Notification of changes to mailing addresses, e-mail addresses or any other subscription information must be received in good time. Notification can be made by sending the new and old
information by mail, fax or e-mail or directly through the website www.minervamedica.it at the section “Your subscriptions - Contact subscriptions department”. Complaints regarding missing issues must be made within six months of the issue’s publication date. Prices for back issues and years are available upon request.
© Edizioni Minerva Medica - Torino 2012
All rights reserved. No part of this publication may be reproduced, stored or transmitted in any form or by any means, without the prior permission of the copyright owner
Bi-monthly publication. Authorized by Turin Court no. 277 of July 2, 1948.
Registered in the national press register as per law no. 416 art. 11 dated 5-8-1981 with number 00 148 vol. 2 sheet 377 dated 18-8-1982.
Bi-monthly publication - Poste Italiane S.p.A. - Shipped on a subscription basis - Decree Law 353/2003 (converted in Law 27/02/2004 n° 46)
art. 1, para 1, DCB/CN.
NORME PER GLI AUTORI
La rivista Giornale Italiano di Dermatologia e Venereologia pubblica
articoli scientifici originali su argomenti di dermatologia e malattie sessualmente trasmesse.I contributi possono essere redatti come editoriali,
articoli originali, review, casi clinici, note di terapia, articoli speciali, lettere alla direzione.
I manoscritti devono essere preparati seguendo rigorosamente le norme per
gli Autori, che sono conformi agli Uniform Requirements for Manuscripts
Submitted to Biomedical Editors editi a cura dell’International Committee
of Medical Journal Editors (www.icmje.org). Non saranno presi in considerazione gli articoli che non si uniformano agli standard internazionali.
I lavori redatti in inglese con riassunto in italiano e in inglese e parole
chiave in italiano e in inglese devono essere inviati alla redazione online
raggiungibile dal sito delle Edizioni Minerva Medica:
www.minervamedica.it
L’invio del manoscritto sottintende che il lavoro è originale e non è ancora
stato pubblicato né totalmente né in parte e che, se accettato, non verrà
pubblicato altrove né integralmente né in parte. Tutto il materiale iconografico deve essere originale. L’iconografia tratta da altre pubblicazioni
deve essere corredata da permesso dell’Editore. Gli Autori accettano di
trasferire la proprietà dei diritti di autore alla rivista Giornale Italiano di
Dermatologia e Venereologia nell’eventualità che il lavoro sia pubblicato.
La rivista recepisce i principi presentati nella Dichiarazione di Helsinki e
ribadisce che tutte le ricerche che coinvolgano esseri umani siano condotte in conformità ad essi. La rivista recepisce altresì gli International
Guiding Principles for Biomedical Research Involving Animals raccomandati dalla WHO e richiede che tutte le ricerche su animali siano condotte in conformità ad essi. Gli Autori, se necessario, devono indicare che
lo studio è stato approvato dal comitato etico e che i pazienti hanno dato il
loro consenso informato. Gli Autori devono inoltre indicare se hanno un
accordo finanziario con organizzazioni coinvolte nella ricerca compilando
il relativo modulo. Il lavoro deve essere accompagnato dalla seguente
dichiarazione relativa ai diritti d’autore, aspetti etici e conflitti di interesse, firmata da tutti gli Autori: “I sottoscritti Autori trasferiscono la proprietà dei diritti di autore alla rivista Giornale Italiano di Dermatologia e
Venereologia, nella eventualità che il loro lavoro sia pubblicato sulla stessa rivista. Essi dichiarano che l’articolo è originale, non è stato inviato per
la pubblicazione ad altra rivista e non è stato già pubblicato né integralmente né in parte. Essi dichiarano di essere responsabili della ricerca, che
hanno progettato e condotto, e di aver partecipato alla stesura e alla revisione del manoscritto presentato, di cui approvano i contenuti. Nel caso di
studi condotti sugli esseri umani gli Autori riferiscono che lo studio è stato approvato dal comitato etico e che i pazienti hanno sottoscritto il consenso informato. Dichiarano inoltre che la ricerca riportata nel loro lavoro
è stata eseguita nel rispetto della Dichiarazione di Helsinki e dei Principi
internazionali che regolano la ricerca sugli animali. Si impegnano, infine,
a segnalare alle Edizioni Minerva Medica eventuali conflitti di interesse,
in particolare accordi finanziari con ditte farmaceutiche o biomedicali i
cui prodotti siano pertinenti all’argomento trattato nel manoscritto”.
Gli Autori accettano implicitamente che il lavoro venga sottoposto a
peer-review. Tutti i lavori saranno esaminati dal Comitato di Lettura che
si riserva il diritto di rifiutare il lavoro senza sottoporlo a revisione nel
caso che l’argomento, il formato o gli aspetti etici siano inadeguati. Tutti
i manoscritti accettati saranno sottoposti a revisione editoriale. In caso di
richiesta di modifiche, la nuova versione corretta deve essere risottoposta alla redazione online sottolineando ed evidenziando le parti modificate. La nuova versione deve essere accompagnata da una lettera con le
risposte punto per punto ai commenti dei revisori.
La correzione delle bozze di stampa dovrà essere limitata alla semplice
revisione tipografica; eventuali modifiche del testo saranno addebitate
agli Autori. Le bozze corrette dovranno essere restituite entro 3 giorni
lavorativi alla redazione online di Giornale Italiano di Dermatologia e
Venereologia. In caso di ritardo, la redazione della rivista potrà correggere d’ufficio le bozze sulla base del manoscritto originale. I moduli per
la richiesta di estratti vengono inviati insieme alle bozze.
Per ulteriori informazioni sulle condizioni di pubblicazione contattare la
redazione di Giornale Italiano di Dermatologia e Venereologia, Edizioni
Minerva Medica, Corso Bramante 83-85, 10126 Torino - Tel. 011
678282 - Fax 011 674502 - E-mail [email protected]
TIPI DI ARTICOLI SCIENTIFICI
Istruzioni per i più frequenti tipi di lavori inviati alla rivista.
Editoriale. Su invito (del Redattore Capo, del Direttore Responsabile),
deve riguardare un argomento di grande rilevanza in cui l’Autore esprime la sua opinione personale. Sono ammesse non più di 1000 parole (3
pagine dattiloscritte con spaziatura doppia) e fino a 15 citazioni bibliografiche.
Articolo originale. Deve portare un contributo originale all’argomento
trattato. Il testo deve essere di 3000-5500 parole (8-16 pagine dattiloscritte con spaziatura doppia) escluse bibliografia, tabelle e figure. Sono
ammesse fino a 50 citazioni bibliografiche. L’articolo deve essere suddiviso nelle sezioni: introduzione, materiali e metodi, risultati, discussione, conclusioni. Nell’introduzione sintetizzare chiaramente lo scopo dello studio. Nella sezione dei materiali e metodi descrivere in sequenza
logica come è stato impostato e portato avanti lo studio, come sono stati
analizzati i dati (quale ipotesi è stata testata, tipo di indagine condotta,
come è stata fatta la randomizzazione, come sono stati reclutati e scelti i
soggetti, fornire dettagli accurati sulle caratteristiche essenziali del trattamento, sui materiali utilizzati, sui dosaggi di farmaci, sulle apparecchiature non comuni, sul metodo statistico ...). Nella sezione dei risultati
dare le risposte alle domande poste nell’introduzione. I risultati devono
essere presentati in modo completo, chiaro, conciso eventualmente correlati di figure, grafici e tabelle. Nella sezione discussione riassumere i
risultati principali, analizzare criticamente i metodi utilizzati, confrontare i risultati ottenuti con gli altri dati della letteratura, discutere le implicazioni dei risultati. Nelle conclusioni riassumere brevemente il significato dello studio e le sue implicazioni future.
Review. Preferibilmente su invito (del Redattore Capo, del Direttore
Responsabile), deve trattare un argomento di attualità ed interesse, presentare lo stato delle conoscenze sull’argomento, analizzare le differenti
opinioni sul problema trattato, essere aggiornata con gli ultimi dati della
letteratura. Il testo deve essere di 6000-12000 parole (17-34 pagine dattiloscritte con spaziatura doppia) escluse bibliografia, tabelle e figure.
Sono ammesse fino a 100 citazioni bibliografiche.
Caso clinico. Descrizione di casi clinici di particolare interesse. Il testo
deve essere di 2000-3000 parole (6-8 pagine dattiloscritte con spaziatura
doppia) escluse bibliografia, tabelle e figure. Sono ammesse fino a 30
citazioni bibliografiche. L’articolo deve essere suddiviso nelle sezioni:
introduzione, caso clinico o casistica clinica, discussione, conclusioni.
Nota di terapia. Presentazione e valutazione di nuovi farmaci e trattamenti chirurgici. Il testo deve essere di 3000-5500 parole (8-16 pagine
dattiloscritte con spaziatura doppia) escluse bibliografia, tabelle e figure.
Sono ammesse fino a 30 citazioni bibliografiche. L’articolo deve essere
suddiviso nelle sezioni: introduzione, materiali e metodi, risultati,
discussione, conclusioni.
Articolo speciale. L’articolo deve trattare argomenti di storia della
medicina, organizzazione sanitaria, etica, politiche economiche e legislative riguardanti la dermatologia. Il testo deve essere di 3000-7000
parole (8-20 pagine dattiloscritte con spaziatura doppia) escluse bibliografia, tabelle e figure. Sono ammesse fino a 50 citazioni bibliografiche.
Lettera alla direzione. Può far riferimento ad articoli precedentemente
pubblicati sulla rivista o ad osservazioni e dati scientifici che gli autori
intendano portare all’attenzione dei lettori in forma sintetica. Il testo
deve essere di 500-1000 parole (1-3 pagine dattiloscritte con spaziatura
doppia) escluse bibliografia, tabelle e figure. Sono ammesse fino a 5
citazioni bibliografiche.
Linee guida. Documenti redatti da comitati speciali o da fonti autorevoli.
Il numero delle figure e delle tabelle deve essere adeguato al tipo e alla
lunghezza del lavoro.
PREPARAZIONE DEL MANOSCRITTO
File del testo
Per la preparazione del manoscritto si prega di utilizzare il modello predisposto per il tipo di lavoro prescelto (editoriale, articolo originale, review,
caso clinico, , nota di terapia, articolo speciale, lettera alla direzione).
L’articolo dovrà essere dattiloscritto con spaziatura doppia e con margini
di almeno 2,5 cm su cartelle del formato 212×297 mm (ISOA4). I formati accettati sono Word e RFT. Il file del manoscritto deve contenere il
titolo, i dati autori, le note, il riassunto, le parole chiave, il testo, la
bibliografia, le didascalie delle tabelle e delle figure. Tabelle e figure
devono essere inviate in file separati.
Titolo e dati autori
• Titolo (in inglese e in italiano) conciso, senza abbreviazioni.
• Nome e Cognome degli Autori.
• Affiliazione (sezione, dipartimento e istituzione) di ciascun autore.
Note
• Dati di eventuali Congressi ai quali il lavoro sia già stato presentato.
• Menzione di eventuali finanziamenti o contratti di ricerca o conflitti
di interesse.
• Ringraziamenti.
• Nome, cognome, indirizzo, e-mail dell’autore di contatto.
Riassunto e parole chiave
Il riassunto (in inglese e in italiano) non deve superare né essere inferiore alle 200-250 parole e, in caso di articolo originale e nota di terapia,
deve essere strutturato nelle sezioni: obiettivo (scopo dello studio),
metodi (disegno sperimentale, pazienti e interventi), risultati (cosa è stato trovato), conclusioni (significato dello studio). Per le parole chiave (in
inglese e in italiano) usare i termini del Medical Subjects Heading
(MeSH) di MEDLINE/PubMed. Gli editoriali e le lettere alla direzione
non necessitano di riassunto.
Testo
Identificare metodologie, apparecchiature (nome e indirizzo del costruttore tra parentesi) e procedure con dettaglio sufficiente a permettere ad
altri studiosi di riprodurre i risultati. Menzionare le metodologie già
definite, incluse quelle statistiche; menzionare e fornire brevi descrizioni
circa metodologie che sono state pubblicate ma non sono ben conosciute; descrivere metodologie nuove o modificate in modo sostanziale; giustificare il loro utilizzo e valutarne i limiti. Di tutti i farmaci si deve citare nome generico, dosaggio e vie di somministrazione. I nomi commerciali dei farmaci vanno citati tra parentesi. Unità di misura, simboli,
abbreviazioni devono essere conformi agli standard internazionali. Le
misure di lunghezza, altezza, peso e volume dovrebbero essere riportate
in unità del sistema metrico (metro, chilogrammo, litro) o in loro multipli decimali. Le temperature dovrebbero essere espresse in gradi
Celsius. Le pressioni arteriose in millimetri di mercurio. Tutte le misurazioni di chimica clinica dovrebbero essere espresse in unità del sistema
metrico nei termini dell’International System of Units (SI). Si scoraggia
l’uso di simboli e sigle poco comuni. Essi vanno comunque spiegati alla
prima apparizione nel testo.
– Supplemento ad un fascicolo
Payne DK, Sullivan MD, Massie MJ. Women’s psychological reactions
to breast cancer. Semin Oncol 1996;23(1 Suppl 2):89-97.
LIBRI E MONOGRAFIE
Per pubblicazioni non periodiche dovranno essere indicati i nomi degli
Autori, il titolo, l’edizione, il luogo di pubblicazione, l’editore e l’anno
di pubblicazione.
Esempi:
– Libro di uno o più Autori.
Rossi G. Manuale di otorinolaringologia. Torino: Edizioni Minerva
Medica; 1987.
– Capitolo di un libro.
De Meester TR. Gastroesophageal reflux disease. In: Moody FG, Carey
LC, Scott Jones R, Kelly KA, Nahrwold DL, Skinner DB, editors.
Surgical treatment of digestive diseases. Chicago: Year Book Medical
Publishers; 1986. p. 132-58.
– Atti congressuali.
Kimura J, Shibasaki H, editors. Recent advances in clinical neurophysiology. Proceedings of the 10th International Congress of EMG and
Clinical Neurophysiology; 1995 Oct 15-19; Kyoto, Japan. Amsterdam:
Elsevier; 1996.
MATERIALE ELETTRONICO
Articolo standard di rivista su Internet
Kaul S, Diamond GA. Good enough: a primer on the analysis and interpretation of noninferiority trials. Ann Intern Med [Internet]. 2006 Jul 4
[cited 2007 Jan 4];145(1):62-9. Available from:
http://www.annals.org/cgi/reprint/145/1/62.pdf
– Citazione standard di un libro su CD-ROM o DVD
Kacmarek RM. Advanced respiratory care [CD-ROM]. Version 3.0.
Philadelphia: Lippincott Williams & Wilkins; © 2000. 1 CD-ROM:
sound, color, 4 3/4 in.
– Citazione standard di una homepage
AMA: helping doctors help patients [Internet]. Chicago: American
Medical Association; © 1995-2007 [cited 2007 Feb 22].
Available from: htpp://www.ama-assn.org/.
Per la redazione della bibliografia non utilizzare le note a pie’ di pagina
e le note di chiusura di Word.
Le voci bibliografiche citate per la prima volta in una tabella o nella
didascalia di una figura devono essere numerate in sequenza con le voci
bibliografiche citate nel testo tenendo conto del punto in cui la tabella o
la figura è richiamata per la prima volta. Di conseguenza tali voci bibliografiche non devono essere elencate in fondo alla bibliografia ma secondo l’ordine di citazione nel testo.
Didascalie delle tabelle e delle figure
Le didascalie di tabelle e figure devono essere inserite sia nel file di testo
sia nel file delle tabelle e delle figure.
Bibliografia
È sottointeso che gli articoli citati in bibliografia siano stati letti dagli
autori. La bibliografia, che deve comprendere i soli Autori citati nel
testo, va numerata con numeri arabi in ordine consecutivo di prima citazione nel testo. Il richiamo delle voci bibliografiche nel testo deve essere
fatto con numeri arabi in apice. La bibliografia deve essere citata nello
stile standardizzato approvato dall’International Committee of Medical
Journals Editors (www.icmje.org).
File delle tabelle
Le tabelle devono essere inviate come file separati. I formati accettati
sono Word e RTF. Ogni tabella deve essere correttamente dattiloscritta,
preparata graficamente secondo lo schema di impaginazione della rivista, numerata in cifre romane, corredata dal rispettivo titolo. Eventuali
annotazioni devono essere inserite al piede della tabella e non nel titolo.
Le tabelle devono essere richiamate nel testo in ordine consecutivo.
RIVISTE
Per ogni voce si devono riportare il cognome e l’iniziale del nome degli
Autori (elencare tutti gli Autori fino a sei, se sette o più elencare solo i
primi sei nomi seguiti da: et al.), il titolo originale dell’articolo, il titolo
della rivista (attenendosi alle abbreviazioni usate di
MEDLINE/PubMed), l’anno di pubblicazione, il numero del volume, il
numero di pagina iniziale e finale.
Nelle citazioni bibliografiche seguire attentamente la punteggiatura standard internazionale.
Esempi:
– Articolo standard.
Sutherland DE, Simmons RL, Howard RJ. Intracapsular technique of
transplant nephrectomy. Surg Gynecol Obstet 1978; 146:951-2.
– Articolo a nome di una commissione.
International Committee of Medical Journal Editors. Uniform requirements for manuscripts submitted to biomedical journals.
Ann Int Med 1988;108:258-65.
File delle figure
Le figure devono essere inviate come file separati. Formati accettati: preferibilmente JPEG con risoluzione di 300 dpi; altri formati accettati sono
TIFF, PNG, PDF (alta qualità) e Word (per i grafici). Le figure devono
essere numerate in cifre arabe e corredate dalla rispettiva didascalia. Le
figure devono essere richiamate nel testo in ordine consecutivo. La
riproduzione deve essere limitata alla parte essenziale ai fini del lavoro.
Le foto istologiche devono sempre essere accompagnate dal rapporto di
ingrandimento e dal metodo di colorazione.
Per le figure a colori specificare sempre se si desidera la riproduzione a
colori o in bianco e nero. Il costo della riproduzione delle figure a colori
sarà addebitato agli Autori.
Le dimensioni ottimali per la riproduzione sulla rivista sono:
• cm 8,6 (base) × cm 4,8 (altezza)
• cm 8,6 (base) × cm 9 (altezza)
• cm 17,6 (base) × cm 9 (altezza)
• cm 17,6 (base) × cm 18,5 (altezza): 1 pagina
INSTRUCTIONS TO AUTHORS
The journal Giornale Italiano di Dermatologia e Venereologia publishes scientific papers on dermatology and sexually transmitted diseases.
Manuscripts may be submitted in the form of editorials, original articles,
review articles, case reports, therapeutical notes, special articles and letters to the Editor.
Manuscripts are expected to comply with the instructions to authors
which conform to the Uniform Requirements for Manuscripts Submitted
to Biomedical Editors by the International Committee of Medical Journal
Editors (www.icmje.org). Articles not conforming to international standards will not be considered for acceptance.
Papers should be submitted directly to the online Editorial Office at the
Edizioni Minerva Medica website:
www.minervamedica.it
Submission of the manuscript means that the paper is original and has
not yet been totally or partially published and, if accepted, will not be
published elsewhere either wholly or in part. All illustrations should be
original. Illustrations taken from other publications must be accompanied
by the publisher’s permission. The Authors agree to transfer the ownership of copyright to Giornale Italiano di Dermatologia e Venereologia in
the event the manuscript is published. The journal adheres to the principles set forth in the Helsinki Declaration and states that all reported
research concerning human beings should be conducted in accordance
with such principles. The journal also adheres to the International
Guiding Principles for Biomedical Research Involving Animals recommended by the WHO and requires that all research on animals be conducted in accordance with these principles. The Authors, if necessary,
must indicate that the study has been approved by the ethics committee
and that patients have given their informed consent. Authors must also
indicate whether they have any financial agreement with any organization that were involved in the research by filling the relevant form. Papers
must be accompanied by the following authors’ statement relative to
copyright, ethics and conflicts of interest, signed by all authors: “The
undersigned authors transfer the ownership of copyright to Giornale
Italiano di Dermatologia e Venereologia should their work be published
in this journal. They state that the article is original, has not been submitted for publication in other journals and has not yet been published either
wholly or in part. They state that they are responsible for the research
that they have designed and carried out; that they have participated in
drafting and revising the manuscript submitted, whose contents they
approve. In the case of studies carried out on human beings, the authors
confirm that the study was approved by the ethics committee and that the
patients gave their informed consent. They also state that the research
reported in the paper was undertaken in compliance with the Helsinki
Declaration and the International Principles governing research on animals. They agree to inform Edizioni Minerva Medica of any conflict of
interest that might arise, particularly any financial agreements they may
have with pharmaceutical or biomedical firms whose products are pertinent to the subject matter dealt with in the manuscript. “
The authors implicitly agree to their paper being peer-reviewed. All manuscripts will be reviewed by Editorial Board members who reserve the
right to reject the manuscript without entering the review process in the
case that the topic, the format or ethical aspects are inappropriate. Once
accepted, all manuscripts are subjected to copy editing. If modifications
to the manuscript are requested, the corrected version should be sent to
the online Editorial Office with the modified parts underlined and highlighted. The revised version should be accompanied by a letter with
point-by-point responses to the reviewers’ comments.
Correction of proofs should be limited to a simple check of the printing;
any changes to the text will be charged to the authors. Corrected proofs
must be sent back within 3 working days to the online Editorial Office of
Giornale Italiano di Dermatologia e Venereologia. In case of delay, the
editorial staff of the journal may correct the proofs on the basis of the
original manuscript. Forms for ordering reprints are sent together with
the proofs.
For further information about publication terms please contact the
Editorial Office of Giornale Italiano di Dermatologia e Venereologia,
Edizioni Minerva Medica, Corso Bramante 83-85, 10126 Torino, Italy –
Phone +39-011-678282 – Fax +39-011-674502 –
E-mail [email protected].
ARTICLE TYPES
Instructions for the most frequent types of articles submitted to the journal.
Editorials. Commissioned by the Editor in Chief or the Managing
Editor, editorials deal with a subject of topical interest about which the
author expresses his/her personal opinion. No more than 1000 words (3
typed, double-spaced pages) and up to 15 references will be accepted.
Original articles. These should be original contributions to the subject.
The text should be 3000-5500 words (8 to 16 typed, double-spaced
pages) not including references, tables, figures. No more than 50 references will be accepted. The article must be subdivided into the following
sections: introduction, materials and methods, results, discussion, conclusions. In the introduction the aim of the study should be clearly summed
up. The materials and methods section should describe in a logical
sequence how the study was designed and carried out, how the data were
analyzed (what hypothesis was tested, what type of study was carried
out, how randomization was done, how the subjects were recruited and
chosen, provide accurate details of the main features of treatment, of the
materials used, of drug dosages, of unusual equipments, of the statistical
method ...). In the results section the answers to the questions posed in
the introduction should be given. The results should be reported fully,
clearly and concisely supported, if necessary, by figures, graphs and
tables. The discussion section should sum up the main results, critically
analyze the methods used, compare the results obtained with other published data and discuss the implications of the results. The conclusions
should briefly sum up the significance of the study and its future implications.
Review articles. Generally commissioned by the Editor in Chief or the
Managing Editor, review articles should discuss a topic of current interest, outline current knowledge of the subject, analyze different opinions
regarding the problem discussed, be up-to-date on the latest data in the
literature. The text should be 6000-12000 words (17 to 34 typed, doublespaced pages) not including references, tables, figures. No more than 100
references will be accepted.
Case reports. These give a description of particularly interesting cases.
The text should be 2000-3000 words (6 to 8 typed, double-spaced pages)
not including references, tables, figures. No more than 30 references will
be accepted. The article must be subdivided into the following sections:
introduction, case report or clinical series, discussion, conclusions.
Therapeutical notes. These are intended for the presentation and assessment of new medical and surgical treatments. The text should be 30005500 words (8 to 16 typed, double-spaced pages) not including references, tables, figures. No more than 30 references will be accepted. The
article must be subdivided into the following sections: introduction,
materials and methods, results, discussion, conclusions.
Special articles. These are articles on the history of medicine, health
care delivery, ethics, economic policy and law concerning dermatology.
The text should be 3000-7000 words (8 to 20 typed, double-spaced
pages) not including references, tables, figures. No more than 50 references will be accepted.
Letters to the Editor. These may refer to articles already published in
the journal or to a subject of topical interest that the authors wish to present to readers in a concise form. The text should be 500-1000 words (1
to 3 typed, double-spaced pages) not including references, tables, figures.
No more than 5 references will be accepted.
Guidelines. These are documents drawn up by special committees or
authoritative sources.
The number of figures and tables should be appropriate for the type and
length of the paper.
PREPARATION OF MANUSCRIPTS
Text file
Manuscripts must be drafted according to the template for each type of
paper (editorial, original article, review, case report, therapeutical note,
special article, letter to the Editor).
The paper should be type written double spaced with margins of at least
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are Word and RFT. The text file must contain title, authors’ details, notes,
abstract, key words, text, references and titles of tables and figures.
Tables and figures should be submitted as separate files.
Title and authors’ details
•
•
•
Short title, with no abbreviations.
First name and surname of the authors.
Affiliation (section, department and institution) of each author.
Notes
•
•
•
•
Dates of any congress where the paper has already been presented.
Mention of any funding or research contracts or conflict of interest.
Acknowledgements.
Name, address, e-mail of the corresponding author.
Abstract and key words
Articles should include an abstract of between 200 and 250 words. For
original articles and therapeutical notes, the abstract should be structured
as follows: aim (aim of the study), methods (experimental design,
patients and interventions), results (what was found), conclusion (meaning of the study). Key words should refer to the terms from Medical
Subject Headings (MeSH) of MEDLINE/PubMed. No abstracts are
required for editorials or letters to the Editor.
Text
Identify methodologies, equipment (give name and address of manufacturer in brackets) and procedures in sufficient detail to allow other
researchers to reproduce results. Specify well-known methods including
statistical procedures; mention and provide a brief description of published methods which are not yet well known; describe new or modified
methods at length; justify their use and evaluate their limits. For each
drug generic name, dosage and administration routes should be given.
Brand names for drugs should be given in brackets. Units of measurement, symbols and abbreviations must conform to international standards. Measurements of length, height, weight and volume should be
given in metric units (meter, kilogram, liter) or their decimal multiples.
Temperatures must be expressed in degrees Celsius. Blood pressure must
be expressed in millimeters of mercury. All clinical chemistry measurements should be expressed in metric units using the International System
of Units (SI). The use of unusual symbols or abbreviations is strongly
discouraged. The first time an abbreviation appears in the text, it should
be preceded by the words for which it stands.
– Issue with supplement
Payne DK, Sullivan MD, Massie MJ. Women’s psychological reactions
to breast cancer. Semin Oncol 1996;23(1 Suppl 2):89-97.
BOOKS AND MONOGRAPHS
For occasional publications, the names of authors, title, edition, place,
publisher and year of publication must be given.
Examples:
– Books by one or more authors
Rossi G. Manual of Otorhinolaryngology. Turin: Edizioni Minerva
Medica; 1987.
– Chapter from book
De Meester TR. Gastroesophageal reflux disease. In: Moody FG, Carey
LC, Scott Jones R, Ketly KA, Nahrwold DL, Skinner DB, editors.
Surgical treatment of digestive diseases. Chicago: Year Book Medical
Publishers; 1986. p. 132-58.
– Congress proceedings
Kimura J, Shibasaki H, editors. Recent advances in clinical neurophysiology. Proceedings of the 10th International Congress of EMG and
Clinical Neurophysiology; 1995 Oct 15-19; Kyoto, Japan. Amsterdam:
Elsevier; 1996.
ELECTRONIC MATERIAL
– Standard journal article on the Internet
Kaul S, Diamond GA. Good enough: a primer on the analysis and interpretation of noninferiority trials. Ann Intern Med [Internet]. 2006 Jul 4
[cited 2007 Jan 4];145(1):62-9. Available from:
http://www.annals.org/cgi/reprint/145/1/62.pdf
– Standard citation to a book on CD-ROM or DVD
Kacmarek RM. Advanced respiratory care [CD-ROM]. Version 3.0.
Philadelphia: Lippincott Williams & Wilkins; ©2000. 1 CD-ROM:
sound, color, 4 3/4 in.
– Standard citation to a homepage
AMA: helping doctors help patients [Internet]. Chicago: American
Medical Association; ©1995-2007 [cited 2007 Feb 22]. Available from:
http://www.ama-assn.org/.
Footnotes and endnotes of Word must not be used in the preparation of
references.
References first cited in a table or figure legend should be numbered so
that they will be in sequence with references cited in the text taking into
consideration the point where the table or figure is first mentioned.
Therefore, those references should not be listed at the end of the reference section but consecutively as they are cited.
Titles of tables and figures
Titles of tables and figures should be included both in the text file and in
the file of tables and figures.
References
File of tables
It is expected that all cited references will have been read by the authors.
The references must contain only the authors cited in the text, be numbered in Arabic numerals and consecutively as they are cited.
Bibliographical entries in the text should be quoted using superscripted
Arabic numerals. References must be set out in the standard format
approved by the International Committee of Medical Journal Editors
(www.icmje.org).
Each table should be submitted as a separate file. Formats accepted are
Word and RTF. Each table must be typed correctly and prepared graphically in keeping with the page layout of the journal, numbered in Roman
numerals and accompanied by the relevant title. Notes should be inserted
at the foot of the table and not in the title. Tables should be referenced in
the text sequentially.
JOURNALS
Each entry must specify the author’s surname and initials (list all authors
when there are six or fewer; when there are seven or more, list only the
first six and then “et al.”), the article’s original title, the name of the
Journal (according to the abbreviations used by MEDLINE/PubMed),
the year of publication, the volume number and the number of the first
and last pages. When citing references, please follow the rules for international standard punctuation carefully.
Examples:
– Standard article.
Sutherland DE, Simmons RL, Howard RJ. Intracapsular technique of
transplant nephrectomy. Surg Gynecol Obstet 1978;146:951-2.
– Organization as author
International Committee of Medical Journal Editors. Uniform requirements for manuscripts submitted to biomedical journals. Ann Int Med
1988;108:258-65.
File of figures
Each figure should be submitted as a separate file. Formats accepted:
JPEG set at 300 dpi resolution preferred; other formats accepted are
TIFF, PNG, PDF (high quality) and Word (for graphs). Figures should be
numbered in Arabic numerals and accompanied by the relevant title.
Figures should be referenced in the text sequentially.
Reproductions should be limited to the part that is essential to the paper.
Histological photographs should always be accompanied by the magnification ratio and the staining method.
If figures are in color, it should always be specified whether color or
black and white reproduction is required. The cost of color figures will
be charged to the Authors.
Optimal dimensions for publication of figures in the journal are:
•
8.6 cm (basis) × 4.8 cm (height)
•
8.6 cm (basis) × 9 cm (height)
• 17.6 cm (basis) × 9 cm (height)
• 17.6 cm (basis) × 18.5 cm (height): 1 page.
Vol. 147
Febbraio 2012
N. 1
INDICE
65
Pag. XXXIII
Congressi
Nuove acquisizioni sull’ipersensibilità allergica ritardata verso i corticosteroidi
Baeck M., Goossens A.
NOVITÀ IN DERMATOLOGIA
1
71
Jaimes N., Marghoob A. A.
Trattamento della Dermatite Atopica in una popolazione pediatrica italiana
21
Ruggiero G., Gelmetti C., Adamo M. C., Baldessarri D.,
Bonfanti R., Brero P., Calzaretti R., Candelori G., Danesi R.,
D’Amanti V., Golinelli L., Guttuso D., La Vecchia di Tocco A.,
Sapia M. G., Sarra E., Zinna M., Ferrara M., Russomando M.,
Mele G.
Un aggiornamento su fattori di rischio, prognosi e
gestione dei pazienti con melanoma
Pitfall chirurgici e istologici nella gestione del melanoma lentigo maligna
Šitum M., Buljan M.
ARTICOLI ORIGINALI
83
Punteggio del Dermatology Life Quality Index in
pazienti affetti da vitiligo: uno studio pilota tra uomini adulti in Italia
29
Riempimento dei tessuti molli e tossina botulinica,
tecniche di trattamento
Ingordo V., Cazzaniga S., Gentile C., Iannazzone S. S., Cusano
F., Naldi L.
Yamauchi P. S.
91
45
Applicazioni cosmetiche della scleroterapia
Duffy D. M.
Vol. 147 - No. 1
Valutazione di noduli tiroidei incidentali in pazienti
affetti da melanoma primario
Fanti P. A., Dika E., Balestri R., Rech G., Bellavista S., Baldi
E., Maibach H. I., Patrizi A.
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
XVII
INDICE
99
Terapia fotodinamica con acido metil-aminolevulinico
per il trattamento della cheilite attinica: valutazione
retrospettiva di 29 pazienti
123
Eritemi reattivi localizzati di differente tipologia in
una famiglia
Capella G. L.
Fai D., Romano I., Cassano N., Vena G. A.
127
LETTERE AL DIRETTORE
103
Sindrome di Sweet con panniculite
REVIEW
Bassi E., Rosso R., Fiandrino G., De Filippi C.
Strumento diagnostico aggiuntivo per la dermatite
allergica da contatto: lo strip patch test
Hessam S., Altmeyer P., Dickel H.
129
Eritema anulare centrifugo
Baglieri F., Scuderi G.
111
131
CASI CLINICI
Pediculosi ed entodermoscopia
Pilomatrixoma, una lesione con diagnosi errata: due
casi clinici in pediatria
Scanni G.
Neri I., Virdi A., Patrizi A.
119
133
Bilenchi R., De Paola M., Poggiali S., Acciai S., Feci L., Sansica
P., Fimiani M.
Rubegni P., Feci L., Fimiani M.
Sindrome papulo-purpurica “guanti e calzini”
XVIII
Talon Noir: utilità della dermoscopia nella diagnosi
differenziale delle lesioni acrali
February 2012
Vol. 147
February 2012
No. 1
CONTENTS
65
Pp. XXXIII
Congresses
New insights about delayed allergic hypersensitivity
to corticosteroids
Baeck M., Goossens A.
PEARLS IN DERMATOLOGY
1
An update on risk factors, prognosis and management of melanoma patients
Jaimes N., Marghoob A. A.
21
Surgical and histologic pitfalls in the management of
lentigo maligna melanoma
71
ORIGINAL ARTICLES
Atopic dermatitis (AD) management in an Italian
pediatric clinic
Ruggiero G., Gelmetti C., Adamo M. C., Baldessarri D.,
Bonfanti R., Brero P., Calzaretti R., Candelori G., Danesi R.,
D’Amanti V., Golinelli L., Guttuso D., La Vecchia di Tocco A.,
Sapia M. G., Sarra E., Zinna M., Ferrara M., Russomando M.,
Mele G.
Šitum M., Buljan M.
83
Dermatology Life Quality Index score in vitiligo
patients: a pilot study among young Italian males
29
Soft tissue filler and botulinum toxin treatment techniques
Ingordo V., Cazzaniga S., Gentile C., Iannazzone S. S., Cusano
F., Naldi L.
Yamauchi P. S.
91
45
Cosmetic applications of sclerotherapy
Duffy D. M.
Vol. 147 - No. 1
Evaluation of incidental thyroid nodules in patients
with primary melanoma
Fanti P. A., Dika E., Balestri R., Rech G., Bellavista S., Baldi
E., Maibach H. I., Patrizi A.
XXI
CONTENTS
99
Methyl-aminolevulinate photodynamic therapy for
the treatment of actinic cheilitis: a retrospective evaluation of 29 patients
123
Localized reactive erythemas of different types in a
family
Capella G. L.
Fai D., Romano I., Cassano N., Vena G. A.
127
LETTERS TO THE EDITOR
103
Sweet’s syndrome with panniculitis
REVIEWS
Add-on diagnostic tool for allergic contact dermatitis:
the strip patch test
Hessam S., Altmeyer P., Dickel H.
Bassi E., Rosso R., Fiandrino G., De Filippi C.
129
Erythema annulare centrifugum: a “deep type” figurate eruption
111
Baglieri F., Scuderi G.
Human phthiriasis. Can dermoscopy really help dermatologists? Entodermoscopy: a new dermatological
discipline on the edge of entomology
131
CASE REPORTS
Scanni G.
Pilomatrixoma, a misdiagnosed lesion: two pediatric
case reports
119
133
Bilenchi R., De Paola M., Poggiali S., Acciai S., Feci L., Sansica
P., Fimiani M.
Rubegni P., Feci L., Fimiani M.
Neri I., Virdi A., Patrizi A.
Papular-purpuric “gloves and socks” syndrome
XXII
Talon Noir: utility of dermoscopy for differential diagnosis with respect to other acral skin growths
February 2012
CONGRESSES
March 16-20, 2012
San Diego (CA, USA)
June 27-July 1, 2012
Stockholm (Sweden)
3rd World Psoriasis
American Academy of
Dermatology
70th AAD Meeting
and
Psoriatic Arthritis Conference
Contact:
Website: www.ifpaworldconference.com
Contact:
Website: www.aad.org
September 6-9, 2012
Riga (Latvia)
21st EADV Congress
May 2-5, 2012
Raleigh (NC, USA)
72nd Annual Meeting
of the Society for Investigative
Dermatology (SID)
Contact:
Website: www.sidnet.org
June 6-10, 2012
Verona (Italy)
9th EADV Spring
Contact:
E-mail: [email protected]
September 10-12, 2012
Cardiff (UK)
Stratum Corneum VII
Symposium
Contact:
Website: www.stratumcorneum2012.
com
Contact:
Website: http://verona2012.eadv.org
June 13-16, 2012
Malmo (Sweden)
11th Congress
of the European Society
of Contact Dermatitis (ESCD)
Contact:
Website: www.escd2012.com
June 21-23, 2012
Barcelona (Spain)
16th meeting of
Geneva (Switzlerland)
17th Meeting of the
European Society
for Pigment Cell Research
(ESPCR)
Contact:
Website: www.espcr.org
Venice (Italy)
the European
Hair Research Society
European Society for
Dermatological Research
42nd Annual ESDR Meeting
Contact:
Website: www.ehrs.org
Contact:
Website: www.esdr.org
Vol. 147 - No. 1
October 4-7, 2012
Mumbai (India)
European Society
of Cosmetic and Aesthetic
Dermatology
COSMODERM - 2012
Contact:
Website: www.escad.org
May 8-11, 2013
Edinburgh (Scotland, UK)
International Investigative
Dermatology 2013
Contact:
Website: www.iid2013.org
July 18-20, 2013
Hamburg (Germany)
8th World Congress
of Melanoma
Contact:
Website: www.worldmelanoma2013.
com
Madrid (Spain)
WCDP 2013
12th World Congress
of Pediatric Dermatology
Contact:
Website: www.wcpd2013.com
XXXIII
[To be continued at page XXIV]

PEARLS IN DERMATOLOGY
G ITAL DERMATOL VENEREOL 2012;147:1-19
An update on risk factors, prognosis and
management of melanoma patients
N. JAIMES, A. A. MARGHOOB
Cutaneous melanoma continues to be a public health problem worldwide and its incidence continues to increase around
the globe. The recognition of melanoma risk factors allows
for the identification of a subgroup of high-risk patients that
will likely benefit most from approaches aimed at minimizing
exposure to ultraviolet radiation and from surveillance strategies geared towards finding melanomas while thin and easily
curable. Herein, we will provide an overview of the most pertinent, novel and newly described melanoma risk factors and
melanoma prognostic factors. The potential benefits of skin
cancer surveillance strategies including physician-based total
body skin examination, total body photography, dermoscopy
and patient-based self-skin examination will be examined.
In addition, management of melanoma patients, focusing on
prevention and early detection strategies will be discussed.
Key words: Melanoma - Risk factors - Nevus - Ultraviolet rays.
C
utaneous melanoma continues to be a public
health problem worldwide.1 The incidence of
invasive melanoma continues to increase in most
regions of the world, with an incidence rate of
7.6/100,000 persons/year in Europe, accounting for
more than 60000 new melanoma cases,2 an incidence
rate of 36.6/100,000 persons/year in Australia, accounting for more than 10300 new cases diagnosed
annually;3 and an incidence rate of 14.3/100,000 persons/year in the United States (USA), accounting for
70230 estimated new cases for 2011.4, 5
Conflicts of interest.—None.
Funding.—None.
Corresponding author: A. A. Marghoob, MD, Department of Dermatology, Memorial Sloan-Kettering Cancer Center, 160 E 53rd Street,
New York, NY, USA. E-mail: [email protected]
Vol. 147 - No. 1
Dermatology Service
Memorial Sloan-Kettering Cancer Center
New York, NY, USA
Comparable to other cancers melanoma susceptibility results from interactions between environmental exposures and inherited genetic factors.6 Therefore, recognizing these environmental and genetic/
personal risk factors will allow for the identification
of a subgroup of high-risk patients that will benefit
most from skin cancer surveillance strategies and
from approaches aimed at minimizing exposure
to ultraviolet radiation. Herein, we will review the
melanoma risk factors, melanoma prognostic factors
and discuss management of melanoma patients, focusing on prevention and early detection strategies.
Melanoma risk factors
Recognizing risk factors for melanoma (Table I)
allows for the identification of high-risk individuals
that will benefit most from strategies aimed at preventing melanoma and detecting it while the tumor
is confined to the skin. Preventive strategies, such
as educational campaigns (primary prevention) and
early-detection programs (secondary prevention)
may help in curtailing melanoma related mortality.1
As mentioned above, cancer susceptibility results
from interactions between environmental and inherited factors.6 Risk factors for melanoma can be broad-
1
JAIMES
An update on melanoma
Table I.—Risk factors for cutaneous melanoma.1-9
High-risk
(RR >=2.1)
Moderate-risk
(RR=1.1-2.0)
Genotype
MC1R (RHC variants)
Phenotype
Phototype I – II
Many atypical nevi
>100 Common nevi
Red hair color
Complex dermoscopic pattern of nevi
Phototype II – III
Few atypical nevi
Fair skin color
Freckles (Medium to high density)
Blond and light brown hair color
Eye color: green, gray, blue
Medical history
Personal history of melanoma
NMSC
Actinic damage
Family history
UVR/Sun exposure
Sunburns in childhood or residing at higher Sunburns in adulthood or residing at lower latitudes
latitudes
Intermittent sun exposure
Tanning bed
Low-risk
(RR <=1.0)
Chronic sun exposure
*RHC: red hair color; NMSC: non-melanoma skin cancer.
ly classified into exogenous (or environmental) and
endogenous (or host) risk factors. The latter can be
further sub-classified into genotypic and phenotypic
factors. The genotype refers to the inherited predisposition of an individual to manifest a particular trait
or disease encoded in his/her genes. However, the expression of any given genetic trait/disease (i.e., penetrance) may be modified by environmental and developmental factors. The phenotype of a person refers to
the traits or observable characteristics that result from
gene expression.7 Risk factors for skin cancer can be
directly and/or indirectly evaluated via history, skin
examination, imaging techniques and genetic testing.
Age and gender
From 2004 to 2008 the median age at diagnosis
for melanoma in the USA was 60 years, with 81%
of the cases diagnosed after age of 45.8 Melanoma
often affects persons at younger age as compared to
other major cancers and the risk increases with advancing age. Studies have shown that melanomas in
the elderly are thicker, predominantly of the nodular
type and often occur on the head and neck of males.9
Males appear to be at increased risk for developing
melanoma and they tend to present with thicker tumors as compared to females.10 The probability of
developing an invasive cutaneous melanoma during
the life-time of an individual in the USA is 1 in 32
for males and 1 in 55 for females.5 In Australia the
2
risk of being diagnosed with a melanoma by age 85
is 1 in 15 males and 1 in 24 females.3
Genes
It is well known that having a family history of
melanoma increases the personal risk for melanoma
(RR=1.74, 95% CI 1.41, 2.14),11 (RR=2.06; 95%
CI: 1.72, 2.45).12 In particular, first-degree relatives
of patients with melanoma are at increased risk for
melanoma, especially if their relatives were diagnosed at a younger age. Begg et al. reported that
the cumulative risk for melanoma in a male relative
ranges from 0.8% by age 50 to 6% by age 80, and
for a female relative it ranges from 1.3% by age 50
to 7% by age 80.13 Similarly, Olsen et al. found that
approximately 7% of melanoma cases are attributable to having an affected family relative.12 The
aforementioned information suggests that germline
mutations or somatic mutations arising in families
presumably from shared environmental carcinogens
may predispose one to melanoma.
Several pathways and genes have been associated
with susceptibility to melanoma (Figure 1). Particularly, there are two recognized high-penetrance gene
mutations (CDKN2A and CDK4), which are often
found in familial cases and rarely in sporadic melanomas.14 Conversely, the low-penetrance gene MC1R
has been more commonly associated with sporadic
melanomas.15 Although germline mutations are the
February 2012
JAIMES
ones that are responsible for familial melanoma, we
will briefly highlight both germline and somatic mutations, since any one of these mutations can increase
the risk of melanoma in the affected individual. Furthermore, with the emergence of targeted therapies
for melanoma, this may be an appropriate time for
physicians managing melanoma patients to become acquainted with the molecular pathways driving melanoma development and progression. This
knowledge will in turn assist ones understanding of
the mechanism of action of many of the emerging
targeted therapies directed against melanoma such as
therapy targeting BRAF and Kit mutations.
Signaling pathways altered in melanoma
1. Mitogen-activated protein (MAP)-kinase pathway (Figure 1A).—The MAP-kinase pathway regulates cell proliferation in response to extracellular
mitogenic signals (i.e., growth factors) through their
respective receptor tyrosine kinase (i.e. c-kit, VEGFR, etc.).16 The RAS-RAF-MEK-ERK-MAP-kinase
pathway mediates cellular responses to growth signals and the majority of melanomas harbor somatic
mutations in this pathway. These mutations are usually mutually exclusive, meaning that two different
mutations are not present in the same cell, for example both RAS and BRAFV600E mutations do not
normally occur in the same cell.17
v-kit Hardy-Zuckerman 4 feline sarcoma viral
oncogene homolog (KIT), 4q11-12.—KIT receptor
is a trans-membrane receptor of the tyrosine kinase
family and it is normally activated by stem cell factor or kit ligand in the extracellular domain. Activation of Kit receptor results in down-stream signal
transduction through different pathways, including
the MAP-Kinase pathway and the PI3K pathway
(Figure 1A). Kit is important for the development
of melanocytes, hematopoietic cells, mast cells,
and primordial germ cells.18 Melanomas with KIT
mutations are most commonly located on acral regions with 9% to 36% of acral melanomas manifesting KIT mutations. This mutation can also occur in 15% to 39% of mucosal melanomas. Lastly,
this mutation has also been shown to occur in 2%
to 28% of melanomas located on chronically sundamaged skin 16, 19-21 (Table II).
Neuroblastoma RAS viral (v-ras) oncogene homolog (N-RAS), 1p13.—N-RAS activates the MAPK
Vol. 147 - No. 1
pathway resulting in cellular proliferation, and it
also activates the phosphatildylinositol 3’ kinase
pathway, which in turn inhibits apoptosis (Figure
1A). Most mutations in N-RAS have been found in
melanocytes on sun-damaged skin and in melanomas lacking BRAF mutations. In addition, NRAS
mutations have been found in mucosal melanoma 21
(Table II).
v-raf murine sarcoma viral oncogene homologue
B1 (BRAF) gene, 7q34.—Somatic mutations in the
BRAF oncogene have been reported in up to 70%
of melanomas and melanocytic nevi.16, 17, 22 The
most common mutation corresponds to a single substitution of glutamic acid for valine at position 600
(V600E).17 This mutation is common in melanomas
arising on intermittently sun-exposed skin and are
rare in acral, mucosae or chronically sun exposed
skin sites.16, 23 Melanomas with BRAF mutations
tend to occur on the trunk, are usually of the superficial spreading or nodular type, and occur at younger
ages, in individuals with high nevus counts and few
freckles 23 (Figure 1A, Table II).
Cyclin-dependent kinase 4 (CDK4), 12q14; and Cyclin D1 (CCND1), 11q13.—The CDK4 gene binds to
CCND1 and is considered a high-risk melanoma susceptibility gene [24]. Both CDK4 and CCND1 genes
have been suggested to be independent oncogenes in
melanoma and are frequently mutated in acral and
mucosal melanomas 16 (Figure 1A, B, Table II).
Cyclin-dependent kinase inhibitor 2A (CDKN2A)
gene, 9p21.—The CDKN2A gene codes for tumor
suppressors p16 and p14. Inactivating mutations in
p16 (also known as INK4a) promotes the uncontrolled transition from G1 to S phase of the cell cycle. Thus CDKN2A mutations lead to alteration of
the cell cycle with uncontrolled proliferation (Figure
1B). On the other hand, p14 (also known as ARF),
regulates the p53 tumor suppressor gene, which controls the transcription of numerous genes that ultimately lead to DNA repair and cell-cycle arrest, or
leads to apoptosis. Hence, p53 dysfunction can result
in melanoma progression 25 (Figure 1B).
CDKN2A is the most well known high-risk
melanoma susceptibility gene in the setting of familiar melanoma.14 Goldstein et al. described 466
melanoma-prone families, of which 38% had CDKN2A mutations that involved the p16 protein.26
Germline mutations have been observed in different
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Figure 1A.—Pathways and genes in melanoma. Left: a-melanocyte stimulating hormone (a-MSH)/Melanocortin-1 Receptor (MC1R)
or Microphtalmia-associated transcription factor (MITF) pathway. UVR stimulates keratinocytes to release a-MSH, which is a cleavage product of pro-opimelanocortin (POMC). a-MSH binds to MC1R on the surface of melanocytes. MC1R activates cyclic AMP
(cAMP), which activates the camp response-element binding protein (CREB), which in turn increases expression of MITF. MITF
can also be regulated by ERK phosphorylation. Right: Mitogen-activated protein kinase and phosphatildylinositol 3’ kinase pathway
(PI3K) pathways. Binding of ligands (i.e. growth factors, stem cell factor, etc) to their respective receptor tirosine kinase (RTK) leads
to activation of RAS. RAS can activate BRAF, which activates MEK, and MEK then activates the extracellular-related kinase (ERK).
Phosporylated ERK (ERK-p) kinases translocates to the nucleus to activate transcription factors, which promote proliferation. ERK
can also interact with the PI3K-AKT pathway. Activated PI3K converts the plasma membrane lipid phosphatidylinositol 4,5-bisphosphonate to phosphatidylinositol triphosphate (PIP3). PIP3 leads to the phosphorylation of AKT and subsequent up-regulation of cell
cycle, growth, and survival proteins. Phosphatase and tensin homolog (PTEN) inhibits the generated PIP3 by PI3K.
4
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mon in mucosal and acral melanomas 16 (Table II).
Furthermore, functional CDKN2A mutations are
more common in individuals with multiple primary melanomas than in persons with single primary
melanomas (2.9% vs. 1.3%). These individuals are
often younger, with more nevi and are more likely to
have a family history of melanoma.27 Regarding sun
exposure, there is no evidence to suggest that sun exposure increases the risk for melanoma in CDKN2A
mutation carriers above and beyond non-carriers.28
Mutations of the p16 gene have also been linked
with pancreatic cancer and this will be discussed in
more detail below within the context of the atypical
mole syndrome.29
Figure 1B.—CDKN2A gene codes for tumor suppressors p16
and p14. Left: p14 can be induced by signals such as DNA damage. p14 binds to the murine double minute-2 (MDM2) protein;
inhibiting the degradation and inactivation of p53. If p14 were
not bind to MDM2 then MDM2 cause p53 degradation. This is
important since p53 controls the transcription of numerous genes
that ultimately results in cell-cycle arrest, DNA repair or apoptosis. Right: CDK4 binds to Cyclin D1 (CCND1) gene. p16 binds to
CDK4 to inhibit phosphorylation of retinoblastoma (Rb) protein,
which prevents release of the E2F1 transcription factor thereby
inhibiting the cell from entering the S-phase.
geographical regions,24 with the highest frequency
of CDKN2A mutations observed in Europe (57%)
and the lowest in Australia (20%).26
Although, this mutation is commonly found in the
familial setting it has also been found in up to 1.2%
of incident cases of primary melanomas. In the nonfamilial setting the presence of CDKN2A confers
a relative risk for melanoma of 4.3.27 Losses of the
CDKN2A locus have been shown to be more com-
2. Phosphatildylinositol 3’ kinase (PI3K) pathway
(Figure 1A).—The PI3K pathway mediates cell survival in response to extracellular signals (i.e., growth
factors, stem cell factor, etc.), through their respective
receptor tyrosine kinase (i.e., VEGFR, c-kit, etc.).16
Phosphatase and tensin homolog (PTEN),
10q23.—PTEN is a negative regulator of AKT in the
PI3K pathway. It inhibits growth factor signaling by
inactivating phosphatidylinostil triphosphate (PIP3)
generated by PI3K. Loss of PTEN decreases apoptosis. Mutations or deletions of PTEN have been demonstrated in up to 37% of cutaneous melanomas and
tend to occur together with BRAF mutations but not
with N-RAS 30 (Figure 1A).
3. a-melanocyte stimulating hormone (a-MSH)/
Melanocortin-1 Receptor (MC1R) or Microphtalmia-associated transcription factor (MITF) pathway.—Mutations of these receptors and factors may
increase the risk of developing melanoma (Figure
1A).
Melanocortin-1 Receptor (MC1R) gene, 16q24.—
MC1R is a transmembrane receptor for the a-MSH
Table II.—Most frequent mutations in melanoma according to anatomic location and sun-exposure.
Most frequent mutation 10, 11
Sun exposure
Chronic
Melanoma subtype
Lentigo maligna melanoma
Anatomical location
Chronically sun-damaged skin
Other mutations
BRAF
NRAS
KIT
11%
15%
28%
CCND1
Intermittent
Superficial spreading melanoma
Intermittently sun-damaged skin
60%
22%
0%
PTEN
Minimal
Acral melanoma
Volar skin of palms and soles, nails
23%
10%
36%
CDK4, CDKN2A
None
Mucosal melanoma
Mucosal
11%
5%
39%
CDK4 CDKN2A
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Table III.—Risk factors for melanoma, phenotypic characteristics.4
Phenotypic characteristics
Phototype I and II
Freckels (medium to high density)
Eye color (Blue, green or gray)
Light hair color (blond or red)
Red hair color
Blond hair
Light brown hair colors
Fair skin
RR (95% CI)
2.99
2.06
1.62
2.06
3.64
1.96
1.62
2.06
that is expressed in melanocytes of the skin and hair
follicles. It contributes to skin pigmentation by regulating the concentrations of eumelanin and pheomelanin. Its activation by ultraviolet radiation results
in increased synthesis of eumelanin and increased
melanocyte dendricity, proliferation, cell survival
and DNA repair capability. On the other hand, loss
of function of MC1R results in increased synthesis
of pheomelanin pigment, as seen in 80% of individuals with red hair color, fair skin and poor tanning
ability (also known as red hair phenotype).31, 32.
MC1R mutations associated with red hair phenotype increases the risk of developing melanoma, independent of pigmentation phenotype.32, 33 Indeed,
results from meta-analyses have shown that MC1R
variants linked with red hair color are associated with
an increased relative risk for melanoma (RR=2.4,
95% 1.72, 3.46).34 In addition, melanomas in these
patients tend not to be overtly conspicuous due to the
fact that they often lack significant color variegation
and often display few dermoscopic structures.35
MITF, 3p14.1-p12.3.—In normal melanocytes
MITF stimulates melanin production and cell cycle
arrest (anti-proliferative) by activating p16. Mutations in MITF have been shown in melanoma, which
result in the inhibition of apoptosis (Figure 1). MITF
gene has been found to be amplified in up to 20% of
metastatic melanomas.36
4. Other genes.—Melanoma has been reported
to occur more often in carriers with breast cancer 2
(BRCA2), or a combination of gene mutations.
BRCA2, 13q12.—Melanoma has been reported
to occur more often in families with BRCA2. The
Breast Cancer Linkage Consortium reported a rel-
6
ative risk of 2.6 (95% CI: 1.3, 2.5) for melanoma
among BRCA2 carriers.37
Combination of genes.—Combination of gene mutations may increase the risk of melanoma by acting synergistically or by enhancing penetrance of
one or the other gene. For example, MC1R variants
in melanoma-prone families can double the risk of
melanoma in CDKN2A mutation carriers. In addition, MC1R variants alleles can increase the penetrance of CDKN2A mutations in melanoma-prone
families.38
Phenotypic characteristics
Individual phenotypic characteristics such as hair
color, eye color, skin color and freckling are strongly related to ultraviolet radiation (UVR) sensitivity,
which is an important risk factor for melanoma (Table III). Two independent phenotypic traits that place
individuals at higher risk for melanoma are fair skin
(see phototype below) and the presence of a large
number of melanocytic nevi (see nevi 5 below).11
Phototype
The Fitzpatrick scale is most commonly used to
determine the skin’s response to UVR and the skin’s
ability to tan. Individuals with fair skin and poor
ability to tan are classified having skin type I or II.
Persons with darker skin are classified as skin types
III-VI. Based on this scale, fairer skin types have an
increased risk for melanoma. In fact, photo-types I
and II have a significant higher risk for developing
melanoma (RR=2.99; 95% CI: 1.75, 5.12) compared
with persons with darker photo-types who rarely or
never burn and tan easily.11
Nevi
There is a recognized association between nevi and
melanoma. On the one hand, there is the observation
that high nevus counts (common and atypical) are a
risk marker for melanoma.39 On the other hand, any
nevus may be a potential precursor to melanoma. In
one study the lifetime risk of a nevus transforming
into a melanoma was estimated to be approximately
0.03% for male and 0.009% for females.40 With that
said it is important to note that only 26% of melanomas arise in association with a pre-existent nevus
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(Figure 2), while the remaining 74% of melanomas
arise de novo (Figure 3).23, 41.
Number of common melanocytic nevi
Nevus counts are correlated with pigmentary
traits, sun-exposure and history of sunburns.39
Studies in twins have demonstrated that genetics
play an important role in predicting total nevus
counts. However, the ultimate nevus count can be
influenced by sun exposure.42 Numerous studies
from different parts of the world have shown that
the relative risk for developing melanoma increases
as the number of common melanocytic nevi increases.39, 43 People with more than 100 nevi are at
significant high risk for melanoma (RR=6.89; 95%
CI: 4.63, 10.25) as compared with people with less
than 15 nevi.39 In addition, 27% of melanoma cases
are found in patients with more than 50 nevi, while
individuals with less than ten nevi account for only
4% of melanoma cases.12 The number of nevi has
been reported to be one of the strongest risk determinants for superficial spreading melanoma (OR
23.22, P<0.001).44
Number of atypical or dysplastic melanocytic
nevi
Clinically, an atypical nevus is considered to be at
least 5 mm in diameter with a macular component
and with at least two of the following three characteristics: variable pigmentation, irregular asymmetric
outline and indistinct borders.45 Numerous studies
have documented that the relative risk for developing melanoma increases as the number of atypical
nevi increase,39, 43 ranging from 1.60 (95% CI: 1.38,
1.85) for the presence of one atypical nevus up to
10.49 (95% CI: 5.05, 21.76) for five atypical nevi.39,
45, 49 In another study, Olsen et al. reported that 25%
of melanoma cases occurred in individuals with one
of more atypical nevi.12
Atypical or dysplastic nevi were first recognized in
rare melanoma-prone families. These families have
one or more first- or second degree relatives with
melanoma, multiple nevi and dysplastic nevi.46 Affected individuals in these families are said to have
the familial atypical multiple-mole melanoma (FAMMM) syndrome or atypical mole syndrome. FAMMM
syndrome is also linked to the development of other
cancers including breast cancer and pancreatic can-
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Figure 2.—Melanoma arising in association with a preexistent nevus on the abdomen of a female patient. A, B) Clinical and close
up images. C) Dermoscopy evaluation demonstrates a peripheral
reticular with central hypopigmented nevus pattern in association
with a focal atypical pigment network and blue-white veil at the
periphery. This lesion was biopsied revealing a melanoma in situ
arising in association within a dysplastic nevus.
cer.29, 46 The FAMMM syndrome may be considered
as a spectrum of phenotypic expressions, in which
there is an associated p16 mutation.29, 47 The lifetime
risk of melanoma in an affected family member has
been reported to approach 100%.47, 48 Clues to help
identify FAMMM syndrome, include families with
multiple cases of melanoma, multiple primary cancers
in the same person and the diagnosis of melanoma at
younger age (before 40 years of age).45
Atypical or dysplastic nevi can also occur in the
non-familial setting. The estimated prevalence in
the general Caucasian population may range from
7% up to 18%, depending on the type of study or
geographical location.49, 50 These individuals have
a lifetime risk for melanoma of approximately
10%. In addition, atypical nevi have been associated with higher risk of developing multiple primary melanomas (OR=3.28).51 One study showed
that up to 38% of patients with multiple primary
melanomas presented with atypical nevi as compared with 18% of patients with only one primary
melanoma.52
It is important to highlight that dysplastic nevi are
stronger risk markers for melanoma than they are
precursors to melanoma.53 Since most melanomas
develop de novo, the prophylactic whole scale removal of dysplastic nevi will not eliminate the risk
for developing melanoma. Hence, these patients will
benefit more from meticulous surveillance than they
will from indiscriminate removal of their nevi.
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Dermoscopy of melanocytic nevi
Dermoscopic patterns further define individuals
at higher risk for developing melanoma.54, 55 Scope
et al. suggested that children with complex pattern
nevi, which includes the presence of both network
and globules in the same lesion, may be individuals at increased risk for developing atypical nevi or
melanoma in the future [55]. Furthermore, Lipoff
et al. demonstrated that nevi manifesting a complex dermoscopic pattern in adults were more frequent in melanoma patients than in controls (OR 2.9,
P=0.003).54
Congenital melanocytic nevi (CMN)
The presence of a CMN is determined in utero and
while they can be visible at birth, some may not become apparent until sometime after birth (“tardive”
CMN).56 Melanoma can develop within any CMN;57
however, the risk for developing melanoma appears
to correlate with the size of the nevus.58 Essentially,
the risk for melanoma developing in a small CMN
(≤1.5 cm) or medium CMN (1.6-19.9 cm) is low, with
a lifetime risk reported to be between 0% and 5%;
with a relative risk of approximately 10. In contrast,
the lifetime risk for melanoma developing in a large
(20-39.9 cm) or giant CMN (≥40 cm) is between 4.5%
and 10%; with a relative risk that ranges from 52 to
1046.45
History of previous melanoma
A personal history of melanoma is considered
an important risk factor for developing subsequent
melanomas.31 Most second primary melanomas tend
to be diagnosed within the first two years after the
diagnosis of the first primary melanoma.11 Ferrone et
al. reviewed a prospective database of 4484 melanoma patients to determine the incidence of multiple
primary melanomas (MPM). They found that the
estimated cumulative five-year risk to develop a second primary melanoma was 11.4%, with more than
half of the risk occurring within the first year. After
the second primary melanoma was diagnosed, the
cumulative five-year risk to develop a third primary
melanoma was estimated to be 31%, with half of that
risk occurring during the first year after the diagnosis
of the second melanoma.59 Subsequent melanoma,
whether synchronous (60%) or metachronous, tend
8
to be thinner; probably a result of increased detection pressure resulting in heightened surveillance,
scrutiny and vigilance.60
Actinic damage and non-melanoma skin cancer
(NMSC)
A positive association between actinic damage
and melanoma has been demonstrated with a reported relative risk of 2.96.11 Chronic actinic damage is
correlated with the number of solar lentigines, elastosis, actinic keratoses and lentigo maligna melanoma (LMM).44, 61, 62 The number of solar lentigines is
considered one of the strongest predictors for LMM
(OR 15.93, P<0.001).44 Intermittent actinic damage
is correlated with number of nevi, sunburns and superficial spreading melanoma.44, 62 In addition, having a history of a basal cell carcinoma or SCC increases the risk for melanoma between 4 to 17-fold
11, 63 (RR=4.28, 95% CI 2.80, 6.55).11
Immunosuppression
Immunosuppression secondary to cancer or acquired immune deficiency syndrome has been shown
to be associated with melanoma. Likewise, organ
transplant recipients have a 3- to 5-fold increased
risk for melanoma and these melanomas tend to be
diagnosed at a mean of 5 years post-transplant.64 In
addition, patients with diagnosis of non-Hodgkin’s
lymphoma or chronic lymphatic leukemia are also at
increased risk for developing melanoma.65
Other medical conditions
Xeroderma pigmentosum (XP)
XP is an autosomal recessive pigmentary skin
disorder characterized by photosensitivity and a
high predisposition for developing skin cancers.15
XP gene mutations result in an inability to repair
DNA damage sustained from UVR. This inability
to repair the damaged DNA is due to defective nucleotide excision enzymes. These patients are at
higher risk for developing melanoma. One study
showed that the frequency of skin, eye and tongue
cancers was increased 1000-fold or more in patients
with XP who were younger than 20 years. Of the
skin cancers diagnosed in these patients 22% were
melanomas and 57% were basal cell or squamous
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cell carcinomas.66 Although XP is a rare disease,
this condition highlights the carcinogenic effect of
UVR and its direct role in induction of mutations
that result in the formation of skin cancer.67
Parkinson disease
Recent studies have shown a moderate association
of Parkinson disease with melanoma, independent of
levodopa treatment.68
Environmental risk factors
Epidemiological, basic science, molecular and
animal studies have demonstrated that UVR plays a
major role in the development of melanoma and is
currently considered the only preventable environmental cause for this malignancy. Both UVB (290320 nm) and UVA (320-400 nm) have been implicated in the development of melanoma by causing
either direct (UVB) or indirect (UVA) DNA damage.69 Specifically, UVB produces direct pyrimidine
dimmer lesions, while UVA triggers damage through
reactive oxygen species intermediates.70
Exposure to UVR can be obtained from natural
sunlight and artificial sources including indoor tanning beds. Both UVR sources have been classified
as “carcinogenic to humans” by the working group
of the International Agency for Research on Cancer
(IARC).71 Recently, Pleasance et al. performed a
comprehensive sequencing of the entire genome of a
melanoma, demonstrating for the first time that most
somatic substitutions in this melanoma were attributable to UVR-induced DNA damage.72
Natural UVR (sunlight)
The amount of UVR an individual receives is often classified as chronic or intermittent. Although
not all melanomas are related to sun exposure, most
melanomas appear to be related to UVR exposure.
Intermittent sun exposure confers a high risk for
melanoma (RR = 1.61 with 95% CI: 1.31, 1.99) of
the superficial spreading type. In contrast, chronic
sun exposure has been linked to the formation of lentigo maligna melanoma 16, 44, 73 (Table II).
Intermittent intense exposure resulting in sunburns has been associated with melanoma (RR=2.03
with 95% CI: 1.73, 2.37). This association is higher
if the sunburn occurs during childhood (RR=2.24) or
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at higher latitudes (RR=2.54) as compared with sunburns during adulthood (RR=1.92) or at lower latitudes (RR=1.91).73 Moreover, it has been shown that
the number of lifetime sunburns is more strongly associated with superficial spreading melanoma than it
is with LMM.44
Artificial UVR
Tanning beds
The amount of UVR obtained from indoor UV
often exceeds that received during normal outdoor
activities 70 and has been associated with melanoma
(OR 2.06 95% CI 1.30-3.26).74 A meta-analysis of
epidemiological studies on indoor tanning and risk
for melanoma concluded that the risk of cutaneous melanoma was higher (RR=1.75) when tanning
beds were used for the first time before the age of 30
years.75
Phototherapy
Photochemotherapy and UVA radiation (PUVA)
has been associated with an increased risk for
melanoma. The latency period from the time of the
PUVA to the time of the melanoma diagnosis was
reported to be as long as 15 years.76
Melanoma prognostic factors
The��
most significant ��
prognostic factors for melanoma are included in the seventh edition of the American Joint Committee on Cancer (AJCC) for melanoma staging and classification 77 (Table IV). The most
important prognostic factors for localized melanoma
(Stage I and II) are tumor thickness, mitotic rate and
ulceration.77, 78 Thus, the initial biopsy is critically important for diagnostic staging and prognosis. If feasible, an excisional biopsy with a narrow 1 to 2 mm
margin is preferred to a shave or punch biopsy since
this provides the necessary prognostic information
and prevents histopathologic misdiagnosis.77, 79 The
most important predictor of disease-specific survival
is the status of the sentinel lymph node. The number
of regional lymph nodes harboring metastatic disease
and the regional node tumor burden are also considered independent predictors of survival.77, 79, 80 Other
prognostic factors in regional metastatic melanoma
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Table IV.—Prognostic factors for melanoma according to the AJCC staging.12, 13
Localized melanoma (Stage I and II)
Tumor thickness (mm)
Ulceration
Mitotic rate
Number of regional lymph nodes harboring metastatic disease
Regional node tumor burden (micro- vs. macroscopic)
Satellites/in-transit metastases
Distant skin, subcutaneous or nodal metastases
Lung metastases
All other visceral metastases
LDH
Regional metastatic melanoma (Stage III)
Distant metastatic melanoma (Stage IV)
Table V.—Other prognostic factors for melanoma.14-18
Prognostic factor
Comment
Age
Gender
Anatomic location of the primary melanoma
Other histological features
Older age has been associated with poor prognosis
Male gender has been associated with poor prognosis
Scalp, neck and lip melanomas have been associated with poor prognosis
Lympho-vascular invasion in the primary tumor
Presence vertical growth-phase
Tumor-infiltrating lymphocytes
Dermal regression
(Stage III) include the presence or absence of satellite/
in-transit metastases.77 In distant metastatic melanoma
(Stage IV), an elevated serum lactate dehydrogenase
(LDH) is an independent and significant predictor of
survival. Additionally, the number and location of metastases at distant sites is also an important prognostic
factor.77
Other factors not included in the AJCC for melanoma staging that have been shown to impact the
prognosis are listed in Table V. Older age has been
reported to be an independent adverse prognostic
factor among patients with melanoma.80 Conversely,
studies in children have demonstrated that children
with melanoma have a higher survival probability as
compared to adults, particularly when diagnosed before puberty.81, 82 Scalp melanomas have more than
a three-fold increased risk for mortality and a higher
rate of recurrence as compared with other sites.83-85
Tseng and Martinez reported a series of 27097 patients with cutaneous melanoma on the head and
neck. They found that scalp/neck and lip melanomas
had a 64% and 55% increased risk of disease-related
death, respectively and were associated with poorer
melanoma-specific survival.86
10
Management of melanoma patients
The cornerstone of melanoma management remains surgical removal of resectable primary and
metastatic tumors.79 For the primary tumor, studies
and meta-analyses have shown that there is no significant difference in overall survival between narrow
versus wide local excision.87 Recently, Gillgren et al.
evaluated the overall survival of 936 patients with
primary tumors thicker than 2 mm (median thickness of 3.1 mm). Patients were randomly assigned
to undergo excision with a 2 cm margin (N.=465)
or 4 cm margin (N.=471) and were followed for up
to 11.8 years. The authors found that the outcome in
both groups was the same, with a five-year overall
survival of 65% for both groups. Thus, it was concluded that 2-cm margins are sufficient for patients
with melanomas thicker than 2 mm 88 (Table VI).
Sentinel lymph node biopsy is a procedure performed in patients with localized disease to identify
those with nodal metastases with a high degree of
accuracy. Candidates for sentinel lymph node biopsy
include patients with melanomas that are 1.0 mm or
more in thickness or patients with melanomas that
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Table VI.—Primary melanoma excision margins.19, 20
Melanoma Breslow thickness (mm)
In-situ
≤1.0
1.01-2.0
≥2.0
Excision margins (cm)
0.5-1.0
1.0
1.0-2.0
2.0
are less than 1.0 mm in thickness with other adverse
prognostic features such as thickness greater than
0.75 mm, positive deep margins, ulceration, high
mitotic rate, lymphovascular invasion and younger
age.79, 89
In the event of unresectable disease, treatments
with systemic therapy utilizing chemotherapy, biotherapy, and/or immunotherapy need consideration;
the most well known of these include Dacarbazine,
interleukin-2, and interferon. Recent advances in
our understanding of the immune system and the
molecular “drivers” of melanoma cell proliferation
have lead to the development of targeted therapies
for melanoma. These new therapies include Vemurafenib, which is a selective BRAF inhibitor, and
Ipilimumab, which is an IgG1 monoclonal antibody
that blocks cytotoxic T-lymphocyte associated antigen-4, which in turn increases T-cell activation and
proliferation.90, 91 It is beyond the scope of this review to discuss the myriad of management choices
available for each stage of melanoma. However, it
is clear that patients with a previous melanoma are
at increased risk for developing subsequent new
primary melanomas and thus, these patients are
likely to benefit from the implementation of prevention strategies. Prevention strategies have been
categorized into primary and secondary prevention. Primary prevention entails the prevention of
the disease via modifying melanoma risk factors.
Secondary prevention involves early detection and
treatment of melanoma (or melanoma precursor lesions) while the tumor is thin and easily curable by
simple surgical excision.92
Primary prevention
Avoiding excessive and unnecessary UV exposure from natural or artificial sources and protecting
the skin from harmful UV radiation constitutes the
mainstay of primary prevention.
Vol. 147 - No. 1
Ultraviolet protection
Physical barriers such as clothing, sun glasses,
hats and seeking shade are important elements for
sun protection.93 Factors that limit the amount of
UV passing through clothing include tightly woven
fibers, thicker and dark-color fabrics, unbleached
fabrics, lax and dry materials.93 The UV protection
factor (UPF) is the rating placed on sun protective
textiles/clothing and it is a measure of the fabric’s
ability to block both UVA and UVB. A UPF rating
of at least 40 blocks more than 96% of the UV radiation and is the current recommended UPF rating
that will provide sufficient protection irrespective of
geographical location.94
The eyelids and the skin surrounding the eyes also
need to be protected from UV rays. One method to
accomplish this task is the wearing of UV-blocking
glasses or sunglasses. An added benefit of wearing
UV protective eyewear is the lowering of the risk
for cataract development. The wearing of a broad
brimmed hat can also decrease the amount of UV
reaching the eyes. Such hats have the added advantage of also protecting the scalp, ears, face and neck
from UVR.95
Topical sunscreens are broadly categorized into
inorganic (also known as physical) and organic (also
known as chemical). The inorganic sunscreens, such
as zinc oxide and titanium dioxide, reflect and scatter UVR and visible light. In contrast, organic sunscreens absorb UVR, and are further categorized into
UVA filters, UVB filters or broad-band filters, which
absorb both UVA and UVB.93 The sunscreen’s ability to protect the skin from UV radiation can be measured. The Sun Protection Factor (SPF) is used as the
worldwide standard gauge for UVB protection and it
is reported as a number, which is a proportion derived
from measurements of the minimal erythema dose
of sunscreen protected skin versus unprotected skin.
Regarding UVA protection measurements, there is
no one worldwide standard. Current labeling regulations of the European Commission (2006), accepts
two methods for measuring UVA protection (i.e.,
persistent-pigment darkening method and the critical
wavelength) divided into four “levels of protection”
categories (i.e., “low”, “medium”, “high”, “very
high”).96 In contrast, the FDA, in June 2011, recommended one pass/fail test using the in vitro critical
wavelength (CW) as the method for measuring UVA
or broad-spectrum protection.97 The CW is an in
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Figure 3.—Melanoma de novo in a patient with the atypical mole syndrome. A) A new lesion on the face was observed on comparison with baseline images; B) dermoscopy evaluation demonstrates a melanoma with a multicomponent pattern. Lesion was biopsied
revealing a melanoma without any associated nevus.
vitro method that measures the absorption spectrum
curve between 290-400 nm for a given sunscreen
(Figure 4). The prerequisite for all sunscreens is that
they must be able to absorb at least 90% of the area
under their respective UV spectral curve. The wavelength at which this is achieved is called the CW.
However, for a sunscreen to be labeled as providing
broad-spectrum coverage requires that the CW be at
least 370 nm. Sunscreen products can claim that they
“decrease risk of skin cancer and early skin aging
caused by the sun” only if they have an SPF of at
least 15 and a CW of at least 370 nm.97
Recommendations pertaining to the application of
sunscreen include applying the sunscreen 15 minutes before anticipated sun exposure, use of waterresistant products if swimming or sweating and reapplication of sunscreen every two hours.97 The regular
use of sunscreens has been demonstrated to lower
the risk for developing skin cancer. Green et al. performed a large randomized clinical trial in Queensland, Australia. The investigators randomly selected
1621 participants, who were randomly assigned to
daily or discretionary sunscreen use to sun-exposed
areas of their skin between the years 1992 to 2006.
After completion of the trial, there was a 50% reduction in primary melanoma incidence in the intervention versus the control group (HR=0.50, 95%
CI, 0.24 to 1.02 P=0.51), with the majority of the
reduction occurring in invasive melanomas (N.=3 vs.
11; HR=0.73, 95% CI 0.29 to 1.81). This is the only
large randomized clinical trial on sunscreens that has
12
demonstrated that the regular use of sunscreen with
an SPF of at least 15 reduces the incidence of new
primary melanomas.98
Primary prevention can also be achieved through
educational campaigns, which can help change behavior and result in reduced UV exposure in the population. Some of these campaigns and educational
resources include the Euromelanoma,99 National
Council in Skin Cancer Prevention (http://www.
skincancerprevention.org/), Skin Cancer Foundation
(www.skincancer.org ), Sunwise (www.epa.gov/sunwise/ ), SunSmart (http://www.sunsmart.com.au/ ) and
the Slip! Slop! Slap! Campaign. Some of these educational programs have demonstrated a general improvement in sun-protective behaviors of individuals
over time, highlighting that population’s sun-protective behavior is amenable to change.100, 101
Chemoprevention of melanoma
Chemoprevention aims to prevent the development
of melanoma. However, chemopreventive agents for
melanoma remain under investigation and, to date,
there are no drugs approved for this purpose. Although chemoprevention agents such as nonsteroidal
anti-inflammatory drugs (NSAIDs, COX-inhibitors),
statins and antioxidants (i.e., resveratrol, betacarotene) have been studied, results have been conflicting.102-104 For example, Curiel et al. performed a
case-control study to assess the association between
melanoma and NSAIDs and found that the con-
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Figure 4.—The critical wavelength measures the absorption spectrum curve between 290 and 400nm for a given sunscreen (red
curve). The prerequisite for all sunscreens is that they must be
able to absorb at least 90% of the area under their respective UV
spectral curve. The wavelength at which this is achieved is called
the CW. However, for a sunscreen to be labeled as providing
broad-spectrum coverage requires that the CW be at least 370 nm.
tinuous use of NSAIDs for more than five years, in
particular aspirin, reduced the risk of melanoma.103
Similarly, Joosse et al. found that the continuous
use of low-dose aspirin for at least three years was
associated with a decrease risk of melanoma in females.105 However, other studies have reported no
effect of NSAIDs on melanoma risk.106, 107
Secondary prevention
Detection of early disease
Early detection of melanoma can reduce both morbidity and mortality. In fact, according to the AJCC
melanoma staging guidelines, melanomas less than 1
mm, without ulceration and mitosis have 5- and 10year survival rates of 97% and 93%, respectively.77
Early detection strategies are directed toward the
identification of potential precursor lesions and the
removal of early and easily curable disease. This endeavor can be accomplished by physician based periodic total body skin cancer surveillance examinations
and patient monthly skin self-examination (SSE).
Physician detection.—Many experts are of the
opinion that screening for melanoma, especially in
people at high risk for melanoma, is prudent and
is strongly advocated. It has been shown that physician screening is associated with higher rates of
Vol. 147 - No. 1
Figure 5.—Dermoscopic melanoma specific structures. Any
melanocytic neoplasm displaying any of the 10 melanoma specific structures highlighted in this figure should be considered for
biopsy.
melanoma detection and the detection of thinner
melanomas. A recent study on melanoma detection
patterns in high-risk individuals under surveillance
demonstrated that physician detected melanomas
were thinner as compared to self-detected melanomas (0.30 mm vs. 0.5 mm).108
The efficiency and effectiveness of physician based
total body skin examination can be enhanced by the
use of imaging technologies. Two of the most commonly used techniques are dermoscopy and total body
photography (TBP). TBP consists of a set of clinical images of the entire skin surface. These images
serve as a baseline to which subsequent skin examinations are compared. Comparing the skin to previ-
13
JAIMES
Figure 6.—Total body photography facilitated the identification of small and clinical inconspicuous new lesions on the chest of two
patients. Dermoscopy evaluation of these lesions allowed the clinician to diagnose patient A with a benign growing nevus with a peripheral globular pattern, and a melanoma in patient B. The lesion of patient A was followed over time and revealed symmetric growth
until reaching senescence, at which time it revealed a reticular pattern only. The lesion of patient B was removed and revealed features
of melanoma in situ.
ously obtained baseline TBP allows for a more objective assessment of the skin for the detection of new
or changing lesions. Dermoscopy on the other hand
is used to evaluate individual lesions more closely to
determine if a biopsy is warranted. Numerous studies and meta-analyses have confirmed that dermoscopy provides improved diagnostic accuracy for the
diagnosis of skin cancer as compared to the naked eye
examination [109]. It should be intuitively obvious to
most that there exists a natural synergy between TBP
and dermoscopy. Whereas TBP facilitates identifying
subtly changing or new lesions, dermoscopy helps
further evaluate these lesions to determine if a biopsy
14
is necessary (Figures 5-7). The combined use of TBP
and dermoscopy is likely to translate into a much improved sensitivity and specificity for the detection of
melanoma, which in turn results in the appropriate removal of skin cancers while at the same time minimizing the unnecessary removal of benign and biologically indolent lesions 110 (Figures 6, 7). Some physicians
have started advocating total body dermoscopy, which
entails obtaining baseline dermoscopic imaging of all
or almost all nevi in a given individual. These lesions
can then be reimaged with dermoscopy in the future
and compared to the baseline dermoscopic images.111
Changes noted on dermoscopic follow-up of lesions
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Figure 7.—Total body photography permitted the identification of two changing lesions on the abdomen and back of a male patient. A) Dermoscopy evaluation of the lesion on the abdomen revealed a benign reticular pattern nevus. This nevus was followed
and revealed no subsequent changes. Thus, the lesion was considered biologically indolent and subjected to continued follow-up;
B) Dermoscopy evaluation of the lesion on the back revealed a multicomponent pattern. This lesion was removed and revealed a
microinvasive melanoma.
may further improve upon the sensitivity of finding
early melanoma 112, 113 (Figure 8).
Patient detection.—Patients also play an important
role in melanoma detection. It has been reported that
more than 68% of melanomas are detected by patients or their relatives.114 Although physicians are
more likely to detect thinner melanomas than patients,114, 115 patients who perform SSE detect thinner melanomas as compared to patients that do not
perform SSE.116 One study showed a reduction in
the incidence of melanoma, less advanced disease
and decreased melanoma mortality by up to 63% in
Vol. 147 - No. 1
patients performing SSE.117 Kovalyshyn et al. demonstrated that high-risk patients that are under active
surveillance detect a greater percentage of their own
melanomas while the melanomas are in situ (70% vs.
57%) and thin (0.45 mm vs. 0.82 mm) as compared to
patients who are not under active surveillance.108 In
other words, SSE and physician based surveillance
examinations should be viewed as complementary
methods that together enhance the discovery of thin
curable melanomas. To assist patients in their SSE
some have advocated provided them with their own
set of baseline TBP and perhaps even their own dermatoscope.108, 118
15
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Figure 8.—Total body dermoscopy performed in a patient. Baseline dermoscopic images of many nevi were obtained at baseline in
2004 (row 1). Nevi were reimaged with dermoscopy two years later and the 4th and 5th lesion revealed changes that warranted a biopsy.
The fourth lesion proved to be a dysplastic nevus and lesion number 5 proved to be a microinvasive melanoma. The other lesions continued to be subjected to dermoscopic imaging and two years later remained unchanged.
Secondary prevention by removing precursor lesions
It is important to point out that there are no known
obligate precursor lesions to melanoma. Although
melanoma can arise in association with dysplastic
nevi, congenital nevi and lentigines, these lesions are
all considered potential non-obligate precursors to
melanoma.40, 41, 57 Furthermore, the absolute risk of
any one of the aforementioned lesions transforming
into melanoma is very small and thus, the prophylactic removal of all these benign lesions would be
unwarranted, impractical and cost prohibitive. Unfortunately, there is currently no method available at
our disposal that can reliably identify which of the
benign lesions is destined to transform into melanoma. However, it is intriguing to speculate that while
biologically indolent (non-changing or senescent)
lesions are likely benign, some of the biologically
dynamic (changing, breaking out of senescence) lesions that are found to be histologically benign may
in fact be lesions that are on the road to melanoma. In
other words, albeit histologically ‘‘benign,’’ a higher
percentage of these changing lesions, matched with
their histologically equivalent, clinically static counterparts, are biologically destined towards melanoma
(i.e., the true melanoma precursor lesion). What this
implies is that some lesions that are histologically diagnosed as benign lesions may in fact be malignant
when viewed on the molecular level.119
Entire textbooks have been written on risk factors,
prognosis and management of melanoma. With that
16
said, the aim of this brief review was to provide a
concise overview and to highlight some of the new
and/or novel research published on this topic over the
past few years. Attempts were made to focus on issues that are likely to be pertinent to busy practicing
dermatologists such as awareness of variables that
predispose an individual to skin cancer, strategies
for UVR protection, and the importance of screening
and surveillance of high-risk patients for the development of new primary melanomas. An emphasis on
the molecular /genetic pathways in melanoma was
deemed important due to the exciting emergence of
targeted therapies for melanoma. In the future it is
highly likely that management of melanoma patients
will be individualized based on identifying a given
patient’s immune system and molecular “drivers” for
their specific melanoma.
Riassunto
Un aggiornamento su fattori di rischio, prognosi e gestione dei pazienti con melanoma
Il melanoma cutaneo continua a essere un problema di
salute pubblica mondiale, con un’incidenza in crescita in
tutto il mondo. Il riconoscimento dei fattori di rischio per
l’insorgenza del melanoma permette di identificare un sottogruppo di pazienti ad alto rischio, i quali hanno un’elevata probabilità di beneficiare da approcci volti a ridurre
l’esposizione alle radiazioni ultraviolette e da strategie di
controllo orientate alla rilevazione dei melanomi quando
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sono sottili e facilmente curabili. In questa review forniamo una panoramica sui fattori prognostici e di rischio più
pertinenti, nuovi e recenti. Esamineremo quindi i potenziali benefici delle strategie di controllo dei tumori cutanei,
inclusi l’esame cutaneo completo da parte del medico, la
valutazione fotografica dell’intera superficie cutanea, la
dermoscopia e l’autovalutazione cutanea da parte del paziente. Oltre a ciò, discuteremo della gestione dei pazienti
con melanoma, con un accento particolare sulla prevenzione e sulle strategie di rilevazione in fase iniziale.
Parole chiave: Melanoma - Rischio, fattori - Neo - Raggi
ultravioletti.
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93. Lautenschlager S, Wulf HC, Pittelkow MR. Photoprotection. Lancet 2007;370;528-37.
94. Gambichler T, Laperre J, Hoffmann K. The European standard for
sun-protective clothing: EN 13758. J Eur Acad Dermatol Venereol
2006;20;125-30.
95. Tuchinda C, Srivannaboon S, Lim HW. Photoprotection by window glass, automobile glass, and sunglasses. J Am Acad Dermatol
2006;54;845-54.
96. European Commission. Commission recommendation on the efficacy of sunscreen products and the claims made relating thereto.
Official Journal of the European Union; 2006.
97. Wang SQ, Lim HW. Current status of the sunscreen regulation
in the United States: 2011 Food and Drug Administration’s final
rule on labeling and effectiveness testing. J Am Acad Dermatol
2011;65;863-9.
98. Green AC, Williams GM, Logan V, Strutton GM. Reduced melanoma after regular sunscreen use: randomized trial follow-up. J Clin
Oncol 2010 [Epub ahead of print].
99. van der Leest RJ, de Vries E, Bulliard JL, Paoli J, Peris K, Stratigos
AJ et al. The Euromelanoma skin cancer prevention campaign in
Europe: characteristics and results of 2009 and 2010. J Eur Acad
Dermatol Venereol 2011 [Epub ahead of print].
100. Dobbinson SJ, Wakefield MA, Jamsen KM, Herd NL, Spittal MJ,
Lipscomb JE et al. Weekend sun protection and sunburn in Australia
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trends (1987-2002) and association with SunSmart television advertising. American Journal of Preventive Medicine 2008;34;94-101.
101.Hill D, White V, Marks R, Borland R. Changes in sun-related attitudes and behaviours, and reduced sunburn prevalence in a population at high risk of melanoma. Eur J Cancer Prev 1993;2:44756.
102. Bonovas S, Nikolopoulos G, Filioussi K, Peponi E, Bagos P, Sitaras NM. Can statin therapy reduce the risk of melanoma? A
meta-analysis of randomized controlled trials. Eur J Epidemiol
2010;25;29-35.
103. Curiel-Lewandrowski C, Nijsten T, Gomez ML, Hollestein LM,
Atkins MB, Stern RS. Long-term use of nonsteroidal anti-inflammatory drugs decreases the risk of cutaneous melanoma:
results of a United States case-control study. J Invest Dermatol
2011;131;1460-8.
104. Szekeres T, Saiko P, Fritzer-Szekeres M, Djavan B, Jager W. Chemopreventive effects of resveratrol and resveratrol derivatives. Ann
N Y Acad Sci 2011;1215:89-95.
105. Joosse A, Koomen ER, Casparie MK, Herings RM, Guchelaar HJ,
Nijsten T. Non-steroidal anti-inflammatory drugs and melanoma
risk: large Dutch population-based case-control study. J Invest Dermatol 2009;129:2620-7.
106. Asgari MM, Maruti SS, White E. A large cohort study of nonsteroidal anti-inflammatory drug use and melanoma incidence. J Natl
Cancer Inst 2008;100:967-71.
107. Jacobs EJ, Thun MJ, Bain EB, Rodriguez C, Henley SJ, Calle EE.
A large cohort study of long-term daily use of adult-strength aspirin and cancer incidence. J Natl Cancer Inst 2007;99:608-15.
108. Kovalyshyn I, Dusza SW, Siamas K, Halpern AC, Argenziano G,
Marghoob AA. The Impact of Physician Screening on Melanoma
Detection. Arch Dermatol 2011 [Epub ahead of print].
109. Kittler HPH, Wolff K, Binder M. Diagnostic accuracy of dermoscopy. Lancet Oncol 2002;3:159-65
110. Malvehy J, Puig S. Follow-up of melanocytic skin lesions with
digital total-body photography and digital dermoscopy: a two-step
method. Clin Dermatol 2002;20:297-304.
111. MoleSafe. MoleSafe. 2008.
112. Kittler H, Pehamberger H, Wolff K, Binder M. Follow-up of
melanocytic skin lesions with digital epiluminescence microscopy:
patterns of modifications observed in early melanoma, atypical
nevi, and common nevi. J Am Acad Dermatol 2000;43:467-76.
113. Kittler H, Binder M. Follow-up of melanocytic skin lesions
with digital dermoscopy: risks and benefits. Arch Dermatol
2002;138;1379.
114. Brady MS, Oliveria SA, Christos PJ, Berwick M, Coit DG, Katz
J, et al. Patterns of detection in patients with cutaneous melanoma.
Cancer 2000;89;342-7.
115. Fisher NM, Schaffer JV, Berwick M, Bolognia JL. Breslow depth
of cutaneous melanoma: impact of factors related to surveillance
of the skin, including prior skin biopsies and family history of
melanoma. J Am Acad Dermatol 2005;53;393-406.
116. Carli P, De Giorgi V, Palli D, Maurichi A, Mulas P, Orlandi C et al.
Dermatologist detection and skin self-examination are associated
with thinner melanomas: results from a survey of the Italian Multidisciplinary Group on Melanoma. Arch Dermatol 2003;139;60712.
117. Berwick M, Begg CB, Fine JA, Roush GC, Barnhill RL. Screening
for cutaneous melanoma by skin self-examination. J Natl Cancer
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118. Goulart JM, Malvehy J, Puig S, Martin G, Marghoob AA. Dermoscopy in skin self-examination: A useful tool for select patients.
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119. Nardone B, Martini M, Busam K, Marghoob A, West DP, Gerami
P. Integrating clinical/dermatoscopic findings and fluorescence in
situ hybridization in diagnosing melanocytic neoplasms with less
than definitive histopathologic features. J Am Acad Dermatol 2011
[Epub ahead of print].
19

Surgical and histologic pitfalls in the
management of lentigo maligna melanoma
M. ŠITUM
Lentigo maligna melanoma (LMM) is a malignancy with increasing incidence, accounting for about 4% to 15% of all
melanomas. Lentigo maligna (LM) is LMM in situ, usually
presenting an irregular tan colored or brownish pigmented
macular lesion persisting for years on chronically sun-exposed
skin. Left untreated, LM may evolve into invasive form of
LMM. Histologic evaluation of LM/LMM can be difficult due
to widespread atypical melanocytes that are present in the area
chronically sun damaged skin. It has been shown that chronically sun-damaged non-lesional skin can display some atypical
features even in the absence of a melanocytic neoplasm. It is
important for dermatopathologists to be aware of these findings so that such features are interpreted appropriately when
making a histological assessment that may ultimately influence
therapy and outcome. LMM is characterized by significant
subclinical lesion extension which makes the treatment another challenge. Nowadays, a variety of therapeutic options are
available in the treatment of LMM. Surgery remains the mainstay of LMM therapy, however the treatment of LM remains
controversial subject in the literature. Non-surgical treatment
modalities for LM include: destructive procedures such radiotherapy, cryotherapy, curettage, laser, electro-destruction
and immunotherapy with the topical application of 5% imiquimod cream. These treatment options should be considered
for a subset of patients with LM, especially in elderly patients
with extensive or unresectable disease in difficult areas on the
face or, as a second-line therapy if surgery is contraindicated.
Surgical options include simple excision and margin-control
techniques such as staged excision and Mohs micrographic
surgery.In this article, authors are reviewing the latest diagnostic and therapeutic advances in the management of LMM.
Key words: Hutchinson’s melanotic freckle - Melanoma - Diagnosis Histology - Therapeutics - Surgical procedures, minimally invasive.
Funding.—No funding sources supported this study.
Corresponding author: M. Šitum, MD, PhD, Department of Dermatovenereology, «Sestre milosrdnice» University Hospital Centre, Vinogradska 29, 10000 Zagreb, Croatia. E-mail: [email protected]
Vol. 147 - No. 1
1, 2 ,
M. BULJAN
1, 2
1Department of Dermatovenereology
«Sestre milosrdnice» University Hospital Centre,
Zagreb, Croatia
2University of Zagreb, School of Dental Medicine,
Zagreb, Croatia
M
elanoma is one of the most aggressive skin tumours, with poor prognosis for patients in advanced stages.1-3 The constant rise in the incidence
of this tumour worldwide is probably connected to
the changes in sun exposure and environmental lev��
recognized histologic subels of UV light.1 Major
types of melanoma include superficial spreading
melanoma (SSM), nodular melanoma (NM), lentigo
maligna melanoma (LMM) and acral lentiginous
melanoma (ALM).4 LMM accounts for 4% to 15%
of all melanomas.5-8 It is a slowly growing tumour
typically presenting in older individuals, in the sixth
or seventh decades of life usually on chronically
sun-exposed skin of the head and neck area.9 Therefore, cumulative UV- exposure of the skin is considered to have crucial role in the development of
LMM.6 The prognosis for patients with the invasive
LMM does not seem to differ from that for other
histologic types of melanoma after controlling for
tumour thickness.6 Women are affected more often
as men by LMM, with the average age of over 60
years. The age of onset has dropped over the past
years and this tumour is nowadays also diagnosed in
middle-aged individuals.5, 6, 10
Lentigo maligna (LM), also called Hutchinson’s
melanotic freckle or precancerous melanosis of Du-
21
ŠITUM
Surgical and histologic pitfalls in the management of lentigo maligna melanoma
breuilh, represents LMM in situ. This lesion was first
described by Hutchinson in 1892 as the presence and
overgrowth of atypical melanocytes at the dermal-epidermal junction in chronically sun-damaged skin.8,
11 Clinically, LM presents as an irregular tan colored
or brownish pigmented macular lesion persisting for
years on chronically sun-damaged skin on the head
and neck.6 Lesions can vary in location, size, and
color, ranging from tan to black.8 Left untreated, LM
may continue to grow and evolve into invasive form
of LMM with dermal invasion.8 The estimated lifetime risk of LM progressing to invasive LMM is estimated to be around 5%.12 In fact, some authors report
that approximately 16% of LM harbor areas of early
invasive LMM.8, 13 Clinical diagnosis of LM and
LMM, especially in early stage may be very difficult.
Early diagnosis of LM requires a high index of suspicion for the often subtle atypical signs of pigmented
lesions on sun-damaged skin.14 Clinical margins of
these melanocytic lesions can be better visualized by
Wood’s light examination.15 Dermatoscopy and confocal laser microscopy are imaging methods that can
be useful tool and aid in diagnosing LM/LMM.12
The progression from LM into LMM is clinically
usually noticeable by the development of darker areas or elevated parts or dark nodules within the previously uniformly pigmented long-lasting macule.6
Since the complete LM or LMM lesion is often an
extensive lesion on cosmetically sensitive parts of
the body, such as face and neck area, in specific situations the prominent parts of the lesion are biopsied
(with full-thickness incisional or punch biopsy) to
confirm the diagnosis.16, 17
Differential diagnoses of LM/LMM include a wide
spectrum of pigmented skin lesions such as: solar
lentigo (early lesions of seborrheic keratoses), lentigo simplex, lichen planus-like keratosis, pigmented
actinic keratosis, pigmented basal cell carcinoma,
squamous cell carcinoma and dysplastic nevus.6, 8,
18-20 A specific problem in clinical recognition and
diagnostics is amelanotic LM which presents as a
pink macule with little to no pigmentation and often resembles an inflammatory lesion rather than a
melanocytic neoplasm.8, 21, 22
Dermatoscopy, a non-invasive clinical technique
which has become a part of an every-day dermatological practice over the last decade, has been shown
to have higher diagnostic accuracy, especially in
the diagnosis of pigmented skin lesions.5, 18, 23 Major dermatoscopical features of LM/LMM include:
22
asymmetrical pigmented follicular openings, rhomboidal structures, annular-granular structures and
gray pseudo-network.18 LM, at first, seems to occur
as asymmetrical pigmented follicular openings and/
or annular-granular structures, then expand and develop into the rhomboidal structures. However, annular-granular structures and gray pseudo-network
can also be found (but usually more homogeneous)
in regressive areas of solar lentigo (early stage of seborrheic keratosis), as well as in lichen planus-like
keratosis and pigmented actinic keratosis.18
One should also keep in mind that previous treatments may alter clinical presentation of LM/LMM.
For example, it has been reported that topical imiquimod may remove visible pigment while having no
effect on the histological findings.8, 24
Histology
The histologic hallmark of LM is the presence of
an increased number of atypical melanocytes in the
basal layer of the epidermis in small nests or single
cells, usually extending into periadnexal structures.12
Other histologic features of LM/LMM are: an atrophic epidermis, solar elastosis, predominance of spindle-shaped melanocytes, poor circumscription, and
melanocytic nuclear atypia, as well as the presence of
an inflammatory dermal infiltrate.7, 12 However, the diagnosis of cutaneous melanocytic lesion requires special expertise and experience of the pathologist.25-27
Establishing the histological diagnosis of LM/LMM
can be challenging due to several reasons. Since LM/
LMM are often large lesions commonly located on
the head and neck area, usually small (subtotal) biopsy samples are taken to confirm the diagnosis before the definitive treatment.17 For dermatopathologists, it can be very difficult to interpret such small
lesion samples. Also, LM is a type of lesion in which
a marked heterogeneity in the histological features in
different portions of the same lesion can be found.17
In certain areas, the lesion of malignant skin tumour
such as LM/LMM, may display features of a benign
skin lesion such as solar lentigo or dysplastic nevus.17
Therefore, interpreting just a small part of an extensive melanocytic lesion like LM may be misleading.
Another problem in diagnosing LM/LMM is the
fact that these lesions typically develop in areas of
chronically sun-exposed skin. These transition areas
between the lesion itself and the surrounding solar
February 2012
damaged skin can lead to inadequate excisions and
recurrent disease depending on the choice of surgical procedure and how the histology is processed
and analyzed.8 The differentiation of melanoma in
situ, including LM from melanocytic hyperplasia
(so-called solar melanocytosis) in sun-damaged skin
can sometimes be difficult. In a study conducted by
Weyers et al., several criteria have been proposed after examining the epidermis adjacent to 50 consecutive basal cell carcinomas and 50 melanomas in situ
(MIS) in the area of the skin with significant solar
elastosis.28 In this study, the most valuable criteria for
the diagnosis of melanoma in situ (MIS), as opposed
to melanocytic hyperplasia, were: presence of nests
of melanocytes, irregular distribution of melanocytes, descent of melanocytes far down adnexal epithelial structures, irregular distribution of pigment,
presence of melanocytes above the junction, a high
number of melanocytes, pleomorphism of melanocytes, and atypical nuclei of melanocytes.28
Furthermore, atypical lentiginous melanocytic lesions, especially when encountered in older patients,
often pose a diagnostic difficulty.29 LM is histologically characterized by a broad atypical lentiginous
growth pattern of moderately atypical melanocytes
showing focal nesting and pagetoid spread without
significant dermal fibroplasia or alteration of the rete
ridges.29 It may show significant overlap in clinical and histologic features with atypical lentiginous
nevus (of the elderly), but the relationship between
these entities has not yet been explained.29
In order to improve diagnosing lesions of LM/
LMM, several immunohistochemical stainig methods have been employed and the most commonly
used stains are HMB-45 and MART-1. Hendi et al.
analyzed the density and distribution of melanocytes
using Melan-A and H&E stains on nonlesional sunexposed skin of the face and neck in 100 patients,
and quantified the presence and extent of features
considered characteristic of melanoma in noncancerous specimens of sun-damaged skin. They report that relatively high melanocyte density, mild to
moderate confluence of melanocytes, focal pagetosis, superficial follicular extension (<1.0 mm), and
mild or moderate cytologic atypia may be observed
in the absence of a melanocytic neoplasm.30 It is important for dermatopathologists to be aware of these
findings to potentially prevent the overdiagnosis of
melanoma.30
Bowen et al., in their study with Melan-A immu-
Vol. 147 - No. 1
ŠITUM
nohistochemical staining found that uninvolved sundamaged skin shows features characteristic of LM.31
In order to identify the immunohistochemical similarities and differences in melanocyte distribution
between LM and LMM and chronically sun-exposed
skin, they retrospectively analyzed Melan-A-stained
original biopsy specimens of LM and LMM and uninvolved sun-damaged skin (negative controls), from
70 LM and LMM cases.31 Their research showed
that histologic features commonly associated with
LM were common in negative controls from chronically sun-exposed skin. Melanocyte confluence
(27/70, 39%), stacking (34/70, 49%), theque formation (9/70, 13%), adnexal extension (59/68, 87%),
and suprabasilar scatter (23/70, 33%) were observed
in the negative controls from sun-damaged skin.
Such features were present nearly uniformly in the
LM and LMM specimens. Epidermal melanocyte
density in LM and LMM differed significantly from
that in negative controls.31 Therefore, greater density
and unusual patterning of melanocytes in chronically
sun-exposed skin may be difficult and, on occasion,
complicate interpretation of intraoperative Melan-A
immunohistochemical stained margins during margin-controlled surgery for LM and LMM.31
Another possible problem in diagnosing LM/
LMM lesions may result from the classification of
LM as MIS. This is because some pathologists make
differentiation between LM as melanoma precursor
and a true MIS according to the number of atypical
melanocytes and the pattern of their arrangement in
the basal epidermis.8 However, today’s nomenclature uses the term LM for malignant melanoma in
situ occurring in the head and neck sun-damaged
skin area in elderly people.8
Treatment
Nowadays, a variety of therapeutic options are
available in the treatment of LMM. Surgery remains
the mainstay of melanoma treatment at all sites.15, 32
However, the treatment of MIS, particularly the LM
subtype, has been a controversial subject in the literature for many years.33 In cases of LM, treatment
modalities other than surgical excision may be used
in certain situations.14, 16 Non-surgical treatment modalities for LM include: destructive procedures such
radiotherapy, cryotherapy, curettage, laser and electro-destruction.14 These treatment options should be
23
ŠITUM
considered for a subset of patients with LM, especially in elderly patients with extensive or unresectable
disease in difficult areas on the face or, as a secondline therapy if surgery is contraindicated.32-34 Immunotherapy with the topical application of 5% imiquimod cream has also been more recently proposed as a
possible therapy for LM.21, 33, 35-36 Initial studies of the
LM treatment with imiquimod 5% cream have shown
promising results with good cosmetic outcome, but the
follow-up duration in most studies was short.21, 33, 35 In
a recently published study with a long-term followup after the treatment of LM with imiquimod cream,
complete clinical clearance was achieved in nine out
of 10 patients, and five out of 10 patients sustained
clinical remission.36 According to these results, imiquimod appears to be an effective treatment for a subset
of patients with LM. However, long-term follow-up
and multiple post-treatment biopsies are strongly recommended, even in the absence of a clinical recurrence.36 On contrary, some authors reported low cure
rates with local imiquimod cream, emphasizing the
importance of caution because some of these lesions
contain an unrecognized invasive component.33 Gen��
erally, n��
on-surgical treatment modalities carry a significantly increased risk of local recurrence.37
As it was already mentioned, surgical excision remains the treatment of choice for LM and LMM.5,
32 Surgical methods that have been used for years
in the treatment of LM/LMM include simple excision and margin-control techniques such as staged
excision and Mohs micrographic surgery, as well
as certain new modifications of the aforementioned
techniques.8, 14, 38
The current recommendation is local resection
with a 0.5 to 1.0 cm margin of normal skin.39 Traditional excisional surgery refers to excision of tumour
with surgical margins defined beyond the clinically
determined borders of the lesion. The excised tissue
is then analyzed by the pathologist. However, the
standard bread-loafing technique enables analysis
of only around 1% of the margins.8 Simple excision
seems to be an appropriate therapy for clinically
well-defined tumours however; LM and LMM are
often large and clinically ill defined lesions. Moreover, subclinical extension of tumour together with
the poikilodermatous aspect of the solar damaged
skin, make the border distinction difficult. Because
of these characteristics, the margins of LM/LMM lesions may be underestimated which carries a risk of
insufficient resection with simple excision surgery.
24
Therefore, margins of at least 10 mm are usually recommended for complete excision of LMM, in some
cases even for in situ lesions.38 Since most LMM lesions occur on the skin of the face and neck area,
the narrowest possible margin is desired in order to
minimize the scarring. Hence, the surgical challenge
is to spare tissue while still achieving clear margins.
Margin-control surgery offers the highest cure rate
while minimizing loss of normal tissue.14 Mohs micrographic surgery (MMS) is still considered a valuable option for the treatment of melanoma in situ,
especially for LM subtype which is usually clinically
ill defined.40 The technique of MMS refers to the removal of lesions in stages, with serial examination
of histologic margins by the Mohs surgeon using
horizontally oriented frozen sections.8, 41 The main
complaint to this technique is the questionable quality of the frozen sections in comparison to the paraffin-embedded permanent sections, along with the
considerable time and expense to its performance.8
So-called “Slow Mohs” is a variant in which the tissue is sent for the overnight rush permanent sections
which lengthens the procedure for 2 days, but reduces the possibility of the frozen section errors.8 The
primary difficulty encountered with the MMS lies in
the accurate identification of atypical single melanocytes to determine tumor-free margins. Numerous
methods have been used to better visualize single
melanocytes, with varying results. The advent of rapid immunostains has made the use of MMS to treat
melanoma more practical.42 In order to simplify margin assessment for MMS, many investigators have
begun to rely on intraoperative immunohistochemistry to identify melanocytes in frozen sections, and
MART-1 seems to be one of the preferred immunostain for this purpose.41, 43-44. Bhardwaj et al. reported
that the combination of MMS with Mel-5 immunostaining yielded excellent results in the treatment of
LM and LMM, with only one recurrence noted in
200 patients.15 In this study, the initial clinical margins were determined by Wood’s light examination,
and an initial debulk specimen was taken and sent
for formalin fixation and later reviewed by a dermatopathologist. The first Mohs layer was then taken,
and staining with hematoxylin and eosin as well as
Mel-5 immunostaining was performed.15 Robinson
et al. described modification of MMS including the
use of fixed histopathologic specimens and HMB45 monoclonal antibody to help delineate atypical
melanocytes and the possibility of narrower margins
February 2012
of resection for LM.39 In their study, a Wood’s light
was used to delineate the clinical margin in 16 cases
of LM that were resected with serial excisions 0.3,
0.6, 1.0, and 1.3 cm from the clinical border of the
tumor. Frozen sections were confirmed by fixed histopathologic specimens. Subsequently these tissue
blocks were examined with HMB-45 monoclonal
antibodies. Patients were observed 5 to 9 years. Only
one of the 16 patients had a recurrence 8 years after
surgery.39 In general, traditional Mohs surgery represents a reliable treatment option for LM/LMM, however this method became less popular over the last
years, due to development of improved alternative
techniques such as staged excision procedures.
Staged excision procedures are specialized surgical techniques that focus on meticulous assessment of peripheral margins prior to closure (staged
margin control) conducted with analysis of either
frozen or permanent histologic sections.13, 43 These
techniques include different excisional patterns and
histologic processing methods. Depending on the
technique, primary tumour is excised with the initial
margin specimens or left in place until margins are
cleared.8 Techniques utilizing permanent sections
include variations like the ‘’square’’, ‘’perimeter’’,
and ‘’contoured’’ excisions, and recurrence rates
with these techniques are reportedly low, however
mostly based on short-term follow-up.43, 45-46 Mahoney et al. describe the perimeter technique as a
simple method of margin-controlled excision of LM.
According to them, the main advantage of perimeter
technique is that all margins are examined with permanent sections, whereas the main drawback is that
multiple operative sessions are required to complete
the procedure. However, this technique does not require specific Mohs training and is therefore applicable to non-Mohs surgeons.45 Bosbous et al. report
their 10-year experience using staged excision for
the treatment of LMM and LMM of the head and
neck.11 In this study, staged excision was performed
on 59 patients. Using staged excision, 62.7% of patients required a 10-mm or greater margin to achieve
clearance of tumor. Two or more stages of excision
were required in 50.9 % of patients. Invasive LMM
was identified in 10.2% of patients initially diagnosed with LM. There was one documented recurrence during a median 2.25-year follow-up period.11
Agarwal-Antal et al. found that 58% of 92 LM lesions required margins greater than 5 mm.13 They
performed polygonal perimeter excisions with se-
Vol. 147 - No. 1
ŠITUM
rial histopathologic permanent sections in a staged
fashion with each stage of resection used a 5-mm
margin.13 Specimens were color-coded and mapped.
Any sites of tumor at resected margins were identified by a dermatopathologist and noted on the map
of the excised specimen. Positive margins and areas
with markedly atypical melanocytes were further resected, color-coded, mapped, and evaluated as previously described until margins free of tumor were
attained. This study demonstrated that the standard
recommendation of 5-mm margins is adequate in
less than 50% of cases.13
Recently, the “spaghetti technique”, as an alternative to Mohs surgery or staged surgery has been described.38 It is a two-phase surgical technique which
can be applied for lentiginous melanomas (LM,
LMM and acral lentiginous melanomas) that are not
suitable for en bloc resection. In the first phase, a
narrow band of skin, “the spaghetti”, is resected just
beyond the clinical outline of the melanoma, immediately sutured, and sent for pathological examination
without removing the tumour. The same procedure is
repeated beyond the segments which are shown not to
be tumour free and so forth until the minimal tumourfree perimeter is outlined. No operative wound is left
between operative sessions. In the second phase, the
melanoma resection and reconstruction are performed
at the same time. In the study performed by GaudyMarqueste et al. on 21 patients with LM (N.=16) or
ALM (N.=5), the mean operative defect size was 27.5
cm2. The mean number of steps in the procedure was
1.55. Grafts were used for reconstruction in all cases.
The relevance of the “spaghetti”-defined outline was
confirmed in 19 of 21 patients. After a median followup period of 25.36 months (range, 0-72 months), the
local control rate was 95.24% with one case (4.76%)
of in-transit invasive recurrence after 48 months. Unlike Mohs surgery, “spaghetti technique” does not
require specific training of surgeons or pathologists.
Unlike staged surgery, it does not leave patients with
an open wound before the final reconstruction. However, this study was performed at a single centre and
included a limited number of patients, with a relatively short follow-up period.38 Further studies are
required to fully explore the advantages and disadvantages of this technique.
However, the treatment of LM, remains controversial subject in the literature for over a decade. Multiple studies of excisional surgery have shown that 5
mm standard margins are often insufficient to clear
25
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the LM lesion due to unseen subclinical extension,
accounting for this treatment’s reported 8-20% recurrence rate.12, 33, 37 Mohs surgery and staged excision may offer better margin control and lower recurrence rates (4-5%).47, 48 Estimates of recurrence rates
following nonsurgical therapies such as cryosurgery,
radiotherapy, electrodessication and curettage, laser
surgery, and topical medications range from 20% to
100% at 5 years.12, 33
Conclusions
LM/LMM are skin tumours with specific clinical
and histologic features characterized by significant
subclinical lesion extension and predilection for sunexposed areas of the skin. When analyzing a lentiginous lesion in the area of chronically damaged skin,
dermatopathologists should be aware of numerous
pitfalls in the histologic and immunohistochemical
analysis.
Since the borders of LM/LMM are often clinically
and histologically ill-defined, treatment of these lesions, including surgical and non-surgical methods,
is another challenge. Margin- control surgical techniques offer the highest cure rate while minimizing
loss of normal tissue. Nowadays, classical Mohs micrographic surgery is modified with the use of rapid
intraoperative immunohistochemistry to identify
melanocytes in frozen sections. Also, staged excision procedures represent an effective treatment for
LM and LMM.
Even though surgery is the treatment of choice,
alternative options should also be considered, especially for the elderly for whom the need for efficiency and acceptability plays a significant role.
Riassunto
Pitfall chirurgici e istologici nella gestione del melanoma
lentigo maligna
Il melanoma lentigo maligna (MLM) è un tumore maligno con crescente incidenza, che rappresenta dal 4% al
15% circa di tutti i melanomi. La lentigo maligna (LM) è
un MLM in situ, che solitamente presenta una lesione maculare pigmentata irregolare di color marrone chiaro o bruno persistente per anni su una pelle cronicamente esposta
al sole. Se non trattata, la LM può evolvere in una forma
invasiva di MLM. La valutazione istologica di LM/MLM
può risultare complessa a causa di diffusi melanociti atipici
26
presenti nell’area della pelle cronicamente danneggiata dal
sole. È stato dimostrato che una cute non-lesionale cronicamente danneggiata dal sole può presentare alcune caratteristiche atipiche anche in assenza di neoplasia melanocitica. È importante che i dermatologi siano a conoscenza
di questi risultati in modo che tali caratteristiche siano interpretate appropriatamente nel momento della valutazione
istologica che è in grado di influenzare, in ultima analisi,
la terapia e l’esito. Il MLM è caratterizzato da significativa lesione subclinica che rende il trattamento difficoltoso.
Oggi, sono disponibili una varietà di opzioni terapeutiche
nel trattamento del MLM. La chirurgia rimane una pietra miliare per quanto riguarda la terapia del MLM, nonostante il trattamento della LM sia ancora un argomento
controverso in letteratura. Le modalità di trattamento non
chirurgico per la LM comprendono: procedure distruttive
quali radioterapia, crioterapia, raschiamento, laser, elettrodistruzione e immunoterapia con applicazione topica di
imiquimod crema al 5%. Queste opzioni di trattamento dovrebbero essere considerate per un sottoinsieme di pazienti
affetti da LM, specialmente nei pazienti anziani con malattia estesa o non resecabile in zone difficili del viso o come
terapia di seconda linea nel caso in cui la chirurgia fosse
controindicata. Le opzioni chirurgiche includono escissione semplice e tecniche margine-controllo quali escissione
a strati e chirurgia micrografica di Mohs. Nel presente articolo gli autori esaminano gli ultimi progressi diagnostici e
terapeutici nella gestione del MLM.
Parole chiave: Macchia melanotica di Hutchinson - Melanoma - Diagnosi - Esame istologico - Trattamenti - Procedure chirurgiche mininvasive.
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of print.
31. Bowen AR, Thacker BN, Goldgar DE, Bowen GM. Immunohistochemical staining with Melan-A of uninvolved sun-damaged skin
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32. Zygogianni A, Kyrgias G, Kouvaris J, Mystakidou K, Gogas H,
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33. Erickson C, Miller SJ. Treatment options in melanoma in situ: topical and radiation therapy, excision and Mohs surgery. Int J Dermatol
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34. Kopera D. Treatment of lentigo maligna with the carbon dioxide
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35. Ventura F, Rocha J, Fernandes JC, Pardal F, Brito C. Topical Imiquimod Treatment of Lentigo Maligna. Case Rep Dermatol 2009;1:78-81.
36. Van Meurs T, Van Doorn R, Kirtschig G. Treatment of lentigo maligna with imiquimod cream: a long-term follow-up study of 10 patients. Dermatol Surg 2010;36:853-8.
37. Zalaudek I, Horn M, Richtig E, Hodl S, Kerl H, Smolle J. Local recurrence in melanoma in situ: influence of sex, age, site
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38. Gaudy-Marqueste C, Perchenet AS, Tasei AM, Madjlessi N, Magalon G, Richard MA, et al. The “spaghetti technique”: an alternative to Mohs surgery or staged surgery for problematic lentiginous
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39. Robinson JK. Margin control for lentigo maligna. J Am Acad Dermatol 1994;31:79-85.
40. Kwon SY, Miller SJ. Mohs surgery for melanoma in situ. Dermatol
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micrographic surgery for melanoma: a case series, a comparative
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43. Raziano RM, Clark GS, Cherpelis BS, Sondak VK, Cruse CW, Fenske NA, et al. Staged margin control techniques for surgical excision of lentigo maligna. G Ital Dermatol Venereol 2009;144:259-70.
44. Kelley LC, Starkus L. Immunohistochemical staining of lentigo maligna during Mohs micrographic surgery using MART-1. J Am Acad
Dermatol 2002;46:78-84.
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Prakash A, et al. Surgical management of melanoma-in-situ using
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options. Am J Clin Dermatol 2005;6:151-64.
48. Bub JL, Berg D, Slee A, Odland PB. Management of lentigo maligna and lentigo maligna melanoma with staged excision: a 5-year
follow-up. Arch Dermatol 2004;140:552-8.
27

Soft tissue filler and botulinum toxin treatment techniques
P. S. YAMAUCHI
A variety of non-invasive techniques have been utilized for
the enhancement of cutaneous changes seen with photoaging. Such methods include chemical peels, microdermabrasion, ablative and nonablative lasers, and various rejuvenating light sources. However, the most widely used minimally
invasive cosmetic procedures for the correction of undesired
rhytides and enhance facial features through contouring and
volumization are injections with botulinum toxin and soft tissue fillers. Their extensive long term safety and relative ease
of procedural techniques have led to high satisfaction levels
worldwide. Nonetheless, proper training of the fundamentals
in injection technique, the choice of the appropriate candidate, and knowledge of potential adverse events are imperative to ensure an excellent and safe outcome.
Key words: Botulinum toxins - Rejuvenation - Skin aging.
Fillers
I
njectable fillers have become of the mainstay treatments for nonsurgical treatment of wrinkles and
facial contouring. A plethora of fillers are currently
available and even more so internationally. Because
of unique characteristics for each kind of filler, there
are different indications for each filler type as well
as advantages and disadvantages. How these fillers
are distinguished from one another depends on the
active ingredient used, the degree of viscosity, the
source of the material, and the indications for use.
Proper selection type of the filler for the appropriate
Funding.—None.
Corresponding author: P. S. Yamauchi, MD, PhD, Dermatology Institute and Skin Care Center, 2001 Santa Monica Blvd, Ste 490W, Santa
Monica, CA 90404, USA. E-mail: [email protected]
Vol. 147 - No. 1
1, 2
1Dermatology
Institute and Skin Care Center
Santa Monica, CA, USA
2Division of Dermatology, David Geffen School
of Medicine at UCLA, Los Angeles, CA, USA
areas to be injected is paramount to avoid potential
complications and to achieve the desired outcome.
Using the wrong filler class can lead to disastrous
consequences. For example, injecting calcium hydroxyapatite or poly-L-lactic acid into the fine
rhytides of the upper lip or the infraorbital area for
tear trough deformity (nasaljugal groove) may lead
to unevenness and unwanted papules of significant
duration that ultimately results in a highly dissatisfied patient.
Types of fillers
Fillers are divided into three classes: non-permanent, semipermanent, and permanent. Nonpermanent fillers are the most commonly used. Some common materials that make up nonpermanent fillers
include hyaluronic acid and collagen. These are of
short duration with typical lengths of several months
to 1 year and are eventually reabsorbed through
macrophage activation. Semipermanent fillers have
a longer duration of placement with time periods of
years and typically result in a foreign body reaction
that elicits fibroblast activation and collagenesis at
the site of the material placed in the dermis. Calcium hydroxyapatite and poly-L-lactic are examples
of semipermanent fillers. Permanent fillers are the
29
YAMAUCHI
Soft tissue filler and botulinum toxin
longest acting and also involve fibrogenesis and collagen production. Such fillers include materials composed of silicon and polymethymethacrylate.
Calcium hydroxyapatite
Collagen-based fillers
There are several types of collagen-based fillers
depending on the source of origin. These include
bovine collagen (Zyplast, Zyderm) and recombinant
human collagen derived from neonatal human foreskin fibroblasts (Cosmoplast, Cosmoderm). The bovine-based collagen requires intradermal skin testing
prior to usage but the human derived collagen does
not. Zyderm and Cosmoderm are injected into the
papillary dermis whereas Zyplast and Cosmoplast
are injected into the reticular dermis due to the collagen fibers crosslinked with glutaraldehyde. These
collagen fillers already contain 0.3% lidocaine making injections easier to tolerate. Collagen based fillers are nonpermanent. Another collagen-based product called Evolence which was derived from porcine
was previously available in the United States but was
voluntarily withdrawn from the market by the supplier.
Hyaluronic acid
The hyaluronic acid derivatives are the most popular filler agents for rejuvenation. Like collagen, they
are also nonpermanent. Hyaluronic acid is a naturally occurring glycosaminoglycan polysaccharide
polymer that is important in the matrix of the skin,
subcutaneous tissue, connective tissue, and synovial
tissue. With age, less hyaluronic acid is produced
intrinsically and the molecular weight decreases.
Hyaluronic acid has properties of being elastic and
hydrating and therefore temporary water retention
occurs at the site of injection. There are several hyaluronic acid agents available commercially. Restylane, Perlane, and Juvederm are nonanimal stabilized hyaluronic acid (NASHA) derivatives. The
properties of NASHA derivatives are they are slowly
biodegradable and undergo isovolumic degradation.
When such materials are injected into the dermis, the
NASHA products bind water more water and the volume of correction is maintained during degradation
due to retention of water. The differences between
the NASHA derivatives depend on the concentration
of hyaluronic acid, the gel particle size, and the degree of viscosity. Such differences dictate the level
30
of placement of the within the dermis as well as the
gauge of the needle.
Calcium hydroxyapatite fillers are composed of
spherical particles blended in an aqueous cellulose
based carrier. They are considered semipermanent
fillers. The gel carrier is resorbed by macrophages
and the calcium hydroxyapatite particles are left behind and become encapsulated by the fibroblastic
stroma. Radiesse is filler agent that is composed of
calcium hydroxyapatite and is used for volume restoration and for deep and prominent folds. The level
of injection is accomplished with a 27-gauge needle at the lower dermis to subdermal junction or just
above the periosteum.
Poly-L-lactic acid
Sculptra is a volumizing agent that is composed
synthetic polymer of poly-L-lactic acid microspheres
that are immunologically inert and no skin testing is
required. Sculptra is considered a semipermanent,
long acting filler in which the poly-L-lactic acid
stimulates dermal and subcutaneous macrophages,
fibroblasts, and neovascularized fibroplasia with
subsequent collagen formation. Sculptra requires a
series of injections by cross-hatching and fanning
over a period of several weeks to months. The initial
correction attained disappears within a few days but
gradual volumization occurs over the next several
weeks through collagenesis. Sculptra is supplied in
vials and requires reconstitution with sterile water
prior to injection with a 26 gauge needle.
Polymethylmethacrylate
Artefill is a filling agent that is comprised of
a suspension of microspheres composed of 20%
polymethylmethacrylate and 80% bovine collagen.
Artefill is considered a permanent filler and has
dual action. Immediate correction is achieved with
the bovine collagen component of the filler. The
polymethylmethacrylate spheres are permanent and
collagenesis and fibrogenesis occur on the spheres
which leads to volumetric enhancement. Implantation is performed with a 27-gauge needle into the
deep reticular dermis and skin testing is required due
to the collagen derived from bovine.
February 2012
Injection techniques
Various injection techniques are performed when
injecting different fillers. The method used most often depends on the injector’s preference and experience but in some situations, it may be necessary
to employ a specific placement technique to attain
the desired outcome. These procedural methods are
used to deliver the filler material into the different
levels of the skin ranging from upper-, mid, and lower-dermis and deeper into the dermal-subcutaneous
junction and immediately above the periosteum. One
must take into account the properties of the filler material such as the material, viscosity, and degree of
cross-linking as well the area to be injected.
YAMAUCHI
beads. Gentle molding can be performed afterwards
to evenly spread out the filler and avoid unwanted
papules.
Serial threading
This is an intermediate placement technique between serial puncture and linear threading. Unlike
linear threading, the body of the needle is partially
placed into the skin and the material slowly injected.
The injector has the choice of either withdrawing the
needle if placement was done at a 30° angle or injecting a larger droplet of material similar to serial
puncture if the needle was inserted more upright.
Cross-hatching and fanning
Linear threading
This is the most commonly employed technique
for injecting a filler, particularly in the nasolabial
folds and lips and other rhytides and furrows. Typically, the filler is injected in a linear manner, either
in a retrograde or anterograde direction. For the retrograde method, the body of the needle (typically
30- or 27-gauge) is inserted entirely into the tissue
(e.g., mid-dermis) at a 30 degree angle and the filler
is injected with gentle pressure while slowly withdrawing the needle. Care is taken to stop injecting
just as the bevel of the needle reaches the point of
total withdrawal to avoid formation of an unwanted
papule. Gentle molding can be performed afterwards
with the gloved injectors’ fingers to evenly distribute
the filler along the rhytide. The use of a lubricant
such as ultrasound gel facilitates molding.
This technique is useful for covering a wide area
such as the cheeks for lipodystrophy and where a
larger amount of filler is required. Cross-hatching
and fanning is used primarily for volumetric enhancement and facial contouring. One commonly
used filler for cross-hatching and fanning is poly-Llactic acid. A series of retrograde injections are performed into the deep dermal or subdermal layer or in
a unidirectional fashion. This is followed by another
series of retrograde injections in a direction perpendicular to the initial set of injections. For example
for injecting a very prominent nasolabial fold with
this technique, a series of short retrograde injections
are performed 90 degrees across the nasolabial fold
throughout its length. Another set of longer retrograde injections is then performed through the length
of the fold perpendicular to the first set of injections.
Serial puncture
Deep depot
This is another common technique for injecting a
filler. Typically the filler is of low to medium viscosity to minimize formation of unwanted papules and
is injected more superficially into the upper and mid
dermis. Serial puncture is used to treat fine rhytides
such as perioral wrinkles and minimally shallow nasolabial wrinkles and depressions such as acne scars.
A 30- or sometimes 32- gauge needle is commonly
employed. The needle is directed at an upright angle
(90 degrees or less) and just when the bevel of the
needle is fully inserted into the skin or slightly more
deep, a tiny droplet of material is injected. Injections
are spaced very closely apart, similar to a string of
This technique in utilized for facial contouring
and volumetric enhancement. Deep depot is used
with certain fillers such as those containing calcium
hydroxyapatite. For example, to augment the malar eminences, a larger bore needle such as a 26- or
27-gauge needle is deeply inserted perpendicular
into the skin over the zygoma until the tip touches
the periosteum. A droplet of filler is injected over the
periosteum of the zygoma until noticeable visible
enhancement is seen. A series of injections is performed over the zygoma followed by gentle molding.
The patient should be seated comfortably on the
Vol. 147 - No. 1
31
YAMAUCHI
examination chair in an upright to semi-upright position to allow for normal downward sagging of the
face to occur with gravity. Critical features of the
folds will be more evident in a more upright position.
If the patient is placed prone on the table, then essential details of rhytides, particularly in the midface,
will not be as clearly evident as they will be partially
lost due to backward forces. Therefore, the prone
position is not recommended for injected fillers into
the face. Good light is essential and sometimes folds
maybe become more prominent and easier to visualize if the light is adjusted at an angle to cast shadows
on the wrinkles.
Consent forms authorizing the injector to perform
the procedure are required for the patient to read, understand, and sign. The risks and benefits as well as
reasonable outcomes should be detailed in the consent form. Dispensing post-procedural handouts explaining what the patient should or should not do at
home following the injections is a good practice.
The patient should be told that injections with soft
tissue fillers elicit pain. Some of the fillers are already pre-mixed with lidocaine to minimize discomfort during the course of injections. Other fillers can
be combined with lidocaine manually by connecting
the syringe containing the filler to another prefilled
syringe containing the appropriate volume of lidocaine through a Luer-lock connector and mixing
the two together by alternatively depressing the syringe plungers. Most patients require application of
a topical anesthetic preparation containing different
combinations and strengths of lidocaine, prilocaine,
tetracaine, or benzocaine to the areas to be injected.
Typical application times are 30 minutes to 1 hour.
One should note that the skin and tissue surrounding the folds and wrinkles frequently swell when anesthetic creams are applied and the features of the
rhytides may become distorted or lost. Therefore,
critical examination of the areas to be injected as
well as preprocedural photographs are essential prior
to application of the anesthetic creams. Marking the
injection sites with an easy to remove marker pen or
pencil may be beneficial. Regional nerve blocks are
usually unnecessary unless the site to be injected is
particularly sensitive. Injecting fillers into the body
of the lips can be quite painful and an infraorbital
and submental nerve block can be performed. The
absence of epinephrine in performing nerve blocks
is recommended to allow for the anesthesia to retreat
faster after completion of the injections and mini-
32
mize the duration of numbness for the patient afterwards. The placement of ice or cold compresses before, during, and after the injections can be utilized
to provide comfort to the patient and to induce partial vasoconstriction locally and minimize purpura.
Following injections, gentle molding and massaging may be performed to evenly distribute the filling
agent beneath the skin. Immediate post-procedural
photographs are also recommended. The patient
should be told not to excessively touch the injected
areasand minimize exaggerated facial expression for
the next 24 hours. Transient swelling and bruising
should be warned to the patient beforehand and are
natural to occur and frequently inevitable. The occurrence of any unwanted bumps or unevenness is
a risk of any filler agent and is usually due to faulty
technique. The patient should call and follow-up in
the office should this occur and corrective actions
should be exercised.
Finally, during the course of injections, the degree
of patient discomfort should be noted throughout
the procedure. In the event that the patient experiences sudden extreme pain, then injections should
be immediately halted due to the possibility of vascular occlusion which can result in subsequent tissue
necrosis. The possible occurrence of blanching of
the skin should be inspected for at all times. Should
be happen, application of a topical mixture containing nitroglycerin is recommended in order to induce
vasodilatation and minimize the incident of necrosis.
Areas of injection
Although soft tissue fillers may be injected almost
in any part of the body, only the face and dorsum of
the hands will be discussed. For practitioners who
casually inject fillers, the nasolabial folds are the
most common location. Advanced injectors address
other areas of the face including upper, mid, and
lower face as well as the dorsum of the hands. Soft
tissue fillers may be utilized as monotherapy for rejuvenation or is frequently used in combination with
other minimally invasive procedures such as neurotoxins, laser therapies, and chemical peels.
Upper face
Injection of soft tissue in the upper areas of the
face is limited. The skin is thinner and the risk of
unwanted adverse events is higher than in other
February 2012
parts of the face. For atrophy of the temporal area,
non-permanent: 1) or semipermanent fillers may
be injected for volumetric enhancement. Care must
be taken to avoid injury to the temporal nerve. A
small retrospective study was conducted for treating temple volume loss and orbitofacial asymmetry.1
Patients initially received approximately 1 mL of a
hyaluronic filler injected into the superficial fascia
of each temple which was injected behind the frontozygomatic process to soften the bony contour of
the lateral orbital rim. The majority of patients who
enrolled in the study were very or moderately satisfied with the results.
Preperiosteal placement of hyaluronic acid fillers
may be placed at the superior orbital rim to achieve a
nonsurgical “brow lift”. Approximately 0.4 cc can be
injected per upper eyelid inferior to the lateral edge
of the upper eyebrow to enhance the contour of the
upper eyelid and brow.2
Injection with neurotoxins is the most common
minimally-invasive treatment method to treat dynamic rhytides of the upper face including the glabella, forehead, and periorbital rhytides (crow’s
feet). However, residual wrinkles may persist despite
maximum muscle relaxation elicited by botulinum
toxin. In these situations, lower viscosity, nonpermanent fillers such as hyaluronic acid or collagen-based
products may be injected to minimize the residual
rhytides remaining after botulinum injections. Caution must be exercised when injecting fillers in the
glabellar area, forehead, and crow’s feet because the
skin is relatively thin and resides over bony prominences. If injected too superficially or excessively,
unevenness and lumpiness may occur. In addition
there are case reports of local necrosis and occlusion
of the retinal artery branch resulting in blindness
have occurred when fillers were injected in the glabellar area.3-5 Nonetheless, soft tissue filler injection
when injected conservatively and using the appropriate non-permanent low-viscous filler may allow
for correction for residual rhytides after neurotoxin
injections. The glabellar area is also quite porous and
the filling agent often times has a tendency to extrude through these dilated pores.
Midface
The midface is the most commonly injected area
of the face for soft tissue fillers. Because of the inherent sagging of the midface that naturally occurs
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YAMAUCHI
with photoaging, treatment of the nasolabial folds is
the most prevalent requested location. Depending on
the depth and length of the nasolabial fold, 1-2 cc of
the appropriate filler is of adequate volume for restoration. Occasionally, more than 2 cc is required for
deeper, prominent folds. The direction of injection
may be superior to inferior starting at the perialar
area and proceeding inferiorly to the corner of the
mouth or in a vice-versa direction. The perialar area
is the most sensitive part of the nasolabial fold and
the author tends to start at the most inferior aspect
of the nasolabial fold and proceed superiorly. Frequently the triangular portion of the nasolabial fold
in the perialar area is quite prominent and larger volumes of filler are necessary to correct this area. Linear threading (retrograde or anterograde) is the most
common technique to inject the nasolabial fold but
serial puncture can be used if the fold is quite thin or
superficial. Some injectors also use the cross-hatching technique to fill the nasolabial folds, especially
when they are very deep.
The ability to correct nasal defects non-surgically
has expanded the utility of filling agents. The more
commonly used agents have been hyaluronic acid
and calcium hydroxyapatite.6-8 However, caution
must be exercised as there have been case reports
of tissue necrosis occurring in the areas of the nose
where a filler was injected, particularly in the nasal
tip and ala.5, 6, 9-11 While such occurrences are rare,
restricting the use of fillers to the nasal dorsum and
sidewalls minimizes complications.6 Whether the
nasal defects are congenital, traumatic, or iatrogenic, injections should be performed in the subdermal
plane above the perichondrium and periosteum. This
is to minimize visible or palpable nodularity. Injecting small boluses of filler through the serial threading/puncture technique usually provides the best outcome. Low nasal tip projections (drooping nose tip)
are common defects that patients seek consultation
for correction. Injections of a filling agent such as
hyaluronic acid into the medial crura area and anterior nasal spine can provide partial, but noticeable
leveling of the nasal tip.12 Non-surgical rhinoplasty
of the nose can be accomplished with the injection
of various soft tissue fillers such as hyaluronic acid.
Contouring the nasal defect involves small bolus injections of the filler into the superior aspect of the
nasal dorsal bridge and sidewall to mask the appearance of the prominent nose.6-9
The malar and submalar areas of the midface are
33
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very commonly corrected with volumizing agents.
Intrinsic lipoatrophy of the cheeks due to aging or induced by certain medications (particularly for HIV)
are ubiquitously requested areas to be enhanced.
Volumetric rejuvenation in these areas is best corrected with fillers of longer duration or semipermanent agents. These include fillers containing hyaluronic acid fillers with higher viscosity and greater
cross-linking, calcium hydroxyapatite, and poly-Llactic acid. There are various techniques to volumize
the malar and submalar areas and the practitioner
can employ a single technique or a combination of
techniques in the same patient to attain the desired
results. Correction with the poly-L-lactic acid suspension involves injecting the product in fanlike
sweeps across the length of the defect which is followed by series of cross-hatching injections in a perpendicular direction for even distribution. Injection
with calcium hydroxyapatite can also be utilized in
the same manner as an alternative to poly-L-lactic
acid. A non-surgical malar lift can be accomplished
with volumizers. This method has provided greater
versatility and utility to treat the sagging face or persons with lower cheekbones and patient satisfaction
is generally high. Either calcium hydroxyapatite or
high viscosity hyaluronic acid may be utilized the
enhance the malar eminences. A series of droplets of
product using the deep depot technique are injected
over the zygomatic area to produce instantaneous
enhancement. Both techniques can be used in the
same patient to augment the malar eminences and
to correct the lipoatrophy in the cheeks with various
agents. The versatility of combining soft tissue fillers in different areas of the face is clearly manifested
here.
Hyaluronic acid fillers can also be injected into
the earlobe to enhance its appearance and volume.13
Care should be exercised not to inject excessive
amounts due to potential, although unlikely, occurrence of tamponade.
Lower face
The lower area of the face is another common
location for correction with soft tissue fillers. The
treatment of vertical perioral rhyides is a frequently
requested procedure. However, such fine rhytides
are difficult to correct fully. The three most common
modalities to treat perioral rhytides are fillers, neurotoxins, and laser resurfacing. Most often a com-
34
bination of methods is necessary. A lower viscosity,
small particle sized hyaluronic acid filler or a collagen based filler is frequently used to treat perioral
rhytides. The serial puncture technique is the best
method to used and either a 30- or 32-gauge needle
is used. Either topical anesthesia or a regional nerve
block may be utilized to minimize discomfort.
Increasing the volume of the lips is a commonly
requested aesthetic procedure, especially among
women. In general, the bottom lip is one-third fuller
than the upper lip. Preserving or reestablishing natural symmetry on both contralateral halves of the lips
is essential for a proper appearance. For the most
part, most women want a natural, subtle enhancement to their lips and do not desire disproportionate or excessively full lips. Occasionally, a woman
will request unnaturally fuller lips and it is up to
the practitioner whether to fulfill that request or not.
Because injections into the lips are quite painful, an
infraorbital and submental nerve block are recommended for the top and bottom lip. Enhancing the
lips requires a delicate touch and finesse to attain
natural looking results. Linear threading in a retrograde or anterograde manner is the most common
technique. The most common location to inject is in
the vermillion border (white roll) of the upper and
lower lips. The philtrum columns (cupid’s bow) can
also be accentuated and redefined by injecting fillers
to produce aesthetic results. Injecting into the body
of lip (wet roll) requires subtlety but if properly performed by injecting a larger amount in the midzone
of the lip and a lesser amount in the lateral aspects
of the lip will lead to fuller, slightly upturned lip
without producing the “duckbill” look. It is not recommended to inject semipermanent or permanent
fillers into the lips due to the higher potential for
adverse events which sometimes can be permanent
and catastrophic such as palpable or visual nodules,
granulomatous reactions, and excessive, undesired
fullness. The most common fillers utilized are nonpermanent such as those that are hyaluronic acid- or
collagen-based.
The marionette lines are a very common location
to correct in the lower half of the face. Because of
intrinsic photoaging, the corners of the mouth turn
in a downward direction that patients attribute to as
appearing sad or looking old. The goal in correcting marionette lines is not only to fill them, but also
to turn the corners of the mouth upward. Injecting
into the lateral commissures will provide support at
February 2012
the corners of the lip to attain a slight upward curvature of the mouth. In addition, injecting a few units
of botulinum toxin into the depressor anguli oris in
combination with the filler agent will also reverse the
sagging mouth. One cardinal feature in correcting
the marionette lines is to inject slightly more medial
in the folds rather than directly into the fold or laterally. If improperly performed, the marionette lines
may actually be accentuated which is not the desired
outcome.
Other areas in the lower face that are addressed
frequently are the prejowl sulcus area. A nonpermanent or semipermanent filler may be injected in those
areas by using the serial threading or deep depot
method. Some patients are bothered with a prominent mental crease that runs across the chin. This
can be a difficult area to correct and a nonpermanent
filler such as a hyaluronic acid agent be injected by
using a linear threading or serial puncture method.
Dorsum of hands
In addition to the face, the dorsum of the hands
frequently undergoes lipoatrophy due to intrinsic aging that patients become self-conscious about. Hand
volume restoration has recently become more popular and various filler agents are available to restore
fullness.14-17 Calcium hydroxyapatite is probably the
most common filler to restore volume to the hand.14,
15 Hyaluronic acid has also been utilized to correct
lipoatrophy of the hands.16, 17 Techniques to inject
both types of fillers are similar. On the average, approximately 0.65 to 1.3 cc of product is needed to
restore volume in the dorsum of each hand.14-17 The
filler is injected into the deep dermal plane by depositing a globular droplet into the intermetacarpal
spaces using serial threading. The bolus of the filler
agent is then massaged and molded gently to achieve
uniform distribution and a series of injections are
performed throughout the length of the intermetacarpal spaces. Care needs to be taken to ensure no
palpable or visible nodules are present.
Complications
When obtaining informed consent from a patient
who desired treatment with a filling agent, the benefits and the potential risks must be discussed. Common adverse events such as swelling and bruising
are expected sequelae of injections and are consid-
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ered not to be true complications and this needs to
be explained to the patient. Minimizing edema and
purpura can be accomplished through the application of ice packs and cold compresses prior, during,
and after the procedure. The patient can be instructed
to apply cold packs to the injected areas as home as
well. If patient are on anticoagulants such as aspirin, warfarin, or Plavix, the risk of bruising is higher
and should be discussed with the patient. The author
generally does not instruct patients to stop anticoagulants prior to injection. Complications can arise
to due faulty technique or they may arise due to local
tissue reaction to the filler itself. For the most part,
true complications are not common with soft tissue
fillers if proper injection technique is performed and
the appropriate patient is selected.
Asymmetry is probably the most common complication. This can be easily rectified with touch up
injections to circumvent the complication, either at
the patient or physicians’ cost. The author does not
recommend saving and storing leftover filler agents
for future usage with one exception (Sculptra – product label storage time after reconstitution).
Unevenness, ridging, papules, and nodule formation can occur with any filler agent and arise due
to faulty and improper injection technique. Common reasons for inducing bumps are injecting too
superficially, failing to stop injecting just when the
needle exits the skin during retrograde injection,
or selecting the wrong filler type (injecting a heavily crosslinked/viscous filler or a semipermanent
filler into the papillary dermis as well as in a location where the skin is thinner). When caught immediately after injection, massaging the bump can
be performed to even it out. Hyaluronidase preparations can be administered into undesired bumps
where hyaluronic acid fillers were injected to enzymatically break down the polymer. Injections with
hyaluronidase agents often times diminishes the
bumps within 24-48 hours. For bumps that were induced by semipermanent fillers that do not resolve,
physical extraction and excision may be the only alternative to correct the complication.
Allergic reactions to the filler material or one of
its components are rare but have been reported. Skin
testing is required for bovine based products but not
porcine based. For true allergic reactions, treatment
with a topical steroid may suffice for mild reactions
but systemic steroids or other immunosuppressive
agents such as cyclosporine may be necessary to
35
YAMAUCHI
reduce more severe allergic reactions. Granulomatous reactions are rare but have been reported with
permanent filler materials.18 Such occurrences are a
delayed-type hypersensitivity reaction than can happen months to years after initial injections.
Botulinum toxin
Dynamic facial wrinkles can be interpreted as
manifestations of negative emotions, fatigue, stress,
and perceived aging. Such rhytides result as a combination of intrinsic skin aging, ultraviolet damage,
and repetitive action of facial muscles. Of these, the
most contributing force for the persistence of facial
wrinkles is the repetitive contractions of the intrinsic muscles for facial expression. There are a variety
of different treatment options available for this facial lines including the use of filling agents, ablative
and non-ablative laser surgery, dermabrasion, and
chemical peels. However, these procedures do not
adequately address the underlying cause of dynamic
wrinkles as evidenced by the persistence of facial
lines after treatment. The understanding that muscular contraction contributes to etiology of facial lines,
wrinkles, and furrows 19 has broadened the treatment
options for these facial cosmetic blemishes.
Botulinum toxin type A (BTX-A), a potent neurotoxin that irreversibly blocks presynaptic acetylcholine release, has been successfully employed to treat
a variety of hyperkinetic facial lines such as glabellar lines, crow’s feet, horizontal forehead lines, vertical perioral rhytides, and marionette lines have been
successfully treated with BTX-A.20, 21 Currently
there are three commercial formulations of BTX-A,
Botox, Dysport, and Xeomin approved in the United
States. In 2002, Botox was FDA approved for the
temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity in adult patients
aged 65 years or less. In 2009, Dysport was FDA
approved for the same cosmetic indication as Botox. Xeomin is another BTX-A formulation that is
was recently approved in the United States for the
treatment of glabellar lines in adults younger than 65
years of age.
Likewise, botulinum toxin type B (BTX-B) is
another potent neurotoxin that has been employed
to treat spastic conditions such as cervical dystonia. Myobloc, the only commercial formulation for
36
BTX-B and is FDA approved for the treatment of
cervical dystonia but currently not approved in the
United States for any cosmetic usage. A variety of
hyperkinetic facial lines have also been treated successfully with BTX-B.20-29
Structure and mechanism of action
There are seven serologically distinct types of
botulinum neurotoxins, designated types A through
G, which corresponds to the strain of Clostridium
botulinum that produces the specific toxin. These serotypes are all synthesized as single chain polypeptides with molecular weights of approximately 150
kD and share a common structural organization
which consists of one heavy chain (100 kD) and
one light chain (50 kD) polypeptide that is linked
by a single disulfide bond . All botulinum toxins
inhibit acetylcholine release at the neuromuscular
junction in a three-step process. The single-chain
polypeptides are activated by proteases which
are cleaved into a double chain consisting of the
heavy chain and the light chain moieties.30 Upon
cleavage, the heavy chain binds to a high affinity
receptor on the presynaptic nerve terminal which
enables the internalization of the bound toxin into
the cell. The light chain moiety is a zinc-dependant
endopeptidase that cleaves membrane proteins that
are responsible for docking acetylcholine vesicles
on the inner side of the nerve terminal membrane.31
The cleavage of these proteins inhibit the fusion of
the vesicles with the nerve membrane, thereby preventing release of acetylcholine into the neuromuscular junction.32
The intracellular target of BTX-A is the SNAP-25
(synaptosome-associated protein of molecular eight
25 kD) which is a protein essential for the successful docking and release of acetylcholine vesicles
with the pre-synaptic vesicle.33 In contrast, BTX-B
cleaves VAMP (Vesicle Associated Membrane Protein), which is also known as synaptoabrevin.34 Like
SNAP-25, VAMP is essential for the docking and fusion of the synaptic vesicles to the presynaptic membrane for the release of acetylcholine.
Types of botulinum toxins
The various types of botulinum toxin formulations
will be discussed and clinical data supporting their
utilization will be detailed here.
February 2012
Botox
Botox was the first type A botulinum toxin to be
approved by the FDA in the United States. The product is supplied as a vacuum-dried lyophilized power
in vials containing either 50 units or 100 units of Botox. Unreconstituted Botox should be stored at 2-8
degrees Celsius. The official recommendation by the
manufacturer is to reconstitute Botox with 2.5 ml of
0.9% nonpreserved saline for the 100 unit vial (1.25
mL for the 50 unit vial) to a final concentration of 4.0
U/0.1 mL. Practitioners have also used other different dilutions ranging from 1 to 10 mL/100 units and
have reported that dilution at higher volumes can result in more diffusion. In addition, reports have demonstrated no decrease in efficacy using preserved
saline to dilute the Botox that there is less pain associated upon injection using preserved saline.35 The
manufacturer recommends avoided aggressive agitation of the vial upon mixing to prevent denaturation of the product. The reconstituted product should
never be frozen and can be stored for up to six weeks
at 4 °C.
Tuberculin or insulin syringes are frequently used
for injecting Botox since they there is no potential
space in the hub and result in less waste of the product. 30- or 32-gauge needles are the most commonly
used needles to inject Botox.36 Topical anesthesia is
not required but some patients may request their use
to minimize discomfort. The use of ice can also reduce pain and also minimize purpura formation by
constricting the blood vessels prior to injection.
Prior the treating the patient with Botox, a complete medical history should be attained to prevent
unwanted reactions.37 Medications and food products that inhibit platelet aggregation and increase
clotting time should be discontinued for 10-14 days
prior to the procedure. These include aspirin, nonsteroidal anti-inflammatories, garlic, fish oils and
similar). Some medical condition that are contraindicated for botulinum toxin injections include peripheral motor neuropathic diseases or neuromuscular
functional disorders such as myasthenia gravis and
Eaton-Lambert syndrome. Patients who are currently on aminoglycoside antibiotics such as gentamycin
may develop increased inhibition of neuromuscular
transmission and concomitant usage together with
botulinum toxin is contraindicated. The presence
of any infection or inflammation on the skin at the
site of injection is also a contraindication. Finally,
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YAMAUCHI
females who are pregnant or lactating should not receive injections of botulinum toxin.
The upper face.—Facial wrinkles involving the
forehead, glabella, and lateral periorbital regions are
common aesthetic areas where botulinum toxin is injected. In treating the glabella, botulinum toxin targets thee bilateral corrugators, depressor supercilii,
and the central procerus muscles that are responsible
for the glabellar lines. Usually, two injections are administered per corrugator muscle and one injection
in the procerus. The first phase 3 study demonstrating the efficacy of Botox for the treatment of glabellar lines was published in 2002.38 Patients with moderate to severe glabellar lines at maximum frown
received intramuscular injections of 20 U Botox or
placebo into 5 glabellar sites. Patients were followed
up for 120 days after injection. Outcome measures were physician rating of glabellar line severity at maximum frown and rest, patient assessment
of improvement, and vital sign and adverse event
monitoring. 264 patients were enrolled with 203 on
Botox and 61 in the placebo group. There was a significantly greater reduction in glabellar line severity with BTX-A than with placebo in all measures
(P < .022) and the effect was maintained for many
patients through day 120. The recommended dosage
for the treatment of glabellar lines is 20 units but can
vary from 15-30 units depending on the strength of
the corrugator and procerus muscles. Typically, men
may need higher doses of botulinum toxin versus
women given the greater strength of the muscles.
The treatment of the glabellar region with botulinum toxin results in a slight brow lift by weakening the central frontalis effect of brow elevation and
thus proportionately increasing the frontalis effect of
lateral brow elevation.39 An advanced technique that
can be utilized to attain a lateral brow lift by weakening the lateral lid depressor muscles is to inject
1-2 units of Botox into the lateral-superior orbicularis muscle just below the lateral brow but above the
superior orbital rim.
A single-center, prospective, double-blind, randomized, dose-comparison study was conducted in
female patients between the ages of 18 to 65 years
of age for the treatment of glabellar, forehead, and
periorbital rhytides with Botox.37 Eligible patients
were assigned randomly to one of 3 treatment groups
representing total doses of 32, 64, or 96 U and were
followed up for up to 52 weeks. Patients were re-
37
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quired to have upper facial wrinkles that met the
following specifications on a 4-point facial wrinkle
scale (FWS) (0 = none; 1 = mild; 2 = moderate; and 3
= severe as determined at maximum attempted muscle contraction by a trained observer): moderate or
severe glabellar lines; mild, moderate, or severe forehead lines; and bilaterally symmetric moderate or severe crow’s-feet. The total dose was divided evenly
among 16 injection sites: 5 injections in the glabellar,
5 injections in the forehead, and 3 injections in each
lateral canthal area for the periorbital wrinkles. Botox treatment, used in total doses of 32, 64, or 96 U,
was shown to be safe and effective for treating multiple upper facial rhytides in female patients in single
sessions. Overall, each dose resulted in significant
improvement in the appearance of facial rhytides,
but a dose-response relationship emerged based on
duration of effect and on between-group differences
on a substantial number of the measures that were assessed. The principal differences between the groups
were in the duration of the effect, although in some
individuals, some areas wore off more rapidly than
other areas. Based on anecdotal information, some
physicians hypothesize that a longer duration of
rhytide effacement may be achieved through treatment of multiple areas, as this eliminates any potential for adjacent muscle recruitment.
When using botulinum toxin to treat forehead
rhytides, typical doses of 15-30 units of Botox is
injected into the frontalis muscle. Because the forehead is the primary brow elevator, care and caution
must be exercised not to lower the eyebrows and
flatten them when treating forehead wrinkles, especially in women where an arched brow is of aesthetic
importance.40 To avoid lowering the brow, injecting
higher up in the forehead can minimize this tendency
as well as treating the glabella concomitantly. When
treating the forehead for the first time, practitioners
may reserve treating of the forehead area for 2 weeks
after injecting the glabellar area first and also utilize
a lower dose for the forehead to reduce the chance of
depressing the brow excessively.
Typically, 3 injections are performed on each side
of the lateral orbital of the eye to target the lateral
orbicularis muscle to treat crow’s feet.41 Two-three
units of Botox are used per injection. The distance
from the lateral canthus to the area of injection should
be around 1 1.5 cm to minimize the rare occurrence
of diplopia. In addition, the area around the lateral
orbit is enriched with blood vessels and this is a site
38
more prone to purpura. Care should be exercised to
closely examine for the presence of blood vessels
prior to injection. Sometimes after successful treatment of the crow’s feet, patients may note increased
crinkling and fine rhytide formation immediately below the infraorbital area due to muscle recruitment.
Should this occur, 1 unit of Botox can be placed in
the area of new wrinkle formation to obviate this
effect. A study was conducted to compare the efficacy and safety of 4 doses of Botox with placebo to
treat crow’s feet.4 Subjects received a single bilateral
treatment of 18, 12, 6, or 3 U of BTX-A or placebo
injected into the lateral aspect of the orbicularis oculi
muscle. Investigators and subjects rated crow’s feet
severity at maximum smile on day 7 and at 30-day
intervals from days 30 to 180. As observed by both
investigators and subjects, all doses of BTX-A resulted in improvements in crow’s feet severity when
compared with placebo. A dose-dependent treatment
effect for efficacy was observed, with higher doses
having an increased magnitude and duration of effect. However, a clear differentiation between the 18
U and 12 U doses was not apparent. It was concluded
that BTX-A was safe and effective in decreasing the
severity of crow’s feet, with 12 U per side suggested
as the most appropriate dose.
Mid and lower face.—The mid and lower face is not
a common area to treat with botulinum toxin when
compared to the upper face. Caution must be exercised in these areas since diffusion of toxin and inadvertent injection of adjacent musculature can result in
functional deficits and unwanted limited motion.
Nasal wrinkles on the dorsum of the nose can frequently be treated with botulinum toxin by injecting
a few units into the nasalis muscle. Between 2 and 5
U of botulinum toxin have commonly been used. A
study was conducted to determine the efficacy of Botox in the treatment of nasal wrinkles of the superior
nose (bunny lines);42 250 patients with nasal rhytides
were treated and 3 units of Botox were injected bilaterally into the nasalis muscle. Patients were seen
at 1 month for follow-up, and the remaining rhytides
were documented. 40% of patients had satisfactory
treatment of nasal wrinkles with the initial bilateral
3 U injections. Sixty percent of subjects had remaining nasal rhytides following the nasalis muscle injections. Thirty percent of subjects had persistent wrinkles at the root of the nose (nasal orbicular wrinkles),
and 30% had wrinkles at the nasal root and between
February 2012
the eyes (nasociliary wrinkles). The injection of
botulinum toxin into additional locations according
to the anatomic differences of each person showed
excellent resolution of the rhytides without complications.
A common area in the lower half of the face to
treat with botulinum toxin are the vertical perioral
rhytides. These lines are caused by repeated contraction of the orbicularis oris. Several injections of 2
units of Botox can be placed along the upper and
lower lip to minimize lip furrows. A study was conducted where 18 patients were injected with BTX-A
into the vertical lip rhytides. The effect of treatment
was evaluated at 2 to 3 weeks after procedure and
smoothening of hyperfunctional lines and upper lip
fullness/eversion was observed in patients treated
with BTX-A injections.43
Another usage of botulinum toxin injections is to
target the depressor anguli oris muscle of the mouth
to elevate the corners of the mouth.44 The depressor
anguli oris pulls down on the lateral oral commissures and excessive function causes the corners of
the mouth to droop (marionette lines). The downward angle of the marionette lines can be improved
by injecting 2-5 U of Botox intramuscularly approximately 8-10 mm lateral to the oral commissure and
8-15 mm inferior to this point.
Relaxing the muscles of the mentalis can reduce
the involuntary convolutions or dimpling of the chin
when performing speaking or performing other mundane activities of the face.44 In addition to softening
the pebbling of the chin, injection of botulinum toxin
into the mentalis can reduce the deep transverse labiomental crease that runs horizontally across the
chin. 5-8 U of Botox is typically used to inject the
mentalis muscle.
Cosmetic uses of botulinum toxin in the neck is
primarily for the treatment of platysmal banding
which are the vertical bands found in the central
neck.45 There are also horizontal rhytides caused by
contraction of the platysmal muscle, usually seen
laterally, which can be treated with botulinum toxin
injections. The proper method to inject the platysma
is to have the patient seated upright and contract the
platysma. By doing so, the practitioner can grasp the
platysmal band between the thumb and index finger
with the non-dominant hand and inject 2-4 U of Botox in the lower dermis per injection site along the
vertical extent of the band, starting approximately 2
cm below the inferior border of the mandible. The
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injections are repeated at 1.5 to 2 cm apart from each
other descending down the neck toward the border of
the clavicle. Most patients will require several injection points to treat a platysmal band. It is advisable
to inject no more than 40 to 50 U of Botox total per
treatment session for the platysmal bands.
Dysport
Dysport was the second BTX-A to be approved
in the United States and is indicated for the temporary improvement in the appearance of moderate to
severe glabellar lines associated with procerus and
corrugator muscle activity in adult patients less than
65 years of age.46 The recommendation for reconstituting Dysport for glabellar lines in the 300 U vial
is with 2.5 mL or 1.5 mL of unpreserved normal saline. The recommended dosage for treating glabellar
lines is a total dose of 50 Units of Dysport divided in
five equal aliquots of 10 Units each to the procerus
and corrugator muscles. Re-treatment with Dysport
at standard strength should be administered no more
frequently than every three months. The potency
units of Dysport are not interchangeable with other
preparations of botulinum toxin products and, therefore, units of biological activity of Dysport cannot
be compared to or converted into units of any other
botulinum toxin products.47
The same anatomic areas that were described
above to treat rhytides with Botox can also be applied with Dysport. A study was conducted to compare the efficacy and tolerability between Botox and
Dysport in the treatment of moderate to severe glabellar lines.48 Sixty-two patients with moderate or
severe glabellar lines at maximum contraction were
randomly assigned to receive 20 U of Botox or 50 U
of Dysport (20% in the procerus muscle, 80% in the
corrugator muscles). The incidence of patients with
at least a 1-grade improvement in the severity of
their glabellar lines at maximum contraction peaked at week 8 in both groups. However, the duration
of this improvement was generally more prolonged
with Botox than with Dysport with the overall incidence of such improvement being 77% versus 59%
at week 12 and 53% versus 28% at week 16. In addition, at week 16, the incidence of patients whose
glabellar line severity was none or mild between
Botox and Dysport was 23% versus 10% for all patients (not statistically significant) and 50% versus
13% (P=0.05) for patients with moderate glabellar
39
YAMAUCHI
lines at baseline. Throughout the 16-week follow-up,
patients’ mean scores for how attractive they felt and
how satisfied they felt with their appearance were
consistently higher with Botox than Dysport, with
statistical significance achieved for both at week 12.
There was no significant between-group difference
in the incidence of treatment-related adverse effects.
It was shown that Botox offers more prolonged efficacy than Dysport when the two products were compared in a 2.5:1 dose ratio. At the 2.5:1 dose ratio, the
results of the study presented herein suggest that Botox offers more prolonged efficacy (and comparable
tolerability) relative to Dysport. The data suggest
that the dose of Dysport may need to be higher than
the 50-U dose suggested for the treatment of glabellar lines to achieve a duration of effect and level of
patient satisfaction that is comparable with Botox.
The results of five phase III studies of Dysport
for the treatment of glabellar lines were recently
published.49 Three double-blind, multicenter, randomized, placebo-controlled studies enrolled ethnically diverse healthy adults with glabellar lines of at
least moderate severity at maximum frown. In these
studies, patients were followed for up to 180 days
after treatment. The fixed-dose, single-treatment
study randomized 158 patients to receive placebo or
one dose of Dysport at 50 U. The fixed-dose, repeattreatment study randomized 311 patients to assess
treatment following the prior Dysport treatment of
50 U. The variable-dose study randomized 816 patients to receive placebo or a single variable dose
(50-80 U, based on gender and assessment of muscle mass). Clinical evaluations were performed on
days 14 and 30 and monthly thereafter. The primary
endpoint was a response defined as a composite 2+
grade improvement, at day 30 from baseline, on the
wrinkle severity rating scale from 2 to 0, or from 3 to
0 or 1 (where 3=severe wrinkles/severe, 2=moderate
wrinkles/moderate, 1=mild wrinkles/mild, and 0=no
wrinkles/none), for both the blinded evaluator’s/
blinded investigator’s and patient’s assessments.
Patients (1116 total; 720 Dysport, 396 placebo) given Dysport received 50 to 80 U of treatment. The
median duration of response was 85 days for fixed
dosing and 109 days for variable dosing. Similar
efficacy occurred at doses adjusted for gender and
muscle mass, although males required higher doses
than females in the variable-dose study. Responses
appeared as early as 24 hours, with a median time
to onset of 3 days. Extension studies evaluated 1200
40
patients for 13 months and 768 patients in an interim
analysis for 24 months. Maintenance of efficacy was
seen after multiple cycles, indicating a lack of tolerance. It was concluded that Dysport significantly improved moderate to severe glabellar lines compared
with placebo, with onset seen as soon as 24 hours
after treatment and a median duration of effect of 85
or 109 days for fixed or variable dosing, respectively.
Another study examined the efficacy of Dysport to
treat crow’s feet in a double-blinded placebo controlled trial.50 Subjects with moderate to severe crow‘s
feet at maximum smile (mild to severe at rest) were
randomized to a single bilateral Dysport treatment
(15, 30, or 45 U) or placebo. Independent panel assessments (Week 4) showed that all Dysport doses
resulted in significant improvements in crow‘s feet
severity at maximum smile (P<0.001); a clear dose–
response effect was seen. Improvement over placebo
was seen in the 30-U and 45-U groups to Week 12.
Investigator assessment showed significant improvement for all doses for 12 weeks at maximum smile
and rest (P≤0.01). Patient satisfaction was significantly greater for all doses than for placebo for 16
weeks (all P<0.05).
Xeomin
Xeomin is the third BTX-A to be approved in the
United States in 2011 and is indicated for the treatment of glabellar lines in adults younger than 65
years of age. Unlike other neurotoxins, Xeomin does
not contain protein complexes including bacterial
proteins. Clinical trials have demonstrated that Xeomin is well tolerated and highly effective in treating
the glabella lines and does not require refrigeration
either during transport or in storage.
Myobloc
Myobloc is available in the United States and is
supplied as a sterile liquid formulation of the purified neurotoxin. Each vial contains 5000 units per
milliliter of botulinum toxin B in 0.05% human serum albumin, 0.01 M sodium succinate, and 0.1 M
sodium chloride at a slightly acidic pH of approximately 5.6. Myobloc is available in three different
total dosage strengths, 2500, 5000, and 10,000 units.
The recommended storage condition for Myobloc
is 2° to 8° C for up to 21 months and must not be
frozen. Myobloc may be further diluted with normal
February 2012
saline. Myobloc is FDA approved for the treatment
of cervical dystonia but not for cosmetic uses.
While not used as extensively as Botox or Dysport
for cosmetic purposes, Myobloc may be used to treat
facial rhytides in instances where patients develop
loss of response to BTX-A. Repeated injections with
BTX-A may result in the formation of neutralizing
antibodies that may reduce the effectiveness of subsequent treatments with BTX-A by inactivating the
biological activity of the toxin. However, the rate of
formation of neutralizing antibodies in patients receiving BTX-A has not been well studied and the
critical factors for neutralizing antibody formation
have not been well characterized. The results from
some studies suggest that botulinum toxin injections at more frequent intervals or at higher doses
may lead to greater incidence of antibody formation.
In situations where patients develop intolerance to
BTX-A, transitioning to Myobloc may lead to improved outcomes in the treatment of facial rhytides.
A report demonstrated that BTX-B is an effective
treatment modality for glabellar rhytides refractory
or exhibiting decreased clinical efficacy to BTX-A.51
A study was published to observe the effects of
BTX-B in comparison to BTX-A, on patients with
brow furrows assessing initial efficacy and duration of effect.52 Patients were injected with BTX-B
in two different dose conversions against BTX-A
to the corrugator-procerus complex. Some patients
received a conversion of 50 units of BTX-B (total
of 1000 units) to one unit of BTX-A while others
received a conversion of 100 units of BTX-B (total
of 2000 units) to one unit of BTX-A. The patients
treated with BTX-A received a total of 20 units. Both
types of botulinum toxin were effective at improving
glabellar frown lines. The onset of actions occurred
slightly sooner (2-3 days) with BTX-B than with
BTX-A (3-7 days). Duration of effect with BTXA was at least 16 weeks. The duration of response
was dose dependent with BTX-B with 1000 units of
lasting 6-8 weeks and the higher dose at 2000 units
lasting 10-12 weeks. At least with the doses used,
BTX-B has a quicker onset of action but BTX-A
has longer benefit for glabellar wrinkles. These data
strongly suggest that further dose ranging studies
of BTX-B are necessary and indicated in controlled
double blind studies in a larger patient population.
In addition, there is a higher complaint of pain upon
injection with Myobloc compared to Botox, presumably due to the lower pH of Myobloc.22, 53
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YAMAUCHI
Other studies have also investigated the treatment
of glabellar wrinkles with BTX-B and have observed
a rapid onset of action but a shorter duration. A total
of 1800 units of BTX-B was used for the glabellar
area and mean onset of 1.5 days and a mean duration of 8 weeks was observed.28 At higher doses of
BTX-B used by the same investigator in a follow-up
prospective study, the duration of response was 9.6
and 10.4 weeks with 2400 and 3000 units respectively.12 The onset of action was seen within 2 to 3
days. Another study looked at three different dosages of BTX-B for the treatment of glabellar lines.
Patients received either the low dose of 1875 units,
the medium dose of 2500 units, or the high dose of
3125 units.23 Most patients at all doses showed some
evidence of paralysis at 2 months. At 3 months after
injection, only subjects in the high dose maintained
a significant response with BTX-B. The authors concluded that at the doses utilized in their study, the
effect of BTX-B does not generally appear to last as
long as BTX-A. However, similar to the other studies, the onset of action was sooner with BTX-B.
Safety of botulinum toxin
Cosmetic treatment with botulinum toxin injections has become one of the most common nonsurgical procedures performed by practitioners. It has
been proven as safe and effective for the treatment
of glabellar lines and other rhytides in the face and
neck. Nonetheless, given its long safety track record
and high usage in millions of patients, knowledge
of any potential adverse effect associated with botulinum toxin is essential for any practitioner who
performs such injections. Generalized reactions
that have idiosyncratically occurred from botulinum
toxin injections include nausea, fatigue, malaise, flulike symptoms, and rashes at sites distant from the
injection but the instances of these events occurring
is rare.
Age considerations
It is difficult to tell for sure whether patients over
the age of 65 respond differently to BTX-A than
younger patients since there have been no studies
investigating cosmetic uses of BTX-A specifically
in the elderly, and there have not been enough elderly patients enrolled in clinical studies to make
any meaningful comparisons.54 Since the elderly
41
YAMAUCHI
are more likely to have thinner and less elastic skin,
weaker facial muscles, and wrinkles that over time
are caused by gravity-induced tissue sagging rather
than muscle contraction, the elderly are not expected
to respond as well to BTX-A treatment.55 The site
of injection also warrants special considerations in
the elderly. Treatment of forehead lines, for example, would require injections to the frontalis muscle,
which many older people use to raise their eyebrows
and eyelids to see. Older patients may also have redundant skin under the brow (pseudoptosis) which
could be worsened by BTX-A treatment. Older patients who receive BTX-A for glabellar lines may be
more at risk for complications such as eyelid ptosis
if they have a reduced or absent orbital septum.56
Conservative dosing, injection of low volumes, and
proper placement of the injection can reduce the possibility of spread of the toxin to unintended muscles.
A prudent caution is to start at the lowest possible
effective dose for elderly patients.
Diffusion
The effects of botulinum toxin effects, in some cases, may diffuse beyond the site of local injection.57
The symptoms are consistent with the mechanism of
action of botulinum toxin and may include asthenia,
generalized muscle weakness, diplopia, blurred vision, ptosis, and breathing difficulties. These symptoms have been reported hours to weeks after injection.
To date, no definitive serious adverse event reports of
distant spread of toxin effect associated with cosmetic
use of botulinum toxin has been reported.
Pre-existing neuromuscular disorders
Patients with peripheral motor neuropathic diseases, amyotrophic lateral sclerosis, or neuromuscular
junctional disorders (myasthenia gravis or LambertEaton syndrome) should be monitored particularly
closely when given botulinum toxin.58 Patients with
neuromuscular disorders may be at increased risk of
clinically significant effects including severe dysphagia and respiratory compromise from typical
doses of botulinum toxin injections.
Drug interactions
Concomitant administration of botulinum toxin
and aminoglycosides or other agents interfering with
42
neuromuscular transmission (e.g., curare-like nondepolarizing blockers, lincosamides, polymyxins,
quinidine, magnesium sulfate, anticholinesterases,
succinylcholine chloride) should only be performed
with caution as the effect of the toxin may be potentiated and result in excessive neuromuscular weakness.59
Pregnancy and lactation
Administration of botulinum toxin is not recommended during pregnancy. There are no adequate
and well-controlled studies of botulinum toxin in
pregnant women. Caution should be exercised when
botulinum toxin administered to a nursing woman
because it is not known whether this drug is excreted
in human milk.59
Ptosis and asymmetry
Transient ptosis is the most frequently reported
complication and has been reported in the literature
in approximately 5% of patients.56, 60 Ptosis of the
eyelid results from migration of the botulinum toxin
to the levator palpebrae superioris muscle. The levator allows the eyelid to open properly and fully. To
avoid ptosis, injections should occur at least 1 cm
above the eyebrow and should not cross the midpupillary line. A therapy recommended to treat ptosis
from administration of botulinum toxins A and B is
the use of apraclonidine 0.5% eye drops. The most
common dosing scheme used for apraclonidine is
one or two drops three times daily until ptosis resolves.
The most significant complication of treatment of
the frontalis is brow ptosis. Injections in the forehead
should always be above the lowest fold produced
when the subject is asked to elevate their forehead
(frontalis). If the patient has a low eyebrow, treatment of the forehead lines should be avoided, or limited to that portion of the forehead 4.0 cm or more
above the brow.
The most common reported complications in the
crow’s feet area are bruising, diplopia, ectropion and
an asymmetric smile due to injection of zygomaticus major.56 If severe lower lid weakness occurs, an
exposure keratitis may result. Treatment is symptomatic. These complications are avoided by injecting
at least 1 cm outside the bony orbit or 1.5 cm lateral
to the lateral canthus, not injecting medial to a verti-
February 2012
cal line through the lateral canthus and not injecting
close to the inferior margin of the zygoma. Violating
these boundaries has on occasion also resulted in diplopia due to medial migration of Botox and resultant paralysis of the lateral rectus muscle. Covering
or patching the eye will alleviate some of the double
vision.
Conclusions
The aforementioned therapeutic uses of the various types of fillers and botulinum toxin formulations
have expanded the ability of practitioners to treat
various rhytides of the face and to restore volume
due to atrophy. When used as monotherapy or in
combination, the use of fillers and botulinum toxin
is a simple, minimally-invasive procedure that has
minimal to no downtime, minimal adverse events,
and has turned back the clock on millions of patients.
Riassunto
Riempimento dei tessuti molli e tossina botulinica, tecniche di trattamento
Sono state impiegate una molteplicità di tecniche non invasive nel miglioramento delle alterazioni cutanee causate
dal fotoinvecchiamento. Tali metodi comprendono peeling
chimici, microdermoabrasione, laser ablativi e non ablativi
e varie fonti di luce rigenerante. Tuttavia, le procedure cosmetiche minimamente invasive maggiormente utilizzate
nella correzione delle rughe indesiderate e nella valorizzazione dei tratti del viso attraverso la modellazione e la
volumizzazione sono le iniezioni di tossina botulinica e il
riempimento dei tessuti molli. La loro sicurezza a lungo
termine e la relativa facilità di tecnica procedurale hanno
portato a elevati livelli di soddisfazione in tutto il mondo. Nondimeno sono indispensabili per garantire un esito
eccellente e sicuro un training adeguato sui fondamentali
della tecnica di iniezione, la scelta del candidato idoneo e
la conoscenza di potenziali eventi avversi.
Parole chiave: Botulino, tossine - Ringiovanimento Cute, invecchiamento.
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February 2012

D. M. DUFFY
The aim of this study was to broaden practitioner perspectives regarding the scope, safety, and efficacy of sclerotherapy for cosmetically unattractive veins and other conditions
involving a variety of anatomical sites. The author wrote a
review of results obtained following cosmetic sclerotherapy
for both veins and in other applications is presented. This
study involves hundreds of patients treated in a private phlebology practice spanning 33 years along with a brief review
of pertinent literature. Since treatment of dilated veins involving the dorsa of the hands and face are rarely discussed,
and widely performed, their treatment will be emphasized.
The largely historical usefulness of sclerotherapy for other
applications is also reviewed. As with lower extremity veins
there was a great deal of both regional and patient-to-patient
variability in terms of sensitivity to sclerosants and response
to treatment. However, sclerotherapy carried out for cosmetic purposes has routinely produced satisfactory results
for various applications and in a multiplicity of locations. Potentially serious complications and treatment failures were
rare in properly selected patients. Patient satisfaction with a
few exceptions was uniformly high. The addition of cosmetic
sclerotherapy to an established phlebology practice can be a
rewarding and highly satisfactory application of this versatile technique. Both treatment site, lesion type and the cosmetic nature of this therapy affects every aspect of treatment;
legal, ethical, and procedural. Experience suggests that each
Acknowledgements.—I am always honored to be asked to publish in a
journal as prestigious as journal Giornale Italiano di Dermatologia e Venereologia. I’ve enjoyed presenting this report and hope that those who
carry out these procedures will share their experiences with me. I could
not have completed this article without the generous and absolutely essential assistance of Peggy Goodwin, as well as the tolerance of my staff
and the patience of the editors of this journal.
Corresponding author: Duffy DM, Dermatology, Medicine, University of Southern California, Los Angeles, CA, USA.
Vol. 146 - No. 6
Dermatology, Medicine, University of Southern
California, Los Angeles, CA, USA
area and type of lesion treated exhibits predictable patterns
of response and risks. Vein treatment outcomes varying with
anatomical site may reflect: 1) evolutionarily adaptive processes which have produced veins specialized for specific environments; 2) differences in patterns of cytokine recruitment
and apoptotic processes. It should also be noted that potential
complications reflect area specific patterns of venous anastomoses, nerves, vital structures, and the complexities of arterial architecture.
Key words: Sclerotherapy - Cosmetics - Veins.
A
lthough the term sclerotherapy was coined in the
1930s by H.I. Biegelsen 1-4 to describe palpable
firmness resulting from fibrotic replacement of vascular tissue; the notion of fibrosing these hollow organs “from the inside” using an extraordinary range
of sometimes brutal therapies has been around for
millennia. Hippocrates traumatized varicose veins by
employing a slender piece of iron to induce thrombosis.5 While intravascular therapy for varicose veins
was first performed in 1840 using absolute alcohol;
the modern approach to sclerotherapy probably began in 1851 when Pravaz employed a modified syringe to inject ferric chloride into a varicocele. More
than 160 years later sclerotherapy is still being used
for this purpose.5, 6 Over time more than 24 sclerosants have been employed empirically without oversight and were subsequently abandoned due to horrific complications, as safer and equally efficacious
45
DUFFY
agents became available.5, 7 Although a number of
different types of sclerosants are still employed, by
the mid the 20th century two detergent sclerosants
sodium sotradecol sulfate (STS), and polidocanol
(POL), although by no means perfect, established
sclerotherapy in good hands as a relatively predictable, safe and effective treatment for lower extremity
varicose and telangiectatic veins.8 Some of the drawbacks associated with both of these sclerosants in
specific applications will be discussed in more detail.
Historically the ability of injectable sclerosants to
produce controlled fibrosis has also been exploited
to treat a large number of nonvascular syndromes including rectal prolapse, low back syndrome, hypermobile joints, inguinal hernias, prostatic hypertrophy,
glaucoma and thyroid enlargement.7 Sclerotherapy is
still being used to treat conditions as varied as snoring,9 spermatoceles,10 ganglions,11 and pyogenic
granulomas.12 Conceptually mesotherapy is based on
the same principles underlying sclerotherapy.
Cosmetic sclerotherapy – Future prospects
There are a number of reasons why certain applications of cosmetic sclerotherapy may inevitably
become more popular: 1) women, and increasingly
men, who have come of age in an era which provided
expeditious solutions to almost every aesthetic complaint are increasingly unwilling to accept either real
or perceived flaws in their appearance. These “defects” in times gone by would have been considered
to be the benign stigmata of an aging process to be
“suffered gracefully”. Perhaps some measure of increasing patient dissatisfaction with the ageing process (and determination to do something about it) can
be found in a lay publication, which describes hands
as the “The last virgin body part” “Which can give
away your age like the rings of a tree.” It also notes
that “Women who have peeled, suctioned, lifted, and
tucked away years of facial and body wear and tear
are demanding equal opportunity for their hands”;13
2) wider applications of cosmetic sclerotherapy have
also been facilitated by the development of more sophisticated techniques and FDA approval for the use
of POL to treat lower extremity telangiectasia, reticular and small varicose veins whose treatment rationale is often cosmetic;14-16 3) heavily promoted lasers and other devices have often failed to be as cost
effective, efficacious or as comfortable to use as a
46
simple technique dependent procedure such as sclerotherapy. Lasers have exhibited a particularly striking inability to replace sclerotherapy as the treatment
of choice for both lower extremity telangiectasia and
reticular veins;17 4) finally, more practitioners are
available both skilled and unfortunately unskilled
who are incorporating cosmetic procedures into their
practices as a matter of financial necessity.
Treatment considerations – A new
philosophical paradigm
Challenges facing practitioners who carry out
elective procedures involve issues that are as much
philosophical as procedural. In the case of sclerotherapy the incorporation and application of treatment modifications based upon anatomic site and
lesion type can easily be mastered by experienced
phlebologists who are anatomically knowledgeable,
aware of the shortcomings of various sclerosants,
and adept at recognizing signs of impending complications. Making decisions about whom you should
or shouldn’t treat is often more difficult than actually carrying out the procedure. Patients who seek
cosmetic improvements often differ from patients
who undergo sclerotherapy as a matter of medical
necessity both in terms of motivation and sometimes
unrealistic expectations. Their interest and understanding of these procedures may be fueled by advertisements, lay publications, and internet information. These sources often gloss over the possibility
of complications and treatment failures. The ability
to address patient needs in the United States may be
further complicated by regulatory issues, malpractice concerns, and patient ignorance involving insurance benefits. Phlebologists here who intend to
perform cosmetic sclerotherapy without exposing
themselves to the possibility of regulatory infractions, malpractice inadequacies, or potential lawsuits
must disabuse patients of their misconceptions, acquire a clear understanding of regulations governing
these procedures, and determine the extent of their
malpractice coverage. The USFDA considers sclerotherapy carried out for any purpose other than to
treat lower extremity venous disorders as legal but
off label. The essence of “off-label” status has to do
with the creation of alternative (“innovative protocols”) which employ FDA approved medications for
unapproved purposes on an individual basis. This
December 2011
practice cannot be promoted broadly or advertised.
Moreover, the patient must be fully informed as to
the FDA status of the procedure. To add to the complexity state regulations governing the off –label use
of approved drugs sometimes conflict with federal
standards. Torres 18 outlines the niceties promoting
and using off-label medications in the United States.
Medical establishments’ response –
Sometimes less than welcoming
Finally, those who intend to embrace cosmetic
sclerotherapy must be prepared to encounter some
degree of opprobrium from certain colleagues who
regard any cosmetic procedure associated with potential risks as frivolous, unnecessary and potentially
disastrous. The disparity between patient’s interests
and colleague approval can be a source both of irritation and limited referrals. Communications sent
to colleagues regarding your interest in carrying out
cosmetic sclerotherapy must be accompanied by a
reasonable summary of contraindications, complications, and expected results. Including a peer reviewed article or two will help to substantiate both
the validity of the procedure and your ability to carry
it out. It also does not hurt if you are well known as
an experienced phlebologist in your own community.
Getting started
In the late 1980s at least two major obstacles confronted any American phlebologist who chose to
carry out cosmetic sclerotherapy. The first was the
absence of any published treatment guidelines. The
second, which faced all phlebologists here was an
impoverishment of choices among the few sclerosants legal to use in the United States.
Sclerosants American style
Physicians here faced an astonishing example of
hippocratic dissonance in which the legality of using
highly toxic, older sclerosants was largely unrelated
to the risks they presented. Bureaucratic inertia discouraged the introduction of safer sclerosants which
prolonged the use of outmoded agents such as sodium morrhuate and ethanolamine oleate, which were
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DUFFY
vastly more dangerous than sclerosants widely used
abroad. POL which was illegal to use in the United
States until 2010, was demonstrably as efficacious
and a great deal safer than many of the agents approved or sanctioned solely on the basis of long
term use.8 Finding a sclerosant was like choosing a
politician; your choice was limited to the one you
feared the least. There were several issues of particular concern, they included the risk of allergies, tissue
necrosis and the liabilities of employing a safer, non
FDA approved product for which malpractice insurance may be invalid, not to mention the possibility of
federal prosecution.
Detergent sclerosants
POL and STS (which is 2-3X more potent), have
been used for many years and are well characterized.
Both have numerous advantages and a few drawbacks. Particularly when using high concentrations
detergent sclerosants can cause life threatening allergies, embolic phenomena, tissue necrosis and serious neurological complications. They also have the
potential to cause unintended sclerosis in contiguous
veins many centimeters from the intended target.
STS has the additional drawback of routinely causing extravasation necrosis in concentrations of 1% or
greater, while 3% POL, the equivalent concentration
appears to be much less tissue toxic.19 Both agents
are reputed to exhibit a similar rate of allergies when
the concentrations are matched. The use of POL is
also very rarely associated with cardiotoxicity.8
Detergent foams
Detergent foams are considered to be significantly
(up to 3X) as potent as equivalent concentrations of
liquid sclerosants.20 When these preparations first
came into wider use for the treatment of large refluxing veins, they were found to cause an unexpectedly
high incidence of certain types of complications.
These included sclerosis of interconnected nontargeted veins at an even greater distance than seen with potent liquid sclerosant, increased neovascularization,
and pigmentation. Neurologic phenomena (transient
ischemic episodes and strokes) are also more common.21-25 One mechanism considered to be contributory to these neurologic events is the presence of an
47
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open foramen ovale (which afflicts 25% of the population), and permits P.F.O. foam to enter the cerebral
circulation via a right to left shunt. This condition is
also associated with migraines and an elevated risk of
cardiovascular disease.26-29
Addressing potential complications
Allergies
Although STS was considered to be generally
safe, was FDA approved, and had a reported low incidence of serious allergies, personal enthusiasm for
using it was tempered by a letter received from a colleague who reported an incident in which a patient
died shortly after the administration of a “test dose”
of 0.5 cc of STS. The cause of death was never clearly established, however an experimental laboratory
analysis indicated the death was due to an allergic
reaction [Lakeview Clinic, Ltd. 424 State Hwy, Waconia MN 55387. Lehmann JD, MD, personal communication].8, 30 HS, approved as an abortifacient,
was legal to use “off-label”. Its only virtue was its
non allergenicity. Uncomfortable to use, and extraordinarily prone to causing extravasation ulcers with
the slightest technique mishap, it was also too weak
to use for larger veins.
Tissue necrosis
A study carried out in this office compared the ability of equal volumes of 3% POL, 1% STS, and 23.4%
HS and sodium morrhuate to produce tissue necrosis following deliberate mid-dermal injection. POL,
alone among these agents, did not produce tissue
necrosis. It was surmised from this study that high
concentration POL was minimally tissue toxic.31-34
This finding has been confirmed in a number of other
reports.30, 31, 34 In an earlier investigation, the injection
of 0.4c c of 3% POL into the authors forearm did not
result in tissue necrosis although mild pigmentation
was noted.8, 30-34 Sodium morrhuate produced a large
ulcer associated with so much pain that it required
immediate intervention. What is known now is that
all sclerosants can under certain circumstances cause
tissue necrosis by multiple mechanisms. Factors associated with tissue necrosis include the anatomical
location of the treated veins, AV malformations, concentration and type of sclerosants, depth of injection,
48
injection force and volume. Certain sites are particularly susceptible to tissue necrosis and localized or
distant neurologic phenomena. The medial malleoli
are particularly prone to tissue necrosis as are certain regions of the face and hands. The occurrence of
ulcerations and localized neurological problems led
to the discontinuance of injection of the dorsoradial
hand veins. Sclerotherapy for facial telangiectasia
particularly on the cheeks, hands and nose may also
be associated with an increased incidence of tissue
necrosis.35
Clinical applications - Varicose
and reticular hand veins
The first peer reviewed article describing the treatment of dorsal hand veins published in 1999 37 did
not result in a tidal wave of interest or publications.
Criticism in the form of letters to the editor were
proffered by those who considered dilated veins on
the dorsum of the hands to be “normal”. Quite reasonably, more thoughtful commentaries stressed the
importance of preserving hand veins which were essential to provide potential lifesaving venous access
should medical emergencies occur or the need for
long-term IV medications arise. Some of the most
pointed criticisms mocked both the patients motivation for having the procedure carried out and the
doctors willingness to perform it. Despite these concerns, there’s nothing in the published literature to
suggest that sclerotherapy for the treatment of hand
veins (provided some are spared for emergencies), is
ineffective or carries with it a significant incidence
of serious immediate or delayed complications.
Hand veins unique features
Reticular and varicose veins situated on the dorsa
of the hands are exposed to an extraordinary combination of environmental conditions which exist almost nowhere else on the body. They are subjected to
frequent rapid changes in position (elevation and dependency), as well as muscular activity which combine to produce dramatic fluctuations in both arterial
and venous flow. Sun exposure, trauma and the aging process complicate their environment even more.
Perhaps because of this they often require considerably higher concentrations of sclerosants than those
that would ordinarily be needed to treat vessels of the
December 2011
Table I.—Contraindications to sclerotherapy.
Coagulopathies
Protein S deficiency
Proteins C deficiency
Antiphospholipid antibody syndrome
Chronic fatigue syndrome *
Predisposition to or history of deep venous thrombosis, thrombophlebitis or pulmonary embolism
Migraine headaches with aura (high risk of neurologic complications) **
Severe circulatory disease
Severe allergies or asthma when sclerosants other than hypertonic saline are employed
Debilitating state and poor general health
Pregnancy and lactating state***
Hypersensitivity to the sclerosant or any constituent of sclerosant
Skin or soft tissue infection
Uncontrolled diabetes
Cognitive impairment / inability to understand and comply with
instructions
Severe Collagen vascular disease / connective tissue disease
Drugs which may produce hypercoagulable states (R), e.g.,
Tamoxifen
* Putative association with hypercoagulability
**Putative association with patent foramen ovale/cardiovascular disease
*** Medico-legal consideration
(R) Relative contraindications
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Table III.-Contraindications to treating facial reticular veins/
Periocular reticular veins.
Veins over 2 mm in size
Thick walled inelastic vessels* (vessels of these types are often
resistant to treatment and may represent AV malformations
Patients with a history of post-sclerotherapy necrosis*
Reticular veins involving the temples (R)
Facial muscular weakness
Perioral reticular veins**
Facial asymmetry (ML)
Temporal arteritis (ML)
Glaucoma (ML)
Problems of blurred eyesight (ML)
Lid weakness/retraction (ML)
Extensive eyelid surgery (ML)
Lid lag (ML)
Chronic ocular herpetic infections (ML)
Chronic irritation/inflammation of the lids (ML)
Swollen or painful eyes (ML)
Strabismus (ML)
Scleral show (ML)
Frequent headaches (ML)
Patients with extensive and interconnecting network of temporal
and periorbital veins
(R) Relative contraindication
(ML) Medico-legal risk
* May be at greater risk to develop ulcerations in other treatment areas
** Other authors report good results (45)
Table II.—Contraindications to the treatment of dorsal hand
veins.
Patients with abnormal venous distribution on the hands
Patients with foreseeable need for future IV access at treatment
sites
Patients with limited numbers of arm reticular veins available for
venous access
Need for frequent IV medications
Carpal tunnel syndrome *
Patients who have had hand surgery *
Presence of dialysis shunts *
Chronic hand pain, weakness, edema, severe arthritis or functional abnormalities *
Treatment of veins on the dorsolateral hand (R)
* Medico-legal consideration
(R) Relative contraindication
same size on lower extremities. The need for higher
sclerosant concentrations coupled with the absence of
established protocols and the elective nature of the
procedure mandates an extremely careful patient selection process. Tables appearing at the end of this
presentation discuss both general contraindications
and those which are specific for the areas treated (Tables I-V). The treatment of veins involving the dorsoradial surface of the hand is particularly risky because
of presence of superficial sensory nerves (Figure 1).
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Table IV.—Contraindications for treating Chest/Breast reticular
veins.
Pronounced breast asymmetry (ML)
Unrealistic expectations (ML)
Sternal telangiectasia following cardiac bypass surgery
Chronically painful breasts (ML)
(ML) Medico-legal risk
Examination and clinical approach – The
importance of pre-existing problems
The hands are carefully examined for symmetry, muscle mass, hand strength, atrophic changes in
muscle and bone as well as skin laxity. Patient hand
strength is assessed by having the patient squeeze the
examiners finger. Dexterity should also be evaluated.
Preexisting weakness or any other abnormality if not
acknowledged by the patient before treatment will
surely be attributed by both the patient (and perhaps an
attorney), as a unexpected complication of treatment.
Doppler evaluation
Patients with anomalous distribution of dorsal
hand veins may have unpredictable, dangerous to
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Table V.—Contradictory approaches to treatment of facial veins.
Author
Type of Sclerosant
and Rationale
Green (39) Higher
concentrations
of detergent
solutions are
safe and more
effective than
osmotic or low
concentration
sclerosants
Concentration
of sclerosant
Volume
Intended
outcome
0.75 – 1%
STS
1-3cc
injected
into any
one site
slowly
Vessel
obliteration
Weiss (53) Rapidly acting
detergents
minimize
bleeding
time, damage/
swelling occurs
more quickly
Sotradecol
0.2%
Polidocanol
0.5 – 1% or
saline and
dextrose
(Sclerodex™)
rarely
hypertonic
saline 23.4%.
STS .2%
Polidocanol
0.5 – 1%
Osmotic
Sclerodex
(Sclerodex,
undiluted.
hypertonic
Hypertonic
saline) detergent saline 23.4%
solutions may
travel many cm
from the site
of injection
causing
potential injury
“Use only
a few
drops” We
typically
utilize
0.2 – 5%
sotradecol
volumes
of no more
than 0.1 0.2 cc
Bowes/
Goldman
(45)
Sclerodex
up to 2cc
Technique
Massage after
injections/
compression.
Manual
external
compression
along the
malar margin
of the orbit
during
treatment.
Compression
after delivery
of solution
Reduce
Pressure
vessel size over treated
rather than area for 10
“completely minutes to
obliterate
minimize
them”
bruising
Obliteration Gentle
pressure post
or partial
obliteration treatment.
Multiple
treatments
Success rate
percentage
Minor side
effects
Serious
complications
100%
One
treatment
only
Mild erythema
and edema
persistence 2
days. Bruising
None
Greater
than 50%
Bruising 50 –
75%
None
63 – 75%
Bruising,
matting
None
Comment: Green (39) employs the highest concentrations and volumes of detergent solution, reports the greatest success with the fewest number of treatments. He believes that no direct connection between facial veins and ophthalmologic or neurological structures exists noting that the blood in the face
drains down towards the neck into the internal and external jugular veins not into the ocular or cerebral circulation. Four criticisms have been directed at
his approach. 1) Injections in this area could theoretically produce blindness or neurological injury via multiple anastomoses. 2) “Common sense dictates
the use of small volumes of sclerosant which minimizes the risk of blindness or neurologic injury” 3) Manual external compression on the lower margin
of the orbit after delivery of sclerosant solution could force the solution into the orbital vessels.
Osmotic sclerosants advantages and disadvantages. 1) Sclerodex is less prone to cause tissue necrosis and is more comfortable than hypertonic saline. 2)
These agents are relatively weak sclerosants and may not work as effectively as higher concentration / volumes of detergent sclerosants.
treat circulatory abnormalities. One patient presented
with a thick walled 4mm distended vein on the thenar
eminence of the right hand. Doppler evaluation suggested that this was an artery, however, Doppler evaluation of this area is difficult to interpret because of
a great deal of extraneous arterial background noise.
Patient selection
A suitable candidate for the treatment of hand
veins is healthy, mobile, exhibits normal anatomical
50
distribution of the dorsal hand veins, with no existing deformities of the hands, chronic pain syndromes
and has adequate symmetrical hand strength and coordination. The entire protocol “warts and all” is explained in detail and this explanation is supplemented
by a written handout, careful pre treatment photos,
and consent form. Digital photos are taken with the
hands in a dependent position, both in direct view and
tangentially using side lighting to document the size
of the vessels and degree of protuberance is noted.
The veins are measured both in dependency and el-
December 2011
Basilic
Cephalic
Dorsal venous
network
Dorsal
metacarpals
Venous arch
Figure 1.—Sclerotherapy carried out in the area indicated by the
circle in this diagram appears to pose a significantly higher risk
for nerve damage.
evation. A careful discussion is carried out stressing
the cosmetic nature of the procedure and its FDA
status. Edema, bruising, the need for multiple treatments and occasional treatment failures are carefully
reviewed. An explanation is provided discussing the
reason for restricting each treatment to only one half
of the veins involving each hand (to lessen edema).
The dangers associated with treatment of dorsoradial
hand veins (nerve damage and tissue necrosis) are
also presented. The need to spare veins for I.V. access
is emphasized as is the possibility of potentially serious complications including allergies, the triggering
of migraine headaches and neurologic phenomena.
Common complications particularly bulky thrombi
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DUFFY
(which usually need to be incised and drained) are
carefully discussed. Patients are also told that these
thrombi which typically occur in veins following
treatment are not dangerous, do not break loose, and
represent expected treatment outcomes indicating
that the vein will need no further treatment. Because
thrombi (we call them “trapped” blood to allay patient anxiety) can occur or recur up to three weeks
after treatment, the patients are asked to refrain from
travel during that time frame. Patients who seek treatment often present with large numerous, easily cannulatable veins on the forearms and upper arms as
well, noting that many members of their families are
also “veiny”. These patients are good candidates for
this procedure. Those who do not have other easily
accessible veins should not be treated.
Choosing sclerosant
concentrations/types/foam vs. liquids
Dorsal hand veins can be notoriously resistant to
low concentrations of sclerosants; 23.4% HS and
STS under 1% are generally ineffective even when
treating smaller vessels on younger patients. The
occurrence of treatment failures employing sclerosant concentrations which would be effective on the
lower extremities led to the employment of 3% POL
solution for most of the patients treated. The use of
foams was reserved for patients who did not respond
to 3% POL solution for reasons discussed later.
Although vessel diameter and sclerosant dilution
associated with it are generally considered to be a
major criterion for choosing a particular concentration of sclerosant, the volume of blood within veins
can be reduced simply by raising the hands. Accordingly, the thickness of the vessel wall and robustness
or fragility of the overlying dermis play a major role
in the choice of appropriate sclerosant concentrations. Elderly patients with atrophic skin and thin
walled veins up to 3mm in diameter can have been
effectively treated using 0.75% - 1.5% POL solution
or alternatively 0.25-0.5% STS solution.
Foam preparations
Foams are prepared using room air at 1:4 dilution
employing two syringes and a coupling. Concentrations from 1% - 3% POL foams have been employed
as have STS foams 1% - 2% strength. They are often
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injected using a larger diameter needle as quickly as
possible after being prepared because of foam degradation. Foams have the additional disadvantage
of being very difficult to aspirate, and an increased
risk of bulky and recurrent thrombi (often involving
the forearms), and a well recognized risk of cerebral
neurological complications. Most of the patients
who required foam were younger patients with thick
walled veins and abundant dermal support.
tient or an assistant, or by a tourniquet to minimize
thromboses in this area which is a frequent cause of
post-treatment discomfort. Immediately after treatment with the hand elevated an ice bag (McKesson
Medi-Pak Instant Cold Compress Richmond VA
23228) is applied for several minutes while the patient opens and closes the hands.
Sclerosant volumes
Compression
Although up to 5 cc of polidocanol 1.5-3% liquid,
or 1% STS liquid have been employed, generally 1-2
cc is all that is necessary per treatment. When using foam a smaller volume massaged into the vein is
often effective and minimizes the risks of excessive
thrombosis and neurological phenomena.
A compression dressing consisting of an ace bandage applied over cotton balls or a sanitary napkin is
applied immediately after treatment up to the wrist
when using liquid sclerosant. When using foams the
dressing is extended the length of the forearm and
applied after the hand has been elevated for several
minutes to allow dissipation of the foam distally. Experience has taught us that prolonged elevation of
the hands to at least the level of the chest for as much
of the time as possible for several days after treatment combined with opening and closing the hands
often enhances patient comfort, reduces edema, and
minimizes thrombotic bulk more effectively than
any form of compression. We now leave compression dressings on for no more than 12 hours. Patients
are also asked to refrain from heavy lifting, vigorous
clapping, or physical activity that requires the hands
to be subjected to prolonged episodes of dependency
for at least a week. When using computers patients
are advised to adjust their seating arrangements so
that their hands are above the waist while they are
working. Table II discusses contraindications specifically related to the treatment of hand veins.
Patients are instructed to loosen their dressings
and call the office if severe swelling, throbbing, or
paresthesias occur. If they have a good deal of pain,
they’re also asked to remove the dressings and carefully examine the treated area to determine the presence of crusting (a sign of incipient tissue necrosis).
Latex or non-latex gloves are provided if the patient
wishes to leave the dressings on during brief showers.
Technique
Ordinarily only one half of the veins on each
hand is treated at each session to minimize edema.
When the patient returns the other half of each hand
is treated before incision and drainage of thrombi is
carried out. For patients who are not in a hurry one
vein at a time can be treated. In this case, compression is not necessary but the treatment process is
prolonged. Prior to treatment patients are asked to
remove all jewelry and refrain from taking aspirin or
other agents which would increase bruising. Small
vessels involving the phalanges can also be treated
but this is technically more difficult. After cleansing
the treatment areas with alcohol, patients are treated
in the recumbent or seated position with the treated
hand placed below the level of the treatment table to
facilitate vein distention. A tourniquet may be used
if the room is cold and the veins are constricted.
A 3 cc luer-lock plastic syringe which is only half
full (which permits better control of the injection
process) is attached to a half inch 30 gauge needle.
Before initiating injections the patient makes a fist
which stretches the skin more tightly over the veins
stabilizing them during the cannulation process. After cannulation the hand is elevated and sclerosant
is slowly injected into empty veins. The direction of
the injections proximal to distal or distal to proximal
doesn’t seem to matter. During the injection process
the veins are filled to the dorsum of the wrist where
the vessels are occluded digitally either by the pa-
52
Post-treatment protocols
Pain tolerance – A warning that
is sometimes ignored
Patients are carefully quizzed regarding their ability to tolerate pain. Those who proudly admit to be-
December 2011
ing able to tolerate pain without complaint are asked
not to ignore it, but to remove their dressings and
call us after examining the treated areas if they continue to feel any degree of discomfort in their hands
or forearms or note the presence of a crust which
suggests the possibility of tissue necrosis.
Follow-up care and instructions
Patients are sent home with a topical anesthetic
(compounded 23% lidocaine and 7% tetracaine) to
be applied liberally under plastic wrap two hours before their scheduled follow up visit. They are also
told that thrombi are easier to feel than to see and
that veins sometimes appear unchanged even though
they are thrombosed. Follow up visits are scheduled
arbitrarily at 2 weeks or at the patient’s option when
they first notice signs of vein thrombosis described
to them as firmness or hardness of the treated veins,
palpable or visible nodules, or discomfort when the
treated vein is manually compressed.
Thrombectomies
Local anesthetic (1% xylocaine without epinephrine) is injected into topically anesthetized areas.
The thrombi to be incised are marked in advance
with an eyebrow pencil to prevent difficulties in visualizing the areas to be incised if distortion occurs
following the injection of local anesthetic.
Incision is carried out with either a #11 surgical
blade or an #18 needle. Sometimes cotton tipped
applicators are used to more easily express the viscous contents of the treated veins. Patients have been
warned that waiting longer than two weeks to perform
incision and drainage sometimes makes it difficult to
perform because the thrombus has been encapsulated
by fibrotic tissue. Vein mobility poses further difficulties. Venous movement can be stabilized by having the
patient grip an ace bandage roll tightly which firmly
stretches the skin over the vein during the incision and
drainage process. Traction applied by an assistant or
by the patient can also be employed. Previously untreated veins on the other side of each hand are usually
injected on return visits. Patients are not charged for
thrombectomies which sometimes need to be repeated several times weeks after treatment. They are also
seen for routine checkups without charge, which helps
insure patient compliance. These visits are often carried out monthly for 3 months after treatment.
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Personal observations
Since 1987 in excess of 250 patients with hand
veins varying between 1.5-6mm in size have been
treated in this office. Treatment failures were rare,
serious complications were even rarer. Most patients
were delighted. Patients are provided pretreatment
photographs to document improvements . Results
were long lasting (longest follow-up at this writing
is 15 years). Recurrences were uncommon although
new smaller veins developed particularly in those
who lifted weights or performed hard manual labor.
Treatment details
The second phase of an ongoing study which began in 1990, essentially duplicated results seen in an
earlier study,8 with the exception of absence of neovascularization (matting), neurologic complications
or tissue necrosis. Low concentrations of sclerosants
were often associated with a high incidence of treatment failures (80%). The use of 3% POL liquid or
foams up to 3% concentration produced good results in 95% of treated patients. Treatment of veins
involving the dorsoradial hand near the thenar web
are no longer carried out. Patients with migrainoid
symptomology or other neurological conditions are
carefully avoided.
Minor adverse events
Adverse events common to sclerotherapy including bruising, edema, and palpable thrombi were observed in 90% of the treated patients (Figure 2).
Swelling, persistent discomfort
One patient developed swelling of the index finger
which may have been precipitated by a ring which
she put on shortly after treatment. Four patients developed persistent discomfort in several treated areas which resolved over several months. Although
there were veins that remained untreated further
treatments were deferred. Resistance as measured by
lack of response to three treatments has occurred in
less than 1% of treated patients and often could be
eliminated by increasing sclerosant potency or using foam. Several patients had veins which persisted
despite the injection of 3% POL foam further treatments were not carried out.
53
DUFFY
Figure 2.—Ecchymoses and the first signs of the shallow ulceration is noted in this photograph taken one week post treatment. This
patient developed a long lasting mild sensory deficit.
Figure 3.—Pretreatment appearance of a 1.3 mm periocular reticular vein.
Figure 4.—Transient bruising one week after treatment with 0.75% POL.
Superficial thrombophlebitis involving the forearms has occurred in less than 1% of the treated patients. Immediate relief was afforded by injecting
0.3 cc of 2.5 mg per cc of triamicinolone acetonide
(Kenalog™), in 1% xylocaine without epinephrine
directly into the thrombi followed by incision and
drainage. In one case, this was followed by transient
pseudo atrophy.
sient superficial ulcerations which healed without
scarring. In one case there was no persistent sensory
defects. In the other case mild numbness involving
the distal thumb which had improved with time was
still noted at 2 years. The etiology of nerve damage
was speculative. It may have occurred following extravasation of the sclerosing agent, the inadvertent
injection of an AV malformation, or a neurovascular reflex.8 Avoidance of treatment of the dorsoradial
hand has to date eliminated this problem.
Potentially serious complications
Reported complications
Allergic phenomena and embolization were not
observed. Two patients developed scintillating
scotomata. Both denied the previous existence of migrainoid symptomotology. Neither of them had patent foramen ovale as determined by cardiac evaluations. Both occurred prior to 1999.
Lawsuits have been filed because of persistent, intermittent swelling,35 continuous pain and discomfort, as well as the beginning stages of carpal tunnel
syndrome and a noticeable deep maroon color of the
treated hands.35, 37
Tissue necrosis/Localized neurological complications
Forearms/Bicepital veins
Superficial thrombophlebitis
Treatment of veins involving the dorsoradial surface of the hand may damage superficial sensory
branches of the radial nerve which lie in the superficial subcutaneous tissue. Two cases of nerve damage (neuropraxia) followed the treatment of veins in
close proximity to the thenar web. These complications followed injections of less than 1cc of 3% POL
solution associated with immediate development of
paresthesias, pain, and blanching of the thumb, index and middle finger. Both patients developed tran-
54
Fifteen patients were treated for “excessiveness
veininess” involving the forearms and biceps. All had
excellent alternative veins involving the antecubital
fosse which were spared. Treated veins varied in size
from 2.5 mm to 6 mm in diameter and were treated
with 1.5-3% POL. Treatment failures following the
treatment of the larger veins were noted in four of the
patients treated. No complications other than transient edema and bruising were noted in any of the
patients. Multiple (up to 3 treatments) were the rule.
Patient satisfaction was very high. One patient pre-
December 2011
sented with a 1cm vein involving the dorsal forearm.
This vein was effectively fibrosed using 3% POL solution but developed what can best be described as a
hard intravascular distended hypertrophic scar, which
persisted months after treatment. This was addressed
using 2.5 mg per cc of Intralesional triamicinolone
acetonide in 1% plain xylocaine which was injected
into the fibrotic area. Excellent results were obtained.
Facial reticular veins
As with hand veins, very little has been written since Green 38 published a highly quoted peerreviewed article in 2001 exclusively devoted to the
treatment of periocular reticular veins. His use of
relatively large volumes of 0.75% STS provoked
a torrent of polemical commentary.39 The upshot,
“The safety of periocular vein sclerotherapy was
not established by this report”. It was clear that the
reviewers felt that the potential risks (blindness and
neurological complications), far outweighed potential benefits. In addition, specific aspects of the technique employed including sclerosant type, volume,
concentration and post treatment manipulations were
criticized as being intrinsically dangerous. Table V
presents differences in opinions and approaches to
the treatment of these veins.
Facial reticular veins unique features
First, the presence of the multiple arterial and venous anastomoses and ocular adnexa make the possibility of visual loss, cavernous sinus thrombosis,
and tissue necrosis resulting from inadvertent arterial injections are a major concern. Secondly, venous
pressure is low and theoretically intravenous injection
could reach the orbit where there are no valves. Third,
one publication suggests the use of sclerodex (an osmotic sclerosant) which confines sclerosant damage
to a small area.40 Finally, treatment of each region of
the face is associated with the possibility of specific
types of complications and treatment outcomes.
Examination and clinical approach
As with hand veins, a careful explanation of the
theoretical risks are carefully discussed with the
patient. Digital photographs and consent forms to
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permit their use are also obtained (Figures 3-5). In
addition, a written summary is provided detailing
the occurrence of common complications including bruising and swelling as well as the existence
of a therapeutic conundrum. Patients are told that
although high concentrations and volumes of sclerosants have been employed resulting in a 100%
success rate without complications, the risks of employing such a treatment protocol may outweigh its
benefits necessitating the use of lower, safer concentrations. As a consequence of using lower concentrations, in approximately 50% of patients treated
vessel diameter is substantially reduced but the vessels are not completely obliterated. Two treatments
carried out at four-week intervals are performed.
If further treatment is required it is carried out at
two months. Patients are told that the upper eyelids,
and the central forehead, and reticular veins involving the temple area may present increased risks and
they are not treated. One patient complained bitterly
when a 2.5-mm thick walled “vein” located on the
temple was determined by Duplex scanning to represent an artery. She was angry that treatment had
to be deferred despite the obvious risks associated
with it.
Reasons to be concerned when injecting facial veins
Although at this writing no serious complications
have been reported following cosmetic periocular reticular vein sclerotherapy; monocular blindness has
been reported after STS was injected into a venous
malformation partially located in the orbit. Blindness has also been reported due to embolic occlusion
of the ophthalmic artery as a complication of nasal
steroid injections. In another case severe visual loss
followed the injection of steroids into a chalazion.
Because it is not a suspension, distal embolic phenomena with detergent sclerosants should not be expected. Some of the conflicting opinions regarding
technique specifics are presented in Table V.41, 42
Facial sclerotherapy - Personal observations
Despite the theoretical possibility of horrific complications, I have neither personally observed in the
treatment of over 50 patients nor reviewed articles in
which serious problems occurred following cosmetic injection of reticular veins located on the lower
lid, medial cheek and mandible.
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Figure 5.—Results 1 month post-treatment.
Figure 6.—This patient complained of a “vein” in the forehead which enlarged with exercise. Ultrasound evaluation revealed a small
subcutaneous artery.
Figure 7.—Thromboses are common and are usually incised and drained within 2 weeks of treatment. Occasionally thrombi can become recurrent and require repeated incisions and drainage.
Technique
After cleansing the area, the patient is positioned
supine on the table with the head at 45 degrees supported by a pillow. A 3 cc luer-lock syringe is employed containing only 1cc of solution which facilitates dexterity. A 30 gauge half inch needle is
employed which is very carefully locked onto the
syringe using needle-nose pliers. A small amount
of solution is injected through the needle to insure
patency and reduce piston-to-syringe “stiction”. An
assistant helps provide traction and injections are
carried out with the needle pointing away from the
eye. Injections are carried out very slowly with a
maximum 0.5 cc of 0.75% polidocanol solution in
each injection site. This is the highest concentration
employed in an attempt to minimize the possibility
of serious complications. When attempting to inject
thin walled superficial veins involving the lower lid,
it’s sometimes difficult to induce sclerosant flow
along the length of the vein to be treated. Instead the
vein will simply expand radially resulting in sclerosant pooling at the injection site. This can sometimes
be overcome by pulling the skin of the lower lid over
the orbital rim. During the injection if greater than
56
the expected resistance to flow is observed the possibility of an AV communication must be considered
and the injection terminated.
Immediately after injection, gentle pressure is applied to minimize bruising for a full five minutes.
Subsequently an ice bag may be used both in the office and at home for 5-10 minute intervals to reduce
discomfort and swelling. Patients are instructed to
use two pillows while sleeping, avoid strenuous exercise and alcohol for 2 days post-treatment.
Long- and short-term results - Personal observations
Complete or partial sclerosis following the injection of reticular veins on the face is often quite
gradual mimicking the effect one sees when treating
lower extremity telangiectasia using low concentrations of sclerosants. Bruising, transient swelling and
treatment failures have been the only complications
observed following the treatment of the veins involving the lower lid and medial cheek. Treatment failures after two treatments occurred in approximately
25% of 100 patients treated. Another 25% of patients
treated developed new smaller veins in the same area
over a period of 10 years.
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Figure 8.—Pretreatment 2 mm in diameter reticular veins.
Figure 9.—Results one month after treatment employing 0.75%
POL solution.
Temporal reticular veins –
A high-risk treatment area
Although initially temporal veins were treated without problems other than the occurrence of a thrombus in one patient which developed after injection of
a 1.5 mm reticular vein which required incision and
drainage. Treatment of reticular veins in this area was
discontinued following the occurrence of three frightening events. In one case 0.75% POL failed to affect
temporal veins measuring 1.5 mm in diameter. A second treatment was carried out using 0.25cc of 1.5%
POL (a concentration which may be dangerously high
for the treatment of this area). Two weeks after the
second treatment the patient developed a 2.5 x 2.5 cm
area of crusting superior to the injection site which
was followed by a shallow ulceration of the same size
which was surrounded by a transient loss of hair over a
two month period. Examination revealed exclamation
point hairs suggestive of alopecia areata at the perimeter of the ulcer. Hair regrowth and complete healing
of the ulcer was noted at 6 months. On two other occasions patients undergoing temporal vein injections
developed widespread blanching and ecchymosis,
both of which responded to topical nitroglycerin, and
prophylactic SecondSkin™ (Spenco Medical Corp.,
Waco, TX, USA). When symptoms of impending tissue necrosis are observed, Hyaluronidase (Vitrase™
ISTA Pharmaceuticals, Irvine, CA, USA) as outlined
in a recent article 43 could also be employed. It’s possible that blanching which sometimes precedes tissue
necrosis may represent a neurovascular reflex unrelated to the presence of an AV malformation or intraarterial injection. Commentaries on both phenomena
have appeared in the literature (Figures 6-9).41, 42
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Figure 10.—Although reticular veins involving the temples have
been treated successfully, patient in fig. 36 received .25cc of 1.5%
polidocanol. A shallow ulceration followed by temporary hair
loss ensued. Healing was uneventful.
Temporal reticular veins/Published complications
A lawsuit was filed on behalf of 40-year-old
woman who underwent sclerotherapy for superficial
temporal veins, the first treatment proved ineffective
and a second treatment was carried out using 0.25 cc
of 0.25% sotradecol. Several hours later the patient
complained of nausea, and “severe” migraine. Several weeks after treatment, the patient noted first crusting in the scalp, hair loss, and a little later a large
ulceration 6 inches distal from the point of injection.
This hair loss was permanent. Arterial studies carried
out in the area injected revealed complete occlusion
of the anterior branches of the superficial temporal
artery suggesting the presence of an AV malformation (Figures 10,11).35
Facial telangiectasia
Periodically peer reviewed articles and texts discuss the usefulness and comparative advantages and
disadvantages associated with sclerotherapy for facial telangiectasia. In years past before the advent
of light based devices (lasers, intense pulsed light)
facial telangiectasia were routinely treated in this office employing sclerotherapy. Sclerotherapy is not
and never has been the treatment of choice for most
57
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works when other fail. It is particularly useful for
large telangiectasia (0.6 mm-1mm in diameter), and
considerably less painful than lasers that are used
for that purpose. They are also warned that theoretically sclerotherapy for this purpose could cause serious complications but to date they have not been
reported. The possibility of mild scarring related to
the arteriolar nature of the vessels treated and the
risks of treating certain areas (nose and cheeks), are
discussed. Patients are told that those areas must be
treated very carefully. Bruising which occurs uncommonly is discussed as is the possibility of recurrences which are relatively common varying from
person to person. The reasons for special precautions when treating telangiectasia in close proximity
to facial arteries (angular, temporal, supraorbital and
supratrochlear) are also discussed.
Figure 11.—This patient, whose records were part of a malpractice suit reviewed in this office developed necrosis, scarring and
obliteration of the superficial branch of the temporal artery. This
complication occurred following the use of 0.25cc of 0.25% sodium sotradecol sulfate. Hair loss was permanent. Low volumes
and concentrations of sclerosants do not guarantee risk free results in this area.
facial telangiectasia. It was frequently employed in
this office for patients who had not responded to
electrocautery or had developed hypopigmentation
following its use. Currently, facial telangiectasia are
better treated using lasers or intense pulsed light.
Electrocautery, although uncomfortable, can also be
effective in good hands.
Facial telangiectasia unique features
The same circulatory complexities exist for telangiectasia as do for reticular veins; and the same
risks are theoretically possible but the use of lower
concentrations and volumes make this less probable;
finally, facial telangiectasia may be predominantly arteriolar versus venous in character. Treatment might
be expected to result in increased incidence of tissue
necrosis. Telangiectasia located in close proximity to
facial arteries (angular, temporal, supraorbital and supratrochlear) may be risky to treat.
Examination and clinical approach
Patients are told that sclerotherapy is generally
not a substitute for other modalities, but sometimes
58
Technique
Essentially the same approach is taken as is for
facial reticular veins with the difference being that
very small volumes (measured in a few tenths of a
cc per injection site) were employed. Currently only
0.5% or 0.75% POL liquid are used.
Personal observations
Two cases of tissue necrosis occurred one involving the cheeks the other the nose which were preceded by blanching following the use of POL the other
followed the use of HS. Over 100 patients have been
treated. Sclerotherapy is comfortable and extremely
effective for treating large (>0.6mm diameter) telangiectasia and is no longer used for patients with
large numbers of telangiectasia associated with conditions such as rosacea.
Chest reticular veins
Enlargement of chest reticular veins have been
noted to occur in patients who exercise vigorously
and may be related to increased estrogen levels following pregnancy, or the use of oral contraceptives.
Mondor’s disease may also present as a asymptomatic enlargement of a solitary chest vein. Enlargement
of chest veins has also been seen in certain types of
malignancies. Two patients developed sternal reticular and telangiectatic veins following cardiac bypass
surgery (unpublished observation). Anecdotally they
December 2011
DUFFY
are reported to communicate directly with the cardiac circulation and would be risky to treat.
were seen to occur in less than 2% of the patients
treated.
Reticular veins involving the breasts
Complications
All the patients treated in this office developed
enlarged reticular veins following augmentation
mammoplasty. This procedure is regularly carried
out. The veins ranged in size between 1.3-2.5 mm
in diameter.
Two patients developed palpable thrombi which
required incision and drainage. One patient developed mild superficial thrombophlebitis which responded to nonsteriodal anti-inflammatories and incision and drainage. Pigmentation, matting, allergies
and embolic phenomena have not been observed.
Unique features
Breast reticular veins respond to roughly the same
concentrations and techniques applied for reticular
veins on the lower extremities with the exception
of compression which does not seem to be of value
(unpublished personal observation). Then, the possibility of perforating the breast implant envelopes
must be considered, they are often much closer to the
surface than may be expected. Finally, pigmentation
is rare, as is neovascularization.
Evaluation and clinical approach
The rare occurrence of minor complications including transient pigmentation, neovascularization
(matting), (which I have never observed), is discussed. The need for possible repeated treatments is
also pointed out. The extremely rare occurrence of
tissue necrosis,44, 45 which has never been observed
in this office is also detailed.
Technique
In the past 23.4% HS was employed; currently
0.75-1.5% POL liquid preparations are used. Volumes never exceeded 2 cc. Care must be taken to
avoid perforating the implant envelope, which is
sometimes closer to the cutaneous surface than one
might expect. Consideration in selecting sclerosant
concentration involve included size, vessel wall
thickness, and the depth of the treated veins.
Long- and short-term outcomes
All patients were satisfied at two years following
1-3 treatments. Recurrence was noted in one of 10
patients followed for more than 10 years. Treatment
failures measured by no response to three treatments
Vol. 146 - No. 6
Alternative applications
Only one article 36 describes a wide range of both
successful and unsuccessful treatment of both vascular and non-vascular disorders. Sclerotherapy
for these conditions is essentially no more than an
historical footnote. Cherry angiomata, blue rubber
bleb nevus syndrome, and caput medusa have been
treated. Reticular veins and telangiectasia involving
the inguinal folds were treated effectively as were
reticular veins on the dorsa of the feet. Radiation
telangiectasia involving the neck was treated and
was notable for the lack of good results. Small ulcers were seen at almost every treatment site. Telangiectasia involving the torso, shoulders and back
have been treated successfully. Facial venous lakes
have responded unpredictably and sporadically after
laser treatments had failed. Recurrences were common in the larger venous lakes which filled rapidly
after digital compression.46-51 The ablative potential
of hypertonic saline was employed for the treatment
of several punctuate finger tattoos as well as one
larger tattoo involving the shoulder. Although the results were satisfactory in terms of what was available
at the time they were decidedly inferior than those
achieved using lasers.36 Abdominal caput medusa
which followed the use of contraceptives was eradicated using 23.4% hypertonic saline; previous studies indicated that these veins were not essential as a
bypass. Kaposi’s sarcoma partially resolved following sclerotherapy. Three patients with a nodular basal cell carcinoma were treated intratumorally with
23.4% hypertonic saline one day before excisional
biopsy. In all three cases histological evaluation revealed total destruction of the carcinoma). It was
speculated that sclerotherapy might also be useful
for the ablation of tumor induced vasculature. Scle-
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Figure 12.—Grossly abnormal anatomical detail as displayed in this photograph would be an absolute contraindication to sclerotherapy. In this case, the patient informed us that he had been told that he had an AV malformation.
Figure 13.—Pretreatment photograph revealing 3-4mm veins.
Figure 14.—Results 8 years post-treatment with 3% POL solution.
Figure 15.—Edema was a common sequelae following the treatment of all visible hand veins, in this case, the patient viewed the appearance of her hands as a welcoming cosmetic improvement.
Figure 16.—Pretreatment 1cm vein located on the right forearm.
Figure 17.—Appearance one month after treatment with both 3% and 5% polidocanol liquid. Abundant fibrosis produced this elevated,
even less attractive vein than was noted before treatment.
Figure 18.—Following the injection of intralesional triamicinolone acetonide, 2.5mg per cc, a much improved still present vein is
noted.
Figure 19.—0.4 cc of 3% POL solution injected into the mid dermis of the authors arm did not produce tissue necrosis. In the same
study 1% STS of the same volume did cause tissue necrosis.
Figure 20.—In this case 0.25% of POL produced this ulcer. The retromalleolar area is particularly susceptible to this complication
probably on the basis of arteriolar-venous shunting.
rotherapy also proved effective for the treatment of
epidermal cysts (Figures 12-30).36
Pertinent literature
Peer reviewed reports in general are optimistic
about successes following cosmetic sclerotherapy
in all sorts of applications. These reports are often
incorporated with other procedures as part of reju-
60
venation protocols. Serious complications appear
to be rare. Bowes 45 reported excellent results following sclerotherapy for reticular and telangiectatic
veins on the face and hands. Sclerosants employed
consisted of STS, both liquid and foam. One serious complication was reported occurring in a patient
who had been treated for telangiectasia <0.4 mm in
diameter involving the left breast. 0.5 mL of 0.25%
of STS was used. Two weeks after treatment she presented with a 4cm x 6cm full thickness ulceration
December 2011
Figure 21.—This pretreatment photograph reveals the presence of
thin walled varicosities measuring between 0.5-5 mm.
Figure 22.—Three years post-sclerotherapy with 23.4% hypertonic saline. Patient was very pleased.
Figure 23.—Pretreatment photograph 2 mm vein.
Figure 24.—Complete resolution noted six months after treatment with 1% POL solution.
Figure 25.—Pretreatment appearance of 0.4-0.6 mm facial telangiectasia.
Figure 26.—Two weeks post sclerotherapy facial telangiectasia
with o.75% POL
Figure 27.—This pretreatment photograph reveals veins between
2-3 mm in diameter involving the dorsum of the foot.
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Figure 28.—Results observed following three treatments employing 3% POL liquid and Class II support hose.
Figure 29.—This pretreatment photograph does not clearly reveal
the presence of 0.3 mm telangiectasia treated with 0.75% POL
solution.
Figure 30.—Blanching was noted at the time of injection followed
by crusting and a shallow ulceration two weeks post treatment.
requiring eventual removal of the breast implant to
permit closure and subsequent insertion of another
implant. In this same article it was concluded that
varicose and telangiectatic veins on the face, hands
and chest can be treated safely and effectively. For
the treatment of these areas no serious complications
were reported. No ulcerations, thrombophlebitis,
dysasthesia/paresthesias, motor defects, hyperpigmentation, or telangiectatic matting were reported.
They also note that care must taken when injecting
the breast. In a later article 45 in 2011 the authors employed STS foam 0.25% or 0.5% polidocanol foam
for vessels under 1mm. For vessels 1-3mm they
used 0.5% STS foam or 1% POL foam. Schulman
47 reports the treatment of 208 patients with hand
veins. He notes that “Patients have been uniformly
free of any changes in hand function”. He further
notes “There were no serious complications” asserting that “short-term post-sclerotherapy disturbances
were limited to localized edema and bruising and always resolved in a matter of days”. There were no
treatment failures. Butterwick was optimistic about
the treatment of hand veins and reported no serious complications.47 Lay publications are equally
enthusiastic about the potential for this therapy.48-53
Shamban 50 reported good results following a variety of techniques to eliminate hand veins. Alone
among all the authors reporting she noted “Sclerotherapy may leave hemosiderin stain that may last
for several months”, this statement is not backed by
any references. For facial veins, Kersten 52 briefly
quotes techniques employed by another author. He
also asserts there has been “A general reluctance to
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use sclerotherapy for removal of periocular veins
because of fear of ophthalmologic and neurological
complications”.
Conclusions
Cosmetic sclerotherapy has remained an innovative and fascinating aspect of this practice. With the
passage of time, new precisely targeted therapies
have developed which have rendered sclerotherapy
obsolescent in some applications. Over time, I’ve
become a great deal more conservative. Some of the
procedures, particularly caput medusa I would not
even attempt at this point. Very little is being written
about cosmetic sclerotherapy.
I suspect a great deal more is being carried out
than is being reported. Periodically I receive a terrified phone call from someone or an email which
details some almost horrific experience usually involving potential tissue necrosis on the hands. So far
none of these have proved to be very serious. One
last admonition; training for cosmetic procedures
cannot be obtained from lectures. It requires one-onone instructions from an experienced phlebologist.
Riassunto
Applicazioni cosmetiche della scleroterapia
Lo scopo di questo studio è stato di ampliare le prospettive dei medici riguardanti lo scopo, la sicurezza e l’efficacia della scleroterapia nel trattamento delle vene esteticamente poco attraenti e di altre patologie che coinvolgono
una grande varietà di aree anatomiche. L’autore ha redatto
una review in cui vengono presentati i risultati ottenuti
praticando scleroterapia estetica sia per le vene sia per altre applicazioni. Il presente studio coinvolge centinaia di
pazienti trattati con flebologia privata nell’arco di 33 anni
insieme a una breve review della letteratura pertinente.
Poiché il trattamento delle vene dilatate che coinvolgono
il dorso delle mani e il volto è raramente discusso, ma ampiamente praticato, il trattamento stesso viene posto in evidenza. Viene inoltre recensita l’utilità, in gran parte storica,
della scleroterapia per altre applicazioni. Come per le vene
degli arti inferiori, si è verificata una notevole variabilità
sia a livello regionale che da paziente a paziente in termini
di sensibilità agli sclerosanti e di risposta al trattamento.
Tuttavia, la scleroterapia effettuata per scopi estetici ha regolarmente prodotto risultati soddisfacenti in varie applicazioni e per una molteplicità di aree. Complicanze potenzialmente serie e insuccessi nel trattamento sono stati rari
62
in pazienti opportunamente selezionati. La soddisfazione
del paziente, con poche eccezioni, è stata uniformemente
elevata. L’aggiunta della scleroterapia estetica a una prassi
flebologica stabilita può essere un’applicazione premiante
e altamente soddisfacente di questa tecnica versatile. Le
aree da trattare, la tipologia di lesione e la natura estetica di
questa terapia incide su ogni aspetto del trattamento; legale,
etico e procedurale. L’esperienza suggerisce che ogni area
e tipo di lesione trattata mostra segni prevedibili di risposta
e di rischio. La variazione dei risultati del trattamento delle
vene, a seconda dell’area anatomica trattata, può riflettere:
1) processi di adattamento evolutivo che hanno prodotto
vene adatte alle diverse aree; 2) differenze nei modelli di
reclutamento delle citochine e nei processi apoptotici. Va
inoltre notato che le complicanze potenziali riguardano
condizioni di aree specifiche di anastomosi venosa, nervi,
strutture vitali e la complessità dell’architettura arteriosa.
Parole chiave: Scleroterapia - Cosmetica - Vene.
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47. Peterson JD, Goldman MP. Rejuvenation of the aging chest: a review and our experience. Dermatol Surg 2011;37:555-71.
48. Schulman LG, Schulman ML. Cosmetic rejuvenation of the hands
by injection compression sclerotherapy; Scientific Program Hand
Out. Plastic Surgery 2003;25-9.
49. Butterwick KJ. Rejuvenation of the aging hand. Dermatol Clinics
2005;23:515-27.
50. [No authors listed]. Time on your hands. Longevity March 1993.
51. Shamban AT. Combination hand rejuvenation procedures. Aesthetic
Surg J 2009;29:409-15.
52. Kersten RC. Management of cosmetically objectionable periocular
veins. Seminars in plastics surgery 2007;21:54-6.
53. [No authors listed]. Telangiectasias, spider veins, venous lakes and
angiokeratomas. Geriatric dermatology. Clinical Diagnosis and
Practical Therapy; 1989.
54. Weiss RA, Feied CF, Weiss MA. Vein diagnosis and treatment: a
comprehensive approach. New York, NY: McGraw-Hill Inc.; 2001.
63

New insights about delayed allergic
hypersensitivity to corticosteroids
M. BAECK 1, A. GOOSSENS
Corticosteroids are among the most commonly used drugs,
both topically and systemically. Although unexpected and
paradoxical, allergic hypersensitivity to corticosteroids is a
common finding, delayed-type reactions being much more
frequently encountered than the immediate-type ones. With
regard to cross-reactions between corticosteroids, based on
patch-test results and molecular modelling, we were recently able to simplify the previous classification into 3 different
groups, i.e., Group 1: the non-methylated, most often nonhalogenated molecules (Group A, D2 and budesonide), which
produce most of the allergic reactions; Group 2: the halogenated molecules with a C16/C17 cis ketal/diol structure (acetonide
Group B); and Group 3: the halogenated and C16-methylated
molecules (Group C and D1) that only rarely produce allergy.
Key words: Dermatitis, contact – Cross reactions - Hypersensitivity.
C
orticosteroids (CSs), potent anti-inflammatory
and immunomodulator agents used in the treatment of various inflammatory and allergic diseases,
are among the most commonly used drugs, both
topically and systemically. Although unexpected and
paradoxical, allergic hypersensitivity to corticosteroids is a common finding, delayed-type reactions
being much more frequently encountered than the
immediate-type ones. The frequency of contact-allergic reactions to CSs observed ranges from 0.2% to
5% of patch-tested subjects. Long-standing dermatological diseases, because of the application of numerous CSs over a long period and/or unsupervised
self-treatment with low-potency CSs, are determining factors in the development of CS sensitivity.1-4
Corresponding author: A. Goossens, Departement of Dermatology,
University Hospital Leuven Catholic University Hospital, Leuven, Belgium. E-mail: [email protected]
Vol. 147 - No. 1
2
1Departement
of Dermatology,
Saint-Luc University Clinic
Louvain Catholic University, Bruxelles, Belgium
2Departement of Dermatology, University Hospital
Leuven Catholic University Hospital, Leuven, Belgium
The skin: main sensitization and elicitation route
Although sensitization and elicitation mainly occurs via the skin, other routes, among them inhalation
of corticosteroids may exceptionally be involved.
While few patients are sensitized or do present with
allergic reactions when using inhaled corticosteroids
personally,5-7 exposure to them and to budesonide in
particular has been found to be responsible for primary airborne sensitization and/or airborne allergic
contact dermatitis in subjects not themselves treated by aerosols containing this CS, but taking care
of, or living with, patients who used them regularly
because of a chronic respiratory affection.8 RaisonPeron 9 were the first authors to describe connubial or
consort contact dermatitis in the mother of a 3-year
old boy being treated for asthma with an aerosol containing budesonide. Moreover, Pontén 10 and more
recently also Corraza 11 have reported on airborne
contact dermatitis from occupational exposure to
them, notwithstanding the extremely low concentrations involved. This type of exposure should be routinely searched for in patients suspected of airborne
contact dermatitis or with unexplained positive patch
tests to budesonide.
Moreover, also the conjunctival and nasal mucosa,
65
BAECK
NEW INSIGHTS ABOUT DELAYED ALLERGIC HYPERSENSITIVITY TO CORTICOSTEROIDS
the respiratory and the digestive tract may be causal
routes,3, 7, 12, 13 although a primary sensitizing contact
with the surrounding skin cannot be excluded either.
Not many cases of sensitization and/or allergic reactions due to ocular use of CSs have been reported
in the literature. We observed that 6% of patients
with a CS sensitization presented with allergic manifestations via this route,12 particularly to hydrocortisone, the most prescribed ophthalmic CS. Furthermore, besides CSs, multiple positive tests were also
observed for other potential allergens present in such
preparations, such as topical antibiotics, antiseptics,
and even vehicle components.
Clinical presentation: neither
specific nor spectacular
The clinical signs of CS allergy are usually minor
or display a completely atypical chronology. Allergy
to CSs should be suspected in cases of CS-sensitive
diseases that respond poorly or not at all to CS treatment, become worse following the use of CSs, or reoccur rapidly after CS withdrawal.3
Allergic contact dermatitis from CSs may present
as chronic eczema, often with the eruption being
more pronounced at the periphery of the treated zone
(“edge effect”). Moreover, as there may be a long
delay before diagnosis, the clinical presentation can
be dominated by other ‘classical’ side effects such as
cutaneous atrophy, rosacea and perioral or perinasal
dermatitis. In sensitized patients, ocular use of CSs
may result in facial or periocular oedema and/or eczema, conjunctivitis, burning, itching and tearing,12
while inhaled CSs may provoke eczematous eruptions around the orifices (nostrils, nose, lips), with
possible loco-regional extension, as well as mucosal
reactions, such as stomatitis, nasal congestion and
chronic rhinitis. Moreover, bronchospasm and bronchoconstriction as well as systemic reactions have
also been observed.6
Finally, flare-up reactions at previously affected
skin sites and also generalized eruptions following
systemic administration of CSs have been reported.3
The indisputable value of patch testing
The anti-inflammatory properties of corticosteroids may mask the clinical signs of allergy or render
66
them aspecific, thus rendering the skin-test results
difficult to interpret. Testing with corticosteroidallergy markers in the European baseline series 14
is necessary since both budesonide and tixocortol
pivalate detect 89% of the corticosteroid-sensitized
patients.3 However, it is important to test with the
particular corticosteroids used as well.
Patch tests remain the most adequate and effective
method, with ethanol being the vehicle of choice for
most molecules, and with their removal on Day 2
and readings up to 7 days later.15-18 The association
of intradermal tests allows additional allergy cases
to be diagnosed (mainly when ethanolic preparations
of the active principles are not available for skin testing), thereby avoiding false-negative skin-test results.15, 19-23 Compared to patch tests, ID tests seem
easier to read and become positive sooner (at least on
D1 or D2), but later readings such as D7 are, in most
cases, not useful. Local ID reactions are less intense
and shorter. However, there is an important risk of
atrophy, particularly with potent corticosteroids and
when in suspensions, hence this is a contraindication
for routine use. Prick tests are of minor diagnostic
value for diagnosing CSs delayed allergic hypersensitivity, though no side effects were noted.
The central role of halogenation and
C16-methyl substitution and reappraisal
of the ABCD classification
Sensitized patients frequently (85%) test positively to several corticosteroids.3 Although the existence
of cross-reaction phenomena has been demonstrated
by positive skin tests to synthetic corticosteroids to
which a patient could never have been exposed (simply because they were not available at the time), simultaneous or subsequent sensitization can never be
entirely ruled out.24
In 1989, Coopman 25 classified corticosteroids
(CSs) into 4 reacting groups A, B, C and D in function of clinical and structural characteristics. In 1995,
Lepoittevin 26 supported this classification and the
central role of constituents of the D-ring by means
of conformational analysis of the observed crossreactions.
Later on, Matura ,27 observing the particular behaviour of certain constituents of Group D CS esters,
proposed a further subdivision into 2 subgroups, , the
stable D1 and labile D2 esters.
February 2012
BAECK
Table I.—Corticosteroids classification.
GROUP
Characteristics
1
2
3
No C16-methyl substitution
No halogenation (in most cases)
C16/C17 cis ketal diol structure
C16-methyl substitution
Halogenation (in most cases except*) Halogenation (except*)
Budesonide
Cloprednol
Cortisone acetate
Dichlorisone acetate
Difluprednate
Fludrocortisone acetate
Fluorometholone
Fluprednisolone acetate
Hydrocortisone
Hydrocortisone aceponate
Hydrocortisone acetate
Hydrocortisone 17-butyrate
Hydrocortisone 21-butyrate
Hydrocortisone hemisuccinate
Isofluprednone acetate
Mazipredone
Medrysone
Methylprednisolone aceponate
Methylprednisolone acetate
Methylprednisolone hemisuccinate
Prednicarbate
Prednisolone
Prednisolone caproate
Prednisolone pivalate
Prednisolone sodium metasulphobenzoate
Prednisolone succinate
Prednisone
Tixocortol pivalate
Triamcinolone
Amcinonide
Budesonide (R-isomer)¨
Desonide*
Fluchloronide
Flumoxonide
Flunisolide
Fluocinolone acetonide
Fluocinonide
Halcinonide*
Triamcinolone acetonide
Triamcinolone benetonide
Triamcinolone diacetate
Triamcinolone hexacetonide
Indicative structure
Typical members
Alclomethasone dipropionate
Beclomethasone dipropionate
Betamethasone
Betamethasone 17-valerate
Betamethasone dipropionate
Betamethasone sodium phosphate
Clobetasol propionate
Clobetasone butyrate
Cortivazol*
Desoxymethasone
Dexamethasone
Dexamethasone acetate
Dexamethasone sodium phosphate
Diflucortolone valerate
¨ may exceptionally only cross react with the Diflorasone diacetate
acetonides
Flumethasone pivalate
Fluocortin butyl
Fluocortolone
Fluocortolone caprylate
Fluocortolone pivalate
Fluprednidene acetate
Halomethasone
Meprednisone*
Fluticasone propionate
Mometasone furoate
In addition to the C16/C17 substitutions, Wilkinson 28
considered that the A-ring was a second reactive centre
and that halogenation of the CS structure (C6 and/or
C9) was of critical importance in their cross-sensitivity
pattern.
More recent data indicate that a distinction needs
to be made between C16-methylated and non-methylated molecules, the latter of which selectively bind
with arginine to form stable cyclic adducts and induce more often sensitization than the former.29 Indeed, positive patch-test reactions are, with statistical evidence, much more frequently observed to
corticosteroid molecules without C16-methyl substitution in the D ring and not halogenated in most
Vol. 147 - No. 1
cases,Groups A (esterified or not) and D2, than to
those that are halogenated and have a methyl group
at C16, Groups C and D1.30
C16-methyl substitution interferes with the protein
binding and halogenation of the corticosteroid molecules plays an important role in their stabilization,
which seem to protect them from sensitization properties.
Based on patch-test results and molecular modelling of CS, we were recently able to simplify this
classification of CSs into 3 different groups 31 ,
Group 1: the non-methylated, most often non-halogenated molecules (Group A, D2 and budesonide),
which produce most of the allergic reactions; Group
67
BAECK
2: the halogenated molecules with a C16/C17 cis ketal/
diol structure (acetonide Group B); and Group 3: the
halogenated and C16-methylated molecules (Group
C and D1) that only rarely produce allergy (Table I).
This represents a simplification compared to previous classifications.25-27 However, some patients may
also react exclusively to budesonide (R isomer, 32)
along with molecules from the acetonide group. Indeed, budesonide is a particular molecule with its
acetal function being an equal mixture of two isomers (R and S), hence its resemblance to both Group
1 and Group 2 molecules.26, 32
Moreover, two sub-groups of corticosteroidsensitized patients with probably different areas of
immune recognition have been identified: Profile 1
patients, who react to molecules from one unique
group, Group 1 for whom electrostatic fields (molecular charge) seem important; and Profile 2 patients who may react to the entire spectrum of CSs,
Group 1 and Group 2 and/or Group 3 for whom steric fields (molecular structure) are determinant, and
who probably present a global recognition of the CS
skeleton.
For Profile 1 patients, replacement agents can be
chosen within Group 2 and Group 3, since they only
react to Group 1.
For profile 2 patients, a classification, despite being valuable for orienting the search of a replacement molecule, cannot replace systematic, individualized evaluation of their sensitization/tolerance
profile. The use of a calcineurin inhibitor, i.e, topical
tacrolimus or pimecrolimus may also be an option.
Less is known about the classification and crossreactivity pattern of the less common delayed reactions following systemic administration of CSs, although this might be the same as with topical use.33
Riassunto
Nuove acquisizioni sull’ipersensibilità allergica ritardata
verso i corticosteroidi
I corticosteroidi sono tra i farmaci più comunemente
utilizzati sia per via topica sia per via sistemica. Anche se
inattesa e paradossale, l’ipersensibilità allergica ai corticosteroidi è un risultato comune, in quanto reazioni di tipo
ritardato sono molto più frequente di quelle di tipo immediato. Per quanto riguarda le reazioni crociate tra corticosteroidi, in base ai risultati dei patch test e alla modellistica
molecolare, siamo stati recentemente in grado di semplificare la precedente classificazione in tre diversi gruppi
68
Gruppo 1: molecole non metilato, il più delle volte nonalogenate (Gruppo A, D2 e budesonide) che producono la
maggior parte delle reazioni allergiche; Gruppo 2: le molecole alogenate con una struttura C16/C17 cis chetale/diolo
(acetonide Gruppo B); e Gruppo 3: le molecole alogenate
e C16- metilate (Gruppo C e D1) che soltanto raramente
producono reazioni allergiche.
Parole chiave: Dermatite da contatto - Reazioni incrociate - Ipersensibilità.
References
1. Baeck M, Marot L, Tennstedt D, Nicolas JF, Goossens A. Allergic
hypersensitivity to topical and systemic corticosteroids: a review.
Allergy 2009;64:978-94.
2. Lauerma AI, Reitamo S. Allergic reactions to topical and systemic
corticosteroids. Eur J Dermatol 1994;5:354-8.
3. Baeck M, Drieghe J, Chemelle JA, Terreux R, Goossens A. Delayed
hypersensitivity to corticosteroids in a series of 315 patients: clinical data and patch-test results. Contact Dermatitis 2009;61:163-75.
4. Baeck M. Delayed allergic hypersensitivity to corticosteroids: reappraisal of clinical, molecular and immonupathological aspects.
Doctoral thesis, Université Catholique de Louvain, Brussels, University Press; 2011.
5. Isaksson M. Skin reactions to inhaled corticosteroids. Drug Saf
2001;24:369-73.
6. Isaksson M, Bruze M, Hörnblad Y, Svenonius E, Wihl JA. Contact
allergy to corticosteroids in asthma/rhinitis patients. Contact Dermatitis 1999;40:327-8.
7. Baeck M, Pilette C, Drieghe J, Goossens A. Allergic contact dermatitis to inhalation corticosteroids. Eur J Dermatol 2010;20:102-8.
8. Baeck M, Goossens A. Patients with airborne sensitization/contact
dermatitis from budesonide-containing aerosols “by proxy”. Contact Dermatitis 2009;1:1-8.
9. Raison-Peyron N, Co Minh HB, Vidal-Mazuy A, Guilhou JJ, Guillot B. Connubial contact dermatitis to an inhaled corticosteroid.
Ann Dermatol Venereol 2005;132:143-6.
10. Ponten A. Airborne occupational contact dermatitis caused by extremely low concentrations of budesonide. Contact Dermatitis
2006;55:121-4.
11. Corazza M, Baldo F, Osti F, Virgili A. Airborne allergic contact
dermatitis due to budesonide from professional exposure. Contact
Dermatitis 2008;59:318-9.
12. Baeck M, De Potter P, Goossens A. Allergic contact dermatitis
following ocular use of corticosteroids. J Ocul Pharmacol Ther
2011;27:83-92.
13. Malik M, Tobin AM, Shanahan F, O’Morain C, Kirby B, Bourke J.
Steroid allergy in patients with inflammatory bowel disease. Br J
Dermatol 2007;157:967-9.
14. Isakson M, Brandao FM, Bruze M, Goossens A. Recommendation
to include budesonide and tixocortol pivalate in the European standard series. Contact Dermatitis 2000;43:41-63.
15. Soria A, Baeck M, Marot L, Duveiller V, Derouaux AS, Nicolas JF
Patch, prick, or intradermal tests to detect delayed hypersensitivity
to corticosteroids? Contact Dermatitis 2011;64:313-24.
16. Wilkinson SM, Beck MH. Corticosteroid contact hypersensitivity:
what vehicle and concentration? Contact Dermatitis 1996;34:305-8.
17. Isaksson M, Beck MH, Wilkinson SM. Comparative testing with
budesonide in petrolatum and ethanol in a standard series. Contact
18. Isaksson M. Corticosteroid contact allergy--the importance of late
readings and testing with corticosteroids used by the patients. Contact Dermatitis 2007;56:56-7.
February 2012
19. Räsänen l, Hasan T. Allergy to systemic and intralesional corticosteroids. Br J Dermatol 1993;128:407-11.
20. Wilkinson SM, English JS. Patch tests are poor detectors of corticosteroid allergy. Contact Dermatitis 1992;26:67-8.
21. Wilkinson SM, Heagerty AHM, English JSC. A prospective study
into the value of patch and intradermal tests in identifying topical
corticosteroid allergy. Br J Dermatol 1992;127:22-5.
22. Seukeran DC, Wilkinson SM, Beck MH. Patch testing to detect corticosteroid allergy: is it adequate? Contact dermatitis 1997;36:12730.
23. Mimesh S, Pratt M. Allergic contact dermatitis from corticosteroids: reproductibility of patch testing and correlation with intradermal testing. Dermatitis 2006;17:137-42.
24. Isakson M, Bruze M. Corticosteroid cross-reactivity. Contact Dermatitis 2003;49:53-4.
25. Coopman S, Degreef H, Dooms-Goossens A. Identification of
cross-reaction patterns in allergic contact dermatitis from topical
corticosteroids. Br J dermatol 1989;121:27-34.
26. Lepoittevin JP, Drieghe J, Dooms-Goossens A. Studies in patients
with corticosteroid contact allergy: understanding cross-reactivity
among different steroids. Arch Dermatol 1995;131:31-7.
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27. Matura M, Goossens A. Contact allergy to corticosteroids. Allergy
2000;55:698-704.
28. Wilkinson SM. Corticosteroid cross-reactions: an alternative view.
Contact Dermatitis 2000;42:59-63.
29. Debeuckelaere C, Claudel E, Berl V, Lepoittevin J.P. Allergic contact dermatitis to corticosteroids: group A vs. group C, a mechanistic study. Contact Dermatitis 2010;63(Suppl.1):14.
30. Baeck M, Chemelle JA, Rasse C, Terreux R, Goossens A. C16-methylated corticosteroids are less far allergenic than the non-methylated
molecules. Contact Dermatitis 2011;64:305-12.
31. Baeck M, Chemelle JA, Goossens A, Nicolas JF, Terreux R. Corticosteroids cross-reactivity: clinical and molecular modeling tools.
Allergy 2011;66:1367-74.
32. Isaksson M, Bruze M, Lepoittevin JP, Goossens A. Patch testing
with serial dilutions of budesonide, its R and S diastereomers,
and potentially cross-reacting substances. Am J Contact Dermat
2001;12:170-6.
33. Ventura MT, Calogiuri GF, Muratore L, Di Leo E, Buquicchio R,
Ferrannini A Cross-reactivity in cell-mediated and IgE-mediated
hypersensitivity to corticosteroids. Curr Pharm Design 2006;
12:3383-91.
69

ORIGINAL ARTICLES
Atopic dermatitis (AD) management in an Italian pediatric clinic
G. RUGGIERO 1, C. GELMETTI 2, M. C. ADAMO 3, D. BALDESSARRI 3,
R. BONFANTI 3, P. BRERO 3, R. CALZARETTI 3, G. CANDELORI 3, R. DANESI 3,
V. D’AMANTI 3, L. GOLINELLI 3, D. GUTTUSO 3, A. LA VECCHIA DI TOCCO 3,
M. G. SAPIA 3, E. SARRA 3, M. ZINNA 3, M. FERRARA 4, M. RUSSOMANDO 4, G. MELE 5
Aim. Atopic dermatitis (AD) is a common, chronic relapsing inflammatory skin disease characterized by dry skin and
variable pruritus sometimes associated with allergic disease
in other organs as asthma and rhinoconjunctivitis. AD affects
deeply the Quality of Life, thus can be extremely disabling
and may cause psychological problems for both affected children and their families.
Methods. In order to investigate the estimated prevalence
of the disease and the beliefs of the Italian pediatricians, a
group of 437 Italian family pediatricians covering a population of almost 380000 children participated in a study based
on a questionnaire of 38 items.
Results. According to answers of the participants, the incidence of AD has been estimated around 10% of the population and food allergy is believed to be the trigger of the acute
phase of the disease in infants. As a second opinion, dermatologists are consulted more frequently than allergologists.
Conclusion. The use of emollients is advised in general whilst
topical corticosteroids treatment is prescribed only in selected cases; more than 50% of pediatricians do not prescribe
topical calcineurin inhibitors.
Key words: Dermatitis, atopic - Prevalence - Pediatrics - Child.
A
topic Dermatitis (AD) is a widespread common
skin disease with a frequency peak in infants.
Even though the last decades have seen a growth in
the number of important epidemiological surveys,
the study of the incidence of the disease is compli*FIMP = Federazione Italiana Medici Pediatri (Italian Federation of
Paediatricians).
Received on February 18, 2011.
Accepted for publication on December 12, 2011.
Corresponding author: G. Ruggiero, Via G. D’Annunzio 39, 84091
Battipaglia (SA), Italy. E-mail: [email protected].
C. Gelmetti, Clinica Dermatologica, Via Pace 9, 20122 Milan, Italy.
Vol. 147 - No. 1
1Family Pediatrician, National Coordinator
Dermatology Network, Italian Federation of
Pediatricians (FIMP)
2Department of Anesthesia
Intensive Care and Dermatological Sciences
University of Milan IRCCS Cà Granda
Maggiore Policlinico Hospital, Milan, Italy
3Regional Coordinator, Dermatological Network
4Private Pratictioner
5Italian Federation of Pediatricians (FIMP)
Salerno, Italy
cated by the fact that AD is typically characterized
by alternate aggravation and remission periods. Consequently lifetime incidence measures are to be preferred over incidental or punctual measures. From a
general analysis of the recent literature, in western
countries, lifetime AD incidence is around 20% in
patients from 0 to 14 years of age, with a slight predominance in females.1-3
The ISAAC study 1, 2 showed that, over a oneyear period, AD incidence varied from less that 2%
in Iran and Albania to over 16% in Japan, Sweden,
and urban areas of the African Continent. In general,
the highest values were found in Northern Europe,
Australia, and Japan, whereas the lowest values were
found in Eastern Europe and Asia. Furthermore, in
majority of the considered countries, the highest values were found in urban as opposed to rural areas.
Few epidemiological studies were available in Italy.
The ISAAC study considered children from 14 different Italian cities. Out of a total of 20815 patients ranging from 6 to 7 years of age, the periodic incidence (1
year) was estimated at 5.8%, where acute AD repre-
71
RUGGIERO
Atopic dermatitis management in an Italian pediatric clinic
sented 0.1% of the total. Within the same study, incidence in a sample group of 26477 patients aged from
13 to 14 years, was 5,7% and acute AD was around
0.4% of the children.
In a second study,3 estimated DA incidence in a
sample group of 1369 nine-year old children in 7
Italian cities was 5.8% (95% CI=45-7.1%) with values of 5.7% (95% CI=4.0-7.3%) in males and 6.0%
(95% CI=4.1-7.8%) in females. The findings from
these two studies are comparable and indicate that
in Italy about one child on 20 children suffers from
AD, but only 1-4 in 1,000 patients present acute AD.
A third Italian study 4 aimed to verify the incidence of AD in 1402 children in a pre-school age
(3-5 year old) cohort. For this purpose, a group of
day nursery children was evaluated by mean of the
ISAAC questionnaire whilst the atopic status was
evaluated through the use of prick tests. According
to the researchers, the incidence of AD was 15.4%.
In a last study, carried out in 2009,5 3179 children
(1618 males and 1516 females) were examined and
AD was diagnosed in 224 cases (7.0%). In addition the
study revealed the high frequency of the association
with bronchial asthma (RR=4.5-CI=95% CI), psoriasis (RR 5.5-95% CI=3.0-10.1) and vitiligo (RR 16.195% CI=6.5-39.5).
In 2008 a group of the Italian pediatricians belonging to the FIMP Dermatological Network “photographed” the AD situation from a Family Pediatrician’s point of view. For this objective, an ad-hoc
scientific commission (Prof. C. Gelmetti, Dr. R.
Bonfanti, Dr. M. Ferrara, Dr. M. Russomando, Dr. G.
Ruggiero) elaborated a questionnaire aimed to verify
the perception and the management of AD in the outpatient’s clinics in Italy. The results of this study are
presented and discussed in this article.
Materials and methods
The questionnaire (Table I) was composed of a series of multiple choice questions. One of the authors
(GR) gathered and statistically elaborated the resulting data (software EPI INFO CDC vers.55.1); the
second author (CG) wrote the present study.
The questionnaire was anonymous, filled out by
the doctor on the spot during National or local conferences and without any specific preparation or the help
of educational material (traditional or electronic).
Data were gathered by the Regional Coordinators
72
Table I.—Regions involved.
REGION
Frequency
%
88
40
10
10
16
34
37
10
34
14
50
38
41
11
2
2
20.1%
9.2%
2.3%
2.3%
3.7%
7.8%
8.5%
2.3%
7.8%
3.2%
11.4%
8.7%
9.4%
2.5%
0.5%
0.5%
437
100.0%
1: CAMPANIA
2: TRENTINO
3: CALABRIA
4: SICILIA
5: MOLISE
6: ABRUZZO
7: TOSCANA
8: VALLE D’AOSTA
9: PUGLIA
10: UMBRIA
11: PIEMONTE
12: LOMBARDIA
13: LIGURIA
14: SARDEGNA
15: VENETO
16: BASILICATA
Total
of the FIMP Dermatological Network and hence sent
to the National Coordinator (GR). This method was
chosen to assess what the family pediatricians know
and do, as well to test the awareness of the scientific
knowledge regarding AD and the perception of this
disease within the family pediatrician’s environment.
A total of 437 family pediatricians (FP) took part
in this study out of a total of 6011 FPs registered
members of FIMP (7,27%). FIMP’s registered FP’s
represent 88% of FPs in Italy. The FP’s that participated in the study came from 16 out of the 20 Italian
Regions (Figure 1).
According to the average number of patients per
doctor (i.e. around 864 children per pediatrician), the
total pediatric population can be calculated around
380000 patients. A percentage of 85.1% of the participating FP’s had one or more decades of professional activity (respectively: 43.9% had 10-20 years
and 41.2% had 20-30 years of experience after board
certification).
Discussion
The rapid increase of AD incidence observed over
the last 30-50 years and the consequent considerable
social impact of the disease in terms of are two arguments that can catch pediatricians’ attention. Moreover, the association of AD with other diseases such
February 2012
Figure 1.
as bronchial asthma and allergic rhino-conjunctivitis
together with the devastating impact of AD on the
quality of life of patients and their families are the
main reasons that urged the medical community to
take a closer interest in this problem.
In 2007, during its National Congress, the FIMP
Board decided to create a National network of pediatricians interested in dermatology. Once the group
had been established including pediatricians from all
of the Italian Regions, one of the first themes tackled by the group was AD. In fact, FPs are the first
to observe AD and, as such, should be aware of the
disease and how to correctly manage it. This study,
differently from other studies albeit carried out with
scientific criteria, wished to verify firstly the perception that FP’s had of AD and, secondly, the strategy
of management in their daily practice.
The results were undeniably interesting especially
because they reflect the opinion of a significant percentage of Italian FPs who are in charge of little less
than 400000 children.
Vol. 147 - No. 1
RUGGIERO
From the data obtained, the following should be
highlighted:
1. The percentage of patients affected by AD is
estimated to be around 10%; AD is considered mainly (87.8% of FP’s) triggered by environmental and
genetic factors.
2. About half of the FP’s does not know the classic (i.e., Hanifin and Rajka and UK working group)
diagnostic criteria of AD (48.5%). AD diagnostic criteria published by Bonifazi are the most well known.
3. The majority (68%) of the AD patients seen by
FPs are affected by a mild form of AD.
4. More than half (57.9%) of FPs know SCORAD
index but only 34% of those who know it use SCORAD in their practice.
5. The greater part of FP’s believe that severe
AD in babies is mainly triggered by food allergens
(22.2%), environmental allergens (29.8%), environmental factors with non allergic mechanisms (23%).
6. Laboratory work-up is carried out in cases in
which allergies are suspected (66.5% of FPs) even
if 8,8% of FPs never carry out additional screening
and 8.3% of FPs always advice supplementary tests
regardless of symptoms. Prick tests and specific serum IgE are the most prescribed tests both in first
and second instance; 65.2% of FPs prescribe only
one test in the first instance (68.5% in the second).
7. Specialist advice is requested only in selected
cases. The dermatologist is requested far more than
the allergist.
8. The vast majority (94.1%) of FPs give hygienic
and sanitary advice and 86.2% give advice on how to
apply topical products; only 20.4% give a personal
demonstration of the methods of application.
9. The vast majority (85.8%) of FPs advises the
use of emollients and prescribes topical corticosteroids only for selected cases (83.9%) of moderate
and/or severe forms and only for a short term.
10. Topical calcineurin inhibitors (tacrolimus and
pimecrolimus) are used for AD forms that steroid resistant, however most (56.7%) FPs do not use them.
11. Oral antihistamines are only used in selected
cases (75.6%).
12. In cases of impetigination, the preferred antibiotics are oral amoxiclavulanate or macrolides and,
topical fusidic acid, mupirocin and gentamicine.
13. In breast feeding babies suffering from AD it
is advised to continue breast feeding whilst for babies using artificial milk, in selected cases, special
milk is advised, especially hydrolyzed cow’s milk.
73
RUGGIERO
14. Complementary and alternative medicine is
never advised by most FPs (77.9%). When those
therapies are advised, homeopathy and herbal therapy are preferred (19.5%).
15. Only 27% of FPs believes they have a good
level of AD awareness. Ninety-six% believe that an
in-depth course on AD would be useful.
Almost (49.99%) half of the FPs who participated
in the study came from the Northern Italian Regions
(218/437), 14.64% came from the Central Regions
(64/437), and 35.46% from the Southern Regions
and from the Big Islands (Sicily and Sardinia).
Some considerations can be made: the first is that
the evaluation of AD incidence in this big sample is
in accordance with the scientific data available before the beginning study,1-4 and also with the date
that published in the meantime.5 Curiously, half of
the FPs is not aware of the classic AD diagnostic criteria and that, amongst those they are aware, the most
well known are those described by Bonifazi (Professor Ernesto Bonifazi is, among the Italian Pediatric
Dermatologists, one of most respected; Bonifazi’ s
criteria are less used internationally).
The opinion concerning the etiopathogenesis of AD
which contemporaneously focuses both genetic and
environmental factors is also coherent with the general
opinion of the experts. The opinion that severe AD in
babies is mainly triggered by food allergens is still a
matter of discussion, especially after the data published
in the recent literature. It is encouraging to see that
laboratory set-up is usually carried out only in cases of
suspected allergy even though there is an 8.3% of FPs
that always asks for additional tests. It is also reassuring
to note that specialist consultation is requested only in
selected cases and that the external specialist called by
the FPs is, more frequently, the dermatologist. This has
recently become obvious as the first objective of AD
treatment is correct skin care.
The FPs usually advise emollients and prescribes
topical corticosteroids only in selected cases, however more than half of the FPs does not yet use topical calcineurin inhibitors.
Conclusions
In accordance with scientific literature, it is a common opinion (70.1%) that babies with AD should
continue to be breast-fed; when maternal milk is not
available, FPs advise a special milk only in selected
cases; 67.4% of FPs make only one therapeutic choice
74
between special milks: hydrolyzed milk (37.6%) is
the most common, whilst milks with free amino acids are less frequently used (1.8%). Other “special”
milks (e.g. soya =8% and HA [HypoAntigenic] milk
=8.8%) are ALSO prescribed but in a limited number
of cases. Two foods therapeutic choices are advised
in 25.56% of cases, while 9.52% of FPs prefer a
wider therapeutic range. The caution towards alternative medicine is also reassuring. Lastly, the FPs own
opinion regarding their AD awareness (judged as insufficient by ¾ of the participants) perfectly mirrors
the consideration regarding the need of more updated
informations on this disease which is global and truly
pervasive on children and their families.
The FP is, indeed, the first observer of AD who
has the task of adopting a correct management. In
addition, the FP has the obligation of being informed
and updated on this disease. The data collected by
this study encourage us to continue the work of
diffusion of the informations on the domestic area
throughout meetings giving the correct indications
on the etiopathogenesis, diagnosis, and cure of AD
which, at present, represents the first pediatric cause
for a dermatological visit.
Riassunto
Trattamento della Dermatite Atopica in una popolazione
pediatrica italiana
Obiettivo. La Dermatite Atopica (DA) è una malattia infiammatoria cronica della pelle caratterizzata da cute secca
e prurito intenso che può essere invalidante e causare problemi psicologici per i bambini e le loro famiglie.
Metodi. A questo riguardo 437 pediatri di famiglia
iscritti alla Federazione Italiana Medici Pediatri (FIMP)
che seguono una popolazione di circa 380000 bambini
hanno partecipato ad uno studio basato su un questionario.
Risultati. La prevalenza della malattia è stata stimata intorno al 10% della popolazione e l’allergia ai cibi è ritenuta
la causa di scatenamento delle fasi acute in età infantile. Il
dermatologo è consultato più spesso dell’allergologo.
Conclusione. Gli emollienti sono consigliati comunemente mentre i corticosteroidi topici solo in casi selezionati; mentre più della metà dei pediatri non prescrive gli
inibitori topici della calcineurina.
Parole chiave: Dermatite atopica - Prevalenza - Pediatria Bambini.
References
1. Williams HC, Robertson C, Stewart A, Aït-Khaled N, Anabwani G,
Anderson R et al. Worldwide variations in the prevalence of symp-
February 2012
toms of atopic eczema in the international study of asthma and allergies in childhood. J Allergy Clin Immunol 1999;103:125-38.
2. Girolomoni G, Abeni D, Masini C, Sera F, Ayala F, Belloni-Fortina
A et al. The epidemiology of atopic dermatitis in Italian schoolchildren. Allergy 2003;58:420-5.
3. Asher M, Montefort S, Björkstén B, Lai CK, Strachan DP, Weiland
SK et al. Worldwide time trends in the prevalence of symptoms
of asthma, allergic rhinoconjunctivitis, and eczema in childhood:
ISAAC Phase One and Three repeat multicountry cross-sectional
surveys. Lancet 2006;368:733-43.
4. Peroni DG, Piacentini GL, Bodini A, Rigotti E, Pigozzi R, Boner
AL. Prevalence and risk factors for atopic dermatitis in preschool
children. Br J Dermatol 2008;158:539-43.
5. Naldi L, Parazzini F, Gallus S; GISED Study Centres. Prevalence
of atopic dermatitis in Italian schoolchildren: factors affecting its
variation. Acta Derm Venereol 2009;89:122-5.
RUGGIERO
6. Varjonen E, Kalimo K, Lammintausta K, Terho P. Prevalence of
atopic disorders among adolescents in Turku, Finland. Allergy
1992;47:243-8.
7. Dirven-Meijer PC, Glazenburg EJ, Mulder PG, Oranje AP. [Atopic
eczema in children: a prospective study into prevalence and severity]. Ned Tijdschr Geneeskd. 2009;153:B404.
8. Kremmyda LS, Vlachava M, Noakes PS et al. Atopy Ris in Infants
and Children in Relation to Early Exposure to Fish, Oily Fish, or
Long-Chain Omega-3 Fatty Acids: A Systematic Review. Clin Rev
Allergy Immunol 2009 Dec 9.
9. Horwitz AA, Hossain J, Yousef E. Correlates of outcome for atopic
dermatitis. Ann Allergy Asthma Immunol 2009;103:146-51.
10. Park YH, Kim KW, Choi BS, Jee HM, Sohn MH, Kim KE. Relationship between mode of delivery in childbirth and prevalence of
allergic diseases in Korean children. Allergy Asthma Immunol Res
2010;2:28-33.
APPENDIX
1) What percentage of your present patients suffer from AD?
1. 1-5%
2. 5-10%
3. 10-20%
4. >20%
AD %
2) What percentage of your patients aged up to 1 year suffer from AD?
1. 1-5%
2. 5-10%
3. 10-20%
4. >20%
>3 YRS
3) What percentage of your patients aged from 1 to 3 years suffer from AD?
1. 1-5%
2. 5-10%
3. 10-20%
4. >20%
1-3 YRS
4) What percentage of your patients of 3 years of age suffers from AD?
1. 1-5%
2. 5-10%
3. 10-20%
4. >20%
AD =3YRS
5) From an etiopathogenic point of view. AD depends on
1. Environmental factors
2. Genetic factors
3. Interaction between environmental and genetic factors
4. Other:
FACTOR
Vol. 147 - No. 1
1
2
3
4
Total
1
2
3
4
Total
1
2
3
4
Total
1
2
3
4
Total
1
2
3
4
Total
Frequency
213
159
53
8
433
Frequency
238
122
18
6
384
Frequency
216
139
65
10
430
Frequency
300
53
11
4
368
Frequency
14
29
345
5
393
%
49.2%
36.7%
12.2%
1.8%
100.0%
%
62,0%
31,8%
4,7%
1,6%
100,0%
%
50,2%
32,3%
15,1%
2,3%
100,0%
%
81,5%
14,4%
3,0%
1,1%
100,0%
%
3,6%
7,4%
87,8%
1,3%
100,0%
75
RUGGIERO
6) Which of these diagnostic criteria do you know? (multiple answer)
1. Williams UK Working Party
2. Bonifazi
3. American Academy of Dermatology
4. Hanifin and Rajka
5. None of these
CRITERIA
1
2
3
4
5
13
23
24
34
124
234
1234
Total
7) Amongst your AD patients. indicate the percentage of mild.
moderate and severe forms
1. Mild: %
2. Moderate: %
3. Severe: %
Total: 100%
Severity
Frequency
8
74
39
27
182
2
15
16
5
1
4
2
375
%
2.1%
19.7%
10.4%
7.2%
48.5%
0.5%
4.0%
4.3%
1.3%
0.3%
1.1%
0.5%
100.0%
Observed
%
Mild
Medium
Severe
404
394
361
68,9%
23,3%
7,8%
8) Do you know SCORAD index
1. Yes:
2. No:
SCORAD
Observed
%
220
160
380
57,9%
42,1%
100,00%
9) If you do. do you use it in daily practice?
1. yes
2. No
SCO USE
10) In your opinion. moderate to severe AD in children is mainly
triggered by:
1. Food allergens
2. Environmental allergens
3. Environmental factors with non allergic mechanism
4. Local bacterial infection
5. Only genetic predisposition
BABY
TRIGGER
11) In your opinion. AD in children aged from 2 to 3 years is mainly
triggered by:
1. Food allergens
2. Environmental allergens
3. Environmental factors with non allergic mechanism
4. Local bacterial infection
5. Only genetic predisposition
2-3YRS
TRIGGER
76
1
2
Total
1
2
Total
1
2
3
4
5
Total
1
2
3
4
5
Total
Frequency
86
164
250
Frequency
167
49
57
15
125
413
%
34.4%
65.6%
100.0%
%
40,4%
11,9%
13,8%
3,6%
30,3%
100,0%
Frequency
%
88
118
91
17
82
396
22.2%
29.8%
23.0%
4.3%
20.7%
100.0%
February 2012
12) Do you carry out laboratory set-up?
1. never
2. always
3. in cases of suspected allergy
4. in cases of other associated symptoms
13) Which are the first tests you advise? (multiple answer)
1. immunocap
2. specific IgE
3. skin tests (Prick test)
4. provocation test
5. patch test
6. total IgE
7. Other
14) Which is the second test you advise? (multiple answer)
1. immunocap
2. specific IgE
3. skin tests (Prick test)
4. provocation test
5. patch test
6. total IgE
7. Other
15) Do you ask for a Specialist advice?
1. never
2. always
3. only in selected cases
16) Which Specialist do you consult most often?
1. dermatologist
2. allergist
3. psychologist
4. Other
Vol. 147 - No. 1
RUGGIERO
EXAMS
1
2
3
4
Total
1st EXAM
Frequency
37
35
280
69
421
Frequency
%
8.8%
8.3%
66.5
16.45
100.0%
%
1
2
3
4
5
6
7
Total
15
37
175
8
4
23
9
271
5.5%
13.7%
64.6%
3.0%
1.5%
8.5%
3.3%
100.0%
1 exam
2 exams
3 exams
4 + exams
Total
271
106
32
7
416
65.2 %
25.5%
7.7 %
1.6 %
2nd EXAM
Frequency
%
1
2
3
4
5
6
7
Total
17
101
53
34
15
7
5
232
7.3%
43.5%
22.8%
14.7%
6.5%
3.0%
2.2%
100.0%
1 exam
2 exams
3 exams
4 + exams
Total
232
93
12
2
416
68.5 %
27.4%
3.5 %
0.6 %
SPEC. CONS.
1
2
3
Total
SPECIAL
1
2
3
4
Total
Frequency
17
37
373
427
Frequency
210
193
7
2
412
%
4.0%
8.7%
87.4%
100.0%
%
51.0%
46.8%
1.7%
0.5%
100.0%
77
RUGGIERO
17) If you consult more than one Specialist. please indicate which
(1 indicates most often and 4 indicates least often)
1. dermatologist
2. allergist
3. psychologist
4. Other
SPEC. TYPE Frequency
1
2
3
4
12
13
14
21
18) Do you give sanitary and hygiene advices (cleaning. clothing. etc)?
1. never
2. always
ADVICE
19) Do you advise on application procedures of topic products for
cosmetic or therapeutic use?
1. never
2. always
TOP ADV
20) Do you demonstrate. personally or with the help of audio visual
equipment. how to apply topical products?
1. never
2. always
DEMO
21) Do you suggest the use of moisturizing creams / emollients?
1. never
2. always
SUGGEST
22) Do you prescribe topical corticosteroids?
1. never
2. always
TOP COR
23) When do you prescribe topical corticosteroids?
1. mild forms
2. moderate forms
3. severe forms
4. never
CORT USE
78
1
2
3
Total
1
2
3
Total
1
2
3
Total
1
2
3
Total
1
2
3
Total
1
2
3
4
Total
41
29
4
3
59
6
13
45
%
Cumulative
%
13.5%
9.6%
1.3%
1.0%
19.5%
2.0%
4.3%
14.9%
13.5%
23.1%
24.4%
25.4%
44.9%
46.9%
51.2%
66.0%
Frequency
6
397
19
422
Frequency
8
368
51
427
Frequency
178
78
126
382
Frequency
8
362
52
422
Frequency
9
60
359
428
Frequency
16
137
225
5
383
%
1.4%
94.1%
4.5%
100.0%
%
1.9%
86.2%
11.9%
100.0%
%
46.6%
20.4%
33.0%
100.0%
%
1.9%
85.8%
12.3%
100.0%
%
2.1%
14.0%
83.9%
100.0%
%
4.2%
35.8%
58.7%
1.3%
100.0%
February 2012
24) For how long do you advise use of topical corticosteroids?
1. 1-2 days
2. 3-4 days
3. 5 -8 days
4. until symptoms disappear
RUGGIERO
COR DUR
1
2
3
4
Total
25) Do you use topical calcineurin inhibitors (tacrolimus and
pimecrolimus)?
1. never
2. always
CALC INHIB
26) If you do. for which forms do you use tacrolimus?
1. mild forms
2. moderate forms
3. severe forms
4. those that do not respond to topical corticosteroids
TACRO USE
27) If you do. for which forms do you use pimecrolimus?
1. mild forms
2. moderate forms
3. severe forms
4. those that do not respond to topical corticosteroids
PRIMECRO
28) Do you use oral antihistamines in general?
1. never
2. always
ANTIHIST
29) For the impetiginzed form of AD. which oral antibiotic do you use?
1. Amoxicillin
2. Amoxiclavulanate
3. Macrolides
4. Cephalosporines
5. Other
IMPETIG.
30) For the impetiginzed form of AD. which topical antibiotic do you use?
1. Mupirocin
2. Fusidic Acid
3. Macrolides
4. Gentamicin
5. Other
IMPETIG.
Vol. 147 - No. 1
1
2
3
Total
1
2
3
4
Total
1
2
3
4
Total
1
2
3
Total
1
2
3
4
5
Total
1
2
3
4
5
Total
Frequency
13
120
135
154
422
Frequency
237
7
174
418
Frequency
1
18
55
101
175
Frequency
4
24
58
78
164
Frequency
32
73
325
430
Frequency
38
166
164
10
3
381
Frequency
140
87
48
93
5
373
%
3.1%
28.4%
32.0%
36.5%
100.0%
%
56.7%
1.7%
41.6%
100.0%
%
0.6%
10.4%
31.2%
57.8%
100.0%
%
2.4%
14.6%
35.4%
47.6%
100.0%
%
7.4%
17.0%
75.6%
100.0%
%
10.0%
43.6%
43.0%
2.6%
0.8%
100.0%
%
37.5%
23.3%
12.9%
24.9%
1.3%
100.0%
79
RUGGIERO
31) In a breast feeding baby suffering from AD. you:
1. advise to continue breast feeding
2. suggest special milk
3. suggest a hypoallergenic diet to the mother
4. Other
BREAST
1
2
3
4
Total
32) In a formula feeding baby suffering from AD. you:
1. continue with the same formula
2. suggest special milk
3. advise special milk only in selected cases
4. Other
FORM
33) If you use advice special milk. which one do you suggest
(multiple answer)
1. H.A. (HypoAntigenic milk)
2. strong hydrolyzed casein milk
3. strong hydrolyzed serum protein milk
4. soya milk
5. hydrolyzed soya milk
6) hydrolyzed rice milk
7) amino acid synthesis milk
8) goat milk
9) Other
MILK
34) Do your AD patients use alternative medicine (homeopathy.
herbal medicine. etc)?
1. never
2. always
HOMEOP
35) Do you personally suggest alternative therapy?
1. never
2. always
ALTERNAT
36) If you suggest alternative medicine. which do you prefer?
1. Homeopathy
2. Herbal medicine
3. Cyto test or DRIA based diet
4. Other
TYPE
80
1
2
3
4
Total
1
2
3
4
5
6
7
8
Sub total
remaining
Total
1
2
3
Total
1
2
3
Total
1
2
3
4
Total
Frequency
%
302
14
112
3
431
70.1%
3.2%
26.0%
0.7%
100.0%
Frequency
%
63
72
289
5
429
Frequency
35
60
90
32
3
17
7
1
245
154
399
Frequency
215
10
189
414
Frequency
328
11
82
421
Frequency
61
51
9
6
127
14.7%
16.8%
67.4%
1.2%
100.0%
%
14.3%
24.5%
36.7%
13.1%
1.2%
6.9%
2.9%
0.4%
61.4%
38.6%
100.0%
%
51.9%
2.4%
45.7%
100.0%
%
77.9%
2.6%
19.5%
100.0%
%
48.0%
40.2%
7.1%
4.7%
100.0%
February 2012
37) Do you believe your AD awareness to be:
1. scarce
2. sufficient
3. good
4. very good
38) Do you think an in-depth course on AD would be useful?
1. yes
2. no
Vol. 147 - No. 1
RUGGIERO
DACONO
1
2
3
4
Total
COURSE
1
2
Total
Frequency
57
253
116
4
430
Frequency
404
17
421
%
13.3%
58.8%
27.0%
0.9%
100.0%
%
96.0%
4.0%
100.0%
81

Dermatology Life Quality Index score in vitiligo
patients: a pilot study among young Italian males
V. INGORDO 1, S. CAZZANIGA 4, C. GENTILE 2, S. S. IANNAZZONE 3, F. CUSANO 3, L. NALDI
Aim. A negative impact on vitiligo patients in terms of quality
of life (QoL) has been suggested. The aim of this report was to
study the QoL in a sample of Italian vitiligo patients by using
the Dermatology Life Quality Index (DLQI) questionnaire.
Methods. A sample of forty seven vitiligo subjects, identified
among 34,740 potential conscripts resident in southern Italy
underwent the Italian version of the DLQI questionnaire.
Results. The median total DLQI score was 1 (IQR: 2; mean:
1.82). In univariate analysis, DLQI total score was significantly influenced by the clinical course of vitiligo, disease
extension over the body, and location on face and/or hands.
Multivariate analysis using logistic stepwise regression
showed that only the localization on the hands and on the
face influenced significantly the mean DLQI.
Conclusion. Our study conducted on a random sample of individuals affected by vitiligo selected from the general young
male population in Italy, does not document a large impact of
vitiligo on QoL. However, variations exist and the location of
lesions on the face and/or hands may impact on QoL. Population-based studies are not affected by selection biases connected with seeking medical care and should be more widely
performed.
Key words: Vitiligo - Quality of life - Skin diseases.
V
itiligo is an acquired disorder of pigmentation
affecting 0.1-8.8% of the world’s population,1-5
characterized by the development of white patches
on the skin, often with a typical symmetrical distribution and progressive extension. Although vitiligo
does not cause direct physical impairment, it can
produce an important psychosocial burden.6, 7 PaConflicts of interest.—None.
Corresponding author: V. Ingordo, MD, via Blandamura 31/c, 74100
Taranto, Italy. E-mail: [email protected]
Vol. 147 - No. 1
4
1Department
of Italian Navy Health, Taranto, Italy
Unit, Recruitment and Drilling Centre of the
Italian Navy, Taranto, Italy
3Department of Dermatology, “G. Rummo” Hospital,
Benevento, Italy
4Centro Studi GISED, Research Foundation
Ospedale Maggiore, Bergamo, Italy
2Medical
tients with vitiligo suffer from poor body image, low
self-esteem and experience a high level of disability
from their skin disease.8, 9 Many vitiligo patients feel
distressed and stigmatized by their condition, especially in relation to social activities.10 Exposing the
body causes anxiety and embarrassment, which in
more intimate encounters may have a negative effect
on sexual relationships.11 In other words, there appear to be an impact of vitiligo on the overall patient
quality of life (QoL).12
The aim of this report was to study QoL in a sample of Italian young vitiligo patients by using the Dermatology Life Quality Index (DLQI) questionnaire,
which has been successfully employed for the same
purpose on subjects with vitiligo in other countries.8,
12-19 The DLQI questionnaire is designed for use in
adults (i.e., patients over 16). It is self-explanatory
and can be simply handed to the patients without
the need for detailed explanations. The questions in
DLQI are classified into 6 heading items: symptoms
and feelings (questions 1-2), daily activities (questions 3-4), leisure (questions 5-6), and personal relationships (questions 8-9) each item with a maximum
score of 6; work and school (question 7), and treatment (question 10) each item with a maximum score
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Dermatology Life Quality Index Score in vitiligo patients
of 3 (Table I). The DLQI is calculated by summing
the score of each question resulting in a maximum
of 30 and a minimum of 0. The higher the score, the
more QoL is impaired.20 The DLQI questionnaire
has been translated in 55 languages and extensively
validated.21 Its use in vitiligo patients has been successfully compared with several scales designed to
measure self-esteem (Rosenberg’s scale), perceived
stigma (an adaptation of Ginsburg and Link’s psoriasis stigma questionnaire) and personal distress (12item version of GHQ) 8 and with scales designed to
evaluate the psychiatric morbidity (Montgomery and
Asberg Depression Rating Scale, Hamilton Anxiety
Appreciation Scale).18
Patients, materials and methods
Until December 2004, Italian Armed Forces were
based mainly on the compulsory national service.
The potential conscripts resident in the coastal regions of southern Italy, enlisted for the service in
Italian Navy, were called at the age of 18 to the
Draft’s Council Medical Unit of the Italian Navy in
Taranto to evaluate their psycho-physical fitness to
recruitment. They underwent a general clinical examination, with a complete clinical examination of
the entire skin surface, blood test and urinalysis, cardiologic, ophthalmologic, otorhynolaryngologic examination and psychologic evaluation with psychometric tests. Medical Officers-general practitioners
of the Medical Unit referred to Italian Navy Hospital
subjects showing particular diseases and who need
to be seen by other specialists. All the young men
consecutively visited can be considered a representative sample of the general population of same age
and sex living in the coastal southern Italy. From
January 1998 to April 2004 a dermo-epidemiologic
project, named EpiEnlist (EPIdemiology, in ENLISTed Men) project, was conducted by the Department of Dermatology of Italian Navy Hospital under
the auspices of the Italian Group for Epidemiological Research in Dermatology (GISED).
All the subjects showing skin lesions evocative
of neurofibromatosis (NF), congenital melanocytic
nevus (CMN), Becker nevus (BN) and vitiligo were
referred by Medical Officers-general practitioners
of the Draft’s Council Medical Unit to the Department of Dermatology of Italian Navy Hospital for
confirming the diagnosis and recording the data. The
84
main results of the entire project have been published
by us in another work.5 With regard to diagnosis of
vitiligo, all the individuals who showed some area
of hypopigmentation were referred to Department
of Dermatology, where the diagnosis was stated on
the basis of medical history and clinical appearance
(i.e., achromic areas of the skin with sharp outline).
In doubtful cases, examination by Wood’s lamp was
performed. The subjects provided also their familial
history and the information concerning the previous
therapies and the clinical course (progression, regression, stable) of the disease. The main epidemiological data of this sample have been published by us
in another work.22 From October 2001 to April 2004,
60 patients with vitiligo on 34740 subjects were observed, obtaining a prevalence of 0.17% (95% CI:
0.13-0.22). Generalized (53.3%), focal (41.7%) and
segmental (5%) vitiligo were the observed clinical
forms. No cases of acro-facial and universal vitiligo
were recorded. The disease involved a limited area
of the skin in most cases: in 80% of subjects only
≤5% of the total body surface was affected. Eighteen
subjects (30%) reported a familiarity of the disease.
Out of these people, a random sample of 47 people
were proposed to fill in the Italian version of the
DLQI questionnaire (kind permission was obtained
by professor A.Y. Finlay, University of Wales College of Medicine, Cardiff, UK).
Statistical analysis
Continuous variables are presented as means
with standard deviations and categorical variables
as numbers with percentages and 95% confidence
interval. The variables included: age, duration of the
disease, age of onset of the disease, clinical course
of the disease, extent of affected skin, special sites
involved (face, hands and genitalia). DLQI scores
were both presented as medians with interquartile
ranges and means with standard deviations. Univariate analysis was used to assess differences among
demographical and clinical variables for total DLQI
score and scores of individual DLQI components.
For comparison purpose, continuous variables were
categorized using their median or meaningful clinical values (extent of affected skin) as cut-off points.
Mann-Whitney U-test was employed to test differences in dichotomous variables, while KruskalWallis test, followed by Tukey-Kramer post-hoc
comparison, was used for multiple categorical vari-
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Table I.—DLQI questionnaire.
Heading items
Questions
1. Symptoms and
feelings
Q1. Over the last week, how itchy, sore, painful or stinging has your
skin been?
Q2. Over the last week, how embarrassed or self conscious have you
been because of your skin?
2. Daily activities
Q3. Over the last week, how much has your skin interfered with you
going shopping or looking after your home or garden?
Q4. Over the last week, how much has your skin influenced the
clothes you wear?
3. Leisure
Q5. Over the last week, how much has your skin affected any social
or leisure activities?
Q6. Over the last week, how much has your skin made it difficult for
you to do any sport?
4. Work and school
Q7. Over the last week, has your skin prevented you from working
or studying?
If ‘NO’, over the last week how much has your skin been a problem
at working and studying?
5. Personal
relationships
Q8. Over the last week, how much has your skin created problems
with your partner or any close friends or relatives?
Q9. Over the last week, how much has your skin caused any sexual
difficulties?
6. Treatment
Q10. Over the last week, how much of a problem has the treatment
for your skin been, for example by making your home messy, or by
taking up time?
ables. All variables tested in the univariate analysis
with a P value ≤0.1 were included in a multivariate case-control analysis 23 to assess which factors
influence the total DLQI score. Investigated factors
included: clinical course of the disease, extent of af-
Vol. 147 - No. 1
Answers
Scoring
Very much
A lot
A little
Not at all
Very much
A lot
A little
Not at all
Very much
A lot
A little
Not at all
Not relevant
Very much
A lot
A little
Not at all
Not relevant
Very much
A lot
A little
Not at all
Not relevant
Very much
A lot
A little
Not at all
Not relevant
Yes
No
A lot
A little
Not at all
Very much
A lot
A little
Not at all
Not relevant
Very much
A lot
A little
Not at all
Not relevant
Very much
A lot
A little
Not at all
Not relevant
3
2
1
0
3
2
1
0
3
2
1
0
0
3
2
1
0
0
3
2
1
0
0
3
2
1
0
0
3
0
2
1
0
3
2
1
0
0
3
2
1
0
0
3
2
1
0
0
fected skin, involvement of face and hands. In casecontrol definition the median of total DLQI score
was used as threshold in order to have an homogeneous data partition. Case were defined as subjects
with a score ≥1 (small to large effect on patient’s
85
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life) and control as subjects with zero score (no impact on patient’s life). Multiple logistic regression
with forward stepwise selection was used to identify
main risk factors. C-index was used to assess predictive power of the fitted model. Effects of identified factors were calculated as odds ratios with 95%
confidence interval. The analysis was carried out
using SPSS software, version 17.0 (SPSS, Chicago,
IL, USA).
0
1
2
3
4
5
DLQI score
6
7
8
9
10
11
12
13
14
1
2
3
4
5
6
7
8
9
10
Results
11
The median total DLQI score was 1 (IQR: 2;
mean: 1.82). The median and mean scores for the
individual DLQI components are reported in Table
II. The distribution of DLQI scores in the sample is
represented in Figure 1. The main component influenced by the disease was “symptoms and feelings”,
followed by “personal relationships”, “leisure”
and “daily activities”. The components “work and
school” and “treatment” were influenced very weak-
Table II.—DLQI scores of the sample according to different
DLQI heading items.
Symptoms and feelings (Q.1-2)
Daily activities (Q. 3-4)
Leisure (Q. 5-6)
Work and school (Q. 7)
Personal relationships (Q. 8-9)
Treatment (Q. 10)
Total score
86
13
14
15
16
17
18
19
20
21
22
23
24
25
26-47
DLQI 1-2
DLQI 3-4
DLQI 5-6
DLQI 17
DLQI 18-9
DLQI 10
Figure 1.—DLQI score.
DLQI results
Heading items
Subject
12
Among the 47 patients who compiled the DLQI
questionnaire, the mean age was 19 years (SD ± 1.1).
The mean age of onset of the disease was 12.3 (SD
± 5.5) years and the mean duration of the condition
was 7.7 (SD ± 5.7) years. The mean extent of skin
involved was 3% (SD ± 4.2). Face (36.1%; 95% CI:
±13.7), hands (38.2%; 95% CI: ±13.8) and genitalia (70.2%; 95% CI: ±13) were the most frequently
involved sites. With respect to clinical course in the
last year, vitiligo was stable in 25 (53.1%; 95% CI:
±14.2), progressive in 9 (19.1%; 95% CI: ±11.2), regressive (following therapy or spontaneously) in 13
(27.6%; 95% CI: ±12.7) patients.
Mean (SD)
0.74 (2.95)
0.25 (0.60)
0.29 (0.83)
0.04 (0.20)
0.34 (0.66)
0.14 (0.55)
1.82 (2.95)
Median (IQR)
0 (1)
0 (0)
0 (0)
0 (0)
0 (0.75)
0 (0)
1 (2)
ly by vitiligo. Patient’s age, duration of the disease
and age of onset did not influence significantly the
total DLQI score (Table III). On the contrary, the total DLQI was significantly influenced by the clinical
course of vitiligo (Table III). Moreover, in multiple
comparison analysis, progression/stability and progression/regression pairs showed a significant association with DLQI (corrected P-value <0.05). The
total DLQI score increased significantly when skin
involvement was over 5% (Table III).
The value of the median and mean total DLQI
along with DLQI scores of the different explored
components, evaluated according to the involvement
of specific locations (face, genitalia and hands), are
reported in Table IV. The overall DLQI scores and the
score of specific components, with exception of the
heading item “work and school” were significantly
higher in subjects in whom the face was affected by
the disease. The localization of vitiligo on the hands
showed significantly a higher total DLQI score and
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Table III.—Total DLQI scores according to different demographic and clinical variables.
Age
≤19 years
>19 years
Duration of the disease
≤7 years
>7 years
Age of onset
≤14 years
>14 years
Clinical course
Progression
Regression
Stability
Degree of skin involved
≤5%
>5%
N.
Mean (SD)
Median (IQR)
31
16
2.06 (3.35)
1.37 (2.00)
1 (2)
1 (1.5)
P=not significant
26
21
2.04 (3.55)
1.57 (2.04)
0.5 (2)
1 (2.5)
P=not significant
25
22
1.88 (2.57)
1.77 (3.39)
1 (2.5)
0.5 (2)
P=not significant
9
13
25
4.00 (4.30)
1.61 (3.17)
1.16 (1.79)
2 (4.25)
0 (1.25)
0 (2)
P<0.05
38
9
1.28 (2.40)
4.11 (4.01)
0 (2)
4 (4.5)
P<0.01
Table IV.—DLQI scores according to involvement of special sites by vitiligo.
Face (N.=17)
Heading items
Symptoms and feelings (Q.1-2)
location involvement: yes
location involvement: no
Daily activities (Q. 3-4)
Leisure (Q. 5-6)
Work and school (Q. 7)
Personal relationships (Q. 8-9)
Treatment (Q. 10)
Total score
Genitalia (N.=33)
Hands (N.=18)
Mean (SD)
Median
(IQR)
P value
Mean (SD)
Median
(IQR)
p value
Mean (SD)
Median
(IQR)
P value
1.41 (1.37)
0.37 (0.56)
1 (2)
0 (1)
<0.01
0.69 (0.80)
0.86 (1.51)
1 (1)
0 (1)
ns
1.05 (1.16)
0.55 (0.95)
1 (1)
0 (1)
< 0.05
0.52 (0.87)
0.1 (0.31)
0 (1)
0 (0)
< 0.05
0.21 (0.59)
0.36 (0.63)
0 (0)
0 (1)
ns
0.50 (0.85)
0.10 (0.31)
0 (1)
0 (0)
< 0.05
0.82 (1.23)
0 (0)
1 (1)
0 (0)
< 0.01
0.21 (0.48)
0.50 (1.34)
0 (0)
0 (0)
ns
0.55 (1.24)
0.14 (0.35)
0 (1)
0 (0)
ns
0.11 (0.33)
0 (0)
0 (0)
0 (0)
ns
0.03 (0.17)
0.07 (0.27)
0 (0)
0 (0)
ns
0.05 (0.23)
0.03 (0.19)
0 (0)
0 (0)
ns
0.82 (0.88)
0.07 (0.25)
1 (1)
0 (0)
< 0.01
0.33 (0.69) 0 (0.25)
0.36 (0.63)
0 (1)
ns
0.50 (0.61)
0.24 (0.69)
0 (1)
0 (0)
< 0.05
0.41 (0.87) 0 (0.25) < 0.01
0 (0)
0 (0)
0.15 (0.56)
0.14 (0.53)
0 (0)
0 (0)
ns
0.11 (0.32)
0.17 (0.66)
0 (0)
0 (0)
ns
4.11 (3.90)
0.53 (0.78)
1.68 (2.45)
2.29 (3.95)
1 (2)
0 (2)
ns
2.77 (3.31)
1.24 (2.59)
2 (3)
0 (1)
< 0.01
4 (6)
0 (1)
< 0.01
ns = not significant.
higher partial scores in heading items “symptoms
and feelings”, “daily activities” and “personal relationships”.
Multivariate logistic regression analysis of independent contribution of demographic and clinical variables in people with a DLQI total score
Vol. 147 - No. 1
≥1 (N=25) compared to subjects with zero score
(N=22), showed that only the localization on the
hands (OR: 6.32; 95% CI: 1.35-29.50) and on the
face (OR: 5.03; 95% CI: 1.05-24) were significantly
associated with some impact of vitiligo on patient’s
life (C-index: 0.80; 95% CI: 0.67-0.93).
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Discussion
To the best of our knowledge, based on a systematic search regarding studies published from 1994 to
2009, this is the first report evaluating QoL in Italian
vitiligo patients by using the DLQI questionnaire.
Other studies have been conducted on Italian vitiligo
patients by using different methods to investigate
QoL.24, 25 The present survey was performed on vitiligo patients randomly selected among all vitiligo
young men identified in a representative sample of
Italian young male adults undergoing assessment for
compulsory service in national Navy. Most of the
studies of QoL in vitiligo have been conducted on
patients attending a medical intervention 12-14, 16, 17,
19 or members of vitiligo associations,8, 15 (who were
probably highly conscious of the level of disability
of their disease) and, in some instances, the persons
received the questionnaire by mail 8, 12 and stated by
themselves the severity of the disease,8, 15 pointing to
possible selection bias. One limitation of our study
is the small sample size and the fact that it was con-
ducted almost ten years ago when army service was
compulsory in Italy.
The total mean DLQI in our subjects was surprisingly lower than the mean indexes reported in other
studies (Table V). We believe that this finding could
be explained both by the fact that we studied a population-based sample including many subjects with a
very limited skin involvement and by the male gender of our subjects. In fact, according to most surveys, women affected by vitiligo show a DLQI score
significantly higher than male patients 12, 14, 16, 17, 19
and the severity/extent of the disease significantly
correlated with the DLQI score.8, 12, 14, 15, 17, 19 In the
few instances where no correlation was documented
the average skin involvement in the sample was quite
high.13 In our sample, the total DLQI score was significantly higher in people showing vitiligo involvement >5% of skin surface.
Some authors pointed out a significantly higher
DLQI in young vitiligo patients 8, 13, but this observation was not confirmed by others.12, 14, 17 Since our
study was restricted to younger people we cannot
Table V.—DLQI in vitiligo patients from other studies.
Author, year, country
Kent and Al-Abadie,
1996 8
Parsad et al., India,
2003 13
Aghaei et al., 2004,
Iran 14
Ongenae et al. 2005,
Belgium 12
Ongenae et al.,
2005, Belgium 15
Mechri et al., 2006,
Tunisie 18
N°
patients
Setting
Mean DLQI of
patients (SD)
N. controls
Mean DLQI of
controls (SD)
Statistical
significance
614
Members of Vitiligo Society;
postal survey
Patients referred to a Department
of Dermatology
of Dermatology
of Dermatology; postal survey
Patients attending a meeting
organized by a Vitiligo association
of Dermatology
4.82 (4.84)
nd
//
//
10.67 (4.56)
nd
//
//
7.05 (5.13)
nd
//
//
162 patients
with psoriasis
nd
6.26
P=0.01
//
//
60 patients
with other skin
diseases
nd
2.5 (1.0)
P<0.0001
//
/
2.1 (1.0)
P<0.0001
//
//
//
//
150
70
119
78
60
van Geel et al.,
2006, Belgium 16
20
Belhadjali et al.,
2007, Tunisie 17
60
Al Robaee, 2007,
Saudi Arabia 19
Present study
109
47
4.95
6.9 (5.6)
9.4 (17.1)
of Dermatology attending
treatment by transplantation of
epidermal grafts
of Dermatology
6.95 (4.13)
of Dermatology
Vitiligo subjects randomly
selected among a sample
representative of general
population
14.72 (5.17)
60 patients
with other skin
diseases
nd
1.82 (2.95)
nd
9.4 (4.1)
nd: not done.
88
February 2012
draw any conclusion on such an aspect, but we can
only note the overall low value of DLQI score in our
vitiligo sample.
According to our data, the length of the disease
(i.e., the age of onset: infancy/childhood vs. adolescence/adult age) was not statistically related to the
mean DLQI score. Among the studies which analyzed this variable, only the report of Parsad et al.13
showed differences in DLQI score according to the
length of the disease, on the contrary other authors
were in agreement with us.8, 17
In the present study the clinical course of the disease (progression vs. regression/stability) correlated
significantly with the total DLQI score. Belhadjali et
al.17 did not observe any influence of the aforesaid
variable on the DLQI score in their sample. On the
contrary van Geel et al.16 and Parsad et al.13 showed
a significant decrease of overall DLQI in their patients after a successful therapy.
When DLQI score was considered with respect to
the visibility of the affected sites or to involvement
of special sites, the observations of published studies are inconsistent. According to Ongenae et al., the
overall DLQI score correlated with localization to
face, trunk and feet, but did not correlate with localization to hands. On the contrary the visibility of the
sites involved, grouped together, significantly correlated with higher DLQI score.12 The same author, in
another study, showed that the DLQI score was significantly correlated with the total severity score and
with self-assessed severity of the disease in different
localizations, indicating that visibility was not a major determinant of DLQI score. That was not observed
for involvement of face/head/neck, which seemed to
highly impair the QoL, independently of the disease
severity.15 On the contrary, Belhadjali et al. did not
observe any significant difference in DLQI score between patients with vitiligo involving covered and
uncovered skin, nor in patients in which face and genitalia were respectively involved/ uninvolved.17 According to our data, the involvement of face and hands
significantly correlated with total DLQI score, but
the involvement of genitalia did not correlate with it.
This observation was reinforced by logistic stepwise
regression analysis, which showed that localization of
vitiligo on the face and/or on the hands was the only
variable to determine any worsening of QoL when reciprocal control for other variables was obtained.
In conclusion, QoL does not seem to be significantly impaired in Italian young men affected by vi-
Vol. 147 - No. 1
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tiligo when identified from the general population.
In our sample, multivariate analysis shows that the
only variable to significantly influence DLQI is the
involvement of such socially important areas as face
and hands. Larger studies conducted on populationbased samples are needed to confirm our findings
possibly involving primary care physicians.26
Riassunto
Punteggio del Dermatology Life Quality Index in pazienti
affetti da vitiligo: uno studio pilota tra uomini adulti in
Italia
Obiettivo. È stato suggerito che la vitiligine posa avere
un impatto negativo sulla qualità della vita dei pazienti. Lo
scopo di questo studio è stato quello di studiare la qualità
della vita in un gruppo di pazienti italiani affetti da vitiligine impiegando il questionario Dermatology Life Quality
Index (DLQI).
Metodi. La versione italiana del questionario DLQI è
stata somministrata ad un campione di 47 soggetti affetti
da vitiligine, selezionati fra 34.740 giovani sottoposti alla
visita di leva, residenti nell’Italia meridionale.
Risultati. Lo score totale mediano è risultato 1 (IQR: 2;
medio: 1,82). Lo score totale è stato influenzato significativamente dall’evoluzione clinica della vitiligine, dall’estensione della malattia sulla cute, e dalla localizzazione sulla
faccia e/o sulle mani. L’analisi multivariata, eseguita usando il metodo della regressione logistica per gradi, ha dimostrato che solo la localizzazione sulle mani e sul volto
influenzava significativamente il DLQI medio.
Conclusioni. Il nostro studio, condotto su un campione
randomizzato di individui affetti da vitiligine, selezionati
nell’ambito della popolazione generale di giovani maschi
italiani, non documenta un grosso impatto della vitiligine
sulla qualità della vita. Tuttavia esistono delle variazioni e
la localizzazione delle lesioni sulla faccia e/o sulle mani
possono influenzare la qualità della vita. Gli studi basati
sulla popolazione generale non sono affetti dal “selection
bias” connesso alla richiesta di cure mediche e dovrebbero
essere effettuati in maggior numero.
Parole chiave: Vitiligine - Qualità della vita - Malattie
cutanee.
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JM. Quality of life and stigmatization profile in a cohort of vitiligo patients and effect of the use of camouflage. Dermatology
2005;210:279-85.
90
16. van Geel N, Ongenae K, Vander Heghen Y, Vervaet C, Naeyaert JM.
Subjective and objective evaluation of noncultured epidermal cellular grafting for repigmenting vitiligo. Dermatology 2006;213:23-9.
17. Belhadjali H, Amri M, Mecheri A, Doarika A, Khorchani H, Youssef
M et al. Vitiligo and quality of life: a case-control study. Ann Dermatol Venereol 2007;134:233-6.
18. Mechri A, Amri M, Douarika AA, Ali Hichem BH, Zouari B, Zili J.
Psychiatric morbidity and quality of life in vitiligo: a case controlled study. Tuni Med 2006;84:632-5.
19. Al Robaee AA. Assessment of quality of life in Saudi patients with
vitiligo in a medical school in Qassim province, Saudi Arabia. Saudi
Med J 2007;28:1414-7.
20. Finlay AY, Khan G. Dermatology Life Quality Index (DLQI). A
simple practical measure for routine clinical use. Clin Exp Dermatol
1994;19:210-6.
21. Basra MKA, Fenech R, Gatt RM, Salek MS, Finlay AY. The Dermatology Life Quality Index 1994-2007: a comprehensive review
of validation data and clinical results. Br J Dermatol 2008;159:9971035.
22. Ingordo V, Gentile C, Iannazzone SS, Cusano F, Naldi L. Vitiligo
and autoimmunity. An epidemiological study in a representative
sample of young Italian males. J Eur Acad Dermatol Venereol
2011;25:105-9.
23. Breslow NE, Day NE. Statistical methods in cancer research.
Volume I. The analysis of case-control studies. IARC Sci Publ
1980;5:338.
24. Sampogna F, Picardi A, Chren MM, Melchi CF, Pasquini P, Masini
C et al. Association between poorer quality of life and psychiatric
morbidity in patients with different dermatological conditions. Psychosom Med 2004;66:620-4.
25. Sampogna F, Raskovic D, Guerra L, Pedicelli C, Tabolli S, Leoni
L et al. Identification of categories at risk for high quality of life
impairment in patients with vitiligo. Br J Dermatol 2008;159:351-9.
26. Harlow D, Poyner T, Finlay AY, Dykes PJ. Impaired quality o
life of adults with skin disease in primary care. Br J Dermatol
2000;143:979-82.
February 2012

Evaluation of incidental thyroid nodules
in patients with primary melanoma
P. A. FANTI 1, E. DIKA 1, R. BALESTRI 1, G. RECH 1, S. BELLAVISTA 1, E. BALDI 2,H. I. MAIBACH 3, A. PATRIZI
Aim. Literature data have suggested an increase of incidental thyroid nodules in patients with malignancies, including
melanoma.
Methods. The ultrasound findings of 168 consecutive melanoma patients were revisited in order to evaluate the presence
of incidental thyroid nodules and the results were compared
with clinical features, Breslow thickness and the rate of malignancy of incidental thyroid nodules.
Results. We observed that: 1) incidental thyroid nodules are
more frequent in patients affected by melanoma (60.6%)
than in the healthy population; 2) no statistically significant
difference were found in thyroid involvement on the basis of
gender and age; 3) incidental thyroid nodules frequency is increased in patients with thinner melanoma and this increase
is more evident if we consider melanoma in situ and female
patients; 4) it was not detected malignant incidental thyroid
nodules.
Conclusion. The data revealed a high frequency of incidental
thyroid nodules in patients with melanoma, suggesting that
it is necessary to study this association in a larger group of
patients, also including age/gender matched controls.
Key words: Thyroid nodule - Melanoma - Surgical procedures,
operative - Thyroid neoplasms.
T
hyroid nodules are common and frequently benign. The reported frequency of nodular thyroid
disease depends on the studied population and the
methods used in detecting nodules. Nodule inciFunding.—None.
Acknowledgments.—We would like to thank Associazione Nazionale
Tumori (ANT) for their data contribution, in particular Professor Franco
Panutti, Dr. Valeria Bonazzi, Dr. Domenico Biscotti.
Corresponding author: E. Dika, Via Massarenti 1, Clinica Dermatologica, 40138 Bologna, Italy. E-mail: [email protected]
Vol. 147 - No. 1
1
1Division of Dermatology, Department
of Internal Medicine Geriatric Diseases and Nephrology
University of Bologna, Bologna, Italy
2Department of Medicine and Public Health
University of Bologna, Bologna, Italy
3Department of Dermatology, University of California,
School of Medicine, San Francisco, CA, USA
dence, that increases with age, is more frequent in
women and in subjects with iodine deficiency. Data 1
have shown an increased incidence after radiation
exposure. The mean frequency of incidental thyroid
nodules (ITN) reported is 2-6% with palpation and
19-67% with ultrasound examination (US).2-16
In 2007 Wilhelm et al, reported an increased rate
of malignancy of ITN in patients with other primary
malignancies, including malignant melanoma (2 out
of 41 patients with malignancies)17.
The present study, has taken into consideration:
1) frequency of ITN in melanoma patients detected by ultrasound examination;
2) statistical correlation between US findings of
thyroid nodules, demographic data of patients, clinical features and Breslow thickness of melanoma;
3) risk of malignancy of the nodules.
The study included 185 consecutive patients undergoing MM excision between the 1st of January
2007 and the 10th of December 2009 in the DermatoOncological Surgery Service of our Department. Pa-
91
FANTI
INCIDENTAL THYROID NODULES AND MELANOMA
tients with a known thyroid disease or with a previous malignancy were excluded from the study.
Written informed consent was obtained from all
patients.
All patients after primary MM excision underwent
US neck examination, as a part of their disease surveillance. The US examination was performed using
the Esaote MylabTM 25 Ultrasound unit (Esaote Milano ITALIA) in order to detect possible lymphnodal
recurrences of this region.
All US examinations reports involving head and
neck, were revisited in order to evaluate the presence
of ITN in these patients.
Age, race and gender of patients, upper or lower body
location and MM Breslow thickness were evaluated.
Upper body location included head, neck, upper extremities and over-diaphragmatic portion of the trunk;
lower body location included under-diaphragmatic
portion of the trunk, genital area and lower extremities.
In order to perform statistical analysis patients
were grouped as follows: 1) according to the age,
into 4 groups, respecting our population’s quartiles
of age: younger: <47, aged: ≥47 and <60, aged: ≥60
and <71 and finally ≥71; according to MM Breslow thickness, into 3 groups: in situ (MIS), Breslow
thickness <0.7 mm and ≥0.7 mm.
Blood tests to assess the functioning of the thyroid and/or endocrinological consultations were performed in all patients.
Statistical analysis
Data were analysed with SPSS 17.0® (version
17.0; SPSS Inc,Chicago, IL, USA); a 1st type error
≤0.05 was accepted.
Non-parametric tests were performed for comparison because measures were not in a normal distribution (Mann Witney U test); Fisher test, Pearson χ2,
Odd ratio corrected following Mantel Haenszel were
performed for categorical and ordinal data.
Results
Out of the 192 patients undergoing melanoma excision, 24 were excluded because of previously diagnosed thyroid disease (12), a prior thyroidectomy (5
cases), or previous melanoma excisions (7 patients).
A total of 168 patients successfully completed the
whole examination and their main characteristics are
summarized in Table I.
All patients were Caucasian. They consisted of 80
men and 88 women, aged from 25 to 88 years (with
average age of 60 years); 43 patients were younger than 47 years, 47 were between 47 years and 60
years, 39 were between 60yrs and 71 years, and 39
older than 71 years (interquartile range (IQR): 4771 years). Comparison between groups of different
age showed no statistically significant difference in
IQR, revealing an acceptable distribution of patients
(Table II).
The characteristics of patients and their MM are
summarized in Table II.
In our population, upper body MMs were more
frequent in men (58/80=72.5%) than in women
(50/88=56.8), who often show lower body MM, and
the difference is statistically significant at Fisher exact test with P<0.04 (Table II).
MMs of major Breslow thickness (>0.7 mm) were
more frequent in men than in women. MIS were de-
Table I.—Description of demographic and clinical caracteristics of the sample of 168 consecutive melanomas.
Age<47 yrs
Gender (80 males and 88 females)
MIS
(N.=26)
<0,7mm.
Breslow thickness (N.=76)
>=0,7mm
(N.=66)
Present
(N.=100)
Thyroid involvAbsent
ment
(N.=68)
92
47yrs>=Age<60yrs
60yrs>=Age<71yrs
Age>=71yrs
Males
Females
Males
Females
Males
Females
Males
Females
18
25
20
27
22
17
20
19
0
4
3
3
1
4
4
7
10
11
10
15
5
11
8
6
8
10
7
9
16
2
8
6
9
15
15
11
14
14
10
12
9
10
5
16
8
3
10
7
February 2012
FANTI
Table II.—Description of the studied sample: demographic data, breslow thickness of melanoma, thyroid involvement.
50th P
IQR
Upper body
Lower body
MIS
<0,7
>=0,7
Yes
no
Age
Localization
Breslow thickness
Thyroid involvement
Males
N.=80
Females N.=88
62
48-71.75
58
22
8
33
39
48
32
54,5
47-70
50
38
18
43
27
52
36
Statistic tests
p
Mann-Witney
(z=-1.301)
P=0.192
NSS
Fisher exact test
P<0.04
Pearson
(c2 = 6,979)
P<0.04
Fisher exact test
P=1
NSS
NSS: Non statistically significant.
Table III.—Thyroid involvement in the studied population.
Gender
AGE
Localization
Breslow thickness
Males female
P
IQR
Upper trunk
Lower trunk
MIS
<0.7
≥0.7
50th
Thyroid involvement
N.=100
No thyroid involvement
N.=68
48
52
61
48-71
67
33
24
45
31
32
36
54.5
47-71.75
41
27
2
31
35
Statistical tests
P
Fisher exact test
1 NSS
Mann-Witney z=-0.874
0.382 NSS
Fisher exact test
0.414 NSS
Pearson c2=15.919
<0,0001
NSS: Non statistically significant.
tected with a higher incidence in women (P<0.04).
ITN were diagnosed in 100 patients (60.6% CI
95%=53.21-67.99%) on ultrasound examination and
3 types of thyroid nodules were detected on the basis
of US findings: type 1 - cystic, type 2 - mixed (cystic
and solid portion) and type 3 - solid. Most patients
had multiple thyroid nodules.
No statistically significant difference was revealed
regarding ITN distribution while considering gender
and age of patients and of localization of MM (upper
body – lower body) (Table III).
In order to avoid the influence of confounding factors, an odd ratio stratified for age, gender, localization and presence of thyroid involvement was performed, following Mantel Haenszel.
Statistical analysis showed an increased risk of
ITN in MIS vs. “invasive” melanomas (ORMH=
14,777 (CI 95%: 2.837-76.979), with P<0.001) (Tables III, IV). Comparing the presence of ITN in
males with MM thinner than 0.7 mm vs. MM≥0.7
mm the difference was not statistically significant.
In females, on the contrary, patients with melanoma
Vol. 147 - No. 1
<0.7 mm had a 4 times higher risk of thyroid involvement ORMH=4.135 (CI 95%: 1.237-13.428) (P<0.02:
statistically significant). (Table IV, Figure 1).
Blood tests assessing thyroid functioning as well
as an endocrinological check-up were prescribed in
all cases with ITN. No abnormalities were reported
in blood tests. On the basis of the decision of the
endocrinologist a follow-up, including further examinations, was carried out in some patients, involving ultrasound examination and blood test once in
a year. Moreover, in 23 patients a fine-needle aspiration biopsy (FNAB) was requested either by the
endocrinologist or the radiologist. In these patients
histological examination showed primary thyroid
adenomas and was negative for primary thyroid carcinoma or metastatic disease.
Discussion
Incidental thyroid nodules can be discovered
during many radiographic imaging tests since pa-
93
FANTI
Table IV.—Correlation between ITN, gender and Breslow thickness.
Thyroid involvement
Not involved
MIS
Gender
f
m
Total
B.Th. <0.7
Gender
f
m
Total
B.Th.≥0.7
Gender
f
m
Total
N.
%
N.
%
N.
%
N.
%
N.
%
N.
%
N.
%
N.
%
N.
%
2
11.1%
0
0.0%
2
7.7%
16
37.2%
15
45.5%
31
40.8%
18
66.7%
17
43.6%
35
53.0%
Involved
16
88.9%
8
100.0%
24
92.3%
27
62.8%
18
54.5%
45
59.2%
9
33.3%
22
56.4%
31
47.0%
Total
18
100,0%
8
100.0%
26
100.0%
43
100.0%
33
100.0%
76
100.0%
27
100.0%
39
100.0%
66
100.0%
B.Th.: Breslow thickness.
6
No thyroid involvment
Thyroid involvment
5
Thickness
4
3
2
1
0
Males
Females
Figure 1.—Comparison between thyroid involvement and Breslow thickness, in men and women.
94
tients with primary malignancies routinely undergo many of these tests as a part of their disease
surveillance.
The prevalence of ITN in the general population
differs from an ultrasonography study to the other
(10% to 67%).2-14, 17-19
The higher frequency reported by Ezzat et al.18
that indicates a 67% of ITN among the studied population is not significant, because of the unequal distribution of patients (with a prevalence of females
that represent the 84% of the studied population).
Autopsy series indicate that nearly 50% of 1000
subjects undergoing routine consecutive postmortem examination without palpable abnormalilities,
show thyroid nodules on sectioning of the gland.20
Ultrasonographic studies have found a thyroid nodule prevalence of 27% among normal subjects in a
non-goiter-endemic area of Finland21 and only 19%
in Belgium.22
A study of the population carried out in Germany,
which is a country previously iodine-deficient and
currently borderline-iodine-sufficient country, detected thyroid nodules by US in 20% of the population aged 20-79 years.23
Wiest et al. compared the detection of thyroid nodules by physical examination and high-resolution ul-
February 2012
trasonography using small groups of blinded, experienced physician examiners working with a sample
of 2441 persons from Estonia, most of whom were
Chernobyl nuclear reactor clean-up workers. Nodules were found in 249 (10.2%) subjects by highresolution ultrasonography.24
As far as the Italian population is concerned, a
study conducted on 704 consecutive patients (400
women, 304 men) without thyroid diseases and in an
area with a low iodine intake, reported a frequency
of ITN of 33.1%.25
As an additional point of reference, it was also examined the data of the general incidence of thyroid
nodules (TN) among a group of patients evaluated
specifically for thyroid abnormalities by an Italian
no-profit oncologic association (Associazione Nazionale Tumori, ANT). One hundred clinically healthy
subjects (50 men and 50 women), from Bologna
province, underwent thyroid US examination and
blood tests. The clinician of the association reported
that the incidence of TN was 44% (44/100), 54%
in women (27/50) and 34% in men (17/34) (unpublished data).
Considering the literature and the forementioned
data, the present study is the first to report the frequency of ITN specifically in MM patients, although
detection of ITN has been recently described in patients with other malignancies.1 In fact a previous
study exists on ITN detection during routine surveillance of other primary cancers, and the authors report the presence of ITN in two patients with malignant melanoma.17
Our study differs due to the fact that we specifically examined a population of patients with primary
MM on which it was also found a newly discovered
ITN during routine surveillance screening.
Our data reveal a relatively high frequency of ITN
in these patients (60.6%).
Moreover, if the US examination of our patients
would have been performed in order to specifically
evaluate TN, the incidence could have been higher
than the previously reported.
This percentage is distributed equally among all
patients, regardless of gender and age, in contrast
with the data on general population (literature data
report that ITN incidence increases with age and is
higher in women)1.
The average age of our patients with and without
ITN is, as a matter of fact similar (Fisher exact test
with P=0.38) and the difference between males and
Vol. 147 - No. 1
FANTI
females with thyroid involvement is not statistically
significant (Fisher exact test with P=1) (Table III).
An even more interesting observation (Table IV)
was that an increased thickness of MM was associated with an inversely decreasing rate of ITN (from
92.3% of ITN in patients with MIS to 47.0% of ITN
in patients with MM Breslow ≥0.7 mm).
This decreased incidence is even more evident
considering only women, dropping from 88.9% of
ITN in MIS to 33% in women with MM Breslow
≥0.7 mm. The result related to few men with MIS (8
patients) does not permit the same evaluation in this
gender.
According to the collected data, we conclude that:
1) ITN are more frequent in patients affected by
MM than in the healthy population as it is impossible
to find any Italian study reporting a percentage of
ITN similar to that of this study (60.6%).
2) No statistically significant difference were
found in thyroid involvement on the basis of gender
and age, in contrast to literature;
3) ITN frequency is increased in patients with
non-invasive (thinner) melanoma (MIS and MM<7
mm) and this increase is more evident if we consider
MIS (24/100 – 24% patients with ITN and MIS vs.
2/68-2.94% with MIS without ITN) and female patients.
4) It was not detected malignant ITN (FNAB results) while the risk of malignancy reported ranges
from 1.5% to 17% in incidentally detected lesions.15-17, 25-29
The interpretation of these data is not simple and
many questions can be raised.
First of all, it is unknown whether there is a correlation between the development of thyroid nodules
and the development of an oncologic disease, since
ITN are described to have a higher frequency among
patients with malignancies.
While considering our population it is hard to establish whether ITN had preceded or followed MM
initiation, as these nodules were detected only after
melanoma excision.
The crucial point is to understand whether melanoma is more common in people with TN or TN are
more frequent in melanoma patients. Furthermore, if
a hypothesis can be brought about, despite the limited number of patients included here, could these
thyroid nodules be possibly developed as a response
against MM?
Is this a response that represents a defence against
95
FANTI
the progression of MM, considering that ITN have
been detected more frequently in patients with non–
invasive MM? And finally, the co-presence of ITN
and melanoma be perceived as a favourable prognostic factor regarding melanoma progression and ITN
risk of malignancy?
Conclusions
This future project includes a confrontation of
the frequency of ITN between a controlled group
(matched for age and sex, followed by our outpatient
clinic for multiple moles) and melanoma patients.
Riassunto
Valutazione di noduli tiroidei incidentali in pazienti affetti
da melanoma primario
Obiettivo. Dati di letteratura suggeriscono un incremento della frequenza di noduli tiroidei incidentali (NTI), in
pazienti affetti da neoplasie di diverso tipo, compreso il
melanoma. L’obiettivo di questo studio è stato la valutazione della frequenza di NTI in pazienti affetti da melanoma
ritrovati tramite gli esami ecografici di routine prescritti a
questi pazienti.
Metodi. Da gennaio 2007 a dicembre 2009 abbiamo valutato la frequenza di NTI in 168 pazienti consecutivi (80
uomini/88 donne, con età media di 60 anni) mediante ecografie e abbiamo comparato con le caratteristiche cliniche
e istologiche del melanoma escisso.
Risultati. Abbiamo trovato la presenza di NTI in 100 pazienti: le analisi statistiche hanno mostrato una prevalenza
di questi noduli fra la popolazione femminile e in pazienti
con melanoma in situ o sottile.
Conclusioni. I nostri dati si limitano ad un numero piccolo di pazienti e suggeriscono la necessità di studiare la
presenza e frequenza di NTI in pazienti con melanoma.
Parole chiave: Tiroide, nodulo - Melanoma - Trattamento chirurgico - Tiroide, tumori.
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97

Methyl-aminolevulinate photodynamic therapy for the treatment
of actinic cheilitis: a retrospective evaluation of 29 patients
D. FAI 1, I. ROMANO 1, N. CASSANO 2, G. A. VENA
Aim. Multiple treatment modalities have been proposed for
actinic cheilitis (AC), and topical photodynamic therapy
(PDT) has recently been included among these modalities.
We report our experience with PDT using methyl-aminolevulinate (MAL) in AC.
Methods. We performed a retrospective analysis of 29 patients who had undergone MAL-PDT for treatment of AC: 4
patients received one single session and 25 patients two consecutive weekly sessions.
Results. At 3 months, 21 patients (72%) obtained a complete
clinical response, which was sustained over a follow-up period of 6-36 months (mean, 20 months) in 20 patients. Cosmetic
outcome was generally rated as good or very good. Transient
local adverse events related to the procedure were common
and mild to moderate in the majority of cases.
Conclusion. Our preliminary experience suggests that MALPDT may be considered a valid modality for the treatment
of AC, although long-term follow-up studies in large patient
series are required to obtain precise data about clinical and
histological recurrences.
Key words: Photochemotherapy - Methyl 5-aminolevulinate Actinic cheilitis.
T
opical photodynamic therapy (PDT) is a therapeutic procedure based on the application to the
skin of a photosensitizer which is subsequently activated by light energy, thus producing a photodynamic reaction that is cytotoxic and vasculotoxic.1, 2
PDT has become an established treatment modality
Received on April 18, 2011.
Corresponding author: Prof. Gino A. Vena, MD, Dermatology Clinic,
DIMO Department, University of Bari, Policlinico, Piazza Giulio Cesare 11, 70124 Bari, Italy. E-mail: [email protected]
Vol. 147 - No. 1
1Phototherapy
2
Unit, Dermatology Service, AUSL Lecce,
Gagliano del Capo, Lecce, Italy
2Unit of Dermatology and Venereology
University of Bari, Bari, Italy
for actinic keratosis and nonmelanoma skin cancers,
thanks to the minimal invasiveness of the procedure,
and the ability to achieve high response rate and favourable cosmetic outcome.3, 4 Preliminary reports
have proposed PDT as a new therapeutic approach
to actinic cheilitis (AC).5-10
We describe the cumulative results obtained in a
series of patients with AC treated with PDT using
methyl-aminolevulinate (MAL), the methyl ester of
the porphyrin precursor 5-aminolevulinic acid.
We performed a retrospective chart review involving patients with AC who had undergone treatment
with MAL-PDT in a hospital outpatient setting. The
patient series consisted of 29 subjects, 20 males and
9 females, with a mean age of 71.5 years (range, 5388 years). AC was diagnosed clinically in all cases,
with histological confirmation required in 6 cases.
None of the patients presented any known contraindication to the use of PDT. Ten patients had never
used any treatment for their AC in the past, whereas
19 patients had previously been treated with other
therapeutic modalities (cryosurgery, topical 5-fluorouracil and/or imiquimod cream) without any sub-
99
FAI
Methyl-aminolevulinate photodynamic therapy for the treatment of actinic cheilitis
stantial benefit, and such treatments were interrupted
at least two months before the baseline evaluation.
An informed consent was obtained prior to PDT
treatment. Scales and crusts, when present, were
gently removed. Subsequently, a thick layer (approximately 1 mm) of MAL 160 mg/g cream (Metvix®,
Galderma Italy) was applied for 2-3 hours. Thereafter, the skin was exposed to red light (Aktilite
CL 128, PhotoCure ASA, Oslo, Norway) at a fluence of 37 J/cm2. As concerns the application time
of the cream, it lasted 3 hours in the first 3 patients
but was then reduced to 2 hours in order to improve
the tolerability. All subjects were instructed to apply
local antiseptics and topical preparations containing
antibiotics and corticosteroids for 5-7 days after the
therapeutic procedure.
Patients were evaluated one week after the first
MAL-PDT session, when a second session was
performed as needed. In the post-treatment phase,
patients were assessed monthly during the initial 3
months and every 3 months thereafter.
Information on safety and tolerability of MALPDT treatment was also collected.
Results
Of the 29 patients examined, 25 patients underwent
two consecutive weekly MAL-PDT sessions, whereas only one session was performed in 4 patients. At 3
months, complete remission of AC was achieved in
21 patients (72%), a partial response (with a moderate to good improvement) was observed in 4 subjects,
whereas 3 patients did not have any noticeable clinical change and a patient presented even an evident
enlargement of AC lesions as compared to baseline.
Most patients who were partial responders or nonresponders received alternative treatment modalities.
Among patients with an initial complete response,
20 of them remained disease-free over a follow-up
period of 6 to 36 months (mean, 20 months), while a
patient showed signs of clinical recurrence of AC 30
months after treatment.
Regardless of clinical outcome, cosmetic results
were rated as good to excellent in 28 patients (97%).
Only a patient developed scarring within the treated
area.
The most frequent adverse events were transient
and related to the procedure. Erythema was observed
in 24 patients, edema in 19 patients, and erosions or
100
ulcerative lesions in 16 patients. In patients in whom
the time of MAL cream application lasted 3 hours,
oedema and blistering were particularly intense.
Twenty-six patients complained of pain or burning
sensation during the procedure. Such symptoms
were graded as mild and tolerable in 11 cases, moderate (requiring irradiation period to be split) in 9
cases, and severe (requiring temporary discontinuation of illumination, application of cold dressings
and air cooling) in 6 patients.
Discussion
AC is a common premalignant condition which
can progress into invasive squamous cell carcinoma. Effective treatment is mandatory in order to
minimise the risk of malignant transformation.11
Multiple treatment methods have been reported for
AC, including cryosurgery, electrosurgery, carbon
dioxide laser ablation,5-fluorouracil, imiquimod
or scalpel vermilionectomy, which are aimed at
inducing destruction/removal of the damaged epithelium.
PDT has been proposed as a therapeutic intervention for AC, as suggested by case reports and openlabel studies,5-10 which have however considered
different treatment protocols and photosensitizers,
including 5-aminolevulinic acid (ALA), MAL and
methylaminoxopentanoate. The largest study population evaluated until recently is that described by
Sotiriou et al in 2010,10 consisting of 38 patients with
AC who received two ALA-PDT sessions at 2-week
interval. These authors noted a complete clinical response at 3 months in 68% of cases, being this rate
almost similar to our results, whereas at 18 months
the clinical recurrence and histological recurrence
rates reported by the Greek colleagues were 15.4%
and 34.6%, respectively.10
In our preliminary experience, the cosmetic outcome was very favourable and the recurrence rate
appeared to be particularly low, with only a patient
presenting with signs of recurrence among complete
responders examined over an average follow-up period of 20 months.
Local transient reactions due to the procedure occurred in the majority of our patients. These reactions
were mild to moderate in many cases. The development of severe pain, oedema and blistering in the initial 3 patients in whom MAL cream was applied for
February 2012
Methyl-aminolevulinate photodynamic therapy for the treatment of actinic cheilitis
3 hours prior to the illumination led us to modify our
treatment protocol, changing the application time of
the cream to 2 hours, with an overall improvement of
the tolerability profile of the procedure.
Conclusions
Our study have several limitations, including the
retrospective design, the small patient sample, the
short follow-up period, and the absence of histological assessment of response. Nevertheless, awaiting
more precise information from long-term follow-up
experiences in large patient populations and taking
into account that treatment procedure and protocols
require optimization, our preliminary results suggest that MAL-PDT may be considered a new valid
therapeutic approach to AC, showing an excellent
cosmetic outcome and a sustained clinical response
in most patients.
Riassunto
Terapia fotodinamica con acido metil-aminolevulinico per
il trattamento della cheilite attinica: valutazione retrospettiva di 29 pazienti
Obiettivo. Numerosi approcci terapeutici sono stati proposti per il trattamento della cheilite attinica (CA) e, tra
questi, è stata inclusa recentemente la terapia fotodinamica
(PDT). Riportiamo la nostra esperienza relativa al trattamento della CA con PDT ed acido metil-aminolevulinico
topico (MAL).
Metodi. È stata eseguita un’analisi retrospettiva di 29
pazienti con CA che erano stati sottoposti a trattamento
con MAL-PDT: 4 erano stati trattati con una singola seduta
e 25 con due sedute settimanali consecutive.
Risultati. A 3 mesi, 21 pazienti (72%) hanno ottenuto
una risposta clinica completa, che si è mantenuta in 20
pazienti nell’arco di un periodo di follow-up della durata
media di 20 mesi (range: 6-36 mesi). Il risultato cosmetico
è stato giudicato buono o molto buono nella maggioranza
Vol. 147 - No. 1
FAI
dei pazienti. Eventi avversi locali transitori, correlati alla
procedura, sono stati piuttosto frequenti e di entità lievemoderata in gran parte dei casi.
Conclusione. La nostra esperienza preliminare suggerisce che il trattamento con MAL-PDT può essere considerato un valido approccio alla CA, sebbene siano necessarie
valutazioni a lungo termine in un numero consistente di
pazienti per delineare dati precisi sul tasso di recidiva clinica ed istologica.
Parole chiave: Terapia fotodinamica - 5-metil-aminolevulinato - Cheilite attinica.
References
1. Ortel B, Shea CR, Calzavara-Pinton P. Molecular mechanisms of
photodynamic therapy. Front Biosci 2009;14:4157-72.
2. Allison RR, Sibata CH. Photodynamic therapy: mechanism of action and role in the treatment of skin disease. G Ital Dermatol Venereol 2010;145:491-507.
3. Fai D, Arpaia N, Romano I, Vestita M, Cassano N, Vena GA.
Methyl-aminolevulinate photodynamic therapy for the treatment
of actinic keratoses and non-melanoma skin cancers: a retrospective analysis of response in 462 patients. G Ital Dermatol Venereol
2009;144:281-5.
4. Stebbins WG, Hanke CW. MAL-PDT for difficult to treat nonmelanoma skin cancer. Dermatol Ther 2011;24:82-93.
5.Hauschild A, Lischner S, Lange-Asschenfeldt B, Egberts F. Treat��
ment of actinic cheilitis using photodynamic therapy with methyl
aminolevulinate: report of three cases. Dermatol Surg 2005;31:13448.
6. Kodama M, Watanabe D, Akita Y, Tamada Y, Matsumoto Y. Photo��
dynamic therapy for the treatment of actinic cheilitis. Photodermatol Photoimmunol Photomed 2007;23:209-10.
7. Berking C, Herzinger T, Flaig MJ, Brenner M, Borelli C, Degitz
K. The efficacy of photodynamic therapy in actinic cheilitis of
the lower lip: a prospective study of 15 patients. Dermatol Surg
2007;33:825-30.
8. Sotiriou E, Apalla Z, Koussidou-Erremonti T, Ioannides D. Actinic cheilitis treated with one cycle of 5-aminolaevulinic acidbased photodynamic therapy: report of 10 cases. Br J Dermatol
2008;159:261-2.
9. Rossi R, Assad GB, Buggiani G, Lotti T. ��
Photodynamic therapy: treatment of choice for actinic cheilitis? Dermatol Ther
2008;21:412-5.
10. Sotiriou E, Apalla Z, Chovarda E, Panagiotidou D, Ioannides D.
Photodynamic therapy with 5-aminolevulinic acid in actinic cheilitis: an 18-month clinical and histological follow-up. J Eur Acad
Dermatol Venereol 2010;24:916-20.
11. Shah AY, Doherty SD, Rosen T. Actinic cheilitis: a treatment review. Int J Dermatol 2010;49:1225-34.
101

REVIEWS
Add-on diagnostic tool for allergic
contact dermatitis: the strip patch test
S. HESSAM, P. ALTMEYER, H. DICKEL
The “conventional” patch test (PT) is considered to be the
“gold standard” in diagnosing allergic contact dermatitis.
However, the method of patch testing has repeatedly been
criticized for its limited diagnostic accuracy and it is therefore
by no means uniformly accepted as a reliable test method. Basic idea of the “strip” patch test (SPT), a modification by repeated tape stripping prior to patch testing, is to increase the
quantity of allergen reaching the deeper epidermal cell layers
and, thus, to increase the test sensitivity. The SPT according to
our proposed standardized protocol is promising to improve
diagnosis of allergic contact dermatitis which is demonstrated
exemplarily in the field of occupational contact dermatitis.
Key words: Dermatitis, allergic contact - Patch tests - Diagnosis.
T
he “conventional” patch test (PT), as introduced
by Jadassohn in 1895,1 is commonly considered
to be the “gold standard” in diagnosing allergic contact dermatitis. Even though its global sensitivity
and specificity is assumed to be between 70% and
80%,2-5 standard indices of diagnostic accuracy for
individual patch test substances turned out to be considerably lower.6, 7 Against this background, it stands
to reason that diagnostic accuracy and reliability of
the PT is discussed quite controversially.8-10
Patch test results can be false negative, even if the
patient has a sensitization. To date, the magnitude of
this problem is only marginally discussed in the litConflicts of interest.—The authors declare that they have no competing interests directly related to this manuscript.
Corresponding author: H. Dickel, MD, PhD, Department of Dermatology, Venereology and Allergology, St. Josef-Hospital, Ruhr University
Bochum, Gudrunstrasse 56, D-44791 Bochum, Germany.
Vol. 147 - No. 1
Department of Dermatology, Venereology and Allergology
St. Josef-Hospital, Ruhr University Bochum, Germany
erature. However, it is for quite some time assumed
that false-negative results in patch testing are more
common than generally believed.2, 3, 8, 9, 11-13 A patch
test reaction may remain not only negative, but also
undetected.11 In this context it is interesting to note
that despite absence of a morphologically visible
skin reaction immunohistological investigations of
negative patch test sites have shown cellular traffic
comparable to a positive skin reaction, i.e., with an
increase of monocytes and T cells and a decrease of
antigen presenting cells.14, 15 On account of these
findings, negative patch test results are no proof of
the absence of immunosensitivity in a patient.
Allergic contact dermatitis depends considerably on the ability of the allergen to permeate the
epidermal barrier, i.e., to penetrate in the vital epidermis. Thus, the quantity of allergen reaching the
deeper epidermal cell layers is rather crucial than the
amount of allergen on the skin surface. However, the
elicitation of allergic contact dermatitis depends not
only on the penetration of the allergen in the epidermis. The epidermis is composed of a physical, a
biochemical and an immunological barrier.16 First,
the stratum corneum represents the physical barrier against percutaneous penetration of allergens.
Percutaneous penetration is depending on various
influencing factors such as repetitive allergen contact to the skin, skin friction, skin maceration, and
micro traumata of the skin.17, 18 Second, according
to today’s knowledge of the mechanisms of allergic
103
HESSAM
ADD-ON DIAGNOSTIC TOOL FOR ALLERGIC CONTACT DERMATITIS
contact dermatitis, elicitation requires some type
of irritative, non-antigen-specific pro-inflammatory
stimulus preceding antigen-specific effector cell activation.19 For example, mechanical removal of the
upper layers of the stratum corneum by tape stripping
not only causes harm to the physical skin barrier and
facilitates percutaneous penetration of allergens,20
but also induces an immunological stimulus in the
form of subclinical inflammation by upregulation
of non-antigen-specific pro-inflammatory cytokines
(e.g., TNF-α), adhesion molecules and growth factors.21 Additionally, it was found that Langerhans’
cells in tape stripped skin showed increased epidermal cell density and stimulatory activity in terms of
maturation, respectively.22, 23
Hence, skin barrier disruption and immunological
stimulus seem to be both essential, too, for eliciting
a positive patch test reaction.
The strip patch test
Various modifications of the PT have been described in the past.24 Fundamental intention was always to increase the patch test sensitivity and thus
to enhance diagnostic accuracy and reliability of the
patch test results.
Among these modifications, the “strip” patch test
(SPT), inaugurated by Spier and Natzel in 1953,25
still enjoys a use as supplemental tool in the diagnosis of allergic contact dermatitis.26 Basic idea behind
this modification of patch testing was to increase the
quantity of allergen reaching the deeper epidermal
cell layers and, hence, to lower elicitation thresholds
for patch test substances in a sensitized patient. This
was primarily achieved by reduction of the stratum
corneum at the test site on the back by repeated tape
stripping prior to patch testing.27 However, it was
Spier who himself realized early on that there may
be additional stimuli explaining an increased responsiveness of the epidermis to patch test substances.28
Previous application in clinical practice
Since its inauguration until today, a standardized
procedure for the SPT was missing, which not only
has made it difficult to implement widely the SPT in
clinical practice, but also complicated comparability
as well as reproducibility of the test results.
Extensive literature search revealed the use of
the SPT primarily in the diagnosis of allergic contact dermatitis to systemically and topically applied
drugs, metal salts and aeroallergens (Table I).29-55
Drugs are normally characterized by a poor permea-
Table I.—Fields of application of the non-uniformly performed strip patch test.
Author (and co-author/s)
Bruynzeel-Koomen et al.41
Buckley et al.15
Langeveld-Wildschut et al.35
Oldhoff et al.42
van Voorst Vader et al.43
Bahmer44
Veien et al.45
Fernandes et al.46
Frosch et al.47
Koch et al.48
Akita et al.49
Maucher et al.28
Bircher50
Trautmann51
Lückerath et al.52
Ozkaya-Bayazit et al.53
Trautmann 54
White 55
Test substance
Adhesive tape
Aeroallergens
Aeroallergens
Aeroallergens
Aeroallergens
Aeroallergens
Formaldehyde
Metal salts
European standard series
Opthalmics
NS
Sellotape®
Transpor® hypoallergenic tape
Transpor® hypoallergenic tape
Transelasta adhesive plastic tape
NS
Nopi®
Micropore®
NS
Opthalmics
Opthalmics
Opthalmics / dental materials
Opthalmics/systemic drugs
Drugs with mucosal contact
Systemic drugs
Systemic drugs
Heparins
Photopatch test substances
N. of tape strips
15
12
10 or 20
10
8 or 15
down to the stratum lucidum
6
2
calculated individually
for each patient
as proposed by Frosch et al.47
Micropore®
10
NS
NS
Scotch Tape®
10
Tesafilm®
10
NS
30
NS
25-30
As proposed by Oldhoff et al.42
NS
NS
NS: not specified
104
February 2012
HESSAM
Table II.—Protocol for standardized performance of the strip patch test.36
3M® Blenderm® surgical tape (width 25 mm) is used
1. If hair removal is necessary, clippers are used (e.g., 3M® surgical clipper)
2. Stripping of the healthy skin at one upper side of the back is done until the stratum lucidum is reached, i.e., the surface shows
three small glistening spots
a) Tape is vertically (parallel to the spine) applied onto the skin without tension
b) Tape is smoothed out and gently pressed downward by fingertips for about 2 seconds
c) Tape is removed in one quick movement at an angle of 45° in the direction of adherence
d) For each single strip a new tape cut is used and positioned on exactly the same skin area
3. The number of tape strips required to produce three small glistening spots is multiplied by the tape-specific correction factor
cf=11/26≈0.42
4. The calculated number of tape strips is applied contralateral and/or lateral to spine
i) Tape strips are performed as specified by the subitems 2. a)-d)
ii) The filled patch test device (e.g., Finn Chamber® on Scanpor® tape) is then applied and fixed
iii)Patch test is removed after 24 hours
iv)Test results are read according to the guidelines of conventional patch testing 56, 57
tion of the stratum corneum or a lower percutaneous
penetration at the patch test area than on the site of
clinical exposure, respectively. For example, in line
with other authors 29-31 Corazza et al.32-34 pointed out
that the PT with opthalmic products is often unsuccessful. Differential diagnosis of allergic contact dermatitis to metal salts (e.g., nickel sulfate, potassium
dichromate, and cobalt chloride) represents another
important application field. Tape stripping prior to
patch testing results in a facilitated permeation of the
stratum corneum of these primarily lipophobic substances. Finally, the SPT was repeatedly mentioned
in the diagnosis of delayed hypersensitivity reactions
to inhalant allergens (aeroallergens) in patients with
atopic dermatitis. By reduction of the stratum corneum and by influencing the immunological epidermal barrier at the patch test area the SPT may simulate lesional skin of patients with atopic dermatitis
more accurately than the PT on untreated skin.35
The standardized strip patch test
In a multicenter pilot study we recently proposed
a first protocol for uniformly performing the SPT.36
Protocol
According to the proposed protocol (Table II),
the patient first receives tape strips on the intact,
non-inflamed skin at one upper side of the back until the skin surface starts to glisten (Figure 1A), i.e.,
shows three small glistening spots indicating that the
Vol. 147 - No. 1
stratum lucidum (simple-to-judge visual endpoint)
has been reached. The individual number of tape
strips to the stratum lucidum is then multiplied by
the tape-specific correction factor (cf=11/26≈0.42).
The calculated number of tape strips is finally performed on the untreated patch test area (Figure 1B,
C). After that, patch test substances are applied for
24 hours (Figure 1D) and reading of skin reactions
is performed in the conventional way of patch testing.
Test sensitivity
The increased test sensitivity of the standardized
SPT compared to the PT was exemplarily confirmed
in serial dilution tests with nickel sulfate (1.0%,
0.5%, 0.1%, 0.05%, and 0.005% in distilled water)
and potassium dichromate (0.1%, 0.05%, 0.01%,
0.005%, and 0.0005% in distilled water).37 Use of
the standardized SPT allowed a median reduction of
the necessary test concentration for eliciting a skin
reaction to nickel sulfate by a factor of 10 and to
potassium dichromate by a factor of 5, respectively.
Particularly with regard to declining concentrations
of the patch test substances, the superiority of standardized SPT versus PT became evident.
Furthermore, the reproducibility rates of the preexisting sensitizations to nickel sulfate and potassium dichromate were considerably higher by standardized SPT compared to PT. With the serial dilution
test in the nickel-sensitive subjects, we detected 94%
of the sensitizations by standardized SPT versus
63% by PT and in the dichromate-sensitive subjects,
105
HESSAM
Figure 1.—Illustration of standardized performance of the strip patch test. Determination of the number of tape strips needed to reach
the individual endpoint (in that case = 36), i.e., the stratum lucidum (A). Performance of the calculated number of tape strips (36 × (11
⁄ 26) = 15) on the patch test area (B, C). Application of the patch test substances (D).
respectively, 82% of the sensitizations by standardized SPT versus 47% by PT.
Diagnostic accuracy
In a multicenter validation study we found that the
standardized SPT showed a vastly better sensitivity
than the PT in detecting “truly” sensitized patients to
nickel sulfate and potassium dichromate, respectively,
with only marginal compromises in terms of specificity.7 Differences between sensitivities of standardized SPT and PT were 16.4% (95% CI, 8.7-24.1%)
for nickel sulfate and 25.0% (95% CI, 8.9-41.0%)
for potassium dichromate, both favoring standardized SPT. In contrast, the necessarily resulting advantage of the PT in terms of specificities was only mi-
106
nor: 3.3% (95% CI, 1.7-5.0%) for nickel sulfate and
2.9% (95% CI, 1.5-4.3%) for potassium dichromate.
Hence, even though not error-free, the standardized
SPT balances in a much better way the primary clinical aim of reducing the numbers of false negatives
and the risk of increasing the number of false positives which may result in superior management of
patients and improved patient-important outcomes.
Influence on epidermal barriers
In further investigations we could show that not
only the physical epidermal barrier but also the immunological epidermal barrier is influenced by tape
stripping according to our proposed protocol for
standardized SPT (Table II).36 Study data suggest
February 2012
that the defined reduction of stratum corneum of
31±9% by good interrater agreement in association
with the upregulation of epidermal mRNA expression levels including TNF-α, Hsp90, Hsp70, IL-33,
and IL-8 may be in large part responsible for the
considerably increased test sensitivity of standardized SPT versus PT.38, 39 Evidently, standardized tape
stripping of the skin prior to patch testing not only
facilitates the percutaneous penetration of patch test
substances and, thus, increases the bioavailability of
patch test substances in the vital epidermis, but also
enhances skin immunoreactivity to patch test substances. As a consequence, the standardized SPT has
the potential to detect delayed-type sensitizations in
patients with a negative PT.
However, it can be hardly estimated how much
the observed stratum corneum reduction or changes
in epidermal cell immunology contribute to the enhanced test sensitivity of the standardized SPT. The
pathophysiological significance of these findings
needs to be further scrutinized.
Proposed application in clinical practice
As a direct consequence of the above mentioned
study results, the standardized SPT may be recommended as a promising diagnostic tool for allergic
contact dermatitis beyond the PT. So far, its usage
in routine allergy testing can be recommended:24 1)
if PT fails to reproduce a preexisting delayed-type
sensitization; 2) if PT remains negative or questionable despite continued suspicion of allergic contact
dermatitis or delayed-type hypersensitivity, respectively; 3) in case of patch testing substances with
poor permeation of the stratum corneum or with a
low concentration; 4) if percutaneous penetration of
the substance on the patch test area is lower than on
the site of clinical exposure; and 5) if repeated tape
stripping should simulate lesional or sensitive skin
on the intact patch test area.
From all points of view, the standardized SPT may
particularly enhance the diagnosis of allergic contact
dermatitis in occupational dermatology.
Exemplary practical application in occupational
dermatology
Exposure conditions at the workplace, possibly irritating and/or sensitizing, are inadequately imitated
by the PT leading to false-negative results. As long
Vol. 147 - No. 1
HESSAM
ago as 1931 Sulzberger and Wise wrote that there
is repeated skin contact to working materials during work process.17 Additionally, physico-chemical
abrasion of the skin leads to an enhanced percutaneous penetration of working materials and to an increased responsiveness of the skin.18
The standardized SPT may help to imitate several
of these occupational exposure conditions more adequately than the PT. Thus, the elicitation threshold
for work-related test substances is lowered and even
weak sensitizations can be detected. We recently
demonstrated, for example, the case of a 57-year-old
former heavy-current electrical worker with lowgrade sensitization to nickel sulfate that was only detected twice by strip patch testing.40 This result had
a significant impact on legal and insurance aspects
resulting in a pension entitlement according to no.
5101 of the German ordinance on industrial disease.
Conclusions
The standardized SPT proved to be clinically safe
and particularly accurate for obtaining additional information on a patient’s delayed-type sensitization
status and supporting diagnosis of allergic contact
dermatitis. Thus, the standardized SPT may play a
decisive role and its more time-consuming procedure should be no impediment to implementing this
method in routine allergy testing.
Riassunto
Strumento diagnostico aggiuntivo per la dermatite allergica da contatto: lo strip patch test
Il patch test (PT) “convenzionale” è considerato lo standard di riferimento nella diagnosi della dermatite allergica
da contatto. Tuttavia, il metodo del patch test è stato ripetutamente criticato per la sua limitata precisione diagnostica e non è quindi accettato uniformemente come metodo di test affidabile. L’idea alla base dello “strip” patch
test (SPT), una modifica apportata tramite la tecnica del
tape stripping ripetitivo prima del patch test, è quella di
aumentare la quantità di allergene che raggiunge gli strati
più profondi delle cellule epidermiche, aumentando così la
sensibilità del test. L’SPT, in accordo al protocollo standardizzato da noi proposto, promette di migliorare la diagnosi
della dermatite allergica da contatto, come dimostrato in
maniera esemplare nel settore della dermatite da contatto
occupazionale.
Parole chiave: Dermatite allergica da contatto - Test allergologici - Diagnosi.
107
HESSAM
References
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2. Nethercott JR. ��
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3. Diepgen TL, Coenraads PJ. ��
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4. Uter W, Schnuch A, Gefeller O. Guidelines for the descriptive presentation and statistical analysis of contact allergy data. Contact
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contact dermatitis: an update. Br J Dermatol 2009;160:946-54.
6. Frosch PJ, Pirker C, Rastogi SC, Andersen KE, Bruze M, Svedman
C, et al. Patch testing with a new fragrance mix detects additional
patients sensitive to perfumes and missed by the current fragrance
mix. Contact Dermatitis 2005;52:207-15.
7. Dickel H, Kreft B, Kuss O, Worm M, Soost S, Brasch J et al. In��
creased sensitivity of patch testing by standardized tape stripping
beforehand: a multicenter diagnostic accuracy study. Contact Dermatitis 2010;62:294-302.
8. Nethercott JR. Practical problems in the use of patch testing in the
evaluation of patients with contact dermatitis. Curr Probl Dermatol
1990;2:97-123.
9. Shuster S. Patch-test sensitivity and reproducibility in individuals
and populations. Am J Contact Dermat 1992;3:74-8.
10. Belsito DV, Storrs FJ, Taylor JS, Marks Jr JG, Adams RM, Rietschel
RL et al. Reproducibility of Patch Tests: A United States Multicenter Study. Am J Contact Dermat 1992;3:193-200.
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37. Dickel H, Kamphowe J, Geier J, Altmeyer P, Kuss O. Strip patch
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40. Scola N, Hunzelmann N, Ruzicka T, Kobus S, Adamek E, Altmeyer
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41. Bruynzeel-Koomen CA, van Wichen DF, Spry CJF, Venge P, Bruynzeel PL. Active participation of eosinophils in patch test reactions
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109

CASE REPORTS
Human phthiriasis.
Can dermoscopy really help dermatologists?
Entodermoscopy: a new dermatological
discipline on the edge of entomology
G. SCANNI
The diagnosis of human phtiriasis (often referred to as the
“crab” or the “pubic louse”) can be more difficult than other
types of pediculosis (Pediculus corporis and Pediculus capitis)
because this insect has a smaller body of 1.2x0.8 mm, may
be lighter in color, not as mobile and therefore harder to see
to the naked eye. Can dermoscopy aid to perform a better
analysis of the skin? The clinical experience developed in two
patients gives an affirmative answer, moreover adding useful
information of insect and its eggs already known to entomologists but never used in dermatological diagnosis. The identification in vivo can distinguish Phthirus pubis from other skin
signs while the conical shape of the operculum and the wide
fixing sleeve of egg to hair, tells what species of louse is infesting, even if the insect is unavailable or nits are elsewhere from
the pubic area. Entodermoscopy, provided that dermatologists have some knowledge of entomology, therefore promises
advantages over standard microscopic examination.
Key words: Dermoscopy - Pediculus - Phthirus.
P
hthirus pubis can be more difficult to diagnose
clinically than the other forms of pediculosis,
not only because being smaller it is more difficult to
identify visually, but also because its flattened body
can be only slightly pigmented.
In this context the utility of dermatoscope can be
hypothesized not only for visual magnification 1 but
also because the observation would be locally facilitated as P. pubis does not tend to dart about or hide as
Received on January 27, 2011.
Accepted for publication on June 14, 2011.
Corresponding author: G. Scanni, Dermatology Department, Distretto socio sanitario n° 6, Medicina Polispecialistica Convenzionata, ASL
Bari,Via Cacudi 31 (Piazza Europa), 70123, Bari, Italy.
Vol. 147 - No. 1
Dermatology Department
Distretto Socio Sanitario n° 6 ASL Bari, Italy
happens with the other two louse species. Diagnosis
of phthiriasis could also benefit from dermatoscopy
when the parasite is found on other parts of the body,
such as the trunk or armpit hairs, or on more unusual
areas such as the eyelashes and scalp hair.
Since the literature on the topic of infestation in
these areas does not use universal terminology and as
diagnosis is not so rare, this paper proposes the use
of Phthiriasis capitis, Phthiriasis oculi, Phthiriasis
axillae, Phthiriasis corporis according to the affected body parts, using the term Phthiriasis pubis only
when the parasite primarily is mainly confined to the
pubic-perineal region. A similar classification has
already been formulated in the past.2 This more detailed topographically-based attribution would also
seem to be a more suitable way of describing clinical
cases of primitive extrapubic locations,3 given that
the historical nomenclature might not correspond to
the affected area when it is different from pubis.
Two types of dermatoscope were employed, exploiting the different characteristics of each one. The
observations were performed with a technique previously known as “dry dermatoscopy” 4 i.e. not requiring the use of a glass plate and liquid film interface.
This set-up is the only one that respects the vitality
of the parasite, leaving the host micro habitat intact.
The same area can therefore be examined repeatedly
without causing any undue local changes.
111
SCANNI
HUMAN PHTHIRIASIS AND ENTODERMOSCOPY
A Delta 20 dermatoscope (Heine) manually connected to a Minolta G530 digital camera (5mpx)
was used only to produce unpolarized led light images, while the Dermlite Pro II dermatoscope (3
Gens, LLC) fixed to a Sony W70 (7mpx) with an
adapter, was primarily used to obtain polarized led
light images. The former produces images emphasising shape and texture, whilst the latter highlights
in greater detail the vital internal components of the
bug and eggs.
With regard to devices, entodermoscopy 5 requires
a specific dermatoscope dedicated to parasite study,
capable of using different lighting sources and reaching magnifications far above 10x [see instrumental
specifications on www.entodermoscopy.net;
In fact, most of the photos in this paper are magnified about 30 times, by using the optical zoom,
which on these cameras can magnify 3x. Multiplying the two factors of enlargement (dermatoscope
and zoom) thus gives a “theoretical” magnification
of thirty times. Pictures examined in full-frame format are even more enlightening. Depending on the
megapixel resolution of the sensor, when the image
is not reduced by the screen dimension, it can be enlarged further to show even greater detail.
An instrument designed specifically for searches
such as these (entodermoscope) would eliminate
some current drawbacks, thus making the study of
ectoparasitosis simpler, more efficient and more reproducible in situ.
Figure 1.—Pale, isolated reddish-gray spot on pubis surronded
by large area of normal skin (A), suggestive but not diagnostic.
[Minolta G530]
Clinical series
Case 1.A 61-year-old man experiencing itching in the
inguinal-abdominal region was treated for a significant
time with various moisturizing products, antiseptic soaps,
cortisones or antibiotic creams, but decided to consult a
specialist when the symptoms persisted.
During objective examination, the subject exhibited an
excellent general and local state of hygiene, being a professional; with the naked eye, he showed no signs of macroscopic elements of interest (such as maculae ceruleae or
excoriations), except for very rare dark spots on the pubic
skin strongly suggestive of pediculosis (Figure 1).
Under the dermatoscope, most of his skin and annexes
appeared normal but when focusing on the rare punctiform
lesions, the characteristic triangular body of Phthirus pubis
could be easily identified, clinging with its claws onto the
surrounding hair (Figure 2). What appeared to the naked
eye as indefinite dark spots, showed itself through dermoscopy to be made up really of red fecal granules clustered
112
Figure 2.—Phthirus pubis motionless, hooked onto the hair shafts.
Dark-red fecal granules can be seen on the skin, with a reflecting
surface (A). Brown claws (B). [Dermlite, normal light. 30x].
close to the caudal section and the bug’s pigmented claws
(Figure 2).
Despite observing the parasite for a considerable
length of time, it made no attempt to escape and made no
sudden movements of its limbs. On switching to polarized light, the digestive tract of the parasite (previously
not visible) could clearly be seen because the red color
of the blood inside and it��
’��
s lively peristaltic activity (Figure 3).
February 2012
SCANNI
Figure 3.—Phthirus pubis. Under polarized light, the Phthirus
body becomes transparent enough to distinguish the digestive
tube (C) moved by peristaltic waves (see: www.entodermoscopy.
net). The claws are brown (B), and faeces on the skin now appear
as opaque granules (A). [Dermlite polarized light, 30x].
On searching for other diagnostical signs, only a very
few number of nits were found on pubic hair, some with
operculum, others without. The operculum of the proximal nits (i.e. those unhatched, closer to the skin) exhibited a characteristic conoid shape 6 (Figure 4) thus distinguishing them from the nits of P. capitis, which have a
dome-shaped operculum.7 (Figure 5) These two different
shapes are known enough to dermatologist but they are
available only when lice eggs are analyzed under optical
microscope.
Another microstructural egg feature, never used for dermatological diagnosis but already described
microscopically by P.A. Buxton in 1947, and reported
by Howard V. Weems Jr. in 1980, regards segment attached
to the hair shaft.8, 9
This special portion of the nit that I like to call “fixing
sleeve” assumes considerable evolutionary and therapeutic
importance. In fact it enables the egg to be exposed to the
right degree of heat allowing proper embryo development
and it imposes the use of a fine-toothed comb to mechanically remove the eggs. Rather than to believe that the egg is
simply glued onto the hair shaft, the nit has really to be imagined fixed firmly onto a tubular structure (fixing sleeve)
surrounding and probably tightening the shaft to create the
strong adhesion we know to hair.10 Based on my photographic experience, commonly sleeve of P. capitis appears
as a tubule of even caliber, the same length or longer than
the egg shell (Figure 6).
By contrast in this patient fixing sleeve of P. pubis appears as a shorter sheath which increases in thickness towards the basal pole of the egg then becoming more tu-
Vol. 147 - No. 1
Figure 4.—Phthirus nits on pubis. Conoidal operculum (A) in
eggs fixed at different heights along the hair shaft. Fixing sleeve
at its widest part (B). [Dermlite, detail>30x].
Figure 5.—Example of Pediculus capitis nit with a flattened dome
shape operculum (A). A detail in the foreground (B). Basal egg
pole is well distinguishable by hair shaft (C). [Delta20, 30x; detail
>30x].
bular towards the proximal part of the hair shaft (Figure
7). This wider conformation can be photographed on pubis
with more technical difficulties than crab nits on scalp hair.
113
SCANNI
Figure 6.—Example of Pediculus capitis nit without operculum
(A) with basal pole detached from hair (B). Fixing sleeve has tubular shape (C). [Delta20, 30x].
Figure 8.—Phthiriasis oculi. Nits on eyelashes. Two lateral operculum-free nits (A) and one at center with conoid operculum (B).
All are dark, stained by patient’s mascara. [Dermlite polarized,
30x].
Figure 7.—Phthiriasis pubis. Nit on pubis. The fixing sleeve is
tubular in its proximal part towards skin (A), widening closer to
its distal end (B) where it envelops part of the basal pole of the
egg, clearly visible in transparency (C).
Conoidal operculum (D) [Dermlite, 30x. Small photo >30x].
This feature, if confirmed by further dermatoscopic observations, could be used as a pathognomonic element useful to identify Phthirus nits which are currently unrecognizable because lacking the operculum on unusual parts of
the body. Without a specific operculum and far from usual
site a nit is only a case virtually belonging to any kind of
pediculus.
Case 2.A 38-year-old woman, a primary school teacher,
114
decided to consult a dermatologist, not for a diagnosis (a
diffused pubic phthiriasis already correctly diagnosed by
another colleague) but rather to ensure that her treatment
had been successful. The patient was not only worried for
her health but, even more so, for her relationships with
work colleagues and pupils. When she was visited, therapy
had already been performed, and on her own unauthorized
initiative repeated several times with different pediculicides; nevertheless, the itching did not entirely disappear
and the search for new bugs became a full-time occupation
for the woman. All these psychological pressures resulted
in a severe lack of sleep and a growing anxiety-compulsive
disorder.
The dermatoscopic observation began in the pubic region, which the patient had already completely shaved at
the onset of the illness, continuing in the ocular region and
finally the scalp being infestation widespread all over the
body. The pubic skin looked normal, almost entirely hairless with protruding hair stems only, and of course no direct macroscopic sign of parasites or eggs.
On the other hand, real evidence of past infestation by
P. pubis was irrefutably confirmed by numerous nits on
eyelashes, easily identifiable despite the black mascara on
the patient’s eyes. No parasite was detectable in situ and
no local therapy was refered. Most of the nits were lacking operculum and black in colour as if the mascara had
got through the vacated opening. However, there were also
some black nits that were still closed, with a typically conoid operculum (Figure 8).
February 2012
Figure 9.—Phthiriasis capitis. Nit without operculum (A) on hair.
The hair fixing sleeve (B) is a wide structure that also envelops the
basal pole of the egg, becoming tubular only towards the proximal
side of the hair shaft. [Delta20, 30x].
SCANNI
Here, the fixing sleeve again exhibited in both operculum cases a thickening close to the basal part of the egg as
found in clinical case 1. This conformation found on the
head, and not only on the pubis (Figures 4-7), confirms the
hypothesis that it is a constant characteristic of the bug,
expressed independently from its location.
Given the several cycles of therapy (pluritherapy) with
different drugs (polytherapy) which the patient had undergone, also here it was not possible to find directly any insects on the scalp or surrounding skin.
After the examination, the patient was reassured that the
care she received had been successful, which was the main
reason for her consultation.
But despite her relief because therapy success, on subsequent visits she still reported significant emotional distress,
requiring low dose of Pimozide (2 mg) for 10 days.
At the end of therapy, the patient showed good control
of the fears that heavily compromised her working life and
relationships for several weeks.
Discussion
Considerations about lice and nits are addressed
below in separate sections.
Dermatoscopic markers of mobile forms (insects)
Figure 10.—Phthiriasis capitis. Nit on hair with typical conoidal
operculum (A), and short and wide sleeve (B). Basal egg pole is
absorbed into sleeve. [Delta 20, 30x].
The reason behind this phenomenon is not immediately clear, but suggests that the embryo had somehow been
stained (and probably killed) through the wall of a closed
egg. Other observations would be necessary to define the
type of interference caused by mascara on the normal life
cycle of the lice and nits when exposed to a potentially
very occlusive product.
On the scalp hairs, the dermoscopic features were equally
easy to read, even if reduced to few nits only, some open (Figure 9) and others closed by a conoidal operculum (Figure 10).
Vol. 147 - No. 1
P. pubis in these two cases shows a good ability
to adapt to different temperature, humidity and light
microenvironments, apparently without changing
its behavior. In dermatoscopy, it was identified directly only in patients 1 but not in patient 2, because
she had already been successfully treated, although
some symptoms could suggest a persistence of the
disease as the woman believed, having fallen into a
delusion of parasitosis.
In the first clinical case, previous visits failed to
recognize with naked eye any kind of parasite on
pubis, resulting unsuitable treatments of patient. Diagnostic delay may occur when an infestation, kept
to a very low level because of scrupulous personal
hygiene, is supported by a parasite population limited to very few individuals. Such a situation is insufficient for immediate identification unless the doctor
has already experienced this peculiar clinical eventuality.
The dermatoscope proves useful for identifying
those forms of itchy dermatitis resistant to common
therapies, whose cause is really a pediculosis below
the diagnostic threshold, which would otherwise be
misdiagnosed.
115
SCANNI
The dermoscopic markers that best define Phthirus
are its short, triangular and little colored body, brown
claws, red globular feces near its caudal section, and
red-colored internal digestive tract with its peristaltic
activity under polarized light (Figures 2, 3).
In the second case, entodermoscopy was unusually used to confirm eradication of the infestation,
fairly inevitable given the multiple therapies, the trichotomy over almost the entire body and the interruption of any further potentially contagious contact.
More specifically, it was a useful tool for the patient
because in her particular emotional state (delusion),
she demanded a careful instrumental verification
that treatment had been successful. In patients with
symptoms suggesting active infestation, dermoscopic
examination proves its utility for excluding factors
which could wrongly indicate failure of treatment.
Dermatoscopic markers of fixed forms (nits)
In cases 1 and 2, eggs were found respectively
in course of infestation and as delayed testimony
where trichotomy was impossible to carry out (hair
and eyelashes). Removal of hairs in fact prevents any
direct or indirect diagnosis with existing equipment.
In both patients, the conoidal shape of the operculum confirmed that the parasite was really crab louse,
being this attribute specific for Phthirus, especially
favoring differential diagnosis on the scalp where
nits of P. capitis are statistically more common. The
images in this paper clearly describe this microstructure, which entomologists have already well documented using optical microscopy, but which is, in
dermatological world, very uncommon to see in vivo
and in situ through the dermatoscope (Figures 4-7).
But also a second unexpected indicator can be
documented through dermoscope. It regards the fixing sleeve which could be able to distinguish nits of
Phthirus even when they have lost the specific operculum and the anatomic site is not typical (i.e. head).
According to personally consulted sources, this
item seems to have never been documented in dermatoscopy before this study. The fixing sleeve of P.
capitis is generally a tubular case to which much of
the nit is attached, usually leaving the proximal pole
of the egg detached from the hair shaft (Figure 6) or
however well distinguishable from it (Figure 5). By
contrast, the fixing sleeve of P. pubis in these observations appears to widen as it nears the egg, to
“incorporate” and partially hiding its proximal pole
116
(Figures 4-10). One can also have impression to
watch in side projection a kind of “sail” or “truncated cone”, between egg and the hair shaft. This morphology has been documented consistently in different patients (cases 1-2) and at different sites (pubis,
head) demonstrating that it is not influenced by the
anatomic site in which P. pubis is located.
Conclusions
Dermatoscope in the guise of an “entodermoscope” can provide useful additional information for
both direct diagnosis and differential diagnosis. Entodermoscopy 11 is a young and evolving application
of traditional dermatoscope that can, now with some
technical restrictions, explain those fuzzy red marks
perceptible to the naked eye (made up of pigmented
claws, external faecal pellets and blood within the
gut), that always dermatologists have unknowingly
used in macroscopic clinical diagnosis of Phthiriasis.
It also allows to identify in situ and in vivo certain
microstructural differences between nits species (i.e.
operculum and fixing sleeve) which are otherwise
inaccessible to the naked eye. These items are useful for knowing the infesting kind of Pediculus even
in its absence, when nits have already hatched (i.e
free of specific operculum) and they are in atypical
locations, without interrupt ordinary visit anyway
because optical microscope use.
In addition to still images, dynamic studies of
the parasite can also be carried out by filming the
parasites with a digital camera (clip available on
homepage of www.entodermoscopy.net). Dynamic
information has to be considered an indispensable
complement in the search for specific markers of infestations.
All such observations, preferably obtained from
a specific dermoscope designed “ex novo”, create
the groundwork for a better in situ and in vivo understanding of complex host-parasite relationship
which could in future better define new pathways for
diagnosis and therapeutic strategies.
Riassunto
Pediculosi ed entodermoscopia
La diagnosi ad occhio nudo dello Phthirus pubis può
comportare qualche difficoltà rispetto alle altre forme di
February 2012
pediculosi (Pediculus corporis e Pediculus capitis) a causa delle sue piccole dimensioni 1,2x0,8 mm, per la sua
scarsa colorazione ma anche perché può rimanere fermo
abbastanza a lungo da non richiamare l’attenzione dello
sguardo.
Date queste premesse può l’ausilio del dermatoscopio
ritornare in qualche modo vantaggioso? L’esperienza sviluppata in due casi clinici “limite” sembra dare una risposta positiva grazie all’aggiunta di informazioni specifiche
sull’insetto e sulle uova note agli entomologi ma non correntemente impiegate nella diagnosi clinica dei dermatologi.
Con il dermatoscopio l’identificazione del Phthirus pubis può avvenire in vivo ed in situ per mezzo di due attributi specifici della lendine rappresentati dalla forma conoidale dell’opercolo e dall’ampio manicotto di fissaggio della
stessa al pelo.
Tali aspetti permettono all’operatore di risalire al tipo
di pidocchio infestante specialmente quando l’insetto non
è più reperibile o le uova si trovano in sedi diverse dal
pube.
L’entodermoscopia (la dermoscopia ad indirizzo entomologico) quindi sembra promettere vantaggi importanti
rispetto all’osservazione al microscopio ottico in termini
di immediatezza dell’analisi in corso di visita ma anche in
termini di specificità a condizione che il dermatologo abbia
qualche conoscenza di entomologia sul parassita.
Parole chiave: Dermoscopia - Pediculus - Phthirus.
Vol. 147 - No. 1
SCANNI
References
1. Chuh A, Lee A, Wong W, Ooi C, Zawar V. Diagnosis of pediculosis
pubis: a novel application of digital epiluminescence dermatoscopy.
JEADV 2007;21:822-49.
2. Parish LC. History of pediculosis. LC Parish - Scabies and Pediculosis. Philadelphia: JB Lippincott; 1977.
3. Signore RJ, Love J, Boucree MC. Scalp infestation with phthirus
pubis. Arch Dermatol 1989;125:133.
4. Scanni G, Bonifazi E. Viability of the head louse eggs in pediculosis
capitis. A dermoscopy study. Eur J Pediatric Dermatol 2006;16:201-4.
5. Scanni G, Bonifazi E. Head lice. Eur J Pediatric Dermatol
2008;18:33-64.
6. Burkhart CN, Gunning W, Burkhart CG. Scanning electron microscopic examination of the egg of the pubic louse (Anoplura: Pthirus
pubis). Int J Dermatol 2000;39:201-2.
7. Burkhart CN, Birkart CG, Gunning WT, Arbogast J. Scanning electron microscopy of the of human head louse eggs (Anoplura: Pediculidae) and its clinical ramifications. J Med Entomol 1999;36:4546.
8. Buxton PA. The louse. An account of the lice which infest man,
their medical importance and control. 2ndEd. Edward Arnold & Co.
London viii+164; 1974
9. Howard V, Weems Jr. Crab louse, Pthirus Pubis (anoplura: Pediculidae), its detection and control. Entomology Circular No. 211
February 1980. Fla. Dep. and Consumer Services Division of Plant
Industry.
10. Burkhart CN, Burkhart CG. Head lice: Scientiﬁc assessment of the
nit sheath with clinical ramiﬁcations and therapeutic options. J Am
11. Zalaudek I, Giacomel J, Cabo H, Di Stefani A, Ferrara G, HofmannWellenhof R et al. Entodermoscopy: a new tool for diagnosing skin
infections and infestations. Dermatology 2008;216:14-2.
117

Papular-purpuric “gloves and socks” syndrome
R. BILENCHI, M. DE PAOLA, S. POGGIALI, S. ACCIAI, L. FECI, P. SANSICA, M. FIMIANI
Papular-purpuric “gloves and socks” syndrome (PPGSS),
is an acute dermatosis characterized by a papular-purpuric
edematous rash in a distinct ‘‘gloves and socks’’ distribution often accompanied by fever, asthenia and lymphadenophaties. It is mainly caused by parvovirus B19 (B19V) but
other viruses and drugs such as trimethoprim/sulfametaxol
or chemotherapics may be involved. We describe a case
of PPGSS with a serologically proven B19V infection in a
42-year-old Italian kindergarten teacher suffering from acute
bacterial pharyngitis Immunoglobulin M by enzyme-linked
immunosorbent assay (ELISA) to parvovirus B19 were positive. Histological examination showed dermal-ipodermal
inflammation with evidence of leukocytoclastic vasculitis
principally interesting the small venules The cutaneous rash
resolved after 2 weeks. We reported our case to support that
PPGSS is an immunomediated disease and that B19V morbidity varies with the immunologic and hematologic status of
the host. In addition, a patient with PPGSS might be infectious at the moment of diagnosis, with significant implication
for susceptible contacts.
Key words: Parvovirus B19, Human - Enzyme-linked immunosorbent assay - Skin diseases.
P
apular-Purpuric “Gloves and Socks” Syndrome
(PPGSS), first described by Harms et al. in
1990,1 is an acute dermatosis characterized by a papular-purpuric edematous rash in a distinct “gloves
and socks” distribution. It clinically presents with a
Received on February 8, 2011.
Correspondence to:��
Dr. R. Bilenchi, Section of Dermatology, Department of Clinical and Immunological Medicine, University
��
of Siena, Policlinico, Le Scotte, 53100 Siena, Italy.
E-mail: [email protected]; [email protected]
Vol. 147 - No. 1
Section of Dermatology
Department of Clinical Medicine
and Immunological Sciences
University of Siena, Siena, Italy
painful, pruritic edema and a purpuric erythema rapidly evolving in petechias limited to the palms, soles
and dorsal areas of the hands and feet. Cutaneous
lesions are often accompanied by fever, asthenia and
lymphadenopathies. Less frequently, elbows, knees,
external genitalia and oral mucosa may be involved,
showing enanthema and painful multiple erosions.
The disease is self-limited with a short course and
a benign prognosis in most cases: the exanthema
usually resolves within 1 to 2 weeks under symptomatic treatment. More than half of the reported
cases have implicated parvovirus B19 (B19V) as the
causative agent,2 but other viruses (including Human
Herpes Virus 6, Coxackie A and B, measles, rubella
Virus, Hepatitis B, CMV, EBV) should also be involved.2-4 In addition, drugs such as trimethoprim/
sulfametaxol or chemotherapics have been found to
induce PPGSS.5 We describe a case of PPGSS with
a serologically proven B19V infection in a 42-yearold Italian woman suffering from acute bacterial
pharyngitis.
Case report
A 42-year old kindergarten teacher was admitted to our
department with a 5-day history of painful burning redpurple papules, associated with purpuric erythema, local-
119
BILENCHI
PAPULAR-PURPURIC “GLOVES AND SOCKS” SYNDROME
Figure 1.—Purpuric erythema, localized on the palmo-plantar surface and on the dorsal areas of the feet and hands.
ized on the palmo-plantar surface and on the dorsal areas
of the feet and hands. A well-defined symmetric limit was
evident at the wrists and ankles (Figure 1). Similar but
non itching, non purpuric, erythematous lesions were recognized on the chest, neck, cheeks, chin and nose. Enanthema, lymphadenopathy, liver and spleen enlargement
as well as signs of meningeal irritation, were not evident.
The patient also revealed a 3-day history of pharyngitis,
anorexia, myalgia, arthralgia and joint pain associated with
intermittent fever (up to 39 °C). She denied having taken
any medications and was not aware of any allergies. There
was no history of blood transfusion, foreign travel, insect
bites, tick exposures, or outdoor activities. Blood chemistry revealed an elevated erythrocyte sedimentation rate
and C-reactive protein while the leukocyte count was decreased (with neutrophils raised to 73.4% and lymphocytes
reduced to 15.7%). A crioglobulin study showed the presence of crioglobulin type III, a criofibrinogen and crio
immunofixation (IgA, IgG, IgM) test revealed polyclonal
IgG and IgM. On admission, immunoglobulin M and immunoglobulin G antibodies by enzyme-linked immunosorbent assay (ELISA) to parvovirus B19 were negative,
but after five days the IgM dropped to 17 UE/ml (N.<10).
Serology for CMV, EBV, HIV1, HIV2, HBV, HCV, HSV1,
HSV2, Coxsackie viruses, and rickettsiosis were negative.
A pharynx swab culture showed staphylococcus pyogenes. Histological examination showed dermal-ipodermal
inflammation with evidence of leukocytoclastic vasculitis
principally interesting the small venules. On these bases
a PPGSS was suspected. Considering the positivity of
120
the swabs, our patient was treated with antibiotic therapy
(amoxicillin + clavulanic acid 1 gram twice a day) for 10
days. The cutaneous rash resolved after 2 weeks.
Discussion and conclusions
Since 1991, when IgM antibodies anti-B19 were
first detected in the serum of a patient with PPGS,6
the association between PPGSS and B19V has been
widely reported but serological or DNA evidence of
B19 has been documented so far only in about 50
cases of PPGSS.2
In fact, B19V cannot be grown in conventional
cell cultures. Its diagnosis is not always easy and
is primarily based on the detection of specific antibodies by enzyme-linked immunosorbent assay or
on the detection of viral DNA by dot blot hybridization or PCR. Our case confirms the association of
PPGSS with B19V, demonstrated by seroconversion.
A peculiarity of our case was the presence of the associated symptoms including pharyngitis, anorexia,
myalgia, arthralgia and joint pain associated with
intermittent fever. Adults with B19V infection are
generally asymptomatic or have mild, nonspecific,
cold-like symptoms. We hypothesize that the immune response related to the pharyngitis may have
February 2012
PAPULAR-PURPURIC “GLOVES AND SOCKS” SYNDROME
contributed to the appearance of the viral syndrome
and to the important cutaneous manifestations.
Although the pathogenetic mechanism underlying
the mucocutaneous manifestations of PPGSS is still
unclear, most of the current hypotheses referred to a
vascular reaction to an antigenic stimulus.4 Studies
based on direct immunofluorescence investigations
demonstrated C3, and immunoglobulin depositions
in dermal vessels, and/or a cytotoxic reaction to virally infected cells.7 In our patient, the multiple antigenic stimuli may have contributed to the rise of
significant cutaneous lesions and the vasculitis may
be related to the presence of crioglobulin type III and
criofibrinogen.
In conclusion, we reported our case to support
that PPGSS is an immunomediated disease and that
B19V morbidity varies with the immunologic and hematologic status of the host. B19V infection should
be always considered in the initial workup of any patient presenting with a petechial/purpuric eruption of
unclear origin in particular in patients in close contact with children, as in our case, or in the immunosuppressed. Considering that a patient with B19V
infection might still be infectious at the time of the
diagnosis with significant implications for susceptible contacts, all patients with palmo-plantar petechial
and purpuric eruption should be considered PPGSS
carriers until the contrary has been demonstrated.
The main differential diagnoses of PPGSS include
necrotizing vasculitis, Henoch-Schönlein purpura,
giant-cell arteritis, hepatitis and myocarditis, early
stage of vasculitis, multiform erythema, Kawasaki
disease in the initial phase, idiopathic palmo-plantar
hidradenitis, hand-foot-mouth syndrome, GiannottiCrosti syndrome and acral erythema during chemotherapy.
Vol. 147 - No. 1
BILENCHI
Riassunto
Sindrome papulo-purpurica “guanti e calzini”
La sindrome “Guanti e Calzini” è una dermatosi acuta
delle estremità caratterizzata da un rash eritemato edematoso, con elementi papulari e purpurici, che si interrompe
tipicamente in corrispondenza di polsi e caviglie. Le lesioni cutanee sono sovente accompagnate da febbre, astenia e
linfoadenopatie. Il parvovirus B19 (B19V) è l’agente etiologico più frequente, anche se altri virus o farmaci, come i
sulfamidici, sono stati chiamati in causa. Riportiamo il caso
di una maestra di asilo di 42 anni con Sindrome Guanti e
Calzini associata ad infezione da B19V e faringite batterica.
Parole chiave: Parvovirus B19, umano - Saggio immunoassorbente legato all’enzima - Malattie cutanee.
References
1. Harms M., Feldmann R., Saurat J.H. Papular-purpuric “gloves and
socks” syndrome. J Am Acad Dermatol 1990;23:850-4.
2. Sklavounou-Andrikopoulou A, Lakovou M, Paikos S, Papanikolaou
V, Loukeris D, Voulgarelis M. Oral
��
manifestations of papular-purpuric ‘gloves and socks’ syndrome due to parvovirus B19 infection:
the first case presented in Greece and review of the literature. Oral
Dis 2004;10:118-22.
3. Passoni LF, Ribeiro SR, Giordani ML, Menezes JA, Nascimento JP.
Papular-purpuric “gloves and socks” syndrome due to parvovirus
B19: report of a case with unusual features. Rev Inst Med Trop Sao
Paulo 2001;43:167-70.
4. Smith PT, Landry ML, Carey H, Krasnoff J, Cooney E.��
Papular-purpuric gloves and socks syndrome associated with acute parvovirus
B19 infection: case report and review. Clin infect Dis 1998;27:16489.
5. van Rooijen MM, Brand CU, Ballmer-Weber BK, Yawalkar N,
Hunziker TK. Drug-induced papular-purpuric gloves and socks
syndrome. Hautarzt 1999;50:280-3.
6. Bagot M., Revuz J. Papular-purpuric “gloves and socks” syndrome:
primary infection with parvovirus B19? J Am Acad Dermatol
1991;25:341-2.
7. Aractingi S, Bakhos D, Flageul B, Verola O, Brunet M, Dubertret L et al. Immunohistochemical and virological study of skin
in the papular-purpuric gloves and socks syndrome. Br JDermatol
1996;135:599-602.
121

Localized reactive erythemas of different types in a family
G. L. CAPELLA
“Reactive erythemas” is an umbrella term grouping several
different conditions, all of which have in common the fact of
being stereotypical inflammatory clinical patterns of the skin
in response to disparate infectious, immune, or toxic factors.
Typically, such eruptions are symmetrical or disseminated.
The here reported cases are different. An elderly man underwent recurrent infections of an epidermoid cyst, accompanied
by a typical erythema annulare centrifugum near the infectious
focus. His grandson, aged ten months, presented with an infectious conjunctivitis, during the resolution of which two small
annular lesions, compatible with annular erythema of infancy,
appeared on the face. A man aged 42, respectively son and father of the two former patients, presented with an erythema
multiforme target lesion proximally to an infected wound.
There were no detectable predisposing factors in all cases. Familial cases of reactive erythemas have been reported. However, such limited distributions have not yet been described.
Key words: Erythema - Erythema multiforme - Causality.
S
everal dermatological reactive patterns in response to a wide array of immune, infectious, or
chemical triggers are recognised, which, albeit quite
morphologically and clinically different, arise in similar etiological settings. Examples include 1 certain
subsets of urticaria and vasculitis; erythema nodosum; erythema multiforme (EM); erythema annulare
centrifugum (EAC) and its “microlesional” variants
Previously published in abstract form in the CD “Proceedings of the
Third Italian ADOI-SIDEMaST Unified Congress of Dermatology and
Venereology”, Rome, June 6th-9th, 2007.
Received on April 29, 2008.
Corresponding author: G. L. Capella, Private Practictioner, Dermatology & STD, Via Sauli Sant’Alessandro 7, 20127, Milan, Italy.
E-mail: progderm @ katamail.com
Vol. 147 - No. 1
Private Practictioner
Dermatology & STD, Milan, Italy
(erythema microgyratum perstans or erythema simplex gyratum, which were kept distinct in the former
literature);2 and erythema gyratum not otherwise
specified. 1 In the past, several authors endeavoured to
group some of these hypersensitivity reactions together.3-5 It could be argued that, given their morphoclinical heterogeneity, the analogy between such entities
is merely nominal (i.e., the term “erythema” followed
by a specification). However, because of their evident
aetiopathogenic affinity, it has come natural to gather
these conditions in the maybe provisional, yet well
defined category of “reactive erythemas” (REs).1, 5
Annular erythema of infancy (AEI) seems not
to be associated with definite triggering factors.6, 7
However, it is suspected to represent the manifestation of similar hypersensitivity mechanisms.8 Accordingly, in this paper AEI will be tracked back to
the RE group as well.
All REs usually involve several cutaneous districts, often in a symmetrical fashion, or even the
whole tegument. The here described familial cases
of REs are unusual in this regard, because they presented in a topographical restricted fashion, close to
a focal infection.
Clinical series
Case 1.—In 1997, a man aged 72 consulted because
of recurrent infections of an epidermoid cyst of the right
shoulder with a typical EAC near the infectious focus (Fig-
123
CAPELLA
Figure 1.—Case 1. EAC of the right laterocervical region. The
bleeding corresponded to the superinfected epidermoid cyst.
Figure 3.—Case 3. Monolesional EM of the dorsum of the hand,
proximal to the infected wound of the second finger. The characteristic evolution of the target lesion at days 5 (A), 8 (B), 10 (C)
and 13 (D) is detailed (photographs provided by the patient).
no dermatophytes or yeasts on microscopic examination.
After one week of centrifugal progression (maximum diameter attained 1.5 cm), spontaneous resolution took place
within 15 days. This boy was the grandson of patient n° 1.
Figure 2.—Case 2. Small annular lesion of the left superior eyelid. The faint erythematous macule over the glabella evolved into
an annular pattern within two days. Residual conjunctival hyperhemia can be appreciated.
ure 1). EAC flared up in coincidence with each infectious
episode, and cleared up after proper antibiotic treatment
(oral clarithromycin, 250 mg bid, topical sodium fusidate).
A brisk suppurative recurrence eventually brought about
the destruction of the cyst and the disappearance of EAC.
Case 2.—In autumn 2005, two faint, small, annular erythematous, nonscaling, slightly elevated, apparently nonpruritic lesions appeared on the superior left eyelid and the
forehead of a 10-month-old toddler, just after the resolution
of a bilateral infectious conjunctivitis treated with tobramycin eyedrops (Figure 2). The clinical picture was compatible
with AEI (see below, Discussion). Extemporary scotch-test:
124
Case 3.—A 42-year-old man, son and father of patients
n° 1 and 2, respectively. In summer 2006, 5 days after the
superinfection of an accidental cut wound of the right hand,
treated with topical sodium fusidate cream, an isolate EM
target lesion appeared proximally to the wound (Figure
3). Spontaneous resolution was typical, with detachment
of the central vesicle and re-epithelialization within three
weeks (Figure 3 A-D).
In all cases, proper laboratory investigations, including
ASLO, autoimmunity and tumour markers, thyroid hormones, coprocolture, cold agglutinins, HBV, HCV, CMV,
parvovirus B19, and rubella serology as required, yielded
negative results. Extemporary patch-tests with sodium
fusidate or tobramycin were negative as well. No patients
either presented evidence of arthropod assaults elsewhere
on the skin, or took relevant drugs. Patients n° 1, 2 did not
further develop pityriasis rosea, infectious or drug-related
exanthemas, or rheumatic fever. Patient n° 3 did not suffer
from clinically evident herpes simplex or infections of the
respiratory tract. No recurrences of the REs were observed
any more (follow-up of 14, 6, and 5 years, respectively).
Discussion
The outbreak of different REs in distinct members
of the same kinship is strikingly curious, but probably coincidental. Indeed, familial cases of EAC and
February 2012
erythema gyratum perstans have been observed. 9, 10
However, the peculiar limited topographical distribution of the REs here described is quite unusual and,
to the best knowledge of the author, unreported. In
a previously published case of erythema gyratum, 11
the infection was focal (odontogenic), but the skin
eruption showed a tendency to spread, as usual. Most
REs are known to associate - among others - to an
extended array of bacterial infections, even focal
ones.3, 4, 12, 13 Albeit bacteriological investigations
were not performed, clinical evidence and response
to specific therapy pointed to a staphylococcal aetiology in all of the 3 cases. It could be argued that two
patients (N. 2, 3) had applied topical drugs before
their RE appeared. However, leaving aside the fact
patch tests with the involved chemicals were negative, such an objection does not offer an answer to
the conundrum posed by the strict localisation of the
eruptions. Indeed, either EM or EAC can be triggered by several chemicals as well. 4, 13, 14 Notwithstanding, a merely local pattern of appearance, close
to the contact site of the putative offending drug or
allergen, has not yet been described as well: in the
only reported case of “contact EAC” to nickel and
cobalt,15 skin lesions were widespread. No ordinary
cases of either EM or EAC induced by topical application of sodium fusidate or tobramycin have been
described to date. Anyway, in the localised REs here
reported, the course of the skin lesions strictly paralleled that of the infection and/or the period of application of the topical medication, and their duration was very short as compared with the typically
long-lasting, even multiyear persistence characterising such conditions.6, 7, 16, 17 These considerations
turn out to be further circumstantial confirmations of
a putative causal link between a focal trigger and a
consequent localised RE.
Patient n° 2 posed special problems as to diagnostic classification. Clinical differential diagnosis of
AEI has been thoroughly dealt with by Peterson and
Jarratt.17 The duration and the annular shape of each
lesion, the absence of scaling and of fungi on microscopic examination,18 all pointed to the diagnosis of
a localised, microlesional variant of AEI. It should
be underscored that the diagnostic work-up of EAC
of the adult also applies to AEI.14 Such an operative attitude is dictated by the overt affinity existing
between these REs. Clearly, the apparently benign
clinical course prompted to avoid invasive diagnostic
procedures in a toddler, as purported elsewhere.6
Vol. 147 - No. 1
CAPELLA
In the here described cases, the physiopathological
process which would develop on systemic grounds
in ordinary cases of REs related to infections, autoimmune diseases, neoplasms, or drugs, seemed to
have taken place in a limited fashion instead, just
near a localised infection. The physiopathological
process which would develop on systemic grounds
in ordinary cases of Res, seemed here to have taken
place in a limited fashion. The observed cases apparently extend the variety of skin eruptions which
can be tracked back to the concept of “contiguous inflammation of the skin”.19 From a merely speculative
viewpoint, taking classical induction of tissue injury
by immune complexes 20 as a conceptual frame, it
could be advanced that, whereas in common cases
of REs critical concentrations of the responsible reactant would be reached throughout extended portions of the skin or even in the whole integument, in
localised REs such concentrations would be reached
only at a fixed critical distance from the focal trigger,
somewhere along a diffusion gradient of the reactant
itself. If we consider that EAC and AEI rings are extended lesions, unlike “punctiform” EM target ones,
such a model could be complicated by the speculation that diffusive concentration microfluctuations
on the edge of the critical distance could lead to an
anisotropic surface development of the lesion.21 This
would explain why annular elements were not exactly pivoted on the infectious foci. The author recognises that his interpretations are merely theoretical,
and questionable. Notwithstanding, the surprising
aspects of the clinical pictures he observed, along
with their familial clustering, arouse curiosity, and
should elicit a renewed interest in the understudied
topic of RE pathogenesis.
Riassunto
Eritemi reattivi localizzati di differente tipologia in una
famiglia
“Eritemi reattivi” è un termine generico che indica cumulativamente diverse condizioni, accomunate dal fatto
di costituire modalità stereòtipe ad espressione cutanea di
reazioni infiammatorie in risposta a svariati fattori infettivi, disimmunitari o tossici. Tipicamente, queste eruzioni si
manifestano in regioni tegumentarie simmetriche, o sono
disseminate. I casi qui descritti sono differenti al riguardo.
Un uomo di 73 anni accusava ripetuti episodi di sovrinfezione di una cisti epidermoide, accompagnati da un tipico
eritema anulare centrifugo a ridosso del focolaio infettivo.
125
CAPELLA
Suo nipote, dell’età di dieci mesi, durante la risoluzione
di una congiuntivite infettiva presentò due piccole lesioni
anulari del volto, compatibili con la diagnosi di eritema
anulare dell’infanzia. Un quarantaduenne, rispettivamente
figlio e padre dei due pazienti precedenti, manifestò un eritema polimorfo unilesionale prossimalmente ad una ferita
infetta di una mano. Non si rilevarono altri fattori predisponenti in nessuno dei tre casi. Sono stati descritti casi
familiari di eritemi reattivi, ma del medesimo tipo e non
caratterizzati dalla distribuzione limitata perifocale riscontrabile nella presente casistica.
Parole chiave: Eritema - Eritema multiforme - Causalità.
References
1. White JW Jr. Hypersensitivity and miscellaneous inflammatory disorders. In: Moschella SL, Hurley HJ, editors. Dermatology. 2nd edition. Philadelphia-London: Saunders; 1985. p. 464-98.
2. Harrison PV. The annular erythemas. Int J Dermatol 1979;18:28290.
3. Monacelli M, Nazzaro P. Dermatologia e Venereologia. Milan: Vallardi; 1967. p. 471-87.
4. Dowd PM, Champion RH. ��
Disorders of blood vessels. In: Champion RH, Burton JL, Burns DA, Breathnach SM, editors. Rook/
Wilkinson/Ebling Textbook of Dermatology. 6th edition. OxfordLondon:Blackwell Science; 1998. p. 2073-97.
5. Tyring SK. Reactive erythemas: erythema annulare centrifugum
and erythema gyratum repens. Clin Dermatol 1993;11:135-9.
6. Hebert AA, Esterly NB. Annular erythema of infancy. J Am Acad
Dermatol 1986;14:339-43.
7. Kunz M, Hamm K, Bröcker EB, Hamm H. Das anuläre Erythem des
126
Kindesalters - eine neue eosinophile Dermatose. Hautarzt 1998;49:
131-4.
8. Helm TN, Bass J, Chang LW, Bergfeld WF. Persistent annular erythema of infancy. Pediatr Dermatol 1993;10:46-8.
9. Beare JM, Frogatt P, Jones JH, Neill DW. Familial annular erythema.
An apparently new dominant mutation. Br J Dermatol 1966;78:59-68.
10. Delfino M, Suppa F, Piccirillo A, Bruno G, Monfrecola G. Erythema gyratum perstans: association with a familial neurologic disease. Dermatologica 1986;172:68-71.
11. Monti M, Cavicchini S, de Bitonto A, Caputo R. Gyrate erythema in
a patient with dental radicular cyst. Dermatologica 1987;174:30-3.
12. Degos R:Dermatologie. Paris:Flammarion;1983. p. 263.
13. Saurat JH. Érythème polymorphe et syndrome de Stevens-Johnson. In:Saurat JH, Grosshans E, Laugier P, Lachapelle JM, editors.
Dermatologie et Maladies Sexuellement Transmissibles. 3rd edition.
Paris:Masson; 1999. p. 285-9.
14. Saurat JH, Grosshans E. Dermatoses figurées. In:Saurat JH, Grosshans E, Laugier P, Lachapelle JM, editors. Dermatologie et Maladies Sexuellement Transmissibles. 3rd edition. Paris:Masson; 1999.
p. 816-21.
15. Sànchez Sambucety P, Gil Agapito P, Rodriguez Prieto MÁ. Contact
erythema annulare centrifugum. Contact Dermatitis 2006;55:309-10.
16. Mahood JM. Erythema annulare centrifugum:a review of 24 cases
with special reference to its association with underlying disease.
Clin Exp Dermatol 1983;8:383-7.
17. Peterson AO Jr, Jarratt M. Annular erythema of infancy. Arch Dermatol 1981;117:145-8.
18. Kikuchi I, Ogata K, Inoue S. Pityrosporum infection in an infant
with lesions resembling erythema annulare centrifugum. Arch
��
Dermatol 1984;120:380-2.
19. Helmbold P, Kaufhold A, Hegemann B, Marsch WC. Contiguous
inflammation of the skin. Eur J Dermatol 1999;9:48-50.
20. Halpern B. Hypersensibilité du type immédiat. In:Bordet P, editor.
Immunologie. Paris: Flammarion; 1972. p. 999-1054.
21. Altomare GF, Capella GL, Pigatto PD. L’accrescimento dei frattali
nella genesi delle dermatosi figurate ed arciformi. G Ital Dermatol
Venereol 1993;128:497-501.
February 2012

Sweet’s syndrome with panniculitis
46-year-old woman, with no past medical history,
presented to our Department of Dermatology with
an abrupt eruption localised to her arms. On physical examination, erythematous vescico-bullous plaques of the
upper limbs (Figure 1) together with painful and violaceous infiltrated plaques and nodules of the lower limbs
(Figure 2) were noted. There were no palpable lymphadenopathies, nor associated systemic symptoms. The patient was afebrile. On examination, a concomitant painful
and purulent gingival pocket was noted in her mouth. No
oral swab was performed as the patient had just started
antibiotics.
A punch biopsy of one lesion of her right arm was
performed showing marked oedema of the papilla-ry
dermis with flattening of the rete ridges (Figure 3). A
dense perivascular mainly neutrophilic but also lymphocytic infiltrate was present; some neutrophils sho-wed
bilobated nuclei. Vasodilation and endothelial swelling were noted, with no evidence of vasculitis (Figure
4). The findings appeared consistent with Sweet’s syndrome.
Laboratory showed mild leukocytosis (11000/mm3),
with marked neutrophilia (86%), and elevated markers of
inflammation (ESR: 89 mm/1st hour; C-reactive protein:
11,7 mg/L); renal function, liver function and electrophoresis of seroproteins were in the normal range. Positive
anti-nuclear antibodies (titer 1:160), with homogeneous
pattern and negative anti-extractable nuclear antigens antibodies were found. Chest X-ray was normal.
Cutaneous and parodontal lesions resolved dramatically
within one week of oral Amoxicillin-Clavulanate (2 g/day
for 7 days), Paracetamol (1 g/day) and rest.
A diagnosis of Sweet’s syndrome with Sweet’s panniculitis was made.
Sweet’s panniculitis is rare and idiopathic.1 It presents as
neutrophilic panniculitis, usually from secondary spread-
Figure 1.—An erythematous vescico-bullous plaque of the left
upper arm.
Figure 2.—Violaceous infiltrated plaques and nodules of the right
knee.
E. BASSI 1, R. ROSSO 2, G. FIANDRINO 2,
C. DE FILIPPI 1
1Department of Dermatology
Siro Delmati Hospital, Sant’Angelo Lodigiano, Lodi, Italy
2Department of Human and Hereditary Pathology
Pathology Section, University of Pavia
IRCCS Policlinico San Matteo, Pavia, Italy
Dear Editor,
A
Vol. 147 - No. 1
127
Figure 3.—Edema of the papillary dermis with flattening of the rete
ridges. Dense perivascular mainly neutrophilic infiltrate, vasodilation and endothelial swelling, with no evidence of vasculitis (H&E).
Figure 4.—Dense perivascular mainly neutrophilic infiltrate, vasodilation and endothelial swelling, with no evidence of vasculitis.
ing of dermal neutrophils into the subcutaneous fat.2 Only
in rare cases, it can present as isolated panniculitis, with
neutrophils invading the subcutis alone.3 It can present as
lobular or, less frequently, septal or mixed panniculitis.
Like classical Sweet’s syndrome, it can be associated with
malignant hemopathies.3
As reported in the literature, Sweet’s syndrome can be
associated with infections, such as Yersinia enterocolitica,
Mycoplasma pneumoniae, Mycobacterium tuberculosis,
atypical mycobacteria and HIV infection. In our case, the
cutaneous eruption rapidly followed the oral infection. The
dramatic response to antibiotics leads to the diagnosis of
Sweet’s syndrome associated with parodontal infection, or
post-infectious Sweet’s syndrome. As stated previously, an
oral swab was not performed because the patient had just
started antibiotics.
In the differential diagnosis, even if rare, we considered
the association of Sweet’s syndrome and erythema nodosum.4,5 Both are reactive dermatoses, which can be postinfectious in origin and may be treated with the same drugs
(i.e., corticosteroids, potassium iodide).
We excluded the last diagnosis because of the multiplicity of lower legs lesions and their rapid healing with no
hecchimotic halos: erythema nodosum usually presents
with fewer lesions, which last longer and heal with typical hecchimotic macules. Histopathologically, Sweet’s
panniculitis differs from erythema nodusum as the former
presents as neutrophilic, mainly lobular panniculitis, while
the latter is characterized by a granulomatous inflammation, with a mostly septal panniculitis.
Early lesions of erythema nodosum can contain neutrophils, but more often lymphocytes and histiocytes with
giant cells are present. Since we did not perform a deeper
confirmatory biopsy we are unable to discuss histopatological differential diagnosis in our case.
In conclusion, we describe a rare case of Sweet’s syndrome and panniculitis, after parodontal infection. We
would like to underline the importance of recognizing
this entity, for its abrupt onset and possible associated
disorders. Misdiagnosis of Sweet’s panniculitis can lead
to unnecessary investigations and inappropriate treatment.
128
References
1. Guhl G, Garcia-Diez A. Subcutaneous Sweet syndrome. Dermatol
Clin 2008;26:541-51.
2. Cohen PR. ��
Subcutaneous Sweet’s syndrome: a variant of acute febrile neutrophilic dermatosis that is included in the histopathologic
differential diagnosis of neuthophilic panniculitis. J Am Acad Dermatol 2005;52:927-8.
3. Cullity J, Maguire B, Gebauer K. Sweet’s panniculitis. Australas J
Dermatol 1991;32:61-4.
4. Wasson S, Folzenlogen D. Concurrent occurrence of Sweet’s syndrome and eryhtema nodosum: an overlap in the spectrum of reactive dermatosis. Clin Rheumatol 2006;25:268-72.
5. Mazokopakis E, Kalikaki A, Stathopoulos E, Vrentzos G, Papadakis
JA. Acute febrile neutrophilic dermatosis (Sweet’s syndrome) with
erythema nodosum and anterior scleritis. A case report. Int
��
J Dermatol 2005;44:1051-3.
Funding.—None.
Corresponding author: E. Bassi, Department of Dematology, Siro
Delmati Hospital, strada Provinciale 19, 26866 Sant’Angelo Lodigiano,
Lodi, Italy. E-mail: [email protected]
February 2012

Erythema annulare centrifugum:
a “deep type” figurate eruption
F. BAGLIERI, G. SCUDERI
Department of Dermatology
S. Elia Hospital, Caltanissetta, Italy
Dear Editor,
E
rythema annulare centrifugum (EAC) is an uncommon
inflammatory skin disease with unknown etiology,
nowadays considered a clinical reaction pattern and not
a specific clinicohistologic entity, clinically characterized
by slowly peripherally enlarging annular, arcuate or polycyclic erythematous lesions, preferentially affecting the
trunk, buttocks, thighs and legs.1, 2 The lesions have a tendency for spontaneous resolution and exacerbations over
a period of several months or years. Patients are usually
asymptomatic, except for mild pruritus.
We report a 48-year-old woman presenting with a
5-months history of annular pruritic eruptions on her extremities. Cutaneous examination revealed large, well-defined annular and polycyclic erythematous plaques located
on the buttocks, thighs and lower legs (Figure 1).
The lesions had firm, slightly raised borders with no signs
of scaling. Review of systems as well as the family history
were unremarkable. Routine laboratory investigations were
within normal limits. Tests for anti-nuclear antibodies, Borrelia burgdorferi serology and carcino-embryonic antigen
were negative. Cultures showed no evidence of fungi. A
biopsy specimen was obtained from the active border of
a lesion on the back surface of the right leg. Microscopic
examination revealed a dense perivascular and periadnexal
lymphocytic infiltrate in the superficial and reticular dermis with numerous eosinophils and absence of epidermal
involvement (Figure 2). Periodic acid-Schiff (PAS) staining
was negative. Clinico-pathologic findings were consistent
with the diagnosis of EAC, “deep type”. The patient was
successfully treated with systemic corticosteroids (methylprednisolone, 4 mg/day) in association with twice-daily
application of methylprednisolone aceponate 0.1% cream,
with complete regression of cutaneous lesions within 4
weeks. After a follow-up period of 12 months, no recurrence of cutaneous lesions has been observed.
EAC was first described by Jean Darier in 1916,3 and
classified in 1978 by Ackerman into a deep and a superficial variant.1 The deep variant of EAC clinically appears
with a firm, indurated border, devoid of scales, and is rarely associated with pruritus. Histopathologically, the deep
type shows a moderately dense perivascular lymphocytic
infiltration with a “sleeve-like” arrangement in the upper
and deep dermis, with lack of epidermal involvement. The
superficial form clinically presents with an indistinct bor-
Vol. 147 - No. 1
der with a delicate rim of scale on the inner margin of the
advancing edge of erythema and pruritus. In addition to
a mild superficial perivascular lymphocytic infiltrate, frequent epidermal changes including focal spongiosis, parakeratosis, edema of the papillary dermis and epidermal
hyperplasia are common histopathologic features observed
in the superficial type. In both variants the infiltrating cells
are mostly lymphocytes, but histiocytes, eosinophils and
rarely neutrophils can be observed. [1] Whether the superficial and deep types of EAC are variants of the same entity or unrelated conditions is still controversial. Based on
clinical and histopathologic differences between the superficial and deep type of EAC, several authors indeed support
the clear-cut separation of these two entities.4
Clinical differential diagnoses of EAC include a large
spectrum of cutaneous diseases presenting with annular
lesions such as granuloma annulare, urticaria, tinea corporis, erythema migrans, discoid and subacute lupus erythematosus and cutaneous lymphomas (mycosis fungoides
and B-cell lymphoma). [1, 5] Annular elements can be also
found in the urticarial stage of bullous pemphigoid and
pemphigus vulgaris, lichen planus, sarcoidosis, syphilis,
erythema multiforme, pityriasis rosea and psoriasis. In
the case described here, the clinical aspect of the lesions
was suggestive of granuloma annulare, subacute lupus erythematosus and cutaneous B-cell lymphoma. Histopathologic differential diagnoses of EAC include tumid lupus
erythematosus, Jessner’s lymphocytic infiltration and early
stage of polymorphic light eruption when the superficial
and deep perivascular infiltrate is composed entirely of
lymphocytes.4 However, a marked edema of the papillary
dermis is usually observed in polymorphic light eruption
and mucin in the reticular dermis in tumid discoid lupus
erythematosous. Additional differential diagnoses such
as drug eruption, urticaria and bullous pemphigoid (urticarial stage) should be considered in cases characterized
by numerous eosinophils. In our case, clinico-pathologic
features of the figurate eruption were consistent with the
diagnosis of the deep form of EAC.
The pathogenesis of EAC is not fully understood. EAC
is thought to represent a hypersensitivity reaction triggered
by infections due to bacteria, virus, fungi, mycobacteria or
parasites, medications, autoimmune diseases, hormonal influences, pregnancy and malignant neoplasms.6-8 However,
most cases remain unexplained. Clinical and laboratory
findings may be helpful to prove a causal relationship between EAC and an associated disease and the eruption often
resolves after successful treatment of the underlying disease. No causal relationship could be proved in our patient.
EAC tends to be persistent over several months to a few
years, waxing and waning in severity, but some cases eventually regress spontaneously. No routinely effective therapy is currently available unless a triggering factor can be
identified and eliminated. Systemic and topical corticosteroids usually suppress EAC, as observed in our patient, but
recurrence is common when these drugs are stopped. Oral
antihistamines may be helpful for pruritus. Use of antibiot-
129
Figure 1.—Annular and polycyclic erythemato-infiltrated lesions located on thighs and lower legs.
ics and antifungal medications as well as topical vitamin D
analogues in combination with 311 nm ultraviolet B narrow band phototherapy has been successfully reported in
sporadic cases.9, 10
References
Figure 2.—Superficial and deep dermal dense perivascular and periadnexal lymphocytic infiltrate with numerous eosinophils (HE, x50).
130
1. Weyers W, Diaz-Cascajo C,Weyer I. Erythema annulare centrifugum. Results of a clinicopathologic study of 73 patients. Am J
Dermatopathol 2003;25:451-62.
2. Ziemer M, Eisendle K, Zelger B. New concepts on erythema annulare centrifugum: a clinical reaction pattern that does not represent
a specific clinicopathological entity. Br J Dermatol 2009;160:11926.
3. Darier J. De l’érythème annulaire centrifuge (érythème papulocirciné migrateur et chronique) et de quelques eruptions analogues.
Ann Dermatol Syph 1916;6:57-76.
4. Ackerman AB, Boer A, Bennin B, Gottlieb GJ. Definition of terms.
In: Ackerman AB, editor. Histologic diagnosis of inflammatory skin
February 2012

diseases: an algorithmic method based on pattern analysis. 3rd edition. Baltimore: Williams & Wilkins; 1997. p. 167.
5. Kim KJ, Chang SE, Choi JH, Sung KJ, Moon KC, Koh JK. Clinicopathologic analysis of 66 cases of erythema annulare centrifugum. J
Dermatol 2002;29:61-7.
6. Kurosa K, Yabunami H, Hisanaga Y. Etizolam-induced superficial
erythema annulare centrifugum. Clin Exp Dermatol 2002;27:34-6.
7. Panasiti V, Devirgiliis V, Curzio M, Rossi M, Roberti V, Bottoni U et
al. Erythema annulare centrifugum as the presenting sign of breast
carcinoma. J Eur Acad Dermatol Venereol 2009;23:318-20.
8. Stokkermans-Dubois J, Beylot-Barry M, Vergier B, Bouabdallah K,
Doutre MS. Erythema annulare centrifugum revealing chronic lymphocytic leukaemia. Br J Dermatol 2007;157:1045-7.
9. Minni J, Sarro R. A novel therapeutic approach to erythema annulare centrifugum. J Am Acad Dermatol 2006;54:134-5.
10. Reuter J, Braun-Falco M, Termeer C, Bruckner-Tuderman L. Erythema annulare centrifugum Darier. Successful therapy with topical
calcitriol and 311 nm-ultraviolet B narrow band phototherapy. Hautarzt 2007;58:146-8.
delimited subepidermal nodular lesion with proliferation of
basophilic cells (without atypias), anucleated eosinophilic
cells (shadow cells) and areas of variable keratinisation.
Case 2.—A six-month-old boy consulted us for a
nodule on the right mandibular region present since two
months. Physical examination showed a red-bluish nodule, about 10 mm in diameter, not fixed to underlying tissue, with some telangiectasias and an hard consistence
(Figure 2). Ultrasonography showed: unechogenic lesion
with hyperecogen rim and rich peripheric vascularization. Magnetic resonance imaging (MRI) revealed: round
Conflicts of interest.—None declared.
Corresponding auhtor: F. Baglieri, MD, Department of Dermatology
S. Elia Hospital, Via Luigi Russo 6, 93100 Caltanissetta, Italy.
Pilomatrixoma, a misdiagnosed
lesion: two pediatric case reports
I. NERI, A. VIRDI, A. PATRIZI
Internal Medicine Aging and Nephrologic Disease
Department, Dermatology Division, Sant’Orsola-Malpighi
Hospital, University of Bologna, Bologna, Italy
Figure 1.—Seven-month-old girl with clearly delimited, solid and
protuberant red nodule on the right supraorbital region, surrounded by an erythematous halo.
Dear Editor,
P
ilomatrixoma is a benign cutaneous tumour arisen from
hair follicle matrix cells and common under 20 years of
age and in the sixth decade of life,1 but frequently misdiagnosed. We describe here two atypical pediatric cases of
pilomatrixoma, with an early onset and unusual characteristics at the physical and instrumental examination.
Case 1.—A newborn girl developed a nodule on the
right supraorbital region and was brought to us after seven
months. Physical examination showed a clearly delimited,
solid and protuberant red nodule, 11´7 mm in diameter, surrounded by an erythematous halo (Figure 1). Ultrasonography showed in the soft tissue an oval slightly inhomogeneous, mainly hypoechoic lesion delimited by an hyperechoic
rim with some vascular spots. This picture suggested vascular malformation. After one month the nodule became
twice and we required a surgical excision. Histological
examination was compatible with pilomatrixoma: a well
Vol. 147 - No. 1
Figure 2.—Six-month-old boy with a red-bluish nodule not fixed
to underlying tissue, with some telangiectasias and an hard consistence.
131
formation (about 15 mm in diameter) in soft tissue, with
hypointense signal in T1-weighted images (T1W1) and
hyperintense signal (fluid type) in T2-weighted images
(T2W2); it had a multiple lobular aspect due to internal
septa, and regular margins with cleavage plane; contrast
medium administration produced peripheric rim enhancement and a weak intralesional contrast enhancement. According to radiologists MRI was compatible with cystic
lymphatic dysplasia and a very small vascular component
was associated. After one month after the first dermatological consultation, the lesion increased (as reported with
MRI), became more protuberant and red colored, with
an angiomatous aspect. It was surgically excised: macroscopically it seemed a calcifying and well-delimited
dermal nodule and histologic examination confirmed the
diagnosis of pilomatrixoma.
Generally pilomatrixomas present as single lesions in
the head and maxillofacial zone and less frequently in
limbs and trunk.1 In the early period pilomatrixomas are
usually cystic and consist of uniform basaloid cells lining
the cystic cavity, ghost cells (dead cells without nucleus)
and keratin. Late lesions are characterized by ghost cells,
keratin debris, secondary multinucleate giant cells, dystrophic calcification and sometimes bone formation.2
Often clinical diagnosis is difficult. Lesions that may
be considered in the differential diagnosis with typical pilomatrixoma are: epidermal cysts, calcified lymph nodes,
calcified hematomas, foreign body granulomas, osteomas
of the skin, dermoid cysts, parotid gland tumors and atheromas.3 Unlike dermoid and epidermal cysts, pilomatrixomas
are mobile and may present with irregular nodules.
In our cases lesion appeared very early and presented as
non-tender nodule with a red-bluish discoloration that may
be due to growth of blood vessels into the overlying skin
or to hemorrhage. This angiomatous aspect may mislead
clinicians to hemangioma and vascular malformation. Hemangioma onset generally occurs earlier than pilomatrixoma: at birth in one third of patients and after the birth (in
the first weeks until one year) in the remaining two thirds.
Head and neck are the most frequent localization of both
lesions. Generally hemangioma is softer and compressible
on the palpation and growth is faster than pilomatrixoma,
but is followed by a slow regression in the childhood, while
spontaneous regression has never been observed in the latter lesion. Also vascular malformations do not regress but
grow commensurate with the child.
In the literature there are few report of pilomatrixoma
that have been misdiagnosed as hemangiomas. Some of
these were histologically classified as lymphangiectatic
type for the presence of vascular spaces between the tumor
and the epidermis and atrophic epidermis.1
In patient 1 the rapid growth of the lesion is unusual and
may be mistaken with a malignant feature, although it is
very unlikely.
In both cases we could not make a certain diagnosis on
the basis of instrumental investigations. The ultrasonographic image of fully or partial calcified pilomatrixoma
132
is: a completely echogenic mass (or with inner echogenic
foci), with peripheral hypoechoic rim or with strong posterior or acoustic shadowing in the subcutaneous layer, suggestive of calcifications.4
In the first and in second case the lesions were hypoechogenic and anechogenic, respectively, with peripheral
hyperechoic rim and without posterior shadowing. The
lesion presented vascular spots in the first patient and a
rich peripheric vascularization in the other, resembling a
vascular malformation. Also in four cases of a recent ultrasound study of pilomatrixoma vascular signals are reported, usually peripheric and only rarely intra-lesional.4 Generally calcifications and sign of inflammation occur late 4
and probably in these patients vascularization or vascular
spot may be related to inflammation. Hypoechogenic ultrasound pattern is present also in vascular malformation.
Recently Solivetti et al. have reported new ultrasound pattern of pilomatrixoma with three new types that have never
been described. These may be recognized with the use of
high-frequency probes.4
MRI is considered inconclusive, in fact in the Lim series only 60% of pilomatrixoma were correctly diagnosed.5
As in our case, MRI may reveal internal reticulations and
patchy areas on T2-weighted images and contrast-enhanced
T1-weighted images, corresponding to edematous stroma.5
According to the new ultrasound classification 4 and on the
basis of MRI and ultrasonographic images, in this case pilomatrixoma may belong to type 3 (pseudo-cystic lesion),
one of the new pattern. This ultrasound pattern may be mistaken with sebaceous cyst and more cases are needed to
confirm the real incidence of all new types reported.4
Instrumental investigations may be added to physical
examination in order to view the depth of the lesion and the
surrounding structures, but sometimes they are not enough
for a certain diagnosis. In these cases surgical excision and
histological examination are needed and helpful to distinguish pilomatrixoma with angiomatous aspect from other
childhood lesions like hemangioma and vascular malformations.
References
1. Méndez-Gallart R, Tellado MG, Del Pozo-Losada J, Rois JM. A
rapid onset erythematous facial lesion in a neonatal patient. Pediatr
Dermatol 2009;26:195-6.
2. Rizvi SA, Naim M, Alam MS. A giant upper eyelid ossifying pilomatrixoma. Indian J Ophthalmol 2008;56:509-11.
3. Sari A, Yavuzer R, Isik I, Latifoglu O, Ataoglu O. Atypical presentation of pilomatricoma: a case report. Dermatol Surg 2002;28:603-5.
4. Solivetti FM, Elia F, Drusco A, Panetta C, Amantea A, Di Carlo
A. Epithelioma of Malherbe: new ultrasound patterns. J Exp Clin
Cancer Res 2010;29:42.
5. Lim HW, Im SA, Lim GY, Park HJ, Lee H, Sung MS et al. Pilomatricomas in children: imaging characteristics with pathologic
correlation. Pediatr Radiol 2007;37:549-55.
Corresponding author: A. Virdi, MD, via Massarenti 1, Clinica Dermatologica 40138 Bologna, Italy. E-mail: [email protected]
February 2012

Talon Noir: utility of dermoscopy
for differential diagnosis with
respect to other acral skin growths
P. RUBEGNI, L. FECI, M. FIMIANI
Department of Clinical Medicine and Immunology, Siena
University, Siena, Italy
Dear Editor,
B
lack heel (calcaneal petechiae) is a self-limited,
asymptomatic, trauma-induced darkening of the posterior or posterolateral aspect of the heel that occurs primarily in young adult athletes. It is characterized by speckled
bluish-black areas of macular pigmentation occurring at the
border of the heel slightly above the hyperkeratotic edge of
the plantar surface.1 A similar lesion termed black palm
(tache noir) has been described on the thenar eminence in
weightlifters, gymnasts, golfers, tennis players, and mountain climbers. Although this manifestation is benign and
self-limiting, it may cause apprehension in patients and
general practitioners due to confusion with pigmented skin
lesions such as malignant melanoma. This often explains
the anxiety with which these young patients seek medical
advice, often accompanied by equally worried parents.
The most important goal in such cases is to differentiate
black heel (calcaneal petechiae) from melanoma or other
skin lesions, such as angiomatoid growths and common
warts. Usually no specific workup is necessary to diagnose black heel. The diagnosis is generally clinical and can
be aided by paring down the lesion with a surgical blade.
Melanocytic lesions will not lose their pigmentation with
paring, while black heel may clear completely after the
stratum corneum is removed. Patients may be contrary to
this marginally invasive operation, due to unjustified fear
of a plantar nevus turning malignant or of profuse bleeding
by angiomas and plantar warts.
Epiluminescence techniques, such as dermoscopy and
video macroscopy, can be used to aid differential diagnosis of pathological conditions and/or growths with respect black heel. Dermoscopy is a noninvasive technique
that allows visualization of structures that cannot be detected by clinical examination. If performed by experts, it
increases diagnostic accuracy for pigmented skin lesions,
especially for malignant melanoma.2 Dermoscopic differential diagnosis of melanoma and dysplastic nevi or other
melanocytic lesions is complex and requires the opinion of
a dermatologist. On the other hand, differential diagnosis
of melanocytic pigmented lesions and lesions of vascular
(such as calcaneal petechiae) or other origin (such as common warts) is simple by dermoscopy. Black heel appears
as grouped globular or punctate haemorrhages, often ar-
Vol. 147 - No. 1
ranged in a linear pattern (Figure 1).3 On the other hand,
viral warts are keratinocytic lesions with lobular structure
(like frog spawn), sometimes with a central thrombosed
capillary in each lobule; normal dermatoglyphics are interrupted and some have papilliform structure. Regarding
pigmented skin lesions (PSL), three specific pigment patterns are considered normal in benign melanocytic naevi
of plantar skin: parallel furrows, lattice-like pattern and
fibrillar pattern.4 In each, the pigment is located in the
plantar dermatoglyphic furrows. The patterns arise as a
reflection of normal vertical (parallel furrow) or slanting
melanin columns in the stratum corneum. Finally, malignant melanoma exhibits different patterns on the palmar
and plantar surfaces with respect to other skin areas. Saida
and workers reported asymmetry and irregular (variegated)
color as a common feature (Figure 2). Pigmentation of ma-
Figure 1.—Black heel: macroscopic and dermoscopic aspects.
Figure 2.—Plantar malignant melanoma: macroscopic and dermoscopic aspect.
133
lignant melanoma is often accentuated on dermatoglyphic
ridges, not in the furrows as in benign lesions.5
In conclusion, in cases of black heel, urgent referrals are
common from general practitioners or specialists in sports
medicine wishing to exclude warts, nevi or even melanoma. Patients may be very anxious about this condition.
Since dermoscopy makes diagnosis simple and precise,
general practitioners and specialists in sports medicine
could benefit from at least basic training in this technique.
References
1. Kirton V and Price MW. Black heel. Trans St John Hosp Derm Soc
1965;51:80-4.
134
2. Rubegni P, Burroni M, Andreassi A, Fimiani M. The role of dermoscopy and digital dermoscopy analysis in the diagnosis of pigmented
skin lesions. Arch Dermatol 2005;141:1444-6.
3. Zalaudek I, Argenziano G, Soyer HP, Saurat JH, Braun RP. Dermoscopy of subcorneal hematoma. Dermatol Surg 2004;30:1229-32.
4. Miyazaki A, Saida T, Koga H, Oguchi S, Suzuki T. Anatomical
and histopathological correlates of the dermoscopic patterns seen
in melanocytic nevi on the sole: a retrospective study. J Am Acad
Dermatol 2005;53:230-6.
5. Oguchi S, Saida T, Koganehira Y, Ohkubo S, Ishihara Y, Kawachi
S. Characteristic epiluminescent microscopic features of early malignant melanoma on glabrous skin. A videomicroscopic analysis.
Corresponding author: L. Feci, Dermatology Section, Department of
Clinical Medicine and Immunology, Siena University, viale Bracci 1,
53100 Siena, Italy. E-mail: [email protected]
February 2012