minerva medica

Transcription

minerva medica

EDITORIALS
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G ITAL DERMATOL VENEREOL 2006;141:85-6
The blood supply of the epidermis in psoriasis
R
osina et al. provide a reminder of the characteristic
pattern of the capillary bed in psoriasis.1 It is true
that capillary microscopy was originally focused on the
nail bed, but, when I reviewed this topic in 1969 2 and
1970,3 there was already a substantial use of long
working distance lenses and the whole body was frequently examined and, already too, TV cameras were
being attached. We knew the capillary shape described
by Rosina et al. and were impressed, as they are by its
uniformity in psoriasis. Holti in 1964 4 studied this
extensively. We noted this uniformity only in the typical clinical lesion. It was not observed at the edge of
an evolving lesion, nor in the early phases of generalized pustular psoriasis. Sometimes chronic lichenification, mycoses fungoides, or vascular naevi could
have a low power field identical in appearance but not
consistently. Of course, the nailfold continues to be
the site of study even with videomicroscopy 5 described
diminution of density and dimensions in psoriasis
which they ascribed to injury.
Many, having noticed that the unaffected skin had
higher rates of blood flow,6, 7 looked to see if normal
skin had more capillaries with “psoriatic” morphology. We emphasized that, of course, we were looking
at blood columns and not at the invisible capillary
SEE PAGE 21, VOLUME 141, ISSUE No. 1, FEBRUARY 2006
Address reprint requests to: Dr. T. J. Ryan, Dermatology Department,
Oxford Wound Healing Institute, 68 Church Way, Iffley, Oxon, OX4 4EF UK. E-mail: [email protected]
Vol. 141 - N. 2
T. J. RYAN
Dermatology Department
Oxford Wound Healing Institute, Iflley, Oxon, UK
wall. I noted that resolving psoriasis had capillaries
empty of blood but on obstructing their emptying they
would fill and the characteristic pattern could be
observed. The rate of complete resolution was faster
in the upper part of the body and especially slow in the
legs. This explains in part why studies of blood flow
in resolving plaques is less informative than morphology.8 The development of the pattern could be
inhibited by local pressure or adrenaline and the epidermal changes could also be inhibited. All of this
and others work is reviewed in Ryan.9 In this 1980
text there is a hypothesis which may have become
more relevant and that is that the psoriasis is demanding more oxygen than is consistently supplied by this
pattern of blood supply; even though the basal flux in
the plaque exceeds maximum flux in normal skin.10
Consequently it is a condition that suffers from hypoxic injury. Those interested in the behaviour of the epidermis with respect to growth factors like vascular
endothelial growth factor (VEGF) might reconsider
this as might the antioxidant evangelists. It is not too
different to the discussion by Ryan et al.11 in this
Journal of the paper by Procaccini et al.12
One of the issues is the Koebner phenomenon and
GIORNALE ITALIANO DI DERMATOLOGIA E VENEREOLOGIA
85
RYAN
THE BLOOD SUPPLY OF THE EPIDERMIDIS IN PSORIASIS
porarily the greater consumer to a degree of hypoxic
injury.
Blood supply, the physiological features of which
have recently taken second place to cytokines, is still
worthy of research and Rosina et al. are a welcome
reminder of its importance.
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vulnerability. Psoriasis and its characteristic capillary
are found to develop at sites of injury nearest an existing plaque. The vasculature of psoriasis is vulnerable
in a way that normal blood supply is not. Slight trauma causes bleeding (Auspitz’sign) and close inspection
with in vivo microscopy shows that thrombosis is as
common as bleeding. This led to studies of fibrinolysis in psoriasis.9, 13 It was pointed out that the neutrophils that are such a feature of psoriasis are inhibitory of fibrinolysis but demanding of oxygen. We were
less concerned about dendritic cells and lymphocytes
in those days, but, of course, any activated system
needs oxygen. This is a balance between supply and
demand and our point is that the epidermis in psoriasis coupled with neutrophils takes all Hern et al.10 postulate that the capillary bed takes only 2-10% of the
skin’s blood supply but that the flow through the deeper dermis in psoriasis is increased some 10-13 fold.
Sympathetic and local vasoconstriction is intact in
psoriasis plaques. Further vasodilation above the high
normal is also possible.
There have been several studies of new thermolytic devices (lasers) to destroy only the most superficial blood vessels, reviewed and studied by Hern et
al.14 They refine and quantify what we attempted 30
years earlier but hardly give us more understanding. It
is partially a cure for psoriasis but alters total skin
blood flow very little.15
Endothelial proliferation is normally infrequent and
an increase is confined to the ascending limb of the capillary in psoriasis,16 which, as shown by Braverman and
Yen,17 are arteriolar and should have sufficient oxygen
needed for mitosis. The venous arm may well behave
differently, and like all the venous system be well
equipped to manage slow flow. The role of VEGF and
in its form as a permeability factor, its stimulus by
hypoxia and lactate, all draw attention to the physiology of the capillary without which biochemistry and
angiogenesis cannot be fully interpreted. Further more
until physiology has the resolution of the electron
microscope, and can trace the stops and starts within
a coiled psoriatic capillary, who knows which cell is
well supplied by oxygen or not and which is tem-
86
References
1. Rosina P, Giovannini A, Zamperetti MR, Chieregato C, Barba A.
Video-capillaroscopic aspect in different sites and types of psoriasis.
G Ital Dermatol Venereol 2006;141:21-4.
2. Ryan TJ. A study of the epidermal capillary unit in psoriasis. Dermatologica 1969;138:459-72.
3. Ryan TJ. Capillary microscopy and the skin. Br J Dermatol 1970;82
Suppl 5:74-5.
4. Holti G. Vascular phenomena diagnostic of latent psoriasis. Br J Dermatol 1964;76:503-12.
5. Bhushan M, Moore T, Herrick AL, Griffiths CE. Nailfold video capillaroscopy in psoriasis. Br J Dermatol 2000;142:1171-6.
6. Klemp P, Staberg B. Cutaneous and subcutaneous blood flow in nonlesional skin of patients with minimal psoriatic skin manifestations.
J Invest Dermatol 1986;86:582-4.
7. Klemp P, Staberg B. The effects of antipsoriatic treatment on cutaneous
blood flow in psoriasis measured by 133Xe washout method and laser
Doppler velocimetry. J Invest Dermatol 1985;85:259-63.
8. Goh CL, Khoo L. Laser Doppler perfusion imaging (LDPI) and
transepidermal water loss (TEWL) values in psoriatic lesions treated
with narrow band UVB phototherapy. Dermal vascularity may be
useful indicator of psoriatic activity. Ann Acad Med Singapore
2004;33:75-9.
9. Ryan TJ. Microcirculation in psoriasis: blood vessels and lymphatics
and tissue fluid. Pharmacol Ther 1980;10:27-64.
10. Hern S, Stanton AW, Mellor R, Levick JR, Mortimer PS. Control of
cutaneous blood vessels in psoriatic plaques. J Invest Dermatol
1999;113:127-32.
11. Ryan TJ, Hughes M, Cherry G. How we can modify the cutaneous
microflow. G Ital Dermatol Venereol 2005;140:611-4.
12. Procaccini EM, De Martino G, Picone G, D’Alicandro G, Monfrecola
G. Effects of hyperbaric oxygen on cutaneous microflow. G Ital Dermatol Venereol 2005;140:663-6.
13. Ryan TJ. The blood vessels of psoriasis. Acta Derm Venereol Suppl
(Stockholm) 1979;87:84-6.
14. Hern S, Stanton AW, Mellor RH, Harland CC, Levick JR, Mortimer
PS. Blood flow in psoriatic plaques before and after selective treatment
of the superficial capillaries. Br J Dermatol 2005;152:60-5.
15. Hern S, Stanton AW, Mellor RH, Harland CC, Levick JR, Mortimer
PS. In vivo quantification of the structural abnormalities in psoriatic
microvessels before and after pulsed dye laser treatment. Br J Dermatol
2005;152:505-11.
16. Creamer D, Allen MH, Sousa A, Poston R, Barker JN. Localization
of endothelial proliferation and microvascular expansion in active
plaque psoriasis. Br J Dermatol 1997;136:859-65.
17. Braverman IM, Yen A. Microcirculation in psoriatic skin. J Invest
Dermatol 1974;62:493-502.
Aprile 2006
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Systemic antimycotic treatment for children
State of the art
P. ROMANELLI, L. A. SCHACHNER
I
n this issue of the Giornale Italiano di Dermatologia e Venereologia, Pau et al. publish an elegant
study on the efficacy and tolerability of oral terbinafine
in pediatrics patients affected by tinea capitis and tinea
corporis due to tricophyton mentagrophytes and
microsporum canis.1 Their conclusion is that terbinafine is a highly effective drug for the treatment of cutaneous fungal infections in children but regarding tinea
capitis caused by m. canis additional studies are needed to better standardize dosage and treatment cycles.
Terbinafine is an allylamine that was discovered in
1974.2 Oral terbinafine was first approved for use in the
United Kingdom in February 1991, in Canada May
1993 and in the United States in May 1996.3 When
terbinafine is administered orally, 70% to 80% of the
dose is absorbed, with the bioavailability not being
significantly affected by food intake, after a single
terbinafine dose maximal plasma concentrations are
achieved within 2 h, steady-state levels are reached
after 10 to 14 days,4 high concentrations of terbinafine
are found in the stratum corneum, sebum and hair.
When terbinafine is administered orally, the drug has
been detected in the stratum corneum as early as 24 h
after commencing therapy.5
Terbinafine is first detected in the deeper layers of
SEE PAGE 29, VOLUME 141, ISSUE No. 1, FEBRUARY 2006
Address reprint requests to: Dr. L. A. Schachner, Department of Dermatology and Cutaneous Surgery, Miller School of Medicine, University
of Miami, Miami, FL, 33131 USA. E-mail: [email protected]
Vol. 141 - N. 2
Department of Dermatology and Cutaneous Surgery
Miller School of Medicine
University of Miami, Miami, FL, USA
the stratum corneum and probably reaches this site
by epidermal diffusion. In the hair it has been detected within 1 week of starting therapy. The early detection in hair may be due to delivery of the drug to hair
via the sebum, the drug may become incorporated into
hair by hair matrix cells. When terbinafine is administered for 14 days, the drug has been detected in hair
for at least 50 days. As in Pau et al.’s results it should
be noted that terbinafine may be more effective against
tinea capitis caused by endothrix organisms such as trichophyton mentagrophyte compared with ectotrix
infections like m. canis.
In our experience at the Department of Dermatology
and Cutaneous Surgery at the L. Miller School of Medicine, University of Miami, private and indigent Pediatrics Dermatology Clinics oral terbinafine is considered a second line agent. While extensive safety and
efficacy studies are acknowledged, the use of oral
terbinafine in children is “off label”. Further package
inserts state that the safety and efficacy of lamisil have
not been established in pediatric patients.
In the United States trichophyton tonsurans is the
most prevalent organism. Treatment is usually initiated with griseofulvin at 20-25 mg per kg per day in 1
or 2 doses. It is routinely given with milk or a fatty
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SYSTEMIC ANTIMYCOTIC TREATMENT FOR CHILDREN
cle successfully follows the attempt to establish a safe
and efficacious novel treatment for the dermatomycoses in children.
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meal for duration of 6 weeks. Keratolytics and/or antifungal shampoos are often an adjunct therapy. The
success rate of such treatment is usually highly satisfactory. In those instances where griseofulvin is counter
indicated, ineffective or associated with significant
side effects, then terbinafine becomes an off label
option. The usual doses are 62.5 mg per day for children less than 20 kg; 125 mg per day for 20-40 kg and
250 mg per day for those greater than 40 mg.
It was very interesting to read Pau et al. personal
experience with 50 patients in the attempt to address
the best terbinafine dose and duration regimen to
achieve a complete cure and lack of recurrence of the
cutaneous and hair pediatrics dermatomycoses. Their
effort follows the ones of Lipozencic in the 2002 6 and
of Gupta in the 2003.7 The issue of dermatomycoses
treatment in children was recently reproposed by
Roberts and Friedlander from the Children’s Hospital
and Health Center and University of California San
Diego Medical Center, San Diego, USA with their
article in Pediatrics Annals 8 addressing the need of a
safe and efficacious short-term treatment to replace
or be an alternative to the standard griseofulvin
approach. We are pleased to notice that Pau et al. arti-
88
References
1. Pau M, Aste N, Aste N. Efficacy and tolerability of terbinafine in
children. G Ital Dermatol Venereol 2006;141:29-31.
2. Berney D, Schuh K. Heterocyclic spironaphthalenones. Helv Chir
Acta 1978;61:1262-73.
3. Gupta AK, Shear NH. Terbinafine an update. J Am Acad Dermatol
1997;37:979-88.
4. Faergemann J, Zehender H, Jones T, Maibach I. Terbinafinelevels in
serum, stratum corneum, dermis-epidermis (without stratum corneum),
hair, sebum, and eccrine sweat. Acta Derm Venereol 1991;71:322-6.
5. Faergemann J, Zehender H, Jones T et al. Terbinafine levels in serum,
stratum corneum, dermis-epidermis (without stratum corneum) hair,
sebum and eccrine sweat during and after 250 mg terbinafine orally
once per day in men. J Invest Dermatol 1994;24:523.
6. Lipozencic J, Skerlev M, Orofino-Costa R, Zaitz VC, Horvath A,
Chouela E et al. A randomized, double-blind, parallel-group, durationfinding study of oral terbinafine and open-label, high-dose griseofulvin in children with tinea capitis due to Microsporum species. Br
J Dermatol 2002;146:816-23.
7. Gupta AK, Adamiak A, Cooper EA. The efficacy and safety of
terbinafine in children. J Eur Acad Dermatol Venereol 2003;17:62740.
8. Roberts BJ, Friedlander SF. Tinea capitis: a treatment update. Pediatric Ann 2005;34:191-200.
Aprile 2006
ORIGINAL ARTICLES
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Cytokeratin profile as a clue to origin
and differentiation in cutaneous squamous cell carcinoma
E. ALESSI 1, D. FANONI 1, E. BERTI 2
Aim. Several types of squamous cell carcinoma (SCC) of the skin
are recognized, even if SCCs in situ such as bowenoid actinic
keratosis and Bowen’s disease are histopathologically almost
indistinguishable and the existance of entities such as trichilemmal carcinoma is still discussed. The aim of this study was to verify if the determination of the cytokeratin (CK) profile could be
useful to better characterize some cutaneous SCCs.
Methods. We studied CK1, 5, 6, 7, 8, 10, 14, 15, 16, 17, 18 and
19 expression in normal epithelial structures of the skin and in
bowenoid actinic keratosis, Bowen’s disease, Bowen’s carcinoma, trichilemmal carcinoma, keratoacanthomatous SCC,
acantholytic SCC, conventional cutaneous SCC and malignant
proliferating onycholemmal cyst.
Results. The most significant findings were: (a) CK17 positivity in lower follicle; (b) focal positivity for CK19 in the basal layer of the outer root sheath near the bulge; (c) CK7 positivity with
CK19 negativity in the sebaceous lobules; (d) CK19 positivity
in the secretory portion of both apocrine and eccrine sweat
glands; (e) CK10 negativity with CK17 positivity in the nail
matrix and nail bed; (f) focal expression for CK19 in several cases of Bowen’s disease in contrast with its costant negativity in
bowenoid actinic keratosis; (g) the almost superimposable pattern of CK expression in Bowen’s disease, Bowen’s carcinoma
and trichilemmal carcinoma; (h) the CK10 and CK17 positivity in keratoacanthomatous SCC; (i) the lack of CK10 expression in acantholytic SCC, cutaneous conventional SCC and
malignant proliferating onycholemmal cyst.
Conclusion. The study was in favour of a common origin of
Bowen’s disease, Bowen’s carcinoma and trichilemmal carcinoma from pluripotential cells of the acrothrichium and of
keratoacanthomatous SCC from the lower follicle. It also
showed that a strong and diffuse positivity for CK17 may be use-
Address reprints request to: E. Alessi, MD, Istituto di Scienze Dermatologiche, Via Pace 9, 20122 Milano, Italy. E-mail: [email protected]
Vol. 141 - N. 2
1Institute
of Dermatological Sciences
University of Milan, Fondazione
IRCCS Ospedale Maggiore Policlinico,
Mangiagalli e Regina Elena, Milan, Italy
2Unit of Dermatology
University of Milano-Bicocca, Milan, Italy
ful to differentiate keratoacanthomatous SCC from trichilemmal carcinoma in doubtful cases and that the search for CK10
expression may be useful to distinguish between well differentiated and poorly differentiated SCCs of the skin. This last
statement is not true for onycholemmal carcinomas because
CK10 is negative in the normal nail matrix and nail bed.
KEY WORDS: Cytokeratin - Skin - Epithelia - Skin neoplasms.
C
ytokeratins (CK) are the major structural proteins
of epithelial cells, including keratinocytes.1 They
form a complex family of at least 30 polypeptides,
which are distinguishable from one another on the
basis of molecular weight and are numerically classified as such.2 The CK profile of an individual cell is
dependent on the epithelial cell type, the differentiation program and the rate at which the tissue cells are
turning over.3 CKs are usually conserved during malignant transformation, so that their identification can
help to establish the origin of the malignancy.4
CKs may be detected immunohistochemically and
the recent generation of a number of highly specific
monoclonal antibodies against single CKs, that work
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ALESSI
CYTOKERATIN PROFILE AS A CLUE TO ORIGIN AND DIFFERENTIATION IN CUTANEOUS SQUAMOUS CELL CARCINOMA
TABLE I.—Clinical data of the cases studied.
TABLE II.—Reagents used.
Case
Sex
M/F
Age
(year)
Location
BAK
1
2
3
4
5
1
2
3
4
5
6
7
1
2
1
2
3
4
5
6
7
1
2
3
1
2
1
2
3
4
5
6
1
M
M
M
F
M
F
M
M
M
M
M
M
M
M
M
M
F
M
F
M
M
F
F
F
M
F
M
M
M
F
M
M
F
84
71
75
87
67
67
45
40
74
70
47
72
78
74
80
85
71
71
68
66
73
70
73
80
91
80
70
60
66
74
80
91
74
Scalp
Left leg
Scalp
Right thigh
Left flank
Intergluteal fold
Skin of the penis
Perianal
Scrotum
Intergluteal fold
Thorax
2nd interdigital fold of the right hand
Left leg
Right helix
Forehead
Left helix
Left thigh
Left anthelix
Pubis
Right clavicular region
Left mandibular region
Forehead
Right leg
Face
Forehead
Scalp
Scalp
Scalp
Forehead
Left cheek
Forehead
Forehead
Right thumb
Source
Ab clone
Dilution
Supernatant
Specificity
Dako
ACSC
Novo
Novo
Sigma
Dako
Sigma
Dako
Novo
Novo
Novo
Novo
LP34
CK5
LHK6B
LP5K
M20
DE-K10
CKB1
C8/144B
LL025
E3
5D3
b-170
1:50
1:50
1:20
1:50
1:20
1:50
1:200
1:50
1:20
1:20
1:100
1:100
M717
ByA6084-1
NCL-CK6
NCL-CK7
C5301
M7002
C8791
M7103
NCL-CK18
NCL-CK17
NCL-5D3
NCL-CK19
CK1
CK5
CK6
CK7
CK8
CK10
CK14
CK15
CK16
CK17
CK18
CK19
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Disorder
BD
BC
TC
K-SCC
A-SCC
CC-SCC
MPOC
BAK: bowenoid actinic keratosis; BD: Bowen’s disease; BC: Bowen’s carcinoma; TC: trichilemmal carcinoma; K-SCC: keratoacanthomatous squamous cell
carcinoma (SCC); A-SCC: acantholytic SCC; CC-SCA: cutaneous conventional
SCC; MPOC: malignant proliferating onycholemmal cyst.
on formalin-fixed, paraffin-embedded tissue, prompted us to study the pattern of CK expression in normal
epithelial structures and some squamous cell carcinomas (SCC) of the skin.
Our purpose was to establish if this determination
could be useful to better characterize the origin and the
degree of differentiation of the tumors studied.
Materials and methods
Material
We first determined CK1, 5, 6, 7, 8, 10, 14, 15, 16, 17,
18 and 19 expresssion in normal epithelial structures of
90
Ab: antibody; CK: cytokeratin; Dako: Dako Cytomation, Productionsvej 42,
DK-2600 Glostrup, Denmark; ACSC: Accurate Chemical Scientific Co, Westbury,
NY, USA; Novo: Novocastra Laboratories LTD, D.B.A. Italia s.r.l., Segrate (MI); Sigma: Sigma-Aldrich, 3050 Spruce St., St. Louis, Mo, USA.
the skin from 3 biopsies performed on the scalp, 2 on the
trunk, 1 on the axilla and 1 on the nail unit. We then
examined: (a) 12 cases of SCC in situ, 5 of which localized in sun-exposed areas and classified as bowenoid
actinic keratosis on the basis of the presence of solar
elastosis and sparing of skin appendages 5, 6 and the
other 7 classified as Bowen’s disease on the basis of
their location in areas unexposed to sun and/or involvement ot the pilar infundibulum; (b) 2 cases of invasive
carcinoma composed of islands of squamoid and basaloid cells without horny pearl formation classified as
Bowen’s carcinoma; (c) 7 cases of invasive carcinoma
showing foci of cytologically atypical clear cells and/or
foci of pilar-type keratinization collected during the
last 13 years and classified as trichilemmal carcinoma;
(d) 3 cases of raised verrucous epithelial tumors showing a central keratin-filled crater and peripheral
squamoid proliferation classified as keratoacanthomatous SCC; (e) 2 cases of carcinoma showing what may
appear to be tubular and alveolar formations as a result
of dyskeratosis and subsequent acantholysis classified
as acantholytic SCC; (f) 6 cases of invasive growths
from the epidermis consisting of irregular masses of
atypical epidermal cells, focally keratinising in the form
of horny pearls, that proliferate downward into the dermis, classified as conventional cutaneous SCC; (g) 1 case
of malignant epithelial growth from the nail bed epithelium showing cystic structures and strands of clear atypical keratinocytes penetrating the phalangeal bone classified as malignant proliferating onycholemmal cyst.
Clinical data are reported in Table I. Reagents used
are reported in Table II.
Aprile 2006
ALESSI
TABLE III.—Cytokeratins expression pattern on normal epithelial structures of the skin.
Cytokeratin
Epithelial structure
5
6
7
8
10
14
15
16
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1
Epidermis
Hair follicle outer root sheath
— Infundibulum (u.p.)
— Infundibulum (d.p.)
— Isthmus
— Lower portion
Sebaceous gland
— Duct
— Lobules
Apocrine sweat gland
— Duct
— Secretory tubule
Eccrine sweat gland
— Dermal duct
— Secretory tubule
Nail unit
— Nail matrix
— Nail bed
17
18
19
++
++
–
–
–
++
±b
–
–
–
–
–
++
++
++
++
++
++
++
++
–
+
+±
++
–
–
±b
±b
–
–
±b
±b
++
++
–
–
+b
+b
++
++
–
–
±b
±b
–
+
+
++
–
+
+
++
–
–
±b
+b
–
–
±b
+b
++
++
++
++
++
+
–
++
–
–
++
++
+
+
–
–
+
–
+
–
–
–
–
–
++
+
++
+
+
+
–
++
±
++
++
–
+
–
–
–
+
–
–
–
±
++
±
++
++
+
++
+
+
+
–
++
±
++
++
–
+
–
–
–
+
–
–
–
±
++
±
++
++
++
++
++
+
+
–
–
±b
±b
–
–*
++
++
–
–
++
++
+
++
–
–
–
–
B: basal; u.p.: upper portion; d.p.: deep portion; -*: single cell positivity.
Method
Results
All reactions were performed by one of us (D. F.).
The method was as follows.
Tissue samples were fixed in buffered paraffin, dehydrated, embedded in paraffin wax and sectioned. After
deparaffinizing and rehydrating, each tissue section
was immersed in citrate buffer 0.01 M, boiled 3 times
for 5 min into a pressure cooker and washed with TBS
buffer according to Cattoretti et al.7 Then, each section
was incubated with normal rabbit serum for 10 min and
then with the specific monoclonal antibody overnight
at + 4°C, washed with TBS pH 7.6 and incubated in
rabbit mouse Dako Z259 1:30 at room temperature
for 1 h. After incubation with the secondary antibody
(RAM), it followed a new wash with TBS pH 7.6 and
incubation with the enzymatic immunocomplexes
APAAP (alkaline phoshatase and monoclonal antialkaline phosphatase, Dako D651) 1:50 at room temperature for 1 h according to Cordell et al.8 These last
2 passages (RAM and APAAP) were repeated twice,
but in the second passage the APAAP dilution was
1:100 and the incubation was made at room temperature for 30 min. A new fuchsin-based solution containing naphtol AS-B, phosphate sodium salt, levamisole and Na nitrite was used as enzyme substrate.
Finally, each section was counterstained in Mayer’s
Hematoxylin solution and coverslipped.
Vol. 141 - N. 2
Cytokeratins expression pattern in normal epithelial
structures of the skin
Results are reported in Table III.
In our view, the most significant findings were: (a)
CK17 positivity in the deep part of the infundibulum,
isthmus and, especially, in the lower portion of the
hair follicle outer root sheath (Figure 1A); (b) the focal
CK19 positivity in the basal layer of the isthmus and
lower portion of the hair follicle outer root sheath near
the bulge (Figure 1B); (c) CK7 positivity (Figure 1C)
with CK19 negativity in the sebaceous lobules; (d)
CK19 positivity in the secretory portion of both eccrine
and apocrine sweat glands; (e) CK10 negativity with
CK17 positivity (Figure 1D) in the nail matrix and
nail bed.
Cytokeratins expression pattern in cutaneous squamous cell carcinomas in situ studied
Results are reported in Table IV.
The most significant findings were: (a) CK6 negativity in 4 of 5 cases of bowenoid actinic keratosis and
the almost constant CK6 expression in Bowen’s disease
(Figures 2A, B); (b) the focal expression of CK19 in
5 of 7 cases of Bowen’s disease (Figures 2C, D).
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Figure 1.—Suprabasal positivity for CK17 in lower follicle (A); focal positivity for CK19 in the basal layer of lower follicle near the bulge (B); positivity for CK7 in the sebaceous lobules (C); CK17 positivity in the nail bed (D).
TABLE IV.—CK expression pattern in the cutaneous squamous cell carcinomas in situ studied.
Cytokeratin
Disorder
BAK
BD
Case
1
2
3
4
5
1
2
3
4
5
6
7
1
5
6
7
8
10
14
15
16
17
18
19
++
++
+
++
++
+±
++
++
++
+±
++
++
ND
++
++
++
++
+±
++
++
++
+±
++
++
–
–
–
±
–
–
+
+±f
+±f
+±
+f
++f
–
–
–
–
–
–
–
–
–
–
–
–
–
+±f
–
ND
–
–
–
–
–
–
–
–
++
++
++
++
++
++
++
++
++
++
++
++f
+±
–
–
+
±
–
+±f
++f
–
+±
+
+
–
–
–
–
–
–
–
–
–
–
–
–
++
+±
+±
+
+±
–
+±f
++f
++f
+±
+±
++f
–
–
–
–
–
–
–
–
–
–
–
–
–
+±f
–
–
ND
–
–
–
–
–
–
–
–
–
–
–
–
–
–*
–
+f
+f
++f
+f
SCC: squamous cell carcinoma; BAK: bowenoid actinic keratosis; BD: Bowen’s disease; ND: not done; f: focal; *: single cell positivity.
92
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Figure 2.—Bowen’s disease on the right hand (A) and its focal positivity for CK7 (B); Bowen’s disease on the penis (C) and its focal positivity for
CK19 (D).
Cytokeratins expression pattern in the other cutaneous squamous cell carcinomas studied
Results are reported in Table V.
In our view, the most significant findings were: (a)
the almost superimposable pattern of CK expression
in Bowen’s carcinoma and trichilemmal carcinoma,
that, interestingly, also showed focal CK19 positivity
in the majority of cases (Figures 3A, B); (b) CK10
and 17 positivity in keratoacanthomatous SCC (Figures
3C, D); (c) CK10 negativity in acantholytic SCC, cutaneous conventional SCC and malignant proliferating
onycholemmal cyst.
Vol. 141 - N. 2
Discussion and conclusions
Cytokeratins expression pattern in normal epithelial
structures of the skin
As reported by other authors,9, 10 the epidermis and
the upper part of the infundibular epithelium can not
be differentiated on the basis of their CK profile, while
the deep part of the infundibulum, isthmus and lower
portion of the hair follicle outer root sheath show a
distinctive CK profile especially because of their positivity for CK17. The CK17 positivity, that is
suprabasal, was found to be particularly evident in
93
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TABLE V.—CK expression pattern in the other cutaneous squamous cell carcinomas studied.
Cytokeratin
Case
1
5
6
7
8
10
14
15
16
17
18
19
++
+±
++
ND
+±
++
+±f
++
++
+±
+±
+±
++
+±
++
ND
+±
+±
++
+±
+±f
+
+f
++
+
+±
++
++
+
+±
++
++
++
++
++
++
+±
++
+±
++
+±
+±
+f
+f
±f
+±
+±
+±
+±
+
++f
++f
++
ND
+±f
+±f
+f
+f
+f
+f
+f
+±f
+±
–
–
–
±
–
–
–
±
–
–
–
–
–
–
–
–
+f
–
–
–
–
ND
ND
–
–
–
–
–
–
ND
–
ND
–
–
–
–
–
–
–
–
–
ND
+f
++
++f
++f
++
–
+±f
++
+f
++
++
++
–
–
–
–
–
–
–
+f
–
+±f
+
+±
+
+
+
ND
–
+±
+±
+±
++
+±f
+f
+±f
++f
+±f
+±f
+f
+±f
+±
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
ND
++
+±
++
++
+±
+±
+f
+±
++f
++
+±
+±
+±f
+±f
+f
++f
+f
+f
++f
+±f
+±
–
–
–
++f
ND
+f
–
–
–
+±
+±
++
+f
+f
–
–
–
–
–
–
+f
–
–
–
–
–
–
++
–
–
–*
–
ND
–
–
ND
–
ND
–
–
–
–
–
+f
–
+f
+f
+f
+f
+f
–
–*
+f
–*
–
–
–
–
–
–
–
–
–
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Disorder
BC
TC
KA-SCC
A-SCC
CC-SCC
MPOC
1
2
1
2
3
4
5
6
7
1
2
3
1
2
1
2
3
4
5
6
1
SCC: squamous cell carcinoma; BC: Bowen’s carcinoma; TC: trichilemmal carcinoma; KA-SCC: keratoacanthomatous SCC; A-SCC: acantholytic SCC; CC-SCC: cutaneous conventional SCC; MPCO: malignant proliferating onycholemmal cyst; ND: not done; f: focal; *: single cell positivity.
lower follicle. Therefore, in our view, a strong CK17
expression in a tumor could indicate its origin from
lower follicle.
Likewise, CK7 positivity with CK19 negativity in the
sebaceous lobules, CK19 positivity in both apocrine
and eccrine sweat glands, and CK10 negativity with
CK17 positivity in the nail matrix and nail bed could
be used to identify sebaceous (Figures 4A, B), apocrine-eccrine (Figures 4C, D) or onycholemmal origin
of a tumour, respectively.
As regards the weak CK19 expression in the basal
layer of the isthmus and lower portion of the hair follicle outer root sheath, an explanation could be the
reported presence at this level of epithelial stem cells
migrating from the bulge.11, 12
Cytokeratins expression pattern in squamous cell carcinomas in situ studied
Taking into account that: (a) bowenoid actinic keratosis and Bowen’s disease are possibly different in
origin, the first one originating from epidermal keratinocytes and the second one from germinal cell of
the pilar outer root sheath and the pluripotential cells of
the acrotrichium;13 (b) solar-induced cancerization is
94
worldwide accepted for bowenoid actinic keratosis,
while a viral-induced cancerization has been suggested not only for anogenital Bowen’s disease but also for
cases of cutaneous Bowen’s disease;14-16 (c) invasive
SCC originating from bowenoid actinic keratosis is a
keratinising tumour forming horny pearls in its early
stage, while SCC originating from Bowen’s disease
does not show horny pearl formation and occasionally
shows adnexal differentiation,13, 17-19 we expected to
find some clear differences in the pattern of CK expression between these 2 entities. On the contrary, only a subtle difference seems to exist, namely the almost constant
positivity for CK6 with frequent weak positivity also for
CK19 in Bowen’s disease, while the 5 cases of bowenoid
actinic keratosis studied were negative for CK19 and
only 1 of them showed weak positivity for CK6.
CK6 was found to be positive together with CK16
not only in Bowen’s disease but also in all invasive
SCCs studied, both CKs having been considered as
markers for hyperproliferative keratinocytes.20 Therefore, CK6 expression in 6 of 7 cases of Bowen’s disease and its lack of expression in almost all bowenoid
actinic keratoses examined could be only a sign of a
higher tendency to hyperproliferation in the first disorder in comparison with the second one.
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Figure 3.—Trichilemmal carcinoma on the left thigh (A) and its focal positivity for CK19 (B); keratoacanthomatous SCC (C) and its strong positivity for CK17 (D).
The focal but frequent expression of CK19 is more
interesting in order to establish the origin of Bowen’s
disease considering the positivity for this CK in stem
cells migrating from the bulge.11, 12 A weak positivity
for CK19 in cases of Bowen’s disease is not new having already been reported.9, 21 Taking into account that
in Bowen’s disease the positivity for CK19 is associated with positivity for CK10, while a typical marker
for the lower follicle such as CK17 10 is negative, an
acceptable hypothesis is that Bowen’s disease originates from pluripotential cells of the acrothrichium as
suggested for Bowen’s carcinoma.13 Is this is true, the
tumor could be more properly defined as acrothrichial
carcinoma in situ.
Vol. 141 - N. 2
Cytokeratins expression pattern in the other cutaneous squamous cell carcinomas studied
Bowen’s carcinoma and trichilemmal carcinoma
showed a superimposable pattern of CK expression.
This pattern was also superimposable to that of
Bowen’s disease with the only exceptions of: (a) the
only focal positivity for CK10 in one case of Bowen’s
carcinoma and 4 cases of trichilemmal carcinoma
with CK10 negativity in 1 case of trichilemmal carcinoma; (b) the focal positivity for CK17 in 2 cases of
trichilemmal carcinoma. Based on these findings, we
think that not only Bowen’s carcinoma but also
trichilemmal carcinoma could be viewed as an evo-
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Figure 4.—Sebaceoma (A) with diffuse positivity for CK7 (B); Paget’s disease (C) with strong positivity for CK19 (D).
lutive phase of Bowen’s disease. Different routes of
differentiation toward pilosebaceous and apocrine
unit could easily explain their different histopathologic patterns. The partial or total lack of CK10 espression in some cases of Bowen’s carcinoma and
trichilemmal carcinoma was associated to poor differentiation. Both Bowen’s carcinoma and trichilemmal carcinoma are basically CK10 positive tumours,
but this characteristic may be lost during sdifferentiation as already suggested for invasive malignancies.21
The study was in favour of an origin of keratoacanthomatous SCC from lower follicle because of its
strong and diffuse CK17 positivity. This result is in
96
agreement with the market histopathologic similarities
between keratoacanthomatous SCC and a tumour
worldwide considered to be follicular in origin such as
keratoacanthoma. Interestingly, all the keratoacanthomatous SCCs studied showed also strong expression
of CK10 which seemed to be a marker of differentiation.22, 23 This last statement is confirmed by the constant CK10 negativity in acanholytic SCC and cutaneous conventional SCC, which are invasive and poorly differentiated tumours.
Lastly, malignant proliferating onycholemmal cyst 24
showed positivity for CK6 and 16 and focally also for
CK17 as does the normal nail bed. Interestingly CK10
was negative in spite of the high differentiation of this
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espressione della CK19 in numerosi casi di morbo di Bowen
in contrasto con il suo costante mancato riscontro nella cheratosi solare bowenoide; (g) un profilo citocheratinico quasi sovrapponibile nel morbo di Bowen, nel carcinoma di
Bowen e nel carcinoma trichilemmale; (h) espressione sia della CK10 sia della CK17 nel carcinoma spinocellulare cheratoacantomatoso; (i) mancata espressione della CK10 nel
carcinoma spinocellulare acantolitico, nel carcinoma spinocellulare cutaneo convenzionale e nella cisti onicolemmale proliferante maligna.
Conclusioni. I risultati dell’indagine sono a favore di
una possibile origine comune del morbo di Bowen, del carcinoma di Bowen e del carcinoma trichilemmale da cellule epiteliali pluripotenti dell’acrotrichio e del carcinoma
spinocellulare cheratoacantomatoso dalla porzione profonda del follicolo. Lo studio ha anche evidenziato che un’intensa e diffusa espressione della CK17 risulta nei casi dubbi a favore del carcinoma spinocellulare cheratoacantomatoso rispetto al carcinoma trichilemmale e che la ricerca dell’espressione della CK10 appare utile per distinguere i carcinomi spicocellulari ben differenziati da quelli con
scarsa differenziazione, salvo nei carcinomi onicolemmali, essendo la CK10 negativa nella matrice e nel letto
ungueale normali.
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tumour because CK10 is not expressed in nail matrix
and nail bed.
In conclusion, we found that the search for CK
expression may be useful to better characterize the
origin and the degree of differentiation of the SCCs
studied. In particular: (a) the almost superimposable
CK profile in Bowen’s disease, Bowen’s carcinoma
and trichilemmal carcinoma with CK19 expression in
the majority of cases seemed to be in favour of a common origin of these entities from pluripotential cells of
the acrothrichium; (b) the strong positivity for CK17
in keratoacanyhomatous SCC could indicates its origin from lower follicle; (c) the diffuse positivity for
CK17 may be useful to differentiate keratoacanthomatous SCC from trichilemmal carcinoma in doubtful cases; (d) the lack of CK10 expression is in favour
of high grade cutaneous SCCs such as acantholytic
SCC and cutaneous conventional SCC.
Our results are not comparable with others of the literature because, to the best of our knowledge, no similar study in different cutaneous SCCs with a wide
panel of single CKs has yet been performed.
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plasie.
CHIAVE:
Citocheratine - Epiteli - Cute - Cute, neo-
Riassunto
References
Obiettivo. Si riconoscono numerose varianti del carcinoma spinocellulare della cute, ma carcinomi in situ come la
cheratosi solare bowenoide e il morbo di Bowen sono istologicamente quasi indistinguibili e l’effettiva esistenza del carcinoma trichilemmale risulta ancora discussa. Lo scopo di
questo lavoro era verificare se la determinazione del profilo citocheratinico in alcuni carcinomi cutanei potesse essere utile per caratterizzarli meglio.
Metodi. È stata studiata l’espressione delle citocheratine
(CK) 1, 5, 6, 7, 8, 10, 14, 15, 16, 17, 18 e 19 in primo luogo
nelle strutture epiteliali normali della cute e successivamente
nella cheratosi solare bowenoide, nel morbo di Bowen, nel
carcinoma di Bowen, nel carcinoma trichilemmale, nel carcinoma spinocellulare cheratoacantomatoso, nel carcinoma
spinocellulare acantolitico, nel carcinoma spinocellulare
cutaneo convenzionale e nella cisti onicolemmale proliferante
maligna.
Risultati. I risultati maggiormente significativi sono stati il riscontro di: (a) espressione della CK17 nella guaina
epiteliale esterna in sede soprabasale, particolarmente intensa nella parte profonda del follicolo; (b) focale espressione
in sede basale della CK19 in vicinanza del punto di attacco
del muscolo erettore del pelo; (c) espressione della CK7 con
mancato riscontro della CK19 nei lobuli sebacei; (d) espressione della CK19 nei glomeruli sudoripari sia eccrini sia
apocrini; (e) espressione della CK10 con mancato riscontro della CK17 nella matrice e nel letto ungueale; (f) focale
Vol. 141 - N. 2
1. Osborn M, Weber K. Intermediate filaments: cell-type specif markers
in differentiation and pathology. Cell 1982;31:303-6.
2. Moll R, Franke WW, Schiller DL, Geiger B, Krepler R. The catalog
of human cytokeratins: patterns of expression in normal epithelia,
tumours and cultured cells. Cell 1982;31:11-24.
3. Cooper D, Schermer A, Sun TT. Classification of human epithelia
and their neoplasms using monoclonal antibodies to keratins: strategies, applications, and limitations. Lab Invest 1985;52:243-56.
4. Gabbiani G, Kapancy Y, Barazzone P, Franke WW. Immunochemical
identification of intermediated-sized filaments in human neoplastic
cells. A diagnostic aid for the surgical pathologist. Am J Pathol
1981;104:206-16.
5. Brownstein MH, Rabinowitz AS. The precursors of cutaneous squamous cell carcinoma. Int J Dermatol 1979;18:1-16.
6. Strayer DS, Santa-Cruz DJ. Carcinoma in situ of the skin: a review of
histopathology. J Cutan Pathol 1980;7:244-59.
7. Cattoretti G, Pileri S, Parravicini C, Becker MH, Poggi S, Bifulco C
et al. Antigen unmasking on formalin-fixed, paraffin-embedded tissue sections. J Pathol 1993;171:83-98.
8. Cordell JL, Falini B, Erber WN, Ghosh AK, Abdulaziz Z, MacDonald S et al. Immunoenzymatic labelling of monoclonal antibodies
using immune complexes of alkaline phosphatase and monoclonal
anti-alkaline phosphatase (APAAP complexes). J Histochem Cytochem
1984;32:219-29.
9. Ichikawa E, Watanabe S, Otsuka F. Immunohistochemical localization
of keratins and involucrin in solar keratosis and Bowen’s disease. Am
J Dermatopathol 1995;17:151-7.
10. Moll R, Franke WW, Volc-Platzer B, Krepler R. Different keratin
polypeptides in epidermis and other epithelia of human skin: a specific
cytokeratin of molecular weight 46,000 in epithelia of the pilosebaceous tract and basal cell epitheliomas. J Cell Biol 1982;95:285-95.
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18. Saida T, Okabe Y, Uhara H. Bowen’s disease with invasive carcinoma
showing sweat gland differentiation. J Cutan Pathol 1989;16:222-6.
19. Slater DN, Parsons MA, Mudhar H. In-situ squamous cell carcinoma
(Bowen’s disease) with divergent adnexal differentiation. Histopathology 2003;43:100.
20. Weiss RA, Eichner R, Sun TT. Monoclonal antibody analysis of keratin expression in epidermal diseases: a 48- and 56-kdalton keratin as
molecular markers for hyperproliferative keratinocytes. J Cell Biol
1984;98:1397-406.
21. Markey AC, Lane EB, Churchill LJ, MacDonald DM, Leigh IR.
Expression of simple epithelial keratins 8 and 18 in epidermal neoplasia. J Invest Dermatol 1991;97:763-70.
22. Basta-Juzbasic A, Klenkar S, Jakic-Razumovic J, Pasic A, Loncaric
D. Cytokeratin 10 and Ki-67 nuclear marker expression in keratoacanthoma and squamous cell carcinoma. Acta Dermovenereol Croat
2004;12:251-6.
23. Osiecka BJ, Jelen M, Marciniak Z. [The evaluation of the relationship
between malignancy grade and cytokeratin-10 accumulation in human
skin squamous cell carcinoma]. Przegl Lek 2001;58:435-8. Polish.
24. Alessi E, Zorzi F, Gianotti R. Malignant proliferating onycholemmal
cyst. J Cutan Pathol 1994;21:183-8.
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11. Barthel R, Aberdam D. Epidermal stem cells. J Eur Acad Dermatol
Venereol 1995;19:405-13.
12. Michel M, Torok N, Godbout MJ, Lussier M, Gaudreau P, Royal A et
al. Keratin 19 as a biochemichal marker of skin stem cells in vivo
and in vitro: keratin 19 expressing cells are differentially localized in
function of anatomic sites, and their number varies with donor age and
culture stage. J Cell Sci 1996;109:1017-28.
13. Kao GF. Carcinoma arising in Bowen’s disease. Arch Dermatol
1986;122:1124-6.
14. Sato T, Marimoto A, Ishida Y, Matsuo I. Human papillomavirus associated with Bowen’s disease of the finger. J Dermatol 2004;31:92730.
15. Murao K, Kubo Y, Takiwaki H, Arase S, Matsumoto K. Bowen’s disease on the sole: p16INK4a overexpression associated with human
papillomavirus type 16. Br J Dermatol 2005;152:170-3.
16. Zheng S, Adachi A, Shimizu M, Shibata SI, Yasue S, Sakakibara A et
al. Human papillomaviruses of the mucosal type are present in some
cases of extragenital Bowen’s disease. Br J Dermatol 2005;152:
1243-7.
17. Jacobs DM, Sandles LG, Leboit PE. Sebaceous carcinoma arising
from Bowen’s disease ot the vulva. Arch Dermatol 1986;122:1191-3.
98
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NM23 protein expression in primary melanoma correlates with
disease-free interval and with survival: a ten-year follow-up study
D. FERRARI 1, M. LOMBARDI 1, R. RICCI 2, M. MICHIARA 3, G. PEDRAZZI 4, M. SANTINI 1, G. DE PANFILIS 1
Aim. nm23 is considered a metastasis suppressor gene for some
human cancers. Decreased expression of nm23 mRNA was
found in several metastases of melanoma, and such a lower
expression in metastases correlated to the patient’s shortened
survival. Since the prognostic role of the expression of NM23
protein in primary melanoma is controversial, the aim of this
study was to determine the utility of NM23 protein as an
immunohistochemical indicator of prognosis in patients affected with primary melanoma.
Methods. The expression of NM23 protein was analysed in 30
primary skin melanomas. NM23 protein was detected on paraffin sections using an immunoperoxidase technique. The follow-up period included evaluation of the disease-free interval
at 5 and 10 years and of the survival outcome at 5 and 10 years.
Results. We found that: 1) expression of NM23 protein correlated positively with disease-free interval within 5 years (P<0.01)
and 10 years (P<0.01); 2) expression of NM23 protein correlated
positively with survival within 5 years (P<0.01) and 10 years
(P<0.01).
Conclusion. In this study, NM23 protein correlates inversely
with melanoma progression. However, clinical trials including
larger numbers of patients should be performed to confirm
the favourable prognostic role of NM23 in melanoma.
KEY WORDS: Melanoma - NM23 protein- Survival - Metastases Prognosis.
T
he incidence of melanoma is increasing at a rate
greater than that of any other malignancy.1 Over
Received: October 6, 2005.
Accepted for publication: April 4, 2006.
Address reprint requests to: G. De Panfilis, Clinica Dermatologica Universitaria, Via Gramsci 14, 43100 Parma, Italy.
E-mail: [email protected]
Vol. 141 - N. 2
1Unit
of Dermatology, Department of Surgical Sciences
University of Parma, Parma, Italy
2Unit of Pathology
Department of Pathology and Laboratory Medicine
3Unit of Medical Oncology, Department of Medicine
Parma Hospital, Parma, Italy
4Unit of Physics, Department of Public Health
the past 30 years, the identification of more accurate
predicitive factors has led to multiple modifications
of the American Joint Committee on Cancer (AJCC)
staging system for melanoma.2-5 The most widely used
morphological prognostic indicators, such as melanoma
thickness and ulceration,5 give consistent information
about survival outcome when applied to groups, but
they may not have ideal predictive value in the individual case, because a subgroup of thin melanomas
metastasize at a relatively early stage in their development.6 A constant research of new prognostic parameters is, therefore, very important to define a correct prognosis.
The nm23 gene, discovered in 1988 by Steeg et al.,
is a putative metastasis-suppressor gene.7 In fact, low
levels of nm23 RNA 8, 9 or NM23 protein 10-14 have
been correlated with poor prognosis in breast cancer
patients. In addition, low levels of nm23 RNA or NM23
protein expression have also been correlated with
metastasis in hepatocellular carcinoma,15 diffuse large
B cell lymphoma,16 lung cancer,17 nonsmall cell lung
99
FERRARI
NM23 PROTEIN EXPRESSION IN PRIMARY MELANOMA CORRELATES WITH DISEASE-FREE INTERVAL AND WITH SURVIVAL
TABLE I.—Clinical phenotypes and AJCC staging according to Balch et al.5
Age
Sex
Subtype
Site
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
60
40
51
38
52
62
60
65
68
35
42
60
64
63
72
79
59
85
56
73
68
60
60
54
50
78
67
64
29
33
M
F
F
M
F
F
F
F
F
F
F
M
F
M
F
M
M
M
M
F
M
M
M
M
M
M
M
F
M
M
SS
SS
SS
SS
SS
SS
SS
SS
N
N
SS
SS
N
SS
LM
AL
SS
SS
N
SS
N
N
N
N
SS
AL
SS
SS
SS
N
Abdomen
Knee
Hand
Back
Leg
Leg
Back
Leg
Leg
Arm
Leg
Arm
Leg
Face
Leg
Toe
Back
Back
Scalp
Leg
Back
Back
Foot
Foot
Leg
Foot
Back
Foot
Abdomen
Lumbar
region
TNM
T2a
T1a
T1a
T2b
T1a
T2a
T1a
T1a
T2a
T3b
T1a
T1a
T3b
T2a
T1a
T4b
T3b
T1b
T3a
T3b
T3b
T4b
T4b
T3b
T3b
T3b
T1b
T3b
T3b
T4b
N0 M0
N0 M0
N0 M0
N0 M0
N0 M0
N0 M0
N0 M0
N0 M0
N0 M0
N0 M0
N0 M0
N0 M0
N0 M0
N0 M0
N0 M0
N0 M0
N0 M0
N0 M0
N0 M0
N0 M0
N0 M0
N3 M0
N0 M0
N1b M0
N0 M0
N0 M0
N0 M0
N1b M0
N2c M0
N0 M0
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Case number
Stage
IB
IA
IA
IIA
IA
IB
IA
IA
IB
IIB
IA
IA
IIB
IB
IA
IIC
IIB
IB
IIA
IIB
IIB
IIIC
IIC
IIIB
IIB
IIB
IB
IIIB
IIIB
IIC
SS: superficial spreading, N: nodular, LM: Lentigo maligna, AL: Acral lentiginous
cancer,18, 19 gastrointestinal stromal tumors,20 oral
squamous cell carcinoma.21 However, no similar
inverse relationship with metastatic potential has been
observed in colonic carcinoma,22-25 in neuroblastoma,26
or even in breast cancer.27 On the other hand, an uncertain prognostic role for nm23 gene and NM23 protein
expression was indicated in esophageal squamous cell
carcinoma,28 oesophageal adenocarcinoma 29 and in
colorectal cancer.30
The role of nm23 in the progression of melanoma is
still unclear. By comparing 7 murine K-1735
melanoma cell lines that exhibited either low or high
metastatic potential in spontaneous or experimental
metastasis assays, low-metastatic cells were found to
contain ten-fold higher levels of nm23 RNA, and to
express higher levels of the 17 Kda NM23 protein.31
Similarly, the highly metastatic K-1735 TK melanoma
cell line showed, when transfected with nm23, a significant reduction in metastatic potential in vivo.32 On
100
the other hand, no correlation was found between
nm23 RNA levels and tumor metastatic potential in
murine B16 melanoma cells.33 Finally, microcell-mediated transfer of chromosome 6 (containing the murine
nm23 gene) into C8161 melanoma cells suppressed
metastasis but did not inhibit tumorigenicity.34
In man, studies about nm23 mRNA levels in metastatic melanomas have shown significantly lower levels
in patients developing metastasis within 2 years of
diagnosis than in those with less aggressive disease,35
and longer survival for patients with higher levels of
nm23 mRNA.36 These data allowed to hypothesize
that NM23 protein could be involved in contrasting
melanoma progression and that low levels of NM23
expression could identify patients with high risk of
early metastasis. However, studies evaluating immunohistochemical staining of NM23 protein in melanocytic lesions have not always mirrored the findings of
earlier mRNA studies. In fact, although some papers
Aprile 2006
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TABLE II.—Correlation between NM23 expression in primary melanoma and follow-up results.
NM23%
NM23 intensity
Evolution
Survival after 10 years
1
2
100
100
+++
++
NED after 120 months
NED after 60 months
3
4
5
6
7
8
9
10
11
12
13
14
15
90
80
90
100
100
100
100
90
100
90
70
0
100
+++
++
++
+++
+++
+++
+++
++
+++
+++
++
++
Lymph node met. after 91 months
Visceral met. after 63 months
Local relapse after 14 months
16
17
0
20
+
Local relapse after 14 months
18
19
0
5
+
20
21
10
10
+
+
22
23
0
0
-
24
25
100
10
++
+
26
20
+
27
60
++
28
0
-
29
0
-
Lymph node met. after 16 months,
visceral after 24 months
visceral met. after 60 months
Lymph node and visceral met.
after 21 months
yes
Lost at the follow-up
after 60 months
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
yes
Exitus after 63 months
after 15 months
after 10 months
after 60 months
Yes
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Case number
30
20
+
after 60 months
NM23 %: Percentage of positive cells in the tumor, NM23 intensity: staining intensity of positive cells, NED: mon evident disease, Met.= metastases
demonstrated a correlation between staining and survival outcome 6, 37 or disease-free interval,29 other studies found no correlation between NM23 staining and
the scarcity of metastasis 38-40 or the survival outcome.41-43
The aim of this study was to determine the utility of
NM23 protein, evaluated by immunohistochemical
staining, as a prognostic marker of melanoma. In particular, we asked for the possibility of a relationship
between NM23 protein expression in primary
melanoma and both disease-free interval and ten-year
survival outcome.
Vol. 141 - N. 2
Patients
The study population comprised 30 cases of invasive
melanoma reported during the period 1990-1995 in
the Cancer Registry of Parma University Hospital.
The informations about follow-up and survival outcome were obtained from the Oncologic Center of
Parma University Hospital.
Thirty primary cutaneous melanomas were examined, derived from 17 males and 13 females, between
29 and 85-years-old (Table I). Such cases were clas-
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Figure 1.—NM23-positive superficial-spreading melanoma (case 1): this case showed no metastatic progression and enjoyed a ten-year follow-up survival. (A). Haematoxylin and eosin-stained section. Original magnification 4x. (B). Immunohistochemical staining of NM23 protein of a serial section. Atypical melanocytes show a strong intensity of staining (+++) and 100% cells are NM23 protein-positive. Original magnification 4x.
sified on the basis of the final version of the AJCC
melanoma staging guidelines 5 (Table I). All cases had
a follow-up period of 120 months after the excision of
the primary tumor, other than 5 cases: 1 lost at the follow-up after 10 months, 1 after 15 months and 3 after
60 months. During the follow-up period, disease
relapse (local recurrence, lymph-node and/or visceral metastasis) or the exitus of the patients were evaluated (Table II).
Immunohistochemical identification of NM23 protein
Formalin-fixed, paraffin-embedded blocks were
obtained from the Pathology Department of Parma
University Hospital. Immunohistochemical staining
was made using an immunoperoxidase technique,
according to a previously described routinary procedure.25
For morphological control, a parallel set of sections
were stained with haematoxylin and eosin. For positive controls, dermal adnexal structures as well as nevi
were utilized.40 For negative control, seriated sections
were incubated, other than with the primary antibody,
with normal rabbit serum.
Semiquantitative analysis of the labeling
Staining was assessed in a semiquantitative fashion. In fact, 2 parameters were considered, namely,
102
(i) the extent of staining expressed as percentage of
tumor cells showing a positive reaction, and (ii) the
intensity of labeling graded with reference to the positive internal control (dermal adnexal structures); this
last parameter was graded as + (weak intensity), ++
(moderate intensity), and +++ (strong intensity).
Statistical analysis
The relationship between NM23 protein expression
and the disease-free interval or the survival outcome
were obtained by Kaplan-Meier method, using the
program “Statistica” of the Statsoft Inc.
Results
NM23 protein expression in melanoma
Table II shows that 7 cases resulted completly
NM23 protein-negative, in 4 cases the percentage of
positive cells was between 0% and 10% with a weak
staining intensity, in 3 cases the percentage of positive cells was between 10% and 50% with a weak
staining intensity, and in 16 cases the percentage of
positive cells was greater than 50% with a moderate
or strong staining intensity (Figure 1). Positive controls were immunostained, whilst controls for antibody were negative.
Aprile 2006
1
0.8
Survival (%)
0.7
1
0.95
0.90
0.85
0.80
0.75
0.70
0.65
0.60
0.55
0.50
0.45
0.40
0.35
0.30
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Disease-free interval (%)
0.9
0.6
0.5
0.4
0.3
0.2
0.1
0
0
10
30
40
Months
20
50
60
70
1
1
0.8
0.8
0.6
0.4
0.2
5
10
15
20
25
30 35
Months
40
45
50
55
60
65
Figure 4.—The expression of NM23 protein is correlated with five-year
survival. Kaplan-Mayer graph shows the relationship between the percentage of NM23 protein-positive cells in the primary tumor and the survival of
the patients within 60 months from resection of primary tumor. The 30 cases were divided in 2 groups: NM23 protein expression greater than 50%
(group 1), NM23 protein expression lower than 50% (group 0). Patients of
group 1 showed a significantly longer survival than patients of group 0 (P <
0.01). Data were analyzed by Log Rank Test. - Group 0 (NM23 ≤ ≤50%) --- Group 1 (NM23 > 50%). + Lost at follow-up o Follow-up of 60 months.
Survival (%)
Disease-free interval (%)
Figure 2.—The expression of NM23 protein is correlated with the disease-free interval within 5 years. Kaplan-Mayer graph shows the relationship between the percentage of NM23 protein-positive cells in the primary tumor and the disease-free interval. The 30 cases were divided in 2
groups: percentage of NM23-positive cells greater than 50% (group 1), versus lower than 50% (group 0). Patients of group 1 showed a disease-free
interval significally longer than patients of group 0 (P < 0.01). Data were
analyzed by Log Rank Test. — Group 0 (NM23 ≤ 50%), ..... Group 1
(NM23 >50%), + Lost at follow-up, o Follow-up of 60 months.
0
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0.6
0.4
0.2
0
0
0
20
40
60
Months
80
100
120
Figure 3.—The expression of NM23 protein is correlated with the disease-free interval within 10 years. Kaplan-Mayer graph shows the relationship between the percentage of NM23 protein-positive cells in the primary tumor and the disease-free interval. The 30 cases were divided in 2
groups: percentage of NM23-positive cells greater than 50% (group 1), versus lower than 50% (group 0). Patients of group 1 showed a disease-free
interval significally longer than patients of group 0 (P < 0.01). Data were
analyzed by Log Rank Test. - Group 0 (NM23 ≤ ≤50%) ---- Group 1
(NM23 >50%). + Lost at follow-up.
Relationship between NM23 protein expression and
melanoma progression
NM23 PROTEIN AND DISEASE-FREE INTERVAL
First, we looked for a relationship between the
expression of NM23 protein and the appearance of
Vol. 141 - N. 2
0
20
40
60
Months
80
100
120
Figure 5.—The expression of NM23 protein is correlated with ten-year survival. Kaplan-Mayer graph shows the relationship between the percentage
of NM23 protein-positive cells in the primary tumor and the survival of the
patients within 120 months from resection of primary tumor. The 30 cases were divided in 2 groups: NM23 protein expression greater than 50%
(group 1), NM23 protein expression lower than 50% (group 0). Patients of
group 1 showed a significantly longer survival than patients of group 0 (P
< 0.01). Data were analyzed by Log Rank Test.
lymph-node and/or visceral metastases. In particular,
we considered the time between the excision of primary
tumor and the appearance of the first macrometastasis
(either lymph-nodal or visceral).
As shown in Figure 2 and Figure 3, patients with a
number of NM23-positive cells in the primary tumor
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didn’t show an inverse relationship between these 2
parameters,38-40, 45 others, on the contrary, demonstrated that percentage of NM23-positive cells correlates with disease-free interval.37, 42, 46 The latter result
was obtained in the present study too: it is obligatory
to admit, however, that in our study merely a limited
number of metastatic melanoma cases (only 14) was
studied.
This study demonstrates that NM23 protein expression in melanoma cells correlated with survival outcome within 60 and 120 months from excision of primary melanoma. However, this relationship is still
debated. In fact, some studies didn’t show any association between immunohistochemical NM23-positivity and survival outcome.41-43 On the contrary, other studies demonstrated a direct relationship between
these 2 parameters: specifically, cases developing a
shorter survival showed a percentage of NM23-positive cells lower than 50%,6, 37 and not only the extension but also the staining intensity of NM23 protein was
significantly associated with survival outcome.6 On
the basis of the latter and our data, it’s possible to
hypothesize a potential prognostic role of NM23 protein in the tumoral progression, although the number
of cases studied at this time is still too scarce to achieve
definite conclusions.
This is the first study focusing on a ten-year survival period in melanoma patients investigated for
NM23 expression. Intriguing, in a cohort of breast
carcinoma-affected women, 80% of women with high
NM23 expression were alive after 10 years compared
to 25% with low expression, whereas at 5 years the
survival proportions were 86% and 46% respectively.10
It is worth that, in our cohort of melanoma patients, the
only 2 men who died in the period between 60 and
120 months of follow-up had both an absolutely
NM23-negative primary tumor (patients n. 14 and 23).
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greater than 50% showed a disease-free interval within 5 and 10 years significantly longer (P <0.01) than
patients with a number of positive cells in the tumor
lower than 50%.
NM23 PROTEIN AND SURVIVAL OUTCOME
Moreover, we looked for an association between
the 60-month or 120-month survival and the percentage of NM23 protein-positive cells. As shown in Figure 4 and Figure 5, patients with a percentage of positive cells greater than 50% in the primary tumor had
a survival significantly longer (P <0.01) than patients
with a percentage of positive cells lower than 50%.
Discussion
This study demonstrates that the expression of NM23
protein in the primary melanoma is inversely correlated
with the metastatic potential, and directly correlated
with the survival within 60 and 120 months.
First, a direct relationship is herein shown between
percentage of NM23-positive melanoma cells and disease-free interval. A series of studies, generally investigating nm23 RNA rather than NM23 protein, demonstrated that nm23 in melanoma correlates inversely
with metastasis. In fact, former studies showed that
murine low-metastatic melanoma cells lines contained
ten-fold higher nm23 RNA levels than high-metastatic cells lines 7 and expressed higher levels of the
17KDa NM23 protein.31 Moreover, transfection of
murine nm23 cDNA in murine high-metastatic
melanoma cells lines allowed to reduce their metastatic potential.32, 34, 44 In man, studies about nm23 RNA
levels in metastatic melanoma have shown significantly lower levels in patients developing metastases
within 24 months of diagnosis than in those with less
aggressive disease.35 Therefore, although one study
showed that nm23 mRNA levels were not different in
primary melanoma cells lines or in metastatic
melanoma cells lines,40 the majority of studies agreed
upon the evidence that nm23 mRNA levels are inversely correlated with the metastatic potential of melanoma.
However, studies evaluating immunohistochemical
staining of NM23 protein, other than nm23 RNA, in
melanocytic lesions showed contrasting results about
the relationship between percentage of NM23 protein-positive cells and appearance of macrometastases.
In fact, whereas some immunohistochemical studies
104
Conclusions
This study, in conclusion, showed that the immunohistochemical positivity of NM23 protein in primary
melanoma is positively correlated with the diseasefree interval and the survival outcome. We must underline, however, that, whereas some studies showed similar results, others showed contrasting results, as above
mentioned. Furthermore, even studies about the expression of NM23 protein in tumors other than melanoma
lead to contrasting results: some studies, in fact, showed
Aprile 2006
l’espressione della proteina NM23 è correlata positivamente con la sopravvivenza a 5 anni (P<0,01) e 10 anni (P<0,01).
Conclusioni. In questo studio, la proteina NM23 correla
inversamente con la progressione del melanoma. Dovranno essere eseguiti, tuttavia, studi clinici che includano vaste
casistiche di pazienti per confermare il ruolo prognostico
favorevole di NM23 nel melanoma.
PAROLE CHIAVE: Melanoma - Proteina NM23 - Sopravvivenza - Metastasi - Prognosi.
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that high levels of NM 23 protein are positively correlated with a good prognosis,10, 11, 15, 47 while other
studies show that high levels of NM23 protein are correlated with poor prognosis.26, 48 In this regard, we
agree that the functions of gene nm23 are probably
not fully understood. In fact, the mechanism of action
of NM23 in metastasis suppression was hypothesized
to involve diminished signal transduction downstream
of a particular receptor;49 the downregulating genes
suspected to be involved in NM-23-induced metastasis suppression, however, are complex, and were
hypothesized to be associated with cell adhesion, motility and possibly certain tumor/metastasis suppressor
members of SWI/SNF-related matrix-associated proteins 2 and 5 and PTEN.50 Further uncertainty in the
mechanism of action of NM23 was led by the demonstration that p53 is a regulator of nm23, but such a
regulation is different in different cell types, and this
is an important component in the molecular mechanisms of tumor metastasis.51
Hopefully, the availability of larger casuistries will
help in better understanding the relationship between
immunohistochemical NM23 protein expression in
melanoma and disease-free interval and/or survival.
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Acknowledgements.—Many thanks are due to N. Campanini for excellent technical assistance.
Riassunto
L’espressione della proteina NM23 nel melanoma primario è correlata con l’intervallo libero da malattia e con la
sopravvivenza: dieci anni di follow-up
Obiettivo. nm23 è considerato un gene soppressore delle
metastasi per alcuni tumori umani. Una ridotta espressione
dell’mRNA di nm23 è stata riscontrata in diverse metastasi
di melanoma, con una correlazione fra espressione di tale proteina e sopravvivenza dei pazienti. Dal momento che il ruolo prognostico dell’espressione della proteina NM23 nei
melanomi primari è controverso, lo scopo di questo studio è
stato determinare l’utilità della proteina NM23 come indicatore immunoistochimico della prognosi in pazienti affetti da melanoma primario.
Metodi. L’espressione della proteina NM23 è stata analizzata in 30 melanomi primari. Sono state utilizzate sezioni in paraffina e la tecnica dell’immunoperossidasi. Il periodo di follow-up includeva la valutazione dell’intervallo libero da malattia dopo 5 e 10 anni e la sopravvivenza dopo 5 e
10 anni.
Risultati. È stato dimostrato che: (i) l’espressione della
proteina NM23 è correlata positivamente con l’intervallo
libero da malattia a 5 anni (P<0,01) e 10 anni (P<0,01); (ii)
Vol. 141 - N. 2
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cytokine-mediated modulation of nm23 expression on the invasion and
metastatic behavior of B16F10 melanoma cells. Int J Cancer
1995;60:204-10.
Bodey B, Bodey B Jr, Groger AM, Siegel SE, Kaiser HE. Nm23/nucleoside diphosphate (NDP) kinase expression in human malignant
melanomas: significance and implications in tumor biology. Anticancer Res 1997;17:505-11.
Sarris M, Scolyer RA, Konopka M, Thompson JF, Harper CG, Lee CS.
Cytoplasmic expression of nm23 predicts the potential for cerebral
metastasis in patients with primary cutaneous melanoma. Melanoma
Res 2004;14:23-7.
Nakayma H, Yasui W, Yokozaki H, Tahara E. Reduced expression of
nm23 is associated with metastasis of human gastric carcinomas. Jpn
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Engel M, Theisinger B, Seib T, Seitz G, Huwer H, Zang KD et al. High
levels of nm23-H1 and nm23-H2 messenger RNA in human squamous-cell lung carcinoma are associated with poor differentiation
and advanced tumor stages. Int J Cancer 1993;55:375-9.
Salerno M, Ouatas T, Palmieri D, Steeg PS. Inhibition of signal transduction by the nm23 metastasis suppressor: possible mechanisms.
Clin Exp Metastasis 2003;20:3-10.
Zhao H, Jhanwar-Uniyal M, Datta PK, Yemul S, Ho L, Khitrov G et
al. Expression profile of genes associated with antimetastatic gene:
nm23-mediated metastasis inhibition in breast carcinoma cell. Int J
Cancer 2004;109:65-70.
Chen SL, Wu YS, Shieh HY, Yen CC, Shen JJ, Lin KH. P53 is a regulator of the metastasis suppressor gene Nm23-H1. Mol Carcinog
2003;36:204-14.
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31.
32.
33.
34.
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36.
37.
38.
39.
40.
41.
42.
43.
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45.
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47.
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49.
50.
51.
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Perspective evaluation of a four-year period of application
of a follow-up protocol for melanoma patient management
G. PELLACANI 1, P. GIANNELLI 2, C. LONGO 1, S. BASSOLI 1, S. SEIDENARI 1
Aim. Although numerous follow-up protocols have been proposed, there are no widely accepted guidelines for melanoma
(MM) follow-up. In 2000, the Emilia-Romagna Melanoma
Group agreed upon guidelines for the MM follow-up, considering histological thickness and disease stage. The purpose of
this study was the perspective evaluation of this follow-up protocol, in order to verify the efficacy to identify metastases and
the effectiveness of the therapeutic approaches.
Methods. During a 4-year period (2001-2004), 176 MM patients
were supervised according to our follow-up protocol.
Results. Thirty-nine patients underwent disease progression,
showing in transit metastases in 15 cases, lymph node metastases in 11 cases, and distant metastases in 13 cases. At the end
of the study 11 patients were dead for the complications of the
disease. Disease progression was related with MM thickness,
tumour stage and presence of ulceration, with a significant
proportion of visceral localization in ulcerated MMs. A low
rate of metastases was observed for MMs of the upper limbs,
chest and abdomen. Concerning the metastasis identification,
the majority of the recurrences were diagnosed by the physician,
by means of instrumental examination or during clinical examination. A great part of the first recurrences underwent surgery,
with a significant proportion of complete responses for locoregional ones, whereas distant metastases, although frequently
diagnosed before becaming symptomatic, showed a poor
response to the treatments.
Conclusion. This study represents a critical intermediate analysis of the application of the Emilia-Romagna protocol after 4
years of methodical application.
KEY WORDS: Melanoma, diagnosis - Follow-up - Metastases.
Address reprint requests to: G. Pellacani, Dipartimento di Dermatologia, Università degli Studi di Modena e Reggio Emilia, Via del Pozzo 71,
41100 Modena, Italy.
Vol. 141 - N. 2
1Department of Dermatology
University of Modena and Reggio Emilia, Modena, Italy
2Army Medical Corps
Military Academy of Modena, Modena, Italy
T
he rates of morbidity and mortality due to skin
tumours in the Caucasian population has remarkably increased in the last few decades.1, 2 Since 1997,
dermatological departments and services in Emilia
Romagna have taken care of the collection of epidemiological data on melanoma (MM) observing an
increment in its incidence.3 Moreover, more than 30%
of MMs recorded in Emilia Romagna were thicker
than 1.51 mm, and their incidence was stable in spite
of information, prevention campaigns, and improvement in MM diagnosis. Since MM prognosis is tightly correlated with thickness, the follow-up of patients
at high risk of recurrences is of utmost importance,
also in consideration of the low efficacy of treatment
of the advanced disease.4, 5 In consideration of the
poor prognosis and the low therapeutic effectiveness
in advanced stage disease, in the last decade new
approaches, such as the research of subclinical lymph
nodal metastasis by means of selective lymphadenectomy and the adjuvant immunotherapy with interpheron alpha 6, 7 have been proposed, with the aim to
improve the prognosis to high risk patients. Moreover,
systematic instrumental and clinical follow-up protocols have been proposed in order to rule out operable
asymptomatic metastases.
107
PELLACANI
PERSPECTIVE EVALUATION OF A FOUR-YEAR PERIOD OF APPLICATION OF A FOLLOW-UP PROTOCOL
On the other hand, a tight clinical and instrumental
follow-up, comprehensive of sonography, chest Xray, TC and total body scintigraphy have been applied
by the Turin Melanoma Centre, since 1975. From the
analysis of the patient data base, the authors found
that 33.8% of patients undergone recurrences occurring
as first site in most cases at locoregional sites and in a
smaller, but not irrelevant part, at distant locations.19
Based on the protocol proposed by the Turin Melanoma
Centre and on literature data, in 2000, the EmiliaRomagna Melanoma Group, represented by all the
University and Hospital Dermatological Departments
of the Emilia Romagna (Piacenza, Parma, Reggio
Emilia, Modena, Bologna, Ferrara, Ravenna, ForlìCesena, Rimini, San Marino Republic), agreed upon
guidelines for MM follow-up, considering histological thickness and disease stage. A shared protocol has
been fixed and used in hospitals and universities since
2001.20
The purpose of our study consisted in the perspective evaluation of the follow-up protocol on MM, upon
which the Emilia Romagna group has agreed. In
details, the target was to verify the efficacy of the precocious singling out of metastasis by means of clinical and instrumental examinations. Moreover, the frequency and typology of progression was considered
and correlated to the characteristics of the primary
MM. The therapeutic approach and its effectiveness
was also reported. This study represents a critical intermediate analysis of the application on the EmiliaRomagna protocol after 4 years of methodical application.
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At present, there are no widely accepted guidelines
for MM follow-up, even if it is common opinion that
patient follow-up is necessary to provide an early diagnosis of a progressive disease.8 Protocols proposed so
far took different aspects into account, such as the
ability of early identification of metastases and the
cost/benefit ratio, linked to the poor treatment efficacy in advanced MM. Many of the proposed followup protocols suggested the periodical patient selfexamination and medical clinical inspection, rather
than instrumental examination, based on the retrospective observation that the majority of recurrences
were detected by the patients or were symptomatic,
leading to searching of medical advice.9-13 There is
also a disagreement on the duration of the follow-up
owing to the fact that most recurrences were detected
during the first 3 years after the radical surgery, even
if there are cases of metastases detected after many
years from the operation.14, 15
Recently, the Dermatology German Society proposed
guidelines for follow-up, based on a prospective analysis of a cohort of MM patients including whole skin
inspection, palpation of superficial lymph nodes, instrumental examination, such as abdominal sonography,
chest X-ray and computerized tomography (CT), and
blood tests, scheduled at different intervals according to
the stage of the disease.16 In this study only in few cases symptoms of metastasis were first discovered by the
patient, emphasizing that a careful examination is able
to identify numerous still asymptomatic metastases,
whereas clinical examination and imaging techniques
were useful for the diagnosis of the majority of the
recurrences. Abdominal and lymph node sonography
enabled the identification of metastasis treatable by surgical approach, whereas, chest X-ray was useless, predominantly detecting untreatable lesions.17 In high risk
MMs CT resulted useful especially for studying areas
inaccessible with physical or sonographical examination,
showing a superior sensibility than chest X-ray for the
diagnosis of pulmonary metastases.
The problem of MM patient follow-up was considered in the Italian medical community, leading to the
proposal of CNR guidelines in 2003.18 Periodical clinical controls, with a variable frequency depending on
tumour stage, were considered necessary, whereas
lymph node and hepatic sonography and chest X-ray
were left to medical decision. Additional tests or instrumental exams can be required in presence of revealed
or reported symptoms or warning signals.18
108
The study represented an experimental clinical evaluation based on the use of record charts. The gained
parameters constitute a descriptive and critical analysis, done in a perspective way, on the effectiveness of
the Emilia-Romagna protocol.
Population of the study and collected data
The main rule for the inclusion consisted in the possibility of being operated according to radical surgery
at the Department of Dermatology of the University of
Modena and Reggio Emilia. Patients with a middle
or high risk of recurrences were sent to our Department
for the staging phase, including, if indicated, sentinel
Aprile 2006
PELLACANI
TABLE I.—Follow-up protocol: type and frequency of the examinations according to the tumour stage.
Staging
Clinical examination
Frequency
Once a year for 10 years
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0
Examinations
IA
IB, IIA, IIB, IIC
Laboratory examinations
Sonography:
— locoregional lymph node
— abdomen
Chest X-ray
Total body + brain CT
Twice per year for 5 years, then once per year until the 10th year
Once per year for 5 years
Thrice per year for 3 years, then twice per year until the 5th year, finally once per year until
the 10th year
Laboratory examinations
Sonography:
— Locoregional lymph node
— Abdomen
Chest X-ray
IIIA, IIIB, IIIC
Clinical exam
Laboratory exam
Sonography:
— locoregional lymph node
— abdomen
Chest X-ray
IV
Twice per year for 5 years
—
Twice per year for 5 years, then once per year until the 10th year
*Twice per year for 5 years, then once per year until the 10th year
*Twice per year for 5 years, then once per year until the 10th year
*Once per year in spite of 1 sonography and 1 X-ray
3 times per year for 3 years, then twice per year until the 5th year, finally once per year until
the 10th year
At doctor’s discretion
* Abdomen sonography and chest X-ray can be substituted by total body + brain CT once per year
lymph node biopsy, and total body and brain TC. Necessary conditions to be eligible for the study were
histopathological confirmation of MM and the completion of all the regular staging examinations. All
enlisted patients underwent follow-up examination,
according to the protocol. For each patient a data sheet
was filled in conformity with the following parameters:
1) birth date; 2) gender; 3) date of tumour excision; 4)
histological examination reporting the Breslow’s thickness, ulceration and regression; 5) MM’s site; 6) report
of the number of positive lymph nodes and presence of
distant metastases at tumour staging; 7) TNM and
American Joint Committee on Cancer (AJCC) stage.21
All the patient referred to our centre for MM excision
or staging during the period from the 1st January 2001
to the 31st of December 2004, were considered. The
study was closed on September 2005 in order to have
a minimum follow-up period of 9 months. During follow-up period each case of recurrences was recorded. For each patient 1) the site of metastases, 2) the
source of disease notification (disease notified by the
Vol. 141 - N. 2
patient as symptomatic; disease revealed by clinical
exams or clinical instrumental techniques), 3) the new
TNM, 4) the kind of therapeutic approach (surgery,
chemotherapy, radiotherapy or local hyperthermia
combined with chemotherapy) and 5) its effects, pointing out the disease state (complete or partial response,
stable or progressive disease), were considered. All
data were collected and analyzed using Microsoft
Excel, which permitted the creation of an electric sheet
containing available information for the analysis.
Follow-up protocol
The Emilia-Romagna protocol consisted in minimal texts to be done periodically by each patient as
shown in Table I. Eventual other tests/controls can be
added for specific cases at doctor’s advice. Independently from the belonging stage, guidelines recommended examinations at least until the 10th year from
the first excision. During the consultation, the patient
was educated by the doctor on clinical characteristics
of MM and recurrences, and on the methods of recog-
109
PELLACANI
TABLE II.—Study population divided on the basis of the tumour stage at diagnosis according to the American Joint Committee on
Cancer (AJCC) stage.
AJCC
Total (%)
F
M
Progressive
disease
(%)°
Exitus
(%)°
0
2
(1.1)
48
(27.3)
37
(21)
25
(14.2)
24
(13.6)
8
(4.5)
19
(10.8)
3
(1.7)
9
(5.1)
1
(0.6)
2
(100)
25
(52.1)
25
(67.6)
14
(56)
12
(50)
3
(37)
11
(57.9)
1
(33.3)
4
(44.4)
1
(100)
0
(0)
23
(47.9)
12
(32.4)
11
(44)
12
(50)
5
(62.5)
8
(42.1)
2
(66.7)
5
(55.6)
0
(0)
0
(0)
1
(2.1)
6
(16.2)
8
(32)
8
(33.3)
4
(50)
6
(31.6)
2
(66.7)
3
(33.3)
1
(100)
0
(0)
0
(0)
1
(2.7)
2
(8)
1
(4.2)
2
(25)
3
(15.8)
1
(33.3)
1
(11.1)
0
(0)
176
(100)
98
(55.7)
78
(44.3)
39
(22.2)
11
(6.3)
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nition of signs and symptoms. Particular emphasis
was turned to the skin self-examination. In our study,
in order to compare the effectiveness of the different
instrumental methods of research, we choose the option
of a total body and brain CT alternated with abdomen
sonography and chest X-rays every 6 months for stage
IB and II patients.
In stage IV examinations were executed at doctor’s
discretion, according to the site and number of metastases.
IA
IB
IIA
Treatment protocol for the metastases
The therapeutic approach was divided into surgical
excision, chemotherapy and radiotherapy. If possible,
radical surgery was chosen, while chemotherapy and
radiotherapy were reserved to unresectable metastases. As chemotherapy, dacarbazine 250 mg per m2/die
for 5 days/week for 4 weeks was chosen as front line
therapy. As the second line treatments cisplatin and/or
vinblastin and/or fotemustine was employed singularly or in combination, with or without addition of
immunotherapy (IL-2 and IFN-α). Local recurrences
at the limbs, not operable for spread and number, were
treated with local hyperthermia combined with
chemotherapy (Melphalan). Radiotherapy was reserved
for unresectable brain metastases. Concerning not
operable metastases found in patients already treated
with first and second line chemotherapy, it was opted
for a symptomatic palliative therapy.
Results
From 1st January 2001 to 31st December 2004, 176
patients subjected to MM’s excision at the Department of Dermatology of the University Modena and
Reggio Emilia have been supervised by the service of
Day Hospital, according to the follow-up protocol of
the Emilia-Romagna.
The study population included 78 males and 98
females. The average age was 60 years for both sexes,
with a standard deviation of 17 years ranging between
22 and 94 years. The patients were supervised for an
average period of 34 months, ranging between a minimum of 9 months and a maximum of 57 months. The
average histological thickness of the excised lesions
was 2.27 mm with a standard deviation of 2.09 mm and
a range of 0.15-13 mm. After the completion of the
staging phase, inclusive of selective lymph node biop-
110
IIB
IIC
IIIA
IIIB
IIIC
X
Total
sy for lesions above 0.75 mm or for thinner ones with
ulceration or a diffuse and deeper regression, the population study consisted of 85 patients belonging to
stage I (48 to stage IA and 37 to stage IB), 57 patients
to stage II (25 to stage IIA, 24 to stage IIB and 8 to
stage IIC), and 31 patients to stage III (19 to stage
IIIA, 3 to stage IIIB and 9 to stage IIIC). In our study
no patient revealed distant metastasis at the moment of
enlistment. Two patients with stage 0 disease (in situ
MM) were also included and followed up as stage IA
patients for the presence of extensive regression at
histology. The remaining case, lacking data on tumour
thickness and sentinel lymphadenectomy, clinically
and instrumentally negative for secondary localization, was followed up as stage II lesions (Table II).
During the study 39 out of 176 patients underwent
disease progression, showing recurrences as satellites
and/or in transit metastases in 15 cases, as lymph node
metastases in 11 cases, and as distant metastases in
13 cases (7 in the lung, 5 in the liver, 2 in the brain, presenting in one patient 2 contemporary localizations)
(Table III). During the follow-up 3 patients out of 39
were dead because of metastases complications, while
in 13 patients secondary metastases have been diag-
Aprile 2006
gression in more than 40% of patients with a pT3b or
greater.
The presence of demonstrated histological ulceration
resulted as an unfavourable factor of prognosis since
a progression was noticed in 40.5% of lesions with
ulceration against 17.3% of lesions without (Table V).
Moreover, an increased risk for visceral first localizations was observed in ulcerated lesions compared with
non ulcerated ones (18.9% vs 4.3%).
The primary site of MM was linked to the frequency of recurrences and to their localization, as shown
in Table VI. Head-neck MMs showed the greatest mean
tumour thickness and the highest risk of recurrence
(36.8%), with secondary localizations equally distributed in locoregional and distant sites. MMs of the palm
and soles had an high rate of recurrences predominantly locoregional. MMs on the back and lower limbs
showed recurrences nearly in the 20% of cases, but for
localizations on the back locoregional and distant metastases were equally distributed, while in the lower limbs
MM recurrences were found exclusively in locoregional sites. Localizations on the upper limbs, chest
and abdomen were minimally responsible for recurrences, although did not significantly differ in tumour
thickness with respect to lower limb and back MMs.
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nosed (1 in transit, 2 lymph nodal, 6 pulmonary, 3
hepatic, 4 encephalic, and 2 spleen recurrences, in 5
cases with multiple localizations). In the group of 13
patients who have had a progression of the disease,
currently 8 were dead during the follow-up because of
the disease.
Disease progression was related with MM thickness and tumour stage (Table IV). The majority of
recurrences (69.2%) were diagnosed in patients with
MMs thicker than 2 mm. The risk for developing a
recurrence was related to the pT stage, with a pro-
PELLACANI
TABLE III.—Type and site of the recurrences.
Localization
1st recurrence
Further
recurrences
In transit
Lymph nodes
Lung
Liver
Brain
Other
15
11
7
5
2
0
1
2
6
3
4
2
Total
40
18
1
5
Cases with contemporary involvement
of 2 or more sites
TABLE IV.—Locoregional and visceral recurrences according to the melanoma pT stage.
PT
Tis
T1a
T1b
T2a
T2b
T3a
T3b
T4a
T4b
Tx
Total
Total
(%)*
LN + at staging
(%)°
1st recurrence
locoregional
(%)°
1st recurrence
at distance
(%)°
Progrressive
disease (%)°
Exitus
(%)°
2
(1.1)
49
(27.8)
3
(1.7)
45
(25.6)
9
(5.1)
22
(12.5)
16
(9.1)
17
(9.7)
9
(9.7)
4
(2.3)
0
(0)
(2)
0
(0)
10
(22.2)
3
(33.3)
4
(18.2)
6
(37.5)
2
(11.8)
2
(22.2)
3
(75)
0
(0)
1
(2)
1
(33.3)
5
(11.1)
0
(0)
6
(27.3)
6
(37.5)
4
(23.5)
1
(11.1)
2
(50)
0
(0)
1
(2)
0
(0)
1
(2.2)
3
(33.3)
1
(4.5)
1
(6.3)
3
(17.6)
3
(33.3)
0
(0)
0
(0)
1
(2)
0
(0)
2
(4.4)
2
(22.2)
2
(9.1)
0
(0)
3
(17.6)
2
(22.2)
1
(25)
0
(0)
1
(2)
0
(0)
1
(2.2)
2
(22.2)
1
(4.5)
1
(6.3)
3
(17.6)
2
(22.2)
0
(0)
176
(100)
31
(17.6)
26
(14.8)
13
(7.4)
13
(7.4)
11
(6.3)
*% in respect of the total number of MMs; ° %in respect of the MMs belonging to that pT stage
Vol. 141 - N. 2
111
PELLACANI
TABLE V.—Locoregional and visceral recurrences according to the histologic ulceration.
PT
Total
(%)*
LN + at staging
(%)°
1st recurrence
locoregional
(%)°
1st recurrence
at distance
(%)°
Progrressive
disease (%)°
Exitus
(%)°
139
(79)
37
(21)
20
(14.4)
11
(29.7)
18
(12.9)
8
(21.6)
6
(4.3)
7
(18.9)
8
(6.5)
4
(10.8)
6
(4.3)
5
(13.5)
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Non ulcerated
Ulcerated
*% in respect of the total number of MMs; °% in respect of the MMs belonging to the corresponding group
TABLE VI.—Locoregional and visceral recurrence according to the site of melanoma insurgence.
Melanoma site
Thickness
(mean±DS)
Locoregional
recurrence
Head-neck
Upper limbs
Lower limbs
Chest and abdomen
Back
Palm-plantar
3.75±3.23
1.63±1.26
1.84±1.49
2.26±2.31
1.97±1.67
2.88±2.11
3 (10.5%)
1 (3.8%)
10 (18.2%)
1 (7.7%)
5 (12.5%)
6 (26.3%)
5 (26.3%)
1 (3.8%)
1 (1.8%)
1 (7.7%)
4 (10%)
1 (5.3%)
11 (63.2%)
26 (92.4%)
44 (80%)
11 (84.6%)
32 (77.5%)
13 (68.4%)
26 (100%)
13 (100%)
137 (100%)
Total
At distant
recurrence
No recurrences
TABLE VII.—Modalities of identification of the recurrences.
Total (%)
1st Recurrence type
Total (%)
Patient’s symptoms
6
(15)
4 in transit
2 brain
0
12
(30)
10 in transit
2 LN
2
(11.1)
1 in transit
1 LN
Instrumental examination:
22
(55)
1 in transit
9 LN
7 Lung
5 Liver
16
(88.9)
1 LN
6 lung
2 liver
2 brain
2 others (Spleen)
1 LN
Sonography
8
(36.4)
6 LN
2 Liver
1
(6.3)
Chest X-ray
1
(4.5)
1 Lung
0
13
(59.1)
1 in transit
3 LN
6 Lung
3 Liver
Table VII described the type of recurrence matched
with the source of identification. In over the half of
cases, the first recurrence was diagnosed by means of
instrumental examinations. On the other hand, 12
recurrences (32.4%), mainly in transit metastasis, were
individuated during routinely clinical examination of
the patient. Just 4 out of 37 patients self-reported symp-
112
15
(93.7)
Further recurrence type
6 lung
3 liver
4 brain
2 other
toms and/or signs correlated with a recurrence. Further
metastatisation was diagnosed by instrumental analysis in all cases but 1, found during clinical examination.
In transit metastases were mostly identified by the
physician by clinical inspection (10 cases out of 15
cases), while lymph nodal and visceral metastases
were best diagnosed by instrumental examination.
Aprile 2006
PELLACANI
TABLE VIII.—Therapeutic approaches and effectiveness in first recurrences.
Surgery
13
8 Complete
2 Partial
3 Progression
Chemotherapy
Answer
2
2 Complete
0 Partial
0 Progression
Radiotherapy
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In transit
Answer
Lymph node
Lung
Liver (*)
11
4 Complete
4 Partial
3 Progression
1
0 Complete
0 Partial
1 Progression
6
0 Complete
3 Partial
3 Progression
0 Complete
0 Partial
1 Progression
3
0 Complete
0 Partial
3 Progression
1
Brain
Total
26
12 Complete
6 Partial
8 Progression
11
2 Complete
3 Partial
6 Progression
Answer
2
0 Complete
0 Partial
2 Progression
2
0 Complete
0 Partial
2 Progression
(*1 case withdrawn)
Sonography seemed effective in diagnosing lymph
nodal and hepatic metastases (8 out of 13 recurrences),
whereas CT enabled the identification of the majority of lung metastases compared with chest X-ray. Brain
metastases and spleen localization were recognized
by CT, with the exception of 2 cases of brain metastasis
diagnosed on the basis of symptoms referred by the
patients.
Table VIII showed the employed treatments and
their effectiveness, evaluated 3 month after the therapeutic protocol conclusion by means of total body and
brain CT scans. Twenty-six first metastases underwent surgical excision, obtaining a complete resolution
in 12 cases (4 lymph node and 8 in transit recurrences),
a partial resolution in 6 cases (4 lymph node and 2 in
transit recurrences), and a progression in 8 cases (3
lymph node, 3 in transit, 1 lung and 1 liver recurrences). Chemotherapy was given for 11 first localizations, obtaining 2 complete responses in patients
with in transit metastases by means of local hypertermia with Melphalan and 3 partial responses in patient
with lung recurrences, whereas a progression was
observed in 6 cases referred to 3 lung and 3 liver localizations. None of the 2 patients treated with radiotherapy for brain localization had benefit from the
therapy. One patient with a liver localization withdrew
from our protocol.
Vol. 141 - N. 2
In front of MM metastases the medical choice is
oriented on the radical removal, when possible, because
it offers to the patient the best perspectives, both regarding the quality of life and the possibility of surviving.22 Therefore, instrumental and clinician patient
follow-up have been proposed in order to rule out
operable asymptomatic metastases.
Numerous follow-up protocols, generally based
on retrospective data, have been proposed, which
markedly differ if were held in greater consideration the socio-economical or the medical aspects of
the survey. 9-13, 16, 18-20 In 2003 Garbe et al. 16 perspectively evaluated the efficacy of a follow-up protocol showing that a systematic screening of the
patients allowed to find metastases before the symptoms appearance in many cases, both for locoregional and visceral ones.
In our study we applied since the 1st of January 2001
a pre-established follow-up protocol to all the MM
patients supervised in the Day Hospital service of our
Clinic, systematically recording data on primary
tumour characteristics, recurrence site and diagnostic and therapeutic procedures.
The population examined in the follow-up represents 69.3% of the totality of 254 invasive MMs in
113
PELLACANI
palms/soles could be related to the higher thickness.
Whereas, a low rate of recurrence was recorded in
lesions of the upper limbs, chest and abdomen,
although the mean thickness was similar to the other
sites. A predominant locoregional metastatization
derived from MMs of the palm and soles and of the
lower limbs, whereas distant recurrences were more
frequently observable in patients with MMs of the
head and neck and of the back.
Concerning the metastasis identification, our data
confirmed previous observations,16 since the majority of the recurrences were diagnosed by the physician, during clinical examination in the 30% of cases
and by means of instrumental examination in 55% of
cases. In our population, patients were able to find 4 out
of 15 in transit metastases and 2 brain metastases arisen
as first recurrence. Probably owing to their early recognition, a great part of the first recurrences underwent
surgery, with a significant proportion of complete
responses for locoregional recurrences. On the other
hand, distant metastases, although frequently diagnosed before to became symptomatic, showed a poor
response to the treatments.
In conclusion, the strategy of surveillance examined in this study leaded to a high proportion of early
metastasis recognition, although an effective treatment was recorded only for locoregional recurrences.
Ultrasounds resulted equally effective, compared with
CT, for the identification of lymph node and liver
metastases, whereas CT appeared to be superior to
chest X-ray for lung metastasis recognition. These
data suggest that patients with ulcerated MMs, MMs
of the head-neck and back and cases with positive sentinel lymph node at staging (stage III subjects), should
be accurately investigated both for locoregional and visceral metastases, whereas a particular attention to
locoregional sites should be paid to thick non ulcerated MMs of the limbs, chest, abdomen and palm and
soles.
Although our data are based on a short period, the
critical analysis of the follow-up protocols is of great
importance in order to modify opportunely the rules in
accordance to the resulting data, enabling the improvement of the quality of the service sparing non necessary examination and focusing on the most informative
and effective investigations. Obviously, conclusive
data could derive from a greater number of cases followed for a longer period, suggesting the opportunity
of a multicenter trial.
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the Province of Modena recorded by the Modena Cancer Registry during the 4 year study period.
According to previous data,23 the frequency of progression was strictly correlated to the histological
thickness, to the stage of the disease, to the presence
of ulceration at histology, and to the site of insurgence
of the primary tumour. We observed a recurrence in
22.2% of patients, with a further progression in 1/3
of those. During the course of the study 11 patients
died as a result of MM metastases, in 3 cases in consequence of the first recurrence, while the other 8 of a
visceral widespread of the disease, pointing out how
MM progressions present a poor prognosis. Although
the MM can virtually create metastases in every organ
or tissue, the locoregional district was mainly interested
(65.1% of the cases) from the first recurrences, in
agreement with the literature’s data (Table V).19, 23, 24
Considering also the positive elective and selective
lymph node biopsies, the proportion of locoregional
recurrences increases to 76.6%, since 20 patients with
positive lymph node at staging did not present progression, demonstrating that the disease mainly spread
through contiguity and/or lymphatic way.23 Considering first recurrences in visceral sites, they were found
in lung, liver and brain.
Interestingly, 9 out of the 13 patients with first
visceral localization did not present previous locoregional recurrences, corresponding to a direct haematic spread in a consistent percentage (23%) of the
progressions, while in the remaining 4 cases positive sentinel lymph nodes were found. Moreover,
the presence of ulceration seemed strongly correlated with a bad prognosis, increasing the risk of
progression, with a greater probability to have visceral localizations (Table V). Therefore, an accurate patient check up, comprehensive of CT totalbody and brain, seems to be recommended for MMs
with ulceration, independently from the histological thickness. On the other hand, for patients with
non ulcerated MM clinical examination and lymph
node sonography represented the most relevant
investigations, especially for tumours thicker than
2 mm which presented a progression in 14 out of 39
cases (35.9%), compared with the 8 progressions
in the 96 thinner ones (8.3%).
From our data it emerges that the risk and type of
recurrence was also influenced by the site of the primitive tumour (Table VI). The high risk of recurrence
observed for MMs localized at the head/neck and
114
Aprile 2006
Riassunto
6.
7.
Predicting survival and recurrences in localized melanoma: a multivariate approach. World J Surg 1992;16:191-8.
Shen P, Guenther M, Wanek LA, Morton DL. Can elective lymph
node dissetion decrease the frequenzy and mortality rate of late
melanoma recurrences? Ann Surgic Oncol 2000;7:114-9.
Kirkwood JM, Ibrahim JG, Sosman JA, Sondak VK, Agarwala SS, Ernstoff MS et al. High dose Interferon-a significantly prolongs relapsefree and overall survival in patients with reseced stage IIB-III
melanoma: results of Intergroup trial E1694/S9512/C509801. J Clin
Oncol 2001;19:2370-80.
Johnson TM, Bradford CR, Gruber SB, Sondak VK, Schwartz JL.
Staging work-up, sentinel node biopsy, and follow-up test for
melanoma. Arch Dermatol 2004;140:107-13.
Poo-Hwu WJ, Ariyan S, Lamb L, Papac R, Zelterman D, Hu GL et al.
Follow-up recommendations for patients with American Joint Committee on Cancer Stage I-III malignant melanoma. Cancer
1999;86:2252-8.
Baughan C, Hall V, Leppard B, Perkins P. Follow-up in stage 1 malignant melanoma. Clin Oncol 1993;5:174-80.
Diker TJ, Kavanagh GM, Herd RM, Ahmad T, McLaren KM, Chetty U et al. A rational approach to melanoma follow-up in patients
with primary cutaneous melanoma. Scottisch Melanoma Group. Br J
Dermatol 1999;140:249-54.
Weiss M, Loprinzi CL, Creagan ET, Dalton RJ, Novotny P, O’Fallon
JR. Utility of follow-up tests for detecting recurrent disease in patients
with malignant melanomas. JAMA 1995;274:1703-5.
Roberts DL, Anstey AV, Barlow RJ, Cox NH, Newton Bishop JA,
Corrie PG et al. U.K. Guidelines for the management of cutaneous
melanoma. Br J Dermatol 2002;146:7-17.
Tahery DP, Moy RL. Lack of predictive factors in late recurrence of
stage 1 melanoma. Int J Dermatol 1992;31:629-31.
McEwan L, Smith JG, Matthews JP. Late recurrence of localized
cutaneous melanoma: its influence on follow-up policy. Plast Reconstr Surg 1990;86:527-34.
Garbe C, Andrena P, Hanna KS, Ellwanger U, Stoebel W, Schwarz M
et al. Prospective evaluation of a follow-up schedule in cutaneous
melanoma patients: recommendations for an effective follow-up strategy. J Clin Oncol 2003;21:520-9.
Berman C, Reintgen D. Radiologic imaging in malignant melanoma:
a review. Semin Surg Oncol 1993;9:232-8.
Cascinelli N. Basi scientifiche per la definizione di linee guida in
ambito clinico per il melanoma cutaneo. Progetto Strategico Oncologia Bridge Legge 449/97 - anno 1999, n. 6 CNR, gennaio 2000.
www.progettooncologia.cnr.it/bridge/melanomacutaneo.
Bernengo MG, Quaglino P, Cappello N, Fierro MT, Doveil GC,
Marcripò G et al. Time course and pattern of first relapse in stage I
and II primary cutaneous melanoma: a multivariate analysis of disease-free survival in 3174 patients followed-up at the Turin Melanoma
centre from 1975 to 2004. G Ital Dermatol Venereol 2005;140:191200.
Ascari Raccagni A, Baldassari L, Erbazzi A, Pellacani G, Seidenari S.
Linee guida di follow-up del melanoma in Emilia Romagna. A nome
del gruppo emiliano-romagnolo per il melanoma. 78° Congresso
Nazionale Società Italiana di Dermatologia e Venereologia (SIDEV.,
25-28 Giugno 2003, Roma.
Balch CM, Buzaid CA, Atkins MB, Cascinelli N, Coit DG, Flemming I et al. A New American Joint Committee on Cancer Staging System for Cutaneous Melanoma. Cancer 2000;88:1484-91.
Allen PJ, Coit DG. The surgical management of metastatic melanoma.
Ann Surg Oncol 2002;9:762-70.
Soong SJ, Shaw HM, Balch CM, McCarthy WH, Urist MM, Lee JY.
Predicting survival and recurrence in localized melanoma: a multivariate approach. World J Surg 1992;16:191-5.
Balch CM, Soong SJ, Gershenwald JE, Thompson JF, Reintgen DS,
Cascinelli N et al. Prognostic factors analysis of 17,600 melanoma
patients: validation of the American Joint Committee on Cancer
Melanoma. Staging System. J Clin Oncol 2001;16:3622-34.
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Valutazione prospettica del Protocollo Emiliano-Romagnolo di follow-up dei pazienti affetti da melanoma dopo 4 anni
di applicazione
Obiettivo. Attualmente non esistono linee guida comunemente accettate di follow-up dei pazienti con melanoma,
nonostante numerosi protocolli siano stati proposti negli
anni. Nel 2000 il Gruppo Emiliano Romagnolo sul
melanoma ha concordato su linee guida di follow-up basate
sullo spessore istologico e stadio della malattia. Lo scopo
dello studio era la valutazione prospettica dei risultati dell’applicazione del protocollo, verificandone l’efficacia nell’identificare metastasi e l’effetto del relativo approccio
terapeutico.
Metodi. Nel corso dei 4 anni di studio (2001-2004), sono
stati seguiti secondo le indicazioni del protocollo 176 pazienti affetti da melanoma.
Risultati. Trentanove pazienti sono incorsi in una recidiva della patologia, presentando, come prima localizzazione,
metastasi in transit in 15 casi, ai linfonodi in 11 e a distanza
in 13. Al termine dello studio 11 pazienti erano deceduti
in conseguenza di complicazioni della patologia. La progressione è risultata correlata allo spessore del melanoma,
allo stadio e all’ulcerazione, con una frequenza significativamente maggiore di metastasi viscerali nelle lesioni
ulcerate. Raramente si sono osservate metastasi da lesioni
insorte agli arti superiori, al torace e all’addome. La maggior parte delle recidive sono state identificate dal medico,
mediante esami strumentali o esame clinico. Un elevato
numero di metastasi è stato asportato chirurgicamente,
con risposta completa nella maggior parte delle localizzazioni locoregionali, mentre per le metastasi a distanza,
nonostante venissero frequentemente diagnosticate ancora asintomatiche, si è avuta una scarsa efficacia terapeutica.
Conclusioni. Lo studio rappresenta un’analisi critica intermedia dell’applicazione del Protocollo Emiliano-Romagnolo di follow-up a 4 anni dall’introduzione.
PAROLE CHIAVE: Melanoma, diagnosi - Follow-up - Metastasi.
PELLACANI
References
1. Hall HL, Miller DR, Rogers JD, Bewerse B. Update on the incidence
and mortality from melanoma in the United States. J Am Acad Dermatol 1999;9:178-82.
2. Lens MB, Dawes M. Global perspective of contemporary epidemiological trends of cutaneous malignant melanoma. Br J Dermatol
2004;150:179-85.
3. Lo Scocco G, Arcangeli F, Ascari Raccagni A, Baldassari L, Cimitan
A, Donelli S et al. Epidemiologia del melanoma nella regione Emilia-Romagna negli anni 1997-98. Esperienze Dermatologiche
2000;2:19-27.
4. Bajetta E, Del Vecchio M, Bernard-Marty C, Vitali M, buzzoni R,
Rixe O et al. Metastatic melanoma: chemotherapy. Semin Oncol
2002;29:427-45.
5. Soong S, Shaw HM, Balch CM, McCarthy WH, Urist MM, Lee JY.
Vol. 141 - N. 2
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
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Personal experience on antibiotic resistance
of propionibacteria in Ferrara
V. BETTOLI 1, A. BORGHI 2, R. ROSSI 3, M. FERRONI 2, F. RIGOLIN 3, A. VIRGILI 2
Aim. Antibiotics reducing the number of propionibacteria on
the skin represent powerful agents in the treatment of inflammatory acne. The widespread use of both oral and topical
antibiotics to treat acne has resulted in the dissemination of
propionibacterial-resistant strains. Failure of therapy associated with the selection of antibiotic-resistant propionibacteria
is a well recognized concern. The aim of the study is to determine the prevalence of skin colonization by antibiotic-resistant propionibacteria in a large number of acne patients attending our department and to monitor changes over a six-year
period (April 2000-October 2005).
Methods. From April 2000 we have tested the susceptibility to
the most commonly used antiacne antibiotics of the propionibacterial strains carried by the patients with acne, proposed to
be treated with antibiotic. Propionibacterial samples were
obtained from the skin surface of the face of 1 579 acne patients
using a moistened swab. The swabs were used to inoculate agar
plates containing selective concentrations of tetracycline,
minocycline, erythromycin and clindamycin, as well as antibiotic-free control plates. After 7 days of anaerobic incubation at
37 °C, a semiquantitative method (a scale from 0 to 5+) was
applied to estimate the amount of growth in the presence of
each antibiotic.
Results. Propionibacteria were isolated in 1 508 of 1 579 patients
sampled. The prevalence of carriage of isolates resistant to at
least one antibiotic was 55.9%. Resistance to erythromycin
was the most common in all years ranging from 58.8% in 2000
to 38.5% in 2005 (mean prevalence 47.7%); resistance to clin-
1Dermatology
Unit, Department of Specialistic Medicine
Arcispedale S. Anna University Hospital, Ferrara, Italy
2Dermatology Unit
Department of Clinical and Experimental Medicine
University of Ferrara, Ferrara, Italy
3Microbiology Unit, Department of Pathology and Oncology
Arcispedale S. Anna, Ferrara, Italy
damycin ranged from 44.1% in 2000 to 32.2% in 2005 (mean
39.2%). Thirty-five percent of the isolated strains were resistant
to both erythromycin and clindamycin. Rates of resistance to
tetracyclines were very low (1.9% to tetracycline and 0.6% to
minocycline). Mild reduction in resistance to erythromycin
and clindamycin was noticed over the period of samples collection. The highest rates of resistance were found in older
patients and slightly higher rates in males than in females.
Conclusion. The available data show a wide distribution of
propionibacterial strains resistant to erythromycin and clindamycin in the large number of patients sampled. At present,
resistance rates to oral tetracyclines are very low. These findings support the significance of the cultural definition of antibiotic sensitivity of propionibacteria isolated from acne patients.
This is considered by us useful for both adequate management
of acne and monitoring the phenomenon of bacterial resistance.
KEY WORDS: Acne - Propionibacteria - Antibiotic resistance.
Received: February 7, 2006.
Address reprint requests to: Dr. V. Bettoli, MD, Dipartimento di Medicine Specialistiche, U.O. di Dermatologia, Azienda Ospedaliera Universitaria Arcispedale S. Anna, Corso Giovecca 203, 44100 Ferrara, Italy.
Vol. 141 - N. 2
A
ntibiotics play a major role in acne therapy, working both as bacteriostatic-bactericidal agents on
propionibacteria 1 and as direct anti-inflammatory
agents.2, 3 Antibiotics currently used to treat papulo-
117
BETTOLI
PERSONAL EXPERIENCE ON ANTIBIOTIC RESISTANCE OF PROPIONIBACTERIA IN FERRARA
Propionibacterial samples were obtained from the
skin surface of the face of the acne patients using a
moistened swab. The whole face was rubbed with a
transport swab moistened in wash fluid (0.075 mol L1 sodium phosphate buffer, pH 7.9) containing 0.1%
Triton-X 100. Swabs were used to inoculate plates
containing selective concentrations of tetracycline (5
µg/mL-1), minocycline (5 µg/mL-1), erythromycin (0.5
µg/mL-1) and clindamycin (0.5 µg/mL-1) as well as
antibiotic-free control plates, always inoculated last.
The base medium was TYEG agar containing 2% tryptone, 1% yeast extract agar, 0.5% glucose and 2 µg/mL1 furazolidone to inhibit the growth of staphylococci.
After 7 days anaerobic incubation at 37 °C, a semiquantitative method was used to estimate propionibacterial population densities by recording the level of
growth on isolation plates. Bacterial growth was
assigned a score of 0-5+ where 5+ denoted confluent
growth, 4+ denoted > 101 colonies to semiconfluent
growth, 3+ indicated 51-100 colonies, 2+ indicated
11-50 colonies, and 1+ indicated ≤≤10 colonies.12 The
level of propionibacterial resistance in the plates containing antibiotics was evaluated as follows: no resistance = S (sensitive); mild resistance = MR (1-50
colonies); intermediate resistance = I (51-100 colonies);
relevant resistance = R (101 to confluent). It should be
emphasized that this method is semiquantitative and
was used in this study as it can be employed in situations that are unsuitable for the quantitative sampling
method of Williamson and Kligman.13
All patients were sampled for propionibacterial
resistant to erythromycin and clindamycin sensitivity
(1 579 patients). Because of prescription strategies
and availabilities of the different antibiotics in the Italian market, tetracycline was tested from April 2000
to December 2000 and again from 2002 up to now (1
084 patients). Minocycline was tested until 2002 when
we stopped its use (528 patients).
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pustolar acne are oral tetracyclines, macrolides, sulfonamides and topical macrolides (erythromycin) and
clindamycin. The available agents are suitably used
in combination with topical retinoids, to target various
pathogenic factors involved in acne.4
Antibiotic therapy for acne has to be given for prolonged periods of time, usually several months; the
longer the exposure, the greater is the selection and
overgrowth of resistant strains of propionibacteria. In
P. acnes, antibiotic resistance is acquired by mutations
within genes encoding components of the target to
which the drug binds. In particular, erythromycin resistance is associated with any one of 3 distinct point
mutations within the gene encoding the peptidyl transferase centre of 23S rRNA. Each mutation confers a different cross-resistance pattern to macrolides, lincosamides and type B streptogramins, the so called
MLS antibiotics.5, 6 In the case of tetracycline, resistance
is associated with a mutation in the 16S rRNA of the
small ribosomal subunit at E. coli equivalent base 1058.7
Over the past 30 years, the widespread use of antibiotics to treat acne has resulted in significant dissemination of resistant strains of propionibacteria.8 In clinical practice, the consequence of propionibacterial
antibiotic-resistance consists of a reduced response to
treatment with both the corresponding and the crossresistant antibiotics.1, 9-11 Skin carriage of resistant propionibacteria may be associated to poor therapeutic
outcome to topical as well as to oral antibiotic treatments.1, 10 Although Eady has given advice in clinically recognising patients who may carry antibiotic resistant organisms,9 however, in practice, identification of
patients carrying resistant strains is very difficult.
Undoubtedly, the recognition of specific resistances
may only be achieved by the evidences provided by
propionibacterial culture and subsequent antibiogram.
This is the reason why from April 2000, in cooperation with the Laboratory of Microbiology of our hospital, we tested the antibiotic sensitivities of propionibacteria strains carried by the acne patients who needed antibiotic treatments. Antibiotic prescriptions have
been consequently driven by the laboratory results.
In the present study, we evaluate the prevalence of
skin colonization by antibiotic-resistant propionibacteria among acne patients sampled between April 2000
and October 2005. We have analysed the propionibacterial resistance to each of the tested antibiotics
also analysing the results by years, age-related populations and sex.
118
Results
Between April 2000 and October 2005, a total of 1
579 acne patients (521 males and 1 058 females) of
average age 21 (range 12-42) were sampled for propionibacterial resistant strains. Viable propionibacteria were recovered from 1 508 out of 1 579 (95.5%)
sampled patients. Resistant strains were found on the
Aprile 2006
BETTOLI
TABLE I.—Number and percentage of patients carrying propionibacteial strains susceptible and resistant to each antibiotic: yearly results.
2001
Number
of patients
(%)
2002
Number
of patients
(%)
2003
Number
of patients
(%)
2004
Number
of patients
(%)
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2000
Number
of patients
(%)
Ery
Susceptible
Resistant
Cly
Susceptible
Resistant
Min
Susceptible
Resistant
Tet
Susceptible
Resistant
2005
Number
of patients
(%)
112
(41.2)
160
(58.8)
110
(53.4)
96
(46.6)
167
(51.7)
156
(48.2)
140
(55.5)
112
(44.4)
110
(50.2)
109
(49.8)
88
(61.5)
55
(38.5)
152
(55.9)
120
(44.1)
122
(59.2)
84
(40.8)
183
(56.3)
140
(43.3)
162
(64.3)
90
(35.7)
133
(60.7)
86
(39.3)
97
(67.8)
46
(32.2)
269
(98.9)
3
(1.1)
206
(100)
0
(0)
50
(100)
0
(0)
not tested
not tested
not tested
not tested
not tested
not tested
100
(96.1)
4
(3.9)
not tested
267
(97.8)
6
(2.1)
251
(99.6)
1
(0.4)
215
(98.2)
4
(1.8)
141
(98.6)
2
(1.4)
not tested
Ery: Erithromycin, Cli: Clindamycin, Min: Minocycline, Tet: Tetracycline, Resistant: mild resistance + intermediate resistance + relevant resistance, Percentage: calculated on the total viable count.
TABLE II.—Propionibacterial resistance related to the sex of the
patients.
Number and percentage
of colonized patients
Number and percentage of patients
with any resistant isolates
Males
Females
498 (33%)
1 010 (67%)
298 (59.9% of colonized males)
545 (54% of colonized females)
Total
1 508 (100%)
843 (55.9% of colonized patients)
Resistant: mild resistance + intermediate resistance + relevant resistance
TABLE III.—Age distribution of skin colonization by antibiotic-resistant propionibacteria.
Age range (years)
Percentage of patients with
any resistant isolates
10-14
15-17
18-20
21-24
25-29
> 30
46%
56%
59%
60%
58%
68%
Resistant: mild resistance + intermediate resistance + relevant resistance
facial skin of 843 patients, which represent 55.9% of
the colonized patients. Resistance to erythromycin
was the most prevalent (mean prevalence during the
considered period 47.7%), while the prevalence of
clindamycin-resistant propionibacteria was slightly
lower (mean prevalence 39.2%) (Table I). The proportion of patients carrying strains resistant to erythromycin dropped from 58.8% in 2000 to 38.5% in
2005, while the rates of resistance to clindamycin
dropped from 44.1% in 2000 to 32.2% during 2005.
Combined resistance to both antibiotics was present on
35% of the acne patients carrying resistant propioni-
Vol. 141 - N. 2
bacteria. Thirteen percent of patients carried erythromycin-resistant, clindamycin-susceptible strains
and 4% of patients were colonized by clindamycinresistant, erythromycin-susceptible strains. Resistance
to erythromycin and clindamycin was much more
common than resistance to the tetracyclines (1.9%
and 0.6% rates of propionibacteria resistant to tetracycline and minocycline respectively).
A slight difference in prevalence of antibiotic resistance was found in males in comparison with females
(59.9% and 54% respectively) (Table II).
119
BETTOLI
than resistance to tetracyclines. These data seem to
strongly correlate with prescribing habits.
The chief aim of the present paper has been to evaluate both prevalence and distribution of propionibacterial resistance in patients affected by inflamed acne
attending the acne clinic in Ferrara.
From more than 5 years (April 2000 - October 2005)
we sampled all acne patients who needed antibiotic
treatment in order to detect any skin carriage of antibiotic-resistant propionibacteria. This practice, in addition, allowed monitoring of propionibacterial resistance among acne patients referred to our department.
Resistant strains were found on the facial skin of
55.9% of the colonized patients. Resistance to erythromycin was the most prevalent, while the prevalence of clindamycin-resistant propionibacteria was
slightly lower (Table I). In accordance with the data
available in the literature, resistance to erythromycin
and clindamycin was much more common than resistance to the tetracyclines. In Italy tetracyclines have
usually been prescribed for less than 3 months and
this could explain the low rate of resistance evidenced.
In addition, there are data suggesting that topical erythromycin and clindamycin may be more selective
than the oral tetracyclines.12
Topical erythromycin, alone or in combination with
topical retinoids, was the most frequently used antibiotic among the studied patients, about 40% of our
patients had been previously treated with it. Approximately 14% of the sampled patients had received oral
tetracyclines.
Comparing our annual rates of prevalence of resistant propionibacteria to each antibiotic, there seems to
be a decrease in both erythromycin and clindamycinresistances over time (erythromycin-resistance rate
was 58.8% in 2000 and 38.5% in 2005; clindamycinresistance rate was 44.1% in 2000 and 32.2% in 2005).
This fall in resistance rates might be at least partially
explained by a local change in prescribing practices that
was encouraged in an attempt to prevent the rise in
resistance rates. Available guidelines 2, 9 could help
physicians improve the way they use antibiotics to
treat acne. Prolonging antimicrobial treatment for as
short a time as possible, withdrawing antibiotics once
inflammation is controlled, using in combination with
topical retinoids, using benzoyl peroxide for a minimum of 5-7 days between antibiotic courses to eliminate resistant organisms from the skin, avoiding the
concomitant use of oral and topical therapy with chem-
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The lowest prevalence of propionibacterial resistance (Table III) was found among 10-14-year-old
patients (46%), while 68% of the patients older than 30
years were colonized by resistant strains.
In 1976, a study on 1 000 acne patients exhibited no
propionibacterial antibiotic resistance.14 The first report
of resistance to antiacne antibiotics appeared in the
USA in 1979;15 P. acnes resistant strains were found in
1 in 5 patients treated topically with either erythromycin or clindamycin. Since then, propionibacteria
resistant to one or more antiacne antibiotics have been
isolated all over the world.8, 9, 16
The continuous monitoring carried out in Leeds for
nearly a decade showed a steady increase in prevalence of propionibacterial resistance from 34.5% in
1991 to a peak of 64% in 1997.12 The emergence of
resistance coincided with the introduction in UK of
topical antibiotic formulations in treatment of inflamed
acne, while the increasing number of patients colonized by resistant strains recorded during the aforesaid
period may reflect the increasingly widespread prescription of both oral and topical antibiotics. As erythromycin and clindamycin bind to different regions of
the same target within the bacterial cells, the majority of erythromycin-resistant strains are cross-resistant
to clindamycin. In Leeds studies, resistance to erythromycin and clindamycin was more common in all
years than resistance to tetracyclines. In each year,
rates of resistance to clindamycin and erythromycin
were similar, but resistance to clindamycin was always
lower than resistance to erythromycin.
A multicentre study recently conducted in 6 European countries with the aim of estimating the size of
the resistance problem in Europe, found that, overall,
2/3 of patients were colonized with resistant strains.17
Prevalence rates of skin colonization by antibioticresistant propionibacteria were different among the 6
countries studied, clearly mirroring the treatment histories of the sampled patients. The lowest prevalence
was found in Hungary (50.8%), which also presents the
lowest rate of patients previously treated with any
antibiotics (18%), while the highest prevalence was
noticed in Spain (93.6%), 84% treated with antibiotic therapy. The European study showed, in agreement
with Leeds’ findings, that combined resistance to clindamycin and erythromycin was much more common
120
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Metodi. A partire da aprile 2000 è stata testata la suscettibilità ai più comuni antibiotici usati nella terapia dell’acne
dei ceppi di propionibatteri veicolati dai pazienti acneici con
indicazione al trattamento antibiotico. I campioni di propionibatteri sono stati ottenuti dalla cute del volto di 1 579
pazienti acneici mediante l’impiego di un tampone inumidito.
Quanto prelevato per mezzo dei tamponi è stato inoculato in
terreni di coltura contenenti concentrazioni selettive di tetraciclina, minociclina, eritromicina e clindamicina, oltre che
in una piastra di controllo. Dopo 7 giorni di incubazione in
anaerobiosi a 37°C è stata valutata con metodica semiquantitativa (scala da 0 a 5+) l’entità della crescita delle colonie
in presenza di ciascun antibiotico.
Risultati. Sono stati isolati propionibatteri in 1 508 dei 1
579 pazienti testati. La prevalenza di ceppi resistenti ad
almeno un antibiotico ammonta al 55,9% del totale. La resistenza all’eritromicina è risultata la più comune in tutti gli anni
dello studio, variando dal valore di 58,8% nel 2000 a 38,5%
nel 2005 (prevalenza media 47,7%); la resistenza alla clindamicina è compresa tra 44,1% dell’anno 2000 e 32,2% del
2005 (media 39,2%). Il 35% dei ceppi isolati è risultato resistente contemporaneamente a eritromicina e clindamicina. Si
è rilevata una resistenza molto bassa alle tetracicline (1,9%
alla tetraciclina e 0,6% alla minociclina). Nel lasso temporale in cui sono state condotte le analisi è stata registrata una
sensibile riduzione della resistenza sia all’eritromicina sia alla
clindamicina. Questo andamento è imputabile probabilmente
a una crescente sensibilità dei dermatologi locali al problema dell’antibiotico resistenza e a una maggiore aderenza
alle raccomandazioni impartite dalle attuali linee guida in
tema di prescrizione e gestione della terapia antibiotica nell’acne. Le più alte percentuali di antibiotico-resistenza sono
proprie delle fasce di età più elevate, mentre una prevalenza
soltanto leggermente superiore è documentata nei soggetti di
sesso maschile rispetto a quelli di sesso femminile.
Conclusioni. I dati mostrano la rilevante prevalenza di
ceppi di propionibatteri resistenti a eritromicina e clindamicina nella popolazione di pazienti acneici indagati. Allo stato attuale, viceversa, le percentuali di resistenza alle tetracicline risultano basse. Quanto riscontrato supporta il significato dell’esame colturale nella definizione della sensibilità
agli antibiotici dei propionibatteri isolati dai pazienti acneici. Questa procedura è considerata utile sia per un’adeguata gestione terapeutica dell’acne sia per lo studio del fenomeno della resistenza batterica.
PAROLE CHIAVE: Acne - Propionibatteri - Antibiotico-resistenza.
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ically dissimilar antibiotics, using oral isotretinoin for
resistant cases, are just some of antibiotic prescribing
recommendations.
The prevalence of antibiotic resistance resulted higher in males than in females (59.9% and 54% respectively) (Table II); a better compliance of females
patients to previous treatments for acne should be a
possible explanation for this finding.
Another aspect of interest arises from the analysis of
the age distribution of the prevalence of propionibacterial resistance (Table III). The lowest prevalence was
found among 10-14-year-old patients (46%), while
68% of the patients older than 30 years were colonized by resistant strains. This relevant gap is most
likely explained by the higher rate of previous treatment
with antibiotics among the oldest patients.
In conclusion, the present study shows the wide diffusion of resistant strains of propionibacteria among
acne patients of our department. The large number of
patients sampled allows a precise definition of the
problem in Italy, also because 25% of the patients
come from districts far from Ferrara. A correlation
between the distribution of the resistances and the
available antibiotics is plausible. We agree with the
recommended strategies available in literature to minimize and overcome resistances during antibiotics
treatments.9 Some help in suggesting the presence of
propionibacterial resistance may come from clinical
outcome of acne under antibiotic therapy, but the availability of laboratory data is much better in supporting physicians in antibiotic prescription, thus increasing the probability of more successful and quicker
therapeutical results in acne.
BETTOLI
Riassunto
Antibiotico resistenza propioniatterica a Ferrara
Obiettivo. Gli antibiotici, riducendo il numero di propionibatteri sulla superficie cutanea, rappresentano un efficace
presidio nel trattamento dell’acne infiammatoria. L’impiego
su larga scala di antibiotici, sia sistemici sia topici, per la
cura dell’acne ha determinato la diffusione di ceppi di propionibatteri resistenti. La conseguenza della selezione di
ceppi resistenti consiste essenzialmente nel fallimento della terapia antibiotica. L’obiettivo dello studio è la definizione della prevalenza di propionibatteri antibiotico-resistenti
all’interno di una vasta popolazione di pazienti acneici afferiti alla Sezione di Dermatologia di Ferrara, seguendone
contestualmente le eventuali variazioni nel corso di 6 anni
(aprile 2000 - ottobre 2005).
Vol. 141 - N. 2
References
1. Leyden JJ, McGinley KJ, Cavalieri S, Webster GF, Mills OH, Kligman AM. Propionibacterium acnes resistance to antibiotics in acne
patients. J Am Acad Dermatol 1983;8:41-5.
2. Simpson N. Antibiotics in acne: time for a rethink. Br J Dermatol
2001;144:225-8.
3. Akamatsu H, Niwa Y, Kurokawa I, Masuda R, Nishijima S, Asada Y.
Effects of subminimal inhibitory concentrations of minocycline on neu-
121
BETTOLI
trophil chemotactic factor production in comedonal bacterial, neutrophil phagocytosis and oxygen metabolism. Arch Dermatol Res
1991;283:524-8.
Leyden JL. A review of the use of combination therapies for the treatment of acne vulgaris. J Am Acad Dermatol 2003;49 (3 Suppl):S20010.
Eady EA, Ross JI, Cove JH, Holland KT, Cunliffe WJ. Macrolide-lincosamide-streptogramin B (MLS) resistance in cutaneous propionibacteria: definition of phenotypes. J Antimicrob Chemoter
1989;23:493-502.
Ross JI, Eady EA, Cove JH, Jones CE, Ratyal AH, Miller YW et al.
Clinical resistance to erythromycin and clindamycin in cutaneous
propionibacteria isolated from acne patients is associated with mutations in 23S rRNA. Antimicrob Agents Chemother 1997;41:1162-5.
Ross JI, Eady EA, Cove JH, Cunliffe WJ. 16S rRNA mutation associated with tetracycline resistance in a gram-positive bacterium.
Antimicrob Agents Chemother 1998;42:1702-5.
Eady EA, Gloor M, Leyden JJ. Propionibacterium acnes resistance:
a worldwide problem. Dermatology 2003;206:54-6.
Eady EA. Bacterial resistance in acne. Dermatology 1998;196:5966.
Eady EA, Cove JH, Holland KT, Cunliffe WJ. Erythromycin resistant
11.
12.
propionibacteria in antibiotic treated acne patients: association with
therapeutic failure. Br J Dermatol 1989;121:51-7.
Eady EA, Cove JH, Layton AM. Is antibiotic resistance in Propionibacterium acnes clinically relevant? Implications of resistance for
acne patients and prescribers. Am J Clin Dermatol 2003;4:813-31.
Coates P, Vyakrnam S, Eady EA, Jones CE, Cove JH, Cunliffe WJ.
Prevalence of antibiotic-resistant propionibacteria on the skin of acne
patients: 10-year surveillance data and snapshot distribution study.
Br J Dermatol 2002;146:840-8.
Williamson P, Kligman AM. A new method for the quantitative investigation of cutaneous bacteria. J Invest Dermatol 1965;45:498-503.
Leyden JJ. Antibiotic resistant acne. Cutis 1976;17:593-6.
Crawford WW, Crawford IP, Stoughton RB, Cornell RC. Laboratory
induction and clinical occurrence of combined clindamycin and erythromycin resistance in Corynebacterium acnes. J Invest Dermatol
1979;72:187-90.
Kurokawa I, Nishijima S, Kawabata S. Antimicrobial susceptibility of
Propionibacterium acnes isolated from acne vulgaris. Eur J Dermatol
1999;9:25-8.
Ross JI, Snelling AM, Carnegie E, Coates P, Cunliffe WJ, Bettoli V
et al. Antibiotic-resistant acne: lessons from Europe. Br J Dermatol
2003;148:467-78.
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4.
5.
6.
7.
8.
9.
10.
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13.
14.
15.
16.
17.
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Adverse cutaneous reactions to cardiovascular drugs:
the experience of the Department of Dermatology in Cagliari
L. ATZORI, A. L. PINNA, C. FERRELI, N. ASTE
Aim. Adverse drug reactions (ADR) represent a heterogeneous
group of diseases, often responsible for admission or complication during hospitalization. Risk of ADR increases in elderly and medicated patients, with a high prevalence of cardiovascular diseases. The aim of this prospective study was to
investigate the frequency, clinical pattern and course of cutaneous adverse reaction to cardiovascular drugs.
Methods. From October 1999 until November 2004 all adverse
cutaneous reactions to drugs were recorded on magnetic support, including hospitalized and outpatients of the Dermatology Department of Cagliari University. Cases related to cardiovascular drugs were further investigated for final causality
assessment following the international criteria and algorithm
of the World Health Organization (WHO) Collaborating Centre for Drug Monitoring.
Results. Four-hundred and nine consecutive patients affected
by cutaneous ADR were studied. Antihypertensive drugs were
responsible for 8.5% of the overall cases with ACE inhibitors
and hydrochlorthiazide being the most reported. Exanthematous eruptions and urticaria-angioedema were the main clinical forms, followed by photosensitivity, pityriasis rosea-like
eruption and lichenoid dermatitis, but several life-threatening
cases were also observed, including Stevens-Johnson syndrome,
toxic epidermal necrolysis and drug rash with eosinophilia and
systemic signs. Due to the extension of the eruption and severity of symptoms hospitalization was required in 80% of cases.
The main therapeutic measures involved drug discontinuation, antihistamine administration in all cases, supportive care
and general corticosteroids in unresponsive severe eruptions and
Received November 9, 2005.
Accepted for publication March 15, 2006.
Address reprint requests to: Dott. L. Atzori, Clinica Dermatologica,
Via Ospedale 54, 09124 Cagliari. E-mail: [email protected]
Vol. 141 - N. 2
Department of Dermatology
University of Cagliari, Cagliari, Italy
angioedema, intravenous high dose immunoglobulines in 1
case (toxic epidermal necrolysis).
Conclusion. Adverse cutaneous reactions to cardiovascular
drugs are frequent, often severe and should not be underestimated in the risk-benefit evaluation of long-term treatment,
especially in elderly and medicated patients.
KEY WORDS: Dermatitis, adverse drug reactions - Cardiovascular
agents - Risk factors.
A
dverse cutaneous reaction is one of the most
common undesired effects during systemic pharmacological therapy and often requires admission or
is responsible for complications during hospitalisation.1-4 A decrease in the incidence of adverse drug
reactions (ADRs) seems unlikely at present as
increased average life expectancy and the constant
rise of available drugs on the market should predictably
lead to a corresponding rise in the number of cases
and in the variety of possible reactions to any one specific drug.5 Cardiovascular drugs represent one of the
most widely used groups. These include different categories for a few of which a discreet incidence of
adverse cutaneous reactions has been reported.6-9 Cardiac problems and arterial hypertension are very frequent conditions whose incidence and need for specific
pharmacological treatment increases with the patient’s
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ATZORI
ADVERSE CUTANEOUS REACTIONS TO CARDIOVASCULAR DRUGS
TABLE I.—Adverse cutaneous reactions to cardiovascular drugs: cases report 1999-2004.
Dermatology
hospitalization
Other
department
advice
Outpatient
visits
Females
Males
Age
(mean)
35
28 (80%)
3 (8.5%)
4 (11.5%)
26 (74.3%)
9 (25.7%)
67 years
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Adverse
cutaneous
reactions
age. A combination of drugs is frequently required to
effectively control the pathology and the simultaneous
presence of other systemic illnesses and/or metabolic
disorders that can increase individual susceptibility
to adverse reactions is just as frequent.6 Advanced age
and high dosages are both risk factors for the onset of
adverse reactions to drugs,10 therefore, cardiac and/or
patients with hypertension under treatment could represent a category at risk and hence should be monitored
very closely from a pharmacological viewpoint. The
frequency of adverse cutaneous reactions associated to
the treatment of cardiovascular disorders is reported in
literature as being extremely variable, ranging from
3-4% to 19-24% but it does not highlight the specific
role played by the involvement of the skin in these
adverse events.11-14
A prospective study to collect all the adverse cutaneous reactions associated to cardiovascular drugs in
order to analyse their type, gravity and course has been
carried out at the Pharmacovigilance Centre at the
Dermatological Clinic of the University of Cagliari.
From October 1999 until November 2004 all adverse
cutaneous reactions to drugs were recorded on magnetic support, including hospitalized and outpatients of
the Dermatology Department of the University of
Cagliari. Particular attention was paid to avoid duplicating cases. Information charts in compliance with
those established by the Italian Health Ministry were
used and an original copy was sent to the national network of Pharmacovigilance in accordance with current
laws. Cases correlated to the use of cardiovascular
drugs were selected from the general information and
examined separately. Data on the clinical picture,
pathological and pharmacological histories, predisposing factors, therapy and course of illness were
obtained. Diagnosis of adverse reaction was reached
based on clinical criteria, the time span between drug
administration and onset of adverse reaction, past his-
124
tory, chemical-laboratory and instrumental investigation to exclude any alternative diagnosis.15 Skin biopsy was only carried out in dubious cases. Allergy and
pharmacological anamnesis as well as previous
episodes of reactions to drugs were obtained by interview directly from patients, family members and from
family doctor when more precise details were required.
The algorithm adopted by the Collaborating Centre
for International Drug Monitoring of the World Health
Organization (WHO) was used to determine the level
of probability of the association between the administration of a drug and developing a clinical picture.16
Cases where the contemporary use of cardiovascular
drugs with those with a higher level of responsibility
for adverse reaction such as antibiotics and nonsteroidal anti-inflammatory drugs were excluded from
the study.
Results
Four-hundred and nine cases of adverse cutaneous
reaction from drugs were documented over a 5 year
period at the Dermatology Clinic of the University of
Cagliari. Of these 35 (8.5%) were associated to the
exclusive use of cardiovascular drugs. More specifically
(Table I), they involved 26 women and 9 men average age 67. In 28 cases (80%), the intensity of the
manifestations required hospitalization of the patients
in our clinic, in 3 cases the reactions occurred while
patients were already in other structures, whilst in 4 cases adverse reactions were observed in outpatients units.
The responsible category of drugs was considered to
be primarily the ACE inhibitors, followed by
hydrochlorothiazide in formulations in which the
diuretic was associated with ACE-inhibitors and/or
angiotensin II antagonists; cases ascribable to other
diuretics, beta blockers, antiaggregants, statins,
vasodilators, amlodipine and amiodarone were
observed sporadically (Table II).
The spectrum of clinical symptoms was extremely
polymorphic showing the following order of frequen-
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ATZORI
TABLE II.—Adverse cutaneous reactions to cardiovascular drugs: category, generic names and clinical manifestations.
Total cases
ACE-inhibitors
Generic name (N.)
Cilazapril (1)
Enalapril (1)
Fosinopril (2)
Clinical manifestation
Urticaria – angioedema
Pityriasis rosea-like eruption
Steven-Johnson syndrome
Urticaria - angioedema
Maculo-papular exanthema
Photosensibility
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Drug category
Lisinopril (3)
Perindopril (2)
Ramipril (1)
8
Hydrochlorthiazide + ACE-inhibitors
or angiotensin II antagonists
Captopril + Hydrochlorthiazide (3)
Lisinopril + Hydrochlorthiazide (2)
Ramipril + Hydrochlorthiazide (1)
Candersartan + Hydrochlorthiazide (1)
Irbesartan + Hydrochlorthiazide (1)
4
Diuretics
Furosemide (2)
Maculo-papular exanthema (2)
Vasculitis
Photosensibility
Toxic epidermal necrolysis
Furosemide + Spironolacton (2)
DRESS
Urticaria – angioedema (2)
2
Beta-blockers
Atenolol (1)
Carvedilol (1)
Psoriasis
Lichenoid dermatitis
1
Calcium channel blockers
Amlodipine
1
Antiarrhythmics
Amiodarone
Photosensibility
4
Aggregation inhibitors
Ticlopidine (2)
Warfarin (1)
Acetilsalicilic acid (1)
Erythroderma
3
Vasodilatators
Nitroglycerin (1)
Pentoxifylline (1)
Naftidrofurile (1)
Photosensibility
Photosensibility
2
Hypolipidemic agents
Atorvastatin (1)
Fluvastatin (1)
cy: exanthematic reactions (27.7%), urticaria (22.8%),
photosensitivity (14.2%), pityriasis rosea-like eruptions (8.6%), Stevens-Johnson syndrome (8.6%),
lichenoid dermatitis (5.7%), toxic epidermic necrolisis (TEN) (2.8%), vasculitis (2.8%), erythroderma
(2.8%), psoriasis (2.8%) (Figure 1). Severe adverse
reactions represent circa 20% of the complete total.
Hyperpiressia, considered to be among the main
causes of gravity,16 was present in 8% of the cases,
while hematic eosinophilia was present in 27%. Further clinical-chemical and routine instrumental tests
were within the norm with the exception of the drug
rash with eosinophilia and systemic signs (DRESS)
case where renal and hepatic function were moderately altered in the absence of previous symptoms.
Histological tests were carried out only in severe and/or
in dubious cases and the clinical suspicion of toxidermia from drugs was always confirmed.
Vol. 141 - N. 2
Previous episodes of pharmacological intolerance
were highlighted from case histories in 27% of cases.
These were generally ascribable to the same category
of drugs responsible for the ongoing reaction and this
was considered an involuntary rechallenge with regard
to causality judgement.
The level of correlation, according to the WHO criteria, between taking the drug and the onset of clinical
manifestations was certain in 14.2% of cases, probable in 60% and possible in 18%. The only recognised
risk or predisposing factors were advanced age (77.5%)
and elevated use of the drugs (31.4%).
Therapy included suspension of the drug with the
introduction of a general antihistaminic symptomatic
therapy associated with systemically administered
corticosteroids in aggravating and/or angioedema cases. In more severe cases all the necessary support measures, based on laboratory tests in accordance with
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ATZORI
Erythroderma Psoriasis
Exanthematous reactions
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Vasculitis DRESS
Toxic epidermal necrolysis
Lichenoid dermatitis
Stevenson-Johnson
syndrome
Pityriasi rosea-like
eruption
Photosensitivity
Urticaria-angioedema
Figure 1.—Clinical manifestations in order of frequency.
indications suggested in literature, were taken to affront
the condition of the skin with constant monitoring and
integration of the hydro-electrolytic and protein equilibrium.17-21 Despite this, in 2 cases of Stevens-Johnson syndrome and in 1 of TEN a progressive and dramatic worsening of the clinical picture was seen which
lead to death in 2 cases and the decision to administer
400 mg/kg die of IgG intravenously for 5 days in the
third case. This therapy resulted in a rapid halt of the
auto-aggressive process and to a slow but complete
recovery of skin and mucous function. Clinical recovery was obtained in 94% of cases in a time lapse ranging from 4 to 41 days.
Discussion
The results of this study, even if they have little statistical importance due to the absence of data relative
to the consumption of drugs in the same period of
time, highlight a discrete frequency of adverse cutaneous reaction to cardiovascular drugs (8%). They
also confirm the initial impression matured during the
Dermatology Clinic’s Pharmacovigilance daily activity, which in turn lead to the realisation of this study.
The Dermatology Clinic, part of the Local Health
Authority n. 8 in Cagliari, has about 476 000 patients.
It is, therefore, plausible to take into consideration
that 1/100 000 inhabitants will encounter adverse cutaneous reaction to cardiovascular drugs. In this type of
study, the contemporary use of numerous other drugs
is often a confounding factor and it is difficult to deter-
126
mine the effective responsibility of any specific proximate principle. For this reason, all reactions where
cardiovascular drugs were not the principle cause were
excluded. The rigidity of this exclusion criteria further underlines the possibility that the true incidence
of adverse reaction to cardiovascular drugs is underestimated. The distinct prevalence of ACE-inhibitors,
alone or in association with hydrochlorothiazide, compared to other categories of cardiovascular drugs is
not surprising, given the high incidence of adverse
reactions caused by these drugs,7, 22 but it does indicate
the need for an effective re-evaluation of risk and therapeutic benefit. The minor frequency attributed to other categories of antihypertensive drugs could be due to
their being prescribed less, as ACE-inhibitors benefited immediately from widespread diffusion from the
moment they became available. The ability to induce
adverse cutaneous reactions has been reported for
every category of cardiovascular drugs 6-12 and it is
possible that the rare likelihood of the event occurring is conditioned solely by the number of people
exposed to the drug. The clinical picture has never
been evocative of the drug in question with a notable
polymorphism of manifestations. Further considerations are raised by the frequency of adverse reactions
with the concomitant use of hydrochlorothiazide, in
commercial formulas containing ACE-inhibitors and
more recently with angiotensin antagonists.
Hydrochlorothiazide itself can cause the observed
clinical pictures 23 and the highest number of adverse
cutaneous reactions from the combination of
hydrochlorothiazide and amiloride were reported in
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Figure 2.—Perindopril Steven-Johnson’s syndrome.
a now dated review.22 Specific investigations are needed to re-evaluate safety profiles of this drug and its
use in combination with other proximate principles
especially considering the difficulty in identifying the
effective responsibility of any single drug in cases of
adverse reactions. Hospitalization was required in
most cases (80%), due to the extent and severity of
the reactions irrespective of the nature of the drug,
with a variety of clinical pictures indicative of the
often diagnostic difficulties that adverse reactions to
drugs pose. Atypical reactions simulating pityriasis
rosea, photodermatitis, and lichen planus, normally
considered rare 23 were well represented in case studies observed. This fact may have been conditioned by
the family doctor’s ability to identify the more common
cutaneous reactions without the need to consult a specialist to isolate the responsible drug when faced with
rashes or urticaria. On the other hand, chronic aggravating clinical pictures with polymorph and atypical
manifestations, as with the more severe forms, such as
vasculitis, Steven-Johnson syndrome (Figure 2), TEN
(Figure 3) and DRESS (Figure 4), require complex
classification in terms of specific therapy which is
often long term. Diagnosis of adverse reactions to
Vol. 141 - N. 2
drugs is a complex problem due to scarce knowledge
of pathogenic mechanisms and to a lack of availability of predictive diagnostic tools. The intrinsic and
extrinsic criteria of the WHO algorithm is useful in
clinical practice to arrive at a rapid judgement of the
cause, which is often expressed in standardized terms
of universal interpretation.16 However, the importance
of re-exposure to the drug, though not ethically feasible nor desirable in clinical practice, is essential to
reach judgement with certainty. Consequently, judgement was probable in most represented cases (60%),
which, however, offers a high and reliable level of
responsibility. Fourteen percent of reactions were considered certain where involuntary re-exposure to the
drug occurred, in patients who, in their anamnesis,
referred previous adverse cutaneous reactions whilst
taking the suspected drug. These events not only
occurred after an interval of years, as would be justified by a natural tendency to forget previous events
or hope they did not reoccur, but in some patients the
adverse reactions occurred only a few months earlier
with increasing gravity ranging from exanthematic or
urticarial episodes to severe reactions such as StevensJohnson syndrome in 2 cases. This underevaluation
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Figure 3.—Irbesartan+Hydrochlorothiazide toxic epidermal necrolysis.
of the iatrogenic potential accounts for the patients
lack of information, responsibility which, although
delicate, at present lies entirely in the hands of the
family doctor or specialist and would merit more attention.
Even though reactions have shown a benign course
with a tendency to resolve themselves in most cases,
symptomatic therapy and intense monitoring were
almost always necessary with hospitilization lasting on
average 9 days. Prognosis was particularly conditioned
by patient’s advanced age and by persistent systemic
pathologies which rendered their general conditions
even more unstable. On the other hand, the 2 deaths
make us reflect on the need to increase therapeutic
options as the general support measures suggested in
current guidelines alone do not appear to be sufficient
to help overcome the auto-aggressive process, especially in elderly patients.17-21 Although controversial,
128
the use of intravenous immunoglobulin in high doses
is a therapy based on documented pathogenic mechanisms even if they are not exclusive.24-26 Personal positive experience, even if limited to one case, confirms
the efficacy of this therapeutic approach in grave forms
in which the suspension of the causative drug alone, is
insufficient to block the progression of the autoimmune process.
Conclusions
The frequency of adverse cutaneous reactions during therapy with cardiovascular and, in particular,
antihypertensive drugs would suggest a population at
risk and would merit intense systemic monitoring in
terms of pharmacovigilance. Precious information
regarding drug safety profiles is currently provided by
postmarketing studies. However, this primarily con-
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Figure 4.—Furosemide exfoliative dermatitis+eosinophila+internal organs
involvement (DRESS).
cerns drugs that have only recently been put on the
market and does not provide comparative information
on different categories of drugs used for the same
indications, especially about known proximate principles used over the years, important information
which, on the contrary, could emerge from specific
studies on the population. Some not easily recognised clinical pictures, the severity and extension of
cutaneous reactions in elderly patients are conditions
that require early intervention by a specialised dermatologist to reach a quick and correct diagnosis in
order to prescribe the necessary therapeutic measures. Close collaboration between family doctors
and specialists is desirable to develop a culture of an
appropriate use of drugs and to qualify the activity of
pharmacovigilance, if we consider that every iatrogenic pathology represents an intrinsic risk for the
medical profession and knowledge in this field can
only improve the patients conditions of health and
quality of life.
Riassunto
Reazioni avverse cutanee da farmaci cardiovascolari: esperienza della Clinica Dermatologica di Cagliari
Obiettivo. Le reazioni avverse da farmaci rappresentano
un eterogeneo gruppo di patologie, spesso causa di ricove-
Vol. 141 - N. 2
ro o di prolungamento della degenza in pazienti ospedalizzati. Il rischio di sviluppare una reazione avversa aumenta nei
pazienti anziani, con un’alta prevalenza di patologie cardiovascolari, che assumono contemporaneamente numerosi farmaci. Lo scopo di questo studio prospettico era indagare
la frequenza, le manifestazioni cliniche e il decorso delle
reazioni avverse cutanee associate alla somministrazione di
farmaci cardiovascolari.
Metodi. Dall’ottobre 1999 al novembre 2004 sono state
registrate su supporto magnetico tutte le reazioni avverse
cutanee da farmaci osservate presso la Clinica Dermatologica
dell’Università degli Studi di Cagliari, sia nei pazienti ricoverati sia in quelli ambulatoriali. I casi associati all’assunzione
di farmaci cardiovascolari sono stati ulteriormente studiati ai
fini del giudizio di causalità, formulato in accordo con i criteri internazionali e l’algoritmo suggerito dal Centro di Monitoraggio del Farmaco dell’Organizzazione Mondiale della
Sanità.
Risultati. Di 409 reazioni avverse cutanee osservate, l’8,5%
erano associate all’assunzione di farmaci cardiovascolari,
con gli ACE inibitori e l’idroclortiazide tra i farmaci maggiormente riportati. Le principali forme cliniche sono risultate le reazioni esantematiche e l’orticaria-angioedema,
seguite dalla fotosensibilità, dalle eruzioni pitiriasi rosealike e dalla dermatite lichenoide, ma non è stata trascurabile la frequenza anche di reazioni severe quali la sindrome di
Stevens-Johnson, la necrolisi epidermica tossica e la sindrome da ipersensibilità o drug rash with eosinophilia and
systemic signs (DRESS). L’estensione e la gravità dei sintomi
hanno comportato l’ospedalizzazione nell’80% dei casi. Le
129
ATZORI
10. Veehof LJ, Stewart RE, Meyboom-de Jong B, Haaijer-Ruskamp FM.
Adverse drug reactions and polypharmacy in the elderly in general
practice. Eur J Clin Pharmacol 1999;55:533-6.
11. Torpet LA, Kragelund C, Reibel J, Nauntofte B. Oral adverse drug reactions to cardiovascular drugs. Crit Rev Oral Biol Med 2004;15:28-46.
12. Zaidenstein R, Eyal S, Efrati S, Akivison L, Michowitz MK, Nagornov
V et al. Adverse drug events in hospitalized patients treated with cardiovascular drugs and anticoagulants. Pharmacoepidemiol Drug Saf
2002;11:235-8.
13. Thiessard F, Roux E, Miremont-Salame G, Fourrier-Reglat A, Haramburu F, Tubert-Bitter P et al. Trends in spontaneous adverse drug
reaction reports to the French pharmacovigilance system (1986-2001).
Drug Saf 2005;28:731-40.
14. Teweleit S, Kuschel U, Hippius M, Goettler M, Bornschein B. [Manifestation and prevention of adverse drug reactions in the pharmacotherapy of cardiovascular diseases]. Med Klin 2001;96:442-50.
German.
15. Bachot N, Roujeau JC. [Drug eruption: assessment of causality] Ann
Dermatol Venereol 2000;127:542-5. French.
16. International drug monitoring: the role of national centres. Report of
a WHO meeting. World Health Organ Tech Rep Ser 1972;498:1-25.
17. Djien V, Bocquet H, Dupuy A, Revuz J, Roujeau JC. [Symptomatology and markers of the severity of erythematous drug eruptions] Ann
Dermatol Venereol 1999;126:247-50. French.
18. Garcia-Doval I, Le Cleach L, Bocquet H, Otero XL, Roujeau JC.
Toxic epidermal necrolysis and Stevens- Johnson syndrome: does
early withdrawal of causative drugs decrease the risk of death? Arch
Dermatol 2000;136:323-7.
19. Roujeau JC. Treatment of severe drug eruptions. J Dermatol
1999;26:718-22.
20. Drake LA, Dinehart SM, Farmer EV, Goltz RW, Goltz RW, Graham
GF, Hordinsky MK et al. Linee guida per il trattamento delle reazioni
cutanee da farmaci. J Am Acad Dermatol 1996;35:458-61.
21. Smoot EC. Treatment issues in the care of patients with toxic epidermal necrolysis. Burns 1999;25:439-42.
22. Thestrup-Pedersen K. Adverse reactions in the skin from antihypertensive drugs. Dan Med Bull 1987;34 Suppl 1:3-5.
23. Litt JZ. Pocketbook of drug eruptions and interactions. New York:
The Parthenon Publishing Group Inc.; 1999.
24. Viard I, Wehrli P, Bullani R, Schneider P, Holler N, Salomon D et al.
Inhibition of toxic epidermal necrolysis by blockade of CD 95 with
human intravenous immunoglobulin. Science 1998;282:490-3.
25. Bachot N, Roujeau JC. Intravenous immunoglobulins in the treatment of severe drug eruptions. Curr Opin Allergy Clin Immunol
2003;3:269-74.
26. Brown KM, Silver GM, Halerz M, Walaszek P, Sandroni A, Gamelli RL. Toxic epidermal necrolysis: does immunoglobulin make a difference? J Burn Care Rehabil 2004;25:81-8.
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principali misure terapeutiche adottate sono risultate la
sospensione/sostituzione del farmaco responsabile e la somministrazione di anti-istaminici in tutti i casi, terapia di supporto e corticosteroidi per via sistemica solo nelle eruzioni
severe e nell’angioedema, le immunoglobuline ad alto dosaggio per via endovenosa in 1 caso (necrolisi epidermica tossica).
Conclusioni. Le reazioni avverse cutanee da farmaci cardiovascolari sono frequenti, spesso severe e non dovrebbero essere sottovalutate nella valutazione del rapporto rischibenefici di un trattamento a lungo termine, specialmente nel
paziente anziano che assume contemporaneamente numerosi
farmaci.
PAROLE CHIAVE: Reazioni avverse cutanee da farmaci - Farmaci cardiovascolari - Fattori di rischio.
References
1. Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies.
JAMA 1998;279:1200-5.
2. Hunziker T, Kunzi UP, Braunschweig S, Zehnder D, Hoigne R. Comprehensive hospital drug monitoring (CMDH): adverse skin reactions, a 20-year survey. Allergy 1997;52:388-93.
3. Bigby M, Jick S, Jick H, Arndt K. Drug-induced cutaneous reactions.
A report from the Boston Collaborative Drug Surveillance Program
on 15,438 consecutive inpatients, 1976 to 1982. JAMA 1986;256:335863.
4. Arndt KA, Jick H. Rates of cutaneous reactions to drugs. JAMA
1976;235:918-23.
5. Gruchalla RS. Clinical assessment of drug-induced disease. Lancet
2000;356:1505-11.
6. Brosnan BD, Frishman WH, Sun DK, Grossman M. Adverse dermatologic effects of cardiovascular drug therapy. Heart Dis 2000;2:220-7.
7. Steckelings UM, Artuc M, Wollschlanger S, Wiehsutz S, Henz BM.
Angiotensin-converting enzyme inhibitors as inducers of advers cutaneous reactions. Acta Derm Venereol 2001;81:321-5.
8. Ioulios P, Charalampos M, Efrossini T. The spectrum of cutaneous reactions associated with calcium antagonists: a review of the literature and
the possible etiopathogenetic mechanisms. Dermatol Online J 2003;9:6.
9. Sun DK, Reiner D, Frishman W, Grossman M, Luftschein S. Adverse
dermatologic reactions from antiarrhythmic drug therapy. J Clin Pharmacol 1994;34:953-66.
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REVIEWS
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A new categorizing scheme for skin types
The current understanding of skin types is based on the pioneering work of Helena Rubinstein in the early 1900s. However,
this system, which identifies 4 different skin types - dry, oily,
combination, and sensitive - does not adequately address the
numerous and growing array of needs presented by modern
patients. While the skin care product market has expanded
exponentially into a billion-dollar industry, with commensurate
improvements in sophistication in product formulation based
on a continually growing knowledge base, the dermatologic
establishment has lagged behind, failing to make discernible
progress in more accurately characterizing skin types. Such
an advance would assist patients in finding and using the skin
care products most suitable for their particular skin type. Based
on several yeas of clinical experience, I have developed the
“Baumann Skin Typing System” contingent on the results of a
64-item questionnaire self-administered by patients. The system and corresponding questionnaire are founded on current
classifications of skin based on 4 parameters: dry or oily; sensitive or resistant; pigmented or nonpigmented; and wrinkled
or tight (unwrinkled). These categories are not, of course, mutually exclusive. Therefore, 16 possible Baumann skin types are
identifiable from the permutations found among the standard
4 skin-type parameters.
KEY WORDS: Skin types - Skin - Questionnaires.
T
he first codified descriptions of different skin types
- dry, oily, combination, and sensitive - were presented by Helena Rubinstein in the early 1900s. In the
ensuing century, the skin care product market has
grown into a colossal billion-dollar industry. It is shockAddress reprint requests to: L. Baumann, MD, University of Miami
Cosmetic Center, Miami Heart Institute, 4701 N. Meridian Avenue Suite
7450, Miami Beach, Florida 33140. E-mail: [email protected]
Vol. 141 - N. 2
L. BAUMANN
Division of Cosmetic Dermatology
Department of Dermatology,
University of Miami, Miami, FL, USA
ing that we are still using an outdated skin typing system developed over 80 years ago! A more complete
skin typing system is needed to assist patients in selecting the most suitable formulations for their particular
skin type. Clearly, all products do not work for all skin
types. Over the last 9 years of clinical practice, I have
concluded that rather than 4 skin types, there are actually 4 skin-type parameters and potential permutations of these parameters yield 16 different skin types.
These variations emerge from identifying skin based
on 4 parameters or dichotomies: dry vs oily; sensitive
vs resistant; pigmented vs nonpigmented; and wrinkled vs tight (or unwrinkled). Determination of the
Baumann skin type is made using a questionnaire that
is published in the book The Skin Type Solution.1 While
most skin types will favor one end of each spectrum,
these categories really depict a continuum and many
patients may be identified as having borderline skin
types. Interestingly, traveling or moving to a different environment can affect certain skin types (e.g., a
borderline dry type may not experience skin dryness
until the winter in a northern climate; a borderline
resistant type may not have acne or skin rashes unless
it is induced by stress, at which point the skin reacts in
a more sensitive manner). This article will briefly discuss some of the underlying science pertinent to each
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BAUMANN
A NEW CATEGORIZING SCHEME FOR SKIN TYPES
of the 4 skin parameters. Some ideal product choices
for particular skin types will also be included.
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Skin hydration: dry vs oily
tible to developing eczema. In addition to the above recommendations, DS types are advised to avoid harsh
foaming detergents that can strip lipids from the skin.
Those with very dry skin should also use humidifiers
when possible in low-humidity environments, avoid
prolonged baths especially in hot water or chlorinated
water, and moisturize frequently (2-3 times a day).
DS types with just slightly dry skin likely have a minor
imperfection in the skin barrier and probably experience irritation in the winter, in low-humidity environments, and/or upon using a harsh foaming soap.
Found in keratinocytes, NMF is a substance derived
from the hydrolysis of the protein filaggrin that holds
water inside the cells, making them plump. Filaggrin
confers structural support in the dermal layers, assisting in providing strength to the skin; in the epidermal
layers, the protein is broken down into NMF, which has
a potent capacity to bind water, keeping it in the keratinocyte. The pace at which filaggrin is broken down
into NMF is affected by environment or climate conditions. For instance, after several days of transition
from a high-humidity to low-humidity environment, an
individual’s skin will manufacture more NMF, helping
the skin hold onto water. Further, UV radiation was
shown in the 1970s to disrupt the enzymatic hydrolysis of filaggrin to NMF. Consequently, reducing sun
exposure is understood as one way to ameliorate xerosis due to low NMF levels. Presently, however, there
are no known methods for spurring the breakdown of
filaggrin thereby increasing NMF levels. It is important to note that NMF deficiency can cause dry skin, but
it does not increase skin sensitivity. Indeed, an individual experiencing low NMF levels typically falls
into the dry, resistant (DR) category. Skin that is resistant and just slightly dry is likely supported by an
intact stratum corneum; the dryness more likely is due
to low NMF or sebum secretion. Skin hydration in
these circumstances can be improved through the use
of moisturizing lotions and creams, avoiding harsh
detergents such as those found in foaming cleaners, and
avoiding UV exposure.
HA, which can bind 1 000 times its weight in water,
is another substance found in the skin that holds onto
water. One of the fundamental building blocks of the
skin, HA helps confer structure, providing plumpness
to the skin. Aged skin is characterized by reduced levels of HA, yielding a less plump, more dehydrated
appearance. Such a deficiency in HA, while imparting
dryness, does not increase sensitivity. It is important to
There are several factors involved in the development
of xerotic or dry skin, which is characterized by a dull
gray white color, rough texture and an elevated number of ridges.2 The relative condition or status of the
stratum corneum, natural moisturizing factor (NMF),
hyaluronic acid (HA), and sebum production all play
a role in the level of skin hydration. The stratum
corneum, which is composed of ceramides, cholesterol, and fatty acids, is the skin barrier responsible
for keeping water in the skin, thereby hydrating the
largest organ, and keeping exogenous elements from
penetrating to internal organs. The 3 primary constituents of the stratum corneum actually surround the
barrier in a watertight lipid bilayer and, when present
in the proper proportion, form the barrier that acts
comparably to a brick wall in which the keratinocytes
would represent the bricks and the lipid bilayer, the
mortar. Transepidermal water loss (TEWL), which
leads to skin dehydration and a dry appearance, can be
engendered by various defects or deficiencies in the
stratum corneum. The skin barrier can be genetically
deficient or disturbed by any of several external compounds, such as detergents, acetone, chlorine and other chemicals, as well as prolonged water immersion.
Skin with an impaired stratum corneum would be
both dry and sensitive because besides being incapable of retaining water, it would be more susceptible
to damage from external sources such as plants, chemicals and even water. Further, cholesterol-lowering
drugs are well known to cause xerosis. Topical skin care
products designed for dry skin concentrate on repairing the 3 key constituents of the stratum corneum:
ceramides, cholesterol, and fatty acids. Repair or
replenishment is also possible through diet, given that
cholesterol and fatty acids can be derived from a
healthy diet. Consumption of evening primrose oil,
borage oil, or omega-3 fatty acids has the potential to
assist in improving dry, sensitive (DS type) skin by
replacing the essential skin barrier constituents. Barrier repair moisturizers are especially appropriate for
this type.
A DS type that suffers frequently from erythema
and pruritus also likely has a defect in the stratum
corneum. People with this skin type are more suscep-
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Aprile 2006
oily or very oily skin that is also sensitive (OS) likely
suffer from acne or rosacea. In addition, this skin type
that is accompanied by wrinkled (W) skin with extensive sun damage is more prone to develop rosacea.
OS types are fortunate insofar as they are better able
to tolerate products that DS types cannot.
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note that HA does not penetrate the skin, so topical
products containing HA do not comprise a viable therapy.3 The production of HA can be enhanced, however, through oral supplementation with glucosamine;
wrinkles can be temporarily ameliorated via superficial or deeper injections of HA. Low HA levels are
often associated with the dry, wrinkled (DW) skin
type.
Sebum production is also believed to potentially
play a role in the manifestation of xerosis. Sebaceous
gland secretions contain wax esters, triglycerides, and
squalene, which protect the skin from the environment.4 Fats derived from sebum prevent TEWL through
the formation of a lipid film over the skin surface, and
thereby might protect the skin from dryness. Low
sebaceous gland activity is not correlated with the
occurrence of xerosis, however, and the effects of
sebum on dry skin conditions have not been elucidated.5 In fact, decreased sebum production is an uncommon complaint of patients; rather, many more complain
about increased sebum production, which results in
oily skin, and possibly acne. Sebum production levels
can be influenced by diet, stress and hormones, as
well as heredity. In a study of 20 pairs each of identical and nonidentical like-sex (to eliminate hormonal
considerations) twins, identical twins had virtually
identical sebum excretion rates, despite significantly
different acne severity, whereas the nonidentical twins
differed significantly in terms of sebum excretion rates
and acne severity, suggesting the interplay of both
genetic and environmental influences.6 Postmenopausal
women often experience xerosis correlated with
reduced sebum production as a function of changes
in hormone levels; hormone replacement therapy can
normalize sebum production. Small pores, and minimal acne history along with dry skin is characteristic
of the DR skin type.
Skin that is slightly oily and straddles the sensitive/resistant threshold is ideal in terms of skin hydration. Such skin is characterized by an intact skin barrier, sufficient NMF levels, and adequate sebum secretion such that acne development is less likely. People
with oily, resistant (OR) skin rarely suffer from acne.
However, stress or hormonal fluctuations can induce
acne in such skin types. In these circumstances, oral
contraceptives, when appropriate, can be used to prevent hormonal fluctuations, and a benzoyl peroxidecontaining wash can be used pre-emptively before an
expected stressful situation. Individuals with slightly
BAUMANN
Vol. 141 - N. 2
Skin sensitivity: sensitive vs resistant
Sensitive skin can best be described as hyperreactive
skin characterized by a weaker stratum corneum leaving it more vulnerable to exogenous factors (i.e., environmental influences such as cold, heat, temperature
variation, and wind, as well as pollution and excessive use of topical agents) and more prone to reacting
adversely to such factors. These reactions, in turn, are
characterized by a disrupted stratum corneum and a
tendency to experience exaggerated neurosensory
responses to topically applied products.7
Resistant skin is characterized by a potent, solid
stratum corneum that imparts protection to the skin,
providing a shield around the skin cells thereby keeping out allergens and irritating substances. Such skin
is rarely associated with erythema (unless sunburned)
or acne (unless induced by stress or hormonal changes).
The application of cosmetic products seldom elicits
complaints from people with resistant skin; such types
can typically use any skin care formulation without
developing any adverse reactions. Unfortunately, these
patients may also fail to derive any benefit from skin
care products because the formulations are not sufficiently potent to penetrate the stratum corneum of
resistant skin.
Whereas it seems almost irrelevant as to which products a person with resistant skin might use (in terms of
potential adverse reactions, not efficacy), great care
must be taken in selecting appropriate products for
sensitive skin. Indeed, sensitive skin is a dynamic
process that is reported to occur in as much as 40% of
the population.8 Healthy, premenopausal women comprise the majority population segment complaining of
sensitive skin and the incidence of sensitive skin
appears to decline with age. It is not a subclinical manifestation of contact allergy,9 but can be divided into 4
distinct subtypes all of which feature inflammation as
the common denominator. Consequently, all products
formulated to treat sensitive skin are intended to alleviate and eliminate the cause(s) of inflammation.
Specifically, though, treatment must address the nature
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BAUMANN
typically affects adults between 25 and 60 years of
age. This condition, which itself is classified into several subtypes, is seen most often in fair-skinned people prone to blushing and flushing, particularly in
association with strong emotion. The etiology of
rosacea is not clearly understood. Helicobacter pylori,
the bacteria implicated in stomach ulcers that also
affects nearly half of the world’s population,12 has
long been considered a possible causative agent in
rosacea pathogenesis.13 However, no definitive link
has been shown.14 Rosacea patients with inflammatory papules and facial erythema are advised to get
tested for H. pylori, nevertheless, because treatment
with oral antibiotics for H. pylori has been shown to
improve rosacea outbreaks.15 Topical skin care for
rosacea focuses on preventing exacerbation of the condition. There is no cure. OS types with fair skin, who
also have W skin with a strong history of sun damage, are the most likely to develop rosacea. For OS
patients with rosacea, products that contain feverfew
(such as the Aveeno Ultra calming line), the antiinflammatory quadrinone (such as the Cutanix products), or the licorice extract licochalcone (such as the
Eucerin products) are effective options. For DS rosacea
patients that experience erythema but no stinging,
products containing sulfacetamide (Rosanil, Rosac,
Rosula, Avar), or azelaic acid (such as Azelex and Fincacea) may be suitable choices. Despite the moderate
success seen in the amelioration of rosacea symptoms
from topical prescription medications (e.g., Elidel,
Rosanil and Plexion cleansers, Metro Gel, and Rosac
cream), intense pulsed light therapy may represent the
most significant advance in the arsenal of rosacea treatments.16
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of a patient’s particular sensitive skin subtype: the
acne subtype (predilection for developing acne, blackheads, or whiteheads), the rosacea subtype (tendency
to experience recurrent flushing, facial erythema, and
sensation of warmth or heat), the stinging subtype
(characterized by complaints of stinging or burning
skin), or the allergic subtype (characterized by erythema, pruritus, and skin flaking). Such considerations should be taken into account when considering
the plethora of cosmetic products touted for activity in
sensitive skin.
Exaggerated skin reactivity is most frequently linked
with the face,10 which relates to both the acne and
rosacea sensitive skin subtypes. Both conditions have
been associated with increased skin sensitivity or reactivity.11
Acne type
The etiology of acne is characterized by 3 primary
features: elevated sebum production; clogged pores
(adhering of dead skin cells inside the hair follicles,
which might be further stimulated by increased sebum
production); and the presence of the bacteria Propionibacterium acnes. The pathogenetic pathway proceeds as increased amounts of sebum cause dead skin
cells in the hair follicles to stick together, thus clogging the follicle and forming a papule or pustule. Then,
P. acnes enter the hair follicle, attacking the amassed
sebum and dead skin cells, triggering the release of
cytokines and other inflammatory factors. This engenders the inflammatory response that results in the characteristic redness and pus. Acne prevention is geared
toward attacking the 3 primary etiologic factors, namely reducing sebum production (with retinoids, oral contraceptives or stress reduction), unclogging pores (with
retinoids, AHAs, or BHA), and eliminating bacteria
(with benzoyl peroxide, sulfur, antibiotics, or azelaic
acid). However, not all therapeutic regimens are suitable for all sensitive acne skin types. The OS skin type
is the one most likely to develop acne. For these patients,
salicylic acid (BHA) and benzoyl peroxide are often the
best therapeutic options, unless erythema and stinging
is also exhibited, in which case the anti-inflammatory
salicylic acid is optimal as a single therapy.
Rosacea type
Characterized by facial redness, flushing, pimples,
and the formation of telangiectases in the face, rosacea
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Stinging type
This subtype of sensitive skin refers to nonallergic stinging that results from what is believed to be
amplified neural sensitivity. Referred to as “stingers”,
patients with such skin experience subjective cutaneous irritation in reaction to particular ingredients
to which others do not respond. Several tests can be
used to identify the propensity to experience stinging. In particular, the lactic acid stinging test is a
widely accepted standard method for evaluating
reported subjective cutaneous irritation. In 5% and
10% lactic acid concentrations, the lactic acid stinging test has been used to show that a subset of patients
experience stinging sensations in the treated nasolabi-
Aprile 2006
Skin pigmentation: pigmented vs nonpigmented
This parameter does not consider ethnicity; rather, it
measures the proclivity to develop unwanted dark spots
on the face or chest. For instance, a white person with
freckles and red hair as well as a black person with
melasma would be categorized as pigmented (P) types.
The P skin category is most often correlated with the W
type in fair-skinned individuals because of the causal
link between solar exposure and rhytides and solar lentigos. Many dark-skinned individuals have pigmented
tight (PT) skin, though, by dint of a lesser propensity to
wrinkle. It is important to note, though, that not all darkskinned patients suffer from pigmentary problems. Many
exhibit even skin tones and no hyperpigmentary spots.
Such individuals have nonpigmented (N) type skin.
Several dyspigmentations qualify as dark spots that
evoke cosmetic concerns among patients, including
ephelides, melasma, solar lentigos, seborrheic keratoses, nevi, moles, etc. Some of these conditions are
avoidable, such as ephelides, melasma, and solar lentigos, which can be prevented and treated with skin care
products and procedures. Twenty-one percent of dermatologic visits are made by patients seeking such
treatments and more than 80 000 people in the US
alone annually buy over the counter (OTC) skin care
products to reduce or eliminate such discolorations
(Data on file Galderma).
Individuals with P type skin are best treated with
formulations that contain hydroquinone, kojic acid,
arbutin, tyrostat and mulberry extract. Vitamin C and
retinoid usage is also appropriate for people that have
oily resistant pigmented and wrinkled (ORPW) or dry
resistant pigmented and wrinkled (DRPW) skin. Products containing soy (such as the Aveeno Positively
Radiant line and Neutrogena Visibly Even products) or
niacinamide (such as Olay Regenerist and Olay Total
Effects or the products by Niadyne) successfully prevent the return of undesired hyperpigmentations. Of
course, the best method to prevent the avoidable forms
of skin pigmentation is to curtail or avoid sun exposure,
given that UV exposure increases melanosome transfer from melanocytes to keratinocytes.24 Because most
formulations fail to block both UVA and UVB rays,
sunscreens are less effective and even broad spectrum
products that hinder both UVA and UVB are unable to
block all solar rays. That said, sunscreens remain
important for skin protection in terms of fighting photoaging and skin cancer and, specifically, at reducing
unwanted pigmentary changes as well as wrinkles.
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al fold area unlike healthy controls.17, 18 The stinging
sensation is not necessarily associated with erythema. Rosacea patients that experience facial flushing have a greater tendency to feel stinging in
response to lactic acid.19 Many patients have reported experiencing stinging without redness or irritation,
though.20 Sensitive “stingers” are advised to avoid the
following products or ingredients: benzoic acid,
bronopol, cinnamic acid compounds, Dowicel 200,
formaldehyde, lactic acid, propylene glycol, quaternary ammonium compounds, sodium lauryl sulfate, sorbic acid, urea, vitamin C, and alpha hydroxyl acids (particularly glycolic acid).
BAUMANN
Allergic type
The fourth type of sensitive skin is the allergic
subtype. A recent epidemiologic survey in the UK
indicated that, over the course of a year, 23% of
women and 13.8% of men experience an adverse
reaction to a personal care product (e.g., deodorants
and perfumes, skin care products, hair care products, and nail cosmetics).21 Patch testing is typically used to identify allergies to cosmetic ingredients.
This technique has also revealed that up to 10% of
dermatologic patients patch tested manifest allergic
responses to at least one cosmetic product ingredient.21 This figure is probably an under-representation
because most patients do not consult a physician
upon reacting to new cosmetic products. Patients
aged 20-60 years account for 80% of reported reactions, with the majority occurring in women. 22
Preservatives and fragrances are the most common
allergens in skin care products. The International
Fragrance Association (IFRA) has begun work with
dermatologists to develop and market safe fragrancecontaining products. Given the growing popularity
of aromatherapy, this endeavor is likely to benefit
many people upon the successful use of fragrance
without causing a significant number of allergic
reactions.
As the frequency of exposure to ingredients increases along with exposure to an increasing array of ingredients, an individual becomes more likely to develop
an allergy to cosmetic ingredients. Allergic reactions
to topical allergens are most frequently seen in patients
with an impaired stratum corneum, manifested by dry
skin.23 Therefore, in terms of the new skin typing system, most sensitive skin patients with the allergic subtype are DS types.
Vol. 141 - N. 2
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Skin aging: wrinkled vs tight
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Although there are some products and procedures
that can ameliorate the appearance of hyperpigmenations
and behavioral options that can help one avoid the development of such alterations, the wrinkled/tight (W/T)
skin parameter is actually the only 1 of the 4 skin-type
parameters completely within an individual’s control.
Specifically, in reference to the P/N parameter, an individual cannot change the genetic aspect of skin aging but
can alter one’s lifestyle to eliminate or reduce behaviors
known to spur extrinsic aging, namely excessive use of
alcohol, poor nutrition, smoking, and, most importantly, sun exposure. In fact, sun exposure is routinely cited as the source for 80% of facial aging.25
Wrinkles, the primary manifestation of facial skin
aging (solar lentigos are another significant manifestation), result from damage that occurs in the dermal layers of the skin. Most skin care products lack the capacity to penetrate deeply enough into the dermis to repair
the damage at the base of wrinkles, however. Exceptions to this state of affairs include retinoid products
approved by the US Food and Drug Administration
(FDA) for the indication of wrinkle correction. Several
studies demonstrate that these retinoids, Renova and
Avage, which are available through prescription, are
effective in ameliorating wrinkles. Consistent use of
topical antioxidants likely prevents some extrinsic aging
as well. Treatment options for wrinkle prevention focus
on stopping the erosion of collagen, elastin, and HA
since aged skin is known to possess less of all of these
fundamental structural constituents. Therefore, most
antiaging products are designed to salvage these components, though no known products or procedures can yet
effectively restore elastin. Further, antiaging regimens are
also intended to reduce inflammation since inflammation
can foster the erosion of collagen, elastin, and HA.
Skin aging can be reduced through various behavioral modifications. Specifically, avoiding sun exposure, cigarette smoke, and pollution will benefit all
skin types as will eating a diet high in fruits and vegetables, taking antioxidant supplements, and using
sunscreen. Regularly using prescription retinoids can
also benefit all W types. Differin is likely best suited for sensitive wrinkled (SW) types. For oily wrinkled (OW) types, a retinoid in gel form is recommended; for DWs, a cream retinoid. Dermatologic
procedures (particularly the injection of Botox or
Reloxin) can prevent wrinkles caused in areas of
movement by significantly reducing movement in
those areas. Changing lifestyle habits can change a
skin type from a W to a T.
The topical antioxidants that can benefit W types
include idebenone (found in Prevage), ferulic acid
(found in Skinceuticals C E Ferulic), vitamin C (such
as the La Roche Posey product Active C), and mushroom extract (found in the Dr. Andrew Weil for Origins
Plantidote Mega Mushroom Face Serum). Oral antioxidants such as polypodium leucotomos (found in Heliocare) or pomegranate (found in Murad Pomphenol
Sunguard Supplement) may also be helpful.
In line with the argument that not all skin care formulations are suitable for all skin types, it should be
noted that sunscreen recommendations must also be
tailored to skin type. Generally, people with oily skin prefer gel or powder sunscreens whereas individuals with
dry skin tend to prefer creams. Sensitive skin types may
benefit from using physical sun blocking agents such as
zinc oxide and titanium dioxide while resistant types can
use chemical sunscreens. Avobenzone, a UVA blocker,
can cause stinging in sensitive skin types. Pigmented
types that have darker skin may choose a tinted sunscreen product to avoid the violet hues associated with
the white thicker opaque sunscreens. All types should
use a high sun protection factor sunscreen whether they
have a tendency to wrinkle or not.
136
Conclusions
A new system of skin categorization based on 4 fundamental parameters of describing skin expands our
understanding of particular skin proclivities. Acknowledging that the 4 skin parameters - dry or oily, sensitive
or resistant, pigmented or nonpigmented, and wrinkled
or tight - are not mutually exclusive allows for a more
nuanced picture of skin types, with 16 permutations of
skin types emerging. The more accurate identification
of skin types that is yielded by answers to a 64-item
self-administered questionnaire facilitates the selection, by practitioner and patient alike, of the most suitable topical products to treat the patient’s particular
skin type and conditions, enhancing overall skin health.
Riassunto
Un nuovo schema di classificazione dei tipi cutanei
L’attuale suddivisione dei tipi cutanei è basata sul lavoro
pionieristico di Helena Rubinstein, eseguito nei primi del
Aprile 2006
7. Muizzudin N, Marenus KD, Maes DH. Factors defining sensitive
skin and its treatment. Am J Contact Dermatitis 1998;9:170-5.
8. Jackson EM. The science of cosmetics. Am J Contact Dermatitis
1993;4:108-10.
9. De Lacharriere O, Jourdain R, Bastien P, Garrigue JL. Sensitive skin
is not a subclinical expression of contact allergy. Contact Dermatitis
2001;44:131-2.
10. Maibach HI, Engasser PG. Cosmetic intolerance syndrome. Semin Dermatol 1986;5:273-6.
11. Mills OH, Berger RS. Defining the susceptibility of acne-prone and
sensitive skin populations to extrinsic factors. Dermatol Clin 1991;9:937.
12. Buechner SA. Rosacea: an update. Dermatology 2005;210:100-8.
13. Diaz C, O’Callaghan CJ, Khan A, Ilchyshyn A. Rosacea: a cutaneous
marker of Helicobacter pylori infection? Results of a pilot study. Acta
Dermatol Venereol 2003;83:282-6.
14. Buechner SA. Rosacea: an update. Dermatology 2005;210:100-8.
15. Utas S, Ozbakir O, Turasan A, Utas C. Helicobacter pylori eradication
treatment reduces the severity of rosacea. J Am Acad Dermatol
1999;40:433-5.
16. Ceilley RI. Advances in the topical treatment of acne and rosacea. J
Drugs Dermatol 2004;3 (5 Suppl):S12-22.
17. Frosch PJ, Kligman AM. A method for appraising the stinging capacity of topically applied substances. J Soc Cosmet Chem 1977;28:197-209.
18. Seidenari S, Francomano M, Mantovani L. Baseline biophysical parameters in subjects with sensitive skin. Contact Dermatitis 1998;38:311-5.
19. Lonne-Rahm SB, Fischer T, Berg M. Stinging and rosacea. Acta Derm
Venereol 1999;79:460-1.
20. Basketter DA, Griffiths HA. A study of the relationship between susceptibility to skin stinging and skin irritation. Contact Dermatitis
1993;29:185-8.
21. Orton DI, Wilkinson JD. Cosmetic allergy: incidence, diagnosis, and
management. Am J Clin Dermatol 2004;5:327-37.
22. Mehta SS, Reddy BS. Cosmetic dermatitis current perspectives. Int J
Dermatol 2003;42:533-42.
23. Jovanovic M, Poljacki M, Duran V, Vujanovic L, Sente R, Stojanovic
S. Contact allergy to Compositae plants in patients with atopic dermatitis. Med Pregl 2004;57:209-18. English, Serbian.
24. Hermanns J, Petit L, Martalo O, Pierard-Franchimont C, Cauwenbergh G, Pierard G. Unraveling the patterns of subclinical pheomelaninenriched facial hyperpigmentation: effect of depigmenting agents.
Dermatology 2000;201:118-22.
25. Uitto J. Understanding premature skin aging. N Engl J Med
1997;337:1463-5.
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‘900. Tuttavia, questo sistema, che identifica 4 diversi tipi di
cute - secca, grassa, mista e sensibile - non è più in grado di
soddisfare le crescenti e numerose esigenze presentate dalle pazienti attuali. Mentre l’industria cosmetica si è espansa in modo esponenziale, fatturando miliardi di dollari,
migliorando continuamente la qualità della formulazione
dei prodotti sulla base delle conoscenze di base in continuo
aumento, l’aspetto strettamente dermatologico non ha seguito questo progresso e non è stato in grado di caratterizzare più
accuratamente i tipi cutanei. Un progresso in questo settore
aiuterebbe le pazienti nella scelta e nell’utilizzazione dei
prodotti più adatti per la cura del loro specifico tipo di cute.
Sulla base di diversi anni di esperienza clinica, ho sviluppato
il “Bauman Skin Typing System”, che tiene conto dei risultati ottenuti da un questionario con 64 domande autosomministrato alle pazienti. Il sistema e il corrispondente questionario si basano sull’attuale classificazione della cute che
tiene conto di 4 parametri: cute secca o grassa; sensibile o resistente; pigmentata o non pigmentata; rugosa o liscia (non
rugosa). Naturalmente, queste categorie non sono mutuamente esclusive. Di conseguenza, con il sistema Bauman è
possibile distinguere 16 tipi cutanei nell’ambito dei 4 tipi
standard.
PAROLE CHIAVE: Tipi cutanei - Cute - Questionari.
BAUMANN
References
1. Baumann L. The skin type solution: a revolutionary guide to your
best skin ever. New York: Bantam Books; 2006.
2. Chernosky ME. Clinical aspects of dry skin. J Soc Cosmet Chem
1976;27:365-76.
3. Rieger M. Hyaluronic acid in cosmetics. Cosm Toil 1998;113:35-42.
4. Clarys P, Barel A. Quantitative evaluation of skin surface lipids. Clin
Dermatol 1995;13:307-21.
5. Downing DT, Stewart ME, Wertz PW, Colton SW, Abraham W, Strauss
JS. Skin lipids: an update. J Invest Dermatol 1987;88 (3 Suppl):2s-6s.
6. Walton S, Wyatt EH, Cunliffe WJ. Genetic control of sebum excretion
and acne--a twin study. Br J Dermatol 1988;118:393-6.
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Management of cutaneous B-cell lymphomas
Primary cutaneous B-cell lymphomas (PCBCLs) represent
an heterogeneous group of lymphoid malignancies with various clinicopathologic presentation and prognosis. Primary
cutaneous lymphomas are defined as malignant lymphomas
confined to the skin at presentation after complete staging
procedures. Thus, staging investigations are mandatory for
all patients. The classification of cutaneous lymphomas published by the World Health Organization (WHO) and the
European Organization for Research and Treatment of Cancer (EORTC) – Cutaneous Lymphoma Project Group recognizes four main types of PCBCL: follicle center lymphoma
and marginal zone B-cell lymphoma are in a group characterized by an indolent clinical behavior (five-year survival
>90%), whereas diffuse large B-cell lymphoma, leg type,
and diffuse large B-cell lymphoma, other (this last including
several rare variants) are in a group with intermediate clinical behavior (five-year survival 50-60%). Management of
patients depend on precise classification as well as on clinical presentation (e.g., solitary or multiple tumors, age, general conditions, etc.). The main therapeutic strategies for
PCBCLs include local radiotherapy, surgical excision, antiCD20 antibody (rituximab), interferon-alfa, and systemic
chemotherapy (usually CHOP). It must be stressed that systemic chemotherapy is needed only rarely in cases of PCBCL with indolent behaviour. Cases associated with infection
by Borrelia burgdorferi may be managed with antibiotic
treatment. Selected patients may be followed-up at regular
intervals according to a so-called “watchful waiting” strategy.
KEY WORDS: Skin - B cell cutaneous lymphoma, diagnosis - B
cell cutaneous lymphoma, therapy.
Address reprint requests to: L. Cerroni, MD, Department of Dermatology, Medical University of Graz, Auenbruggerplatz 8, A-8036 Graz
(Austria). E-mail: [email protected]
Vol. 141 - N. 2
L. CERRONI
Medical University of Graz, Graz, Austria
I
n contrast to the lymph nodes, where B-cell lymphomas represent the predominant type of nonHodgkin’s lymphomas, in the skin the majority of
lymphomas are examples of mycosis fungoides, a primary cutaneous T-cell lymphoma. In the classification of cutaneous lymphomas published recently by the
World Health Organization (WHO) and the European
Organization for Research and Treatment of Cancer
(EORTC) – Cutaneous Lymphoma Project Group
(Table I), B-cell lymphomas represent 22.5% of all
primary cutaneous lymphomas (data are based on the
Dutch and Austrian registries for cutaneous lymphomas).1 A similar figure was derived from a large
series of patients observed in Austria between 1960 and
1999, in which B-cell lymphomas represented 26.4%
of all cases of primary cutaneous lymphoma.2 It is
possible that primary cutaneous B-cell lymphomas
(PCBCLs) may occur more frequently in particular
regions of the world. In fact, analysis of data from
four academic centers in the United States showed
that PCBCL represented only 4,5% of all cases of primary cutaneous lymphoma registered in those centers.3 On the other hand, differences in diagnosis and
classification of early lesions may also explain the
discrepancy between centers in Europe and in the United States.
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TABLE I.—WHO-EORTC classification of primary cutaneous lymphomas.
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Cutaneous T-cell and NK-cell lymphomas
Mycosis fungoides
Mycosis fungoides variants and subtypes
— Folliculotropic mycosis fungoides
— Pagetoid reticulosis
— Granulomatous slack skin
Sézary syndrome
Adult T-cell leukemia/lymphoma
Primary cutaneous CD30+ lymphoproliferative disorders
— Primary cutaneous anaplastic large cell lymphoma
— Lymphomatoid papulosis
Subcutaneous panniculitis-like T-cell lymphoma
Extranodal NK/T-cell lymphoma, nasal type
Primary cutaneous peripheral T-cell lymphoma, unspecified
— Primary cutaneous aggressive epidermotropic CD8+ T-cell
lymphoma (provisional)
— Cutaneous γ/δ T-cell lymphoma (provisional)
— Primary cutaneous CD4+ small/medium-sized pleomorphic Tcell lymphoma (provisional)
Cutaneous B-cell lymphomas
Primary cutaneous marginal zone B-cell lymphoma
Primary cutaneous follicle center lymphoma
Primary cutaneous diffuse large B-cell lymphoma, leg type
Primary cutaneous diffuse large B-cell lymphoma, other
— Intravascular large B-cell lymphoma
Precursor hematologic neoplasm
CD4+/CD56+ hematodermic neoplasm (blastic NK-cell lymphoma)
genesis of PCBCL, compelling evidence for association with microorganisms other than Borrelia is lacking.10, 11 The role of T lymphocytes and accessory cells
in the development of PCBCL has been investigated in
the past,12, 13 but at present the exact mechanism of
recruitment and proliferation of neoplastic cells within the skin is not completely understood. In fact,
although T lymphocytes are a constituent of so-called
skin-associated lymphoid tissue (SALT), providing
an explanation for the high percentage of primary cutaneous T-cell lymphomas, B lymphocytes and the corresponding microenvironment are not present in the
skin under normal conditions.
Cutaneous B-cell lymphomas may arise rarely in
the setting of immunodepression due to infection with
the human immunodeficiency virus I (HIV-I) or to
immunosuppressive therapy, or during long-term treatment with methotrexate.4, 14-17 Many of these cases
are associated with infection with the Epstein-Barrvirus (EBV) or the human herpes virus 8 (HHV-8).
Cases due to immunosuppression after transplantation may respond to discontinuation of the immunosuppressive treatment.
Classification
Most patients with CBCL are diagnosed primarily
by dermatologists, as extracutaneous symptoms and
signs are very rare at onset of the disease. Thus, dermatologists should be conversant with the clinicopathologic features of this group of disorders, in order
to be able to establish the diagnosis at an early stage.
Additionally, as aggressive treatment modalities are
needed only in selected cases, these patients may be
managed primarily in dermatology departments with
special expertise in cutaneous lymphomas.4-6
Primary cutaneous B-cell lymphomas can arise at
skin sites affected by acrodermatitis chronica atrophicans, and may be linked to infection by Borrelia spp.7,
8 In fact, Borrelia DNA sequences have been demonstrated by polymerase chain reaction (PCR) analysis
in skin lesions, particularly in cases of cutaneous marginal zone B-cell lymphoma. However, association
with Borrelia infection may be linked to specific
species of the microorganism and/or to particular
regions of the world, as a PCR study from the United
States did not reveal any positivity for Borrelia DNA.9
Although it has been suggested that other infectious
agents may play a role in the etiology and/or patho-
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In the WHO-EORTC classification, PCBCLs have
been divided into four major types.1 Follicle center
lymphoma and marginal zone B-cell lymphoma are
in a group characterized by an indolent clinical behavior, whereas diffuse large B-cell lymphoma, leg type,
and diffuse large B-cell lymphoma, other (this last
including several rare variants) are in a group with
intermediate clinical behavior. Although in the past
some authors suggested that PCBCLs may represent
an homogeneous group of disorders,18-21 the 4 diagnostic categories listed in the WHO-EORTC classification have been widely accepted and provide a common basis for diagnosis of these diseases, thus allowing a meaningful comparison of cases observed in different centers as well as in different countries.22, 23
Besides the entities listed in the WHO-EORTC classification, there are rare reports of other types of B-cell
lymphoma occurring in the skin.24
It must be emphasized that, in addition to PCBCLs,
the skin can be a site of secondary involvement for
practically all types of extracutaneous (usually nodal)
B-cell lymphomas and leukemias.4, 5, 25 Consequently,
complete staging procedures must be performed in all
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Figure 1.—Primary cutaneous follicle center lymphoma. Large tumor on
the face.
patients with a confirmed diagnosis of B-cell lymphoma involving the skin. These include a complete
blood examination, bone marrow biopsy, and computed tomographic (CT) examination of the chest,
abdomen, and pelvis. Primary cutaneous lymphomas
are defined as “malignant lymphomas confined to the
skin at presentation after complete staging procedures”.1, 2
Distinction of some PCBCLs from reactive cutaneous infiltrates may be very difficult (this is particularly true for marginal zone B-cell lymphoma).
Although clinicopathologic correlation and ancillary
techniques may provide important informations on
phenotype, clonality, and genetic features of the infiltrate,26-31 in some cases a precise diagnosis may be
impossible. The term “atypical lymphoid proliferation” is used sometimes to refer to lesions in which the
diagnosis is not clear-cut. Patients are put on shortterm follow-up controls, and eventual new lesions are
biopsied.
(PCFCL) is defined as the neoplastic proliferation of
germinal center cells confined to the skin. It represents a very common subtype of PCBCL, and is
observed usually in adults or elderly patients. Preferential locations are the scalp and forehead or the back.
The prognosis of patients with cutaneous PCFCL is
favorable.1, 2, 32, 33 Recurrences are observed in up to
50% of the cases, but dissemination to lymph nodes or
internal organs is rare.1, 4, 32, 34 It seems that cases of
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Figure 2.—Primary cutaneous follicle center lymphoma. So called Crosti’s
lymphoma with erythematous papules, plaques and tumors on the back.
PCFCL, diffuse type arising on the legs may have a
worse prognosis than those arising at other body sites.35
On the other hand, the difference in prognosis may be
due to the difficulties in separating clearly some cases of PCFCL, diffuse type from those of diffuse large
B-cell lymphoma, leg-type.
Clinically, patients present with solitary or grouped
erythematous to deep red papules, plaques, or tumors
which, especially on the trunk, can be surrounded by
erythematous patches and papules (Figures 1, 2). In the
past, lesions located on the back were referred to as
Crosti’s lymphoma or reticulohistiocytoma of the dorsum.36, 37 The skin lesions are usually asymptomatic,
and systemic symptoms are very rare.
Histopathology shows nodular or diffuse infiltrates
within the entire dermis, often extending into the subcutaneous fat.4, 32, 38 The epidermis is usually spared.
A clear-cut follicular pattern with formation of neoplastic germinal centers can be observed in a minori-
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characterized by predominance of medium-large
cleaved cells (large centrocytes) (Figure 4) and may be
misdiagnosed as cutaneous diffuse large B-cell lymphoma, but the prognosis of these cases is similar to that
of lesions of PCFCL without large cell morphology.1,
35, 41
Morphologic variants of PCFCL include those with
a predominant spindle cell morphology (sometimes
showing a sclerotic or desmoplastic stroma),42-45 and
cases in which a few B-cell blasts are admixed with
numerous T-lymphocytes (‘T-cell rich B-cell lymphoma’), a type of PCBCL that in the skin probably
represents a rare morphologic variant of PCFCL.4, 46
The tumor cells of PCFCL express B-cell-associated antigens (CD20, CD79a). When follicles are present, they are characterized by an irregular network
Figure 3.—Primary cutaneous follicle center lymphoma, follicular type.
Follicular pattern characterized by atypical lymphoid follicles of CD21+ follicular dendritic cells. Bcl-6 is positive in
virtually all cases, irrespective of the pattern of growth.
(reduced/absent mantle zone, lack of polarization).
In all cases with a follicular growth pattern, and in a
minority of those with a diffuse growth pattern, neoty of cases only 4, 32, 39 (Figure 3). However, a higher plastic cells stain positive also for CD10. The prespercentage of cases show at least some follicular archi- ence of small clusters of Bcl-6+ and/or CD10+ cells
tecture. In the cases with a follicular pattern, the neo- outside the follicles is considered strongly suggestive
plastic follicles show morphologic features of malig- of a diagnosis of follicular lymphoma.32, 40 In cases
nancy including a reduced or absent mantle zone, the with large cell morphology (predominance of large
lack of tingible body macrophages, and a monomor- cleaved cells), the main criteria for differential diagphism of the follicles – so-called ‘dark’ and ‘clear’ nosis from diffuse large B-cell lymphoma, leg-type
areas are no longer recognizable.32, 40 Lesions pre- include predominance of large cleaved cells over large
senting with a purely diffuse pattern of growth are round cells, and lack of Bcl-2 and MUM-1 expression
Figure 4.—Primary cutaneous follicle center lymphoma, diffuse type. (A) Diffuse infiltrate throughout the entire dermis without follicular pattern. (B)
Predominance of large cleaved cells.
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(in PCFCL MUM-1 is either negative or expressed by
a small minority of neoplastic cells).1, 35 The clinical
aspect of these cases is also helpful, as the great majority of them present with the features of so-called
Crosti’s lymphoma (tumors and nodules on the trunk,
usually the back, surrounded by erythematous papules
and patches). PCFCL, diffuse type should be distinguished also from cases of Borrelia burgdorferiinduced lymphocytoma cutis, a reactive condition that
may be mistaken for a large B-cell lymphoma, with
catastrophic consequences for the patients.47, 48
In the overwhelming majority of cases, staining for
the protein product of BCL-2 (Bcl-2) yields negative
results, representing a major difference from follicular lymphomas arising within lymph nodes.1, 39, 49-52
When present, Bcl-2 expression is confined usually
to a small minority (<30%) of the neoplastic cells, and
only very rarely shows the strong, uniform positivity
characteristic of nodal follicular lymphoma.4, 53 A useful, though counterintuitive diagnostic immunohistochemical feature is the lower degree of proliferative
activity in malignant follicles as detected by the MIB1 (Ki-67) antibody, contrasting with the strong MIB- Figure 5.—Primary cutaneous marginal zone B-cell lymphoma. Small
1-positivity observed in reactive ones.4, 32, 39, 40
solitary tumor on the arm.
The interchromosomal 14;18 translocation, typically found in nodal follicular lymphomas, is present
only in a very small percentage of cases of PCFCLs.1, neous immunocytoma” and “cutaneous plasmacy49, 50, 52, 54 In fact, presence of the interchromosomal
toma” have been avoided in the new WHO-EORTC
14;18 translocation or expression of Bcl-2 should raise classification.1 Patients are adults, but children can be
suspicion that the patient has a systemic lymphoma rarely affected as well.61, 62 Preferential locations are
involving the skin. Standard molecular analyses are the upper extremities or the trunk. The prognosis of
of limited value in the diagnosis and differential diag- PCMZL is excellent.1, 2 In a study of 32 patients, nonosis of PCFCL, and somatic mutations may hinder the one developed lymph node or internal involvement
evaluation of immunoglobulin heavy chain (JH) gene after a mean follow-up of more than 4 years.57
Clinically, patients present with recurrent red to redrearrangement.55 Data obtained with DNA microarrays revealed that the genetic signature of PCFCL, brown papules, plaques, and nodules (Figure 5). Gendiffuse type differs from that of diffuse large B-cell eralized lesions can be observed in a small number of
patients. Ulceration rarely, if ever, occurs. Skin lesions
lymphoma, leg type.56
are usually asymptomatic, and systemic signs and
Primary cutaneous marginal zone B-cell lymphoma symptoms, such as fever, night sweats, weight loss,
and malaise (B-symptoms), are not present. In some
Primary cutaneous marginal zone B-cell lymphoma instances, resolution of lesions may be accompanied
(PCMZL) has been recognized as a distinct variant of by secondary anetoderma, due to loss of elastic fibers
low-grade malignant PCBCL closely related to in the area of the tumor infiltrate.63
mucosa-associated lymphoid tissue (MALT)-lymHistology of PCMZL shows nodular or diffuse infilphomas.1, 57-60 Cases classified in the past as primary trates involving the dermis and, rarely, the subcutacutaneous immunocytoma or primary cutaneous plas- neous fat. The epidermis is spared. A characteristic
macytoma represent most likely examples of PCM- pattern can be observed at scanning magnification:
ZL with prominent lymphoplasmacytic or plasma- nodules of lymphocytes, sometimes containing reactive
cytic differentiation, respectively, and the terms “cuta- germinal centers, are surrounded by a pale-staining
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Figure 6.—Primary cutaneous marginal zone B-cell lymphoma. (A) Marginal zone cells admixed with lymphoplasmacytoid cells, plasma cells, and
reactive lymphocytes. (B) Predominance of lymphoplasmacytoid cells (note intranuclear inclusion).
population of medium-sized cells with indented nuclei,
inconspicuous nucleoli, and abundant pale cytoplasm
– variously described as marginal zone cells, centrocytelike cells, or monocytoid B-cells.1, 4, 57 In addition, plasma cells (at the margins of the nodules), lymphoplasmacytoid cells, and occasional large blasts are observed.
It must be clearly underlined that in most cases of
PCMZL neoplastic lymphocytes are only a minority of
the infiltrate, which is dominated by reactive T- and
B-lymphocytes, admixed often with eosinophils and
in some cases with a granulomatous reaction.4, 57, 64 In
addition, the neoplastic population in most cases is not
monomorphous, but consists rather of cells with different morphology (marginal zone cells, lymphoplasmacytoid cells, plasma cells) (Figure 6A). Cases with
predominance of lymphoplasmacytoid lymphocytes
were classified as cutaneous immunocytoma in the
past 4, 65 (Figure 6B). In these cases, PAS-positive
intranuclear inclusions (Dutcher bodies) are sometimes
observed and represent a valuable diagnostic clue. In a
few cases, the predominant cell type are plasma cells.
These cases have been classified as primary cutaneous
plasmacytoma in the past, but are considered now to be
most likely variants of PCMZL.1, 4
The centrocyte-like cells stain positively for CD20,
CD79a, and Bcl-2, and are negative for CD5, CD10,
and Bcl-6. In the overwhelming majority of cases,
intracytoplasmic monotypic expression of immunoglobulin light chains (either κ or λ) can be observed
(Figure 7).
A monoclonal rearrangement of the JH gene can be
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observed in the majority of cases (60-80%). A peculiar
t(14;18)(q32;q21) has been detected recently in a subset of PCMZLs, as well as in lesions of MALT lymphomas arising in organs other than the skin.66 Other
genetic aberrations include aneuploidy, trisomy 3 and
rarely the t(11;18).67, 68 However, in more than 50% of
the cases no molecular abnormalities have been found.
Primary cutaneous diffuse large B-cell lymphoma,
leg type
leg type (PCDLBCLLT) represents a type of PCBCL
that is characterized by predominance of large round
cells (centroblasts, immunoblasts) positive for Bcl2.1, 35 It has an intermediate prognosis, and it occurs
almost exclusively in elderly patients, predominantly
women.35, 69, 70 This cutaneous lymphoma is located on
the leg in over 80% of cases, hence the term adopted
by the WHO-EORTC classification.1, 4, 35, 69 The prognosis of PCDLBCLLT is less favorable than that of
other types of primary cutaneous B-cell lymphoma,
with a five-year survival rate of approximately 5060%.1, 2, 35 In the past, prognosis of cutaneous diffuse
large B-cell lymphomas had been linked to several
factors including Bcl-2 expression, morphology of the
cells, number of lesions at presentation, and location
on the legs.71-74 A recent study, however, demonstrated that accurate classification according to the new
WHO-EORTC categories is the single most important prognostic criterion, and that other features are
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Histology shows dense, diffuse infiltrates within
the entire dermis and subcutis. Involvement of the
epidermis by clusters of large atypical cells, simulating the Pautrier’s microabscesses found in cutaneous T-cell lymphoma, can be observed in some
cases (B-cell epidermotropism), representing a potential diagnostic pitfall.4 The neoplastic infiltrate consists predominantly of immunoblasts and centroblasts
(large round cells) (Figure 9). Cases of diffuse large
B-cell lymphoma with predominance of large cleaved
cells are classified among the PCFCLs.1, 35 Reactive
small lymphocytes are few, and mitoses are frequent.
Based on the common finding of immunoglobulin
gene hypermutations, it has been proposed that most
cases of PCDLBCLLT represent large cell lymphomas originating from postgerminal center lymphocytes.75
Neoplastic cells are positive for B-cell markers
(CD20, CD79a), but there can be (partial) loss of antigen expression. MUM-1 is strongly expressed in most
cases.1, 35 This marker is useful in the differential diagnosis of PCDLBCLLT from PCFCL, diffuse type (in
these last cases MUM-1 is usually either negative or
expressed by a small minority of cells). Staining for
Bcl-2 is positive in all cases (Figure 10). In fact, cases with prominent round cell morphology and negative
staining for Bcl-2 are classified as primary cutaneous
diffuse large B-cell lymphoma, other (PCDLBCLO).35
It may be that these last cases represent either a phenotypic (Bcl-2-negative) variant of PCDLBCLLT, or
a morphologic (round cell) variant of PCFCL, diffuse
type.35 Bcl-6 does not provide differential diagnostic
Figure 7.—Primary cutaneous marginal zone B-cell lymphoma. Monotypic
expression of the immunoglobulin light chain lambda.
of little or no relevance when cases are stratified into
specific categories.35 Complete staging investigations
are mandatory before a diagnosis of PCDLBCLLT
can be established.
Clinically, patients present with solitary or clustered erythematous or red-brown nodules, located primarily on the distal aspect of one leg (Figure 8). In
some patients, lesions may arise on both lower extremities. Ulceration is common. Small erythematous
papules can be seen adjacent to larger nodules. It must
be emphasized that tumors with similar morphologic
and phenotypic features can arise in areas other than
the lower extremities.35
Figure 8.—Primary cutaneous diffuse large B-cell lymphoma, leg-type. Multiple tumors on the lower leg. Figure 9.—Primary cutaneous diffuse large
B-cell lymphoma, leg-type. Predominance of large round lymphocytes. Figure 10.—Primary cutaneous diffuse large B-cell lymphoma, leg-type. Strong
positivity for Bcl-2.
Vol. 141 - N. 2
145
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fined to lesions of cherry hemangiomas.82-85 Histopathologically it is characterized by a proliferation of
large atypical lymphocytes filling dilated blood vessels
within the dermis and subcutaneous tissues. It has
been reported that the prognosis of intravascular large
B-cell lymphoma limited to the skin is better than that
of the disseminated form, but only a very limited number of cases has been studied.
Plasmablastic lymphoma is a rare lymphoma arising usually in the oral cavity in patients with severe
immunosuppression, especially HIV-related.86 It is
often associated with infection by HHV-8. It is characterized by a proliferation of plasmablasts (large
eccentric nuclei, abundant cytoplasm, prominent nucleoli).4 The neoplastic cells are positive for CD38 and
CD138, and express monotypic immunoglobulin light
chains.
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clues, as it is positive in the vast majority of cases of
PCFCL, PCDLBCLO, and PCDLBCLLT.
The tumors demonstrate monoclonal rearrangement
of the JH gene. The interchromosomal 14;18 translocation is not present. Phenotypic analyses as well as
genetic data obtained by fluorescence in situ hybridization (FISH) or microarray chip technologies revealed
that PCDLBCLLTs show clear molecular differences
from PCFCL, diffuse type, confirming the need of
classifying these cases separately.56, 76-78 Some of the
aberrations found in PCDLBCLLT are similar to those
observed in diffuse large B-cell lymphomas of the
lymph nodes.
other
This group consists of rare cases of cutaneous large
B-cell lymphoma that do not fit into the category of
PCDLBCLLT, and includes cases of diffuse large Bcell lymphoma with a round cell morphology but without Bcl-2 expression (clinicopathologic features intermediate between PCFCL, diffuse type and PCDLBCLLT), intravascular large B-cell lymphoma, and rare
examples of large B-cell lymphomas in the setting of
immune suppression (e.g., plasmablastic lymphoma).1
Cases of primary cutaneous B-cell lymphoma with
predominance of large round cells but lacking Bcl-2
expression are classified in this group. Other
histopathologic and immunohistochemical features
of these cases are intermediate between those of PCDLBCLLT and PCFCL, diffuse type, suggesting that these
cases represent a morphologic or phenotypic variant of
these 2 groups.35 Prognosis of these patients is similar
to that of PCDLBCLLT, with five-year survival of
approximately 50%.35
Intravascular large B-cell lymphoma is a malignant
proliferation of large B-lymphocytes within blood vessels.79, 80 Most cases have a B-cell phenotype, but a
T-cell variant has been reported. In rare patients, the
skin may be the only affected site, although more often
there is systemic dissemination from the onset, including often lesions located within the central nervous
system. Clinically, patients present with indurated,
erythematous or violaceous patches and plaques, preferentially located on the trunk and thighs. The clinical
appearance is not typical of cutaneous lymphoma, and
it may sometimes suggest a diagnosis of panniculitis
or purpura.81 Interestingly, in some cases intravascular large B-cell lymphoma has been observed con-
146
B-Lymphoblastic Lymphoma
B-lymphoblastic lymphomas are malignant proliferations of precursor B lymphocytes. Reports of
patients presenting with B-lymphoblastic lymphoma
confined to the skin (primary cutaneous B-lymphoblastic lymphoma) have been published.87-92 It
should be emphasized, however, that all patients should
be treated for a systemic disease, even in the absence
of documented extracutaneous involvement at the time
of presentation. B lymphoblastic lymphoma is highly
aggressive, and prognosis of untreated patients is poor.
It has been suggested that expression of CD34, an
antigen known to be present on the surface of normal
hematopoietic stem cells as well as in a subset of
immature thymocytes, is associated with a longer disease-free survival in patients with acute lymphoblastic lymphoma/leukemia compared with those who do
not express CD34, thus implying a prognostic significance for this antigen.93
In contrast to the other cutaneous B-cell lymphomas,
primary cutaneous B-lymphoblastic lymphoma shows
a clear predilection for children and young adults.4, 87,
88 Clinically, patients present with solitary, large erythematous tumors, commonly located on the head and
neck. Patients with primary skin disease often have
asymptomatic lesions of a few weeks duration. Those
with secondary skin lesions may have systemic symptoms (e.g. weight loss, fever, fatigue, malaise, night
sweats). The serum level of LDH is often elevated,
reflecting the aggressive and often systemic nature of
the disease.
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Figure 11.—Cutaneous B-lymphoblastic lymphoma. Neoplastic cells
arranged in a mosaic stone pattern.
Figure 12.—Cutaneous B-lymphoblastic lymphoma. Most neoplastic cells
express TdT.
Histologically, B-lymphoblastic lymphoma shows
a monomorphous proliferation of medium-sized cells
with scanty cytoplasm and round or convoluted nuclei
with fine chromatin. A starry sky pattern is commonly seen at low power, due to the presence of
macrophages with inclusion bodies (‘tingible bodies’). Another characteristic feature is the arrangement
of neoplastic cells in a ‘mosaic stones’ pattern (Figure
11).4 Mitoses and necrotic cells are abundant. It must
be stressed that histological features alone do not allow
differentiation of lymphoblastic lymphomas of B-cell
phenotype from those of T-cell lineage. Immunohistology demonstrates positive staining for TdT, CD10
and the cytoplasmic µ-chain of immunoglobulins, as
well as, in most cases, for CD20 and CD79a (Figure
12). CD20 is negative in the pre-pre-B cell variant,
which is CD34+. Lesions in most patients also express
CD99, and some are positive for CD43. Molecular
analyses usually show a monoclonal rearrangement
of the JH gene and a polyclonal pattern for the T-cell
receptor (TCR) gene, but a lack of rearrangement of the
JH gene or monoclonal rearrangement of both the TCR
and JH genes may be observed.
es, on the other hand, do not have a primary cutaneous
counterpart. The most important among these last is Bcell chronic lymphocytic leukemia (B-CLL). Lesions
of B-CLL are characterized by dense, homogenous
infiltrates of small lymphocytes.94, 95 It is possible to
confirm the diagnosis by immunohistology, demonstrating an aberrant CD20+/CD5+/CD43+ phenotype
of neoplastic cells.4, 94 Molecular analyses show the
presence of a monoclonal population of B lymphocytes in the vast majority of cases. It should be reminded that B-CLL may present at sites of cutaneous
inflammation (e.g., at sites of previous herpes simplex 1/2, herpes zoster, or Borrelia infection).96, 97
Although the overall prognosis of B-CLL is generally not affected by skin involvement, patients with
large cell transformation (so-called Richter syndrome)
have a very aggressive course with poor prognosis.94
Richter syndrome may be clonally related to the original haematological neoplasm, or may represent occurrence of a large cell lymphoma clonally unrelated to
the B-CLL.94, 98
Other B-cell lymphomas involving the skin
As already mentioned, extracutaneous (usually
nodal) B-cell lymphomas may present with secondary
spread to the skin. In many instances, morphologic
aspects are similar to those of the cutaneous counterparts, thus complete staging investigations belong to
the routine management of these patients. Some cas-
Vol. 141 - N. 2
Treatment
The most appropriate treatment modality for patients
with PCBCLs is selected upon exact classification of
the lymphoma, analysis of results of staging investigations, and evaluation of the overall condition of the
patient 4, 99-102 (Table II). Patients with secondary cutaneous manifestations of extracutaneous B-cell lymphoma should be treated in a hematological, not der-
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TABLE I.—Treatment of different entities of cutaneous B-cell lymphoma#.
Entity
Surgical excision
Second line treatment (s)
Other possibilities
Rituximab, Interferon-α, Radiotherapy
Rituximab, Interferon-α
Rituximab, Combination therapies
(§)
Radiotherapy
“Watchful waiting” Antibiotics
(Borrelia burgdorferi+)
Chemotherapy, Surgical excision
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Cutaneous marginal zone B-cell
lymphoma
Cellular follicular lymphoma
Cutaneous diffuse large B-cell
lymphoma, leg-type
Cutaneous diffuse large B-cell
lymphoma, other*
Intravascular large B-cell lymphoma
Cutaneous B-lymphoblastic lymphoma
Specific skin manifestations of
extracutaneous B-cell ly
Specific skin manifestations of BCLL
First line treatment (s)
Radiotherapy
Radiotherapy, chemotherapy
Chemotherapy
Chemotherapy
Rituximab, Combination therapies
(§)
Combination therapies (§); Bone
marrow transplantation
Same as for extracutaneous disease
Treatment planned based on extracutaneous disease
Same as for systemic disease; skin lesions at sites of previous infections (e.g., herpes, Borrelia) may be managed by surgical excision, laser vaporization, or other nonaggressive modalities
#) Choice of a given option depends on classification, number of lesions, distribution of lesions, general conditions, first presentation vs relapse/persistence, and
results of adjunctive studies such as PCR analysis for Borrelia burgdorferi. §) Usually chemotherapy in association with rituximab. *) Treatment depends on specific diagnosis; options reported here are meant for cases that do not fit into a specific category (e.g., plasmablastic lymphoma, methotrexate-associated lymphoma, etc.).
matologic, setting, and will not be discussed in what
follows. The only exception is represented by specific manifestations of B-CLL arising at sites of previous
herpes simplex 1/2, herpes zoster, or Borrelia infection,
which may be treated with surgical excision (or other
non-aggressive modalities).96, 97
Before reviewing the major therapeutic approaches,
it must be emphasized that in some cases patients with
low-grade malignant PCBCL can be managed conservatively with a so called watchful-waiting strategy,
similar to that which is often adopted for indolent Bcell lymphomas and leukemias at extracutaneous
sites.100 Follow-up examinations in these patients
should be performed at least every 6 months or at the
onset of new lesions and/or new symptoms, in order to
treat the patient as soon as it is necessary. Many patients
managed conservatively with a watchful-waiting strategy experience a prolonged course and long survival,
and do not need aggressive treatment.
Most patients with low-grade PCBCLs (PCFCL,
PCMZL) and who have a solitary or few lesions can be
treated by local radiotherapy, simple surgical excision, or surgical excision followed by radiotherapy of
the surgical field.34, 99, 100, 102, 103 In most cases 20 to 30
Gy of conventional orthovoltage X-rays are sufficient,
but relapses are relatively frequent (Figures 13, 14).104
It has been reported that recurrences are less frequently
seen in patients treated by radiotherapy with wide
margins (about 10-20 cm beyond clinically apparent
148
lesions). This approach seems to be justified for so
called Crosti’s lymphoma, a type of PCFCL arising
on the back in which erythematous nodules, papules
and patches surrounding the tumor represent specific
infiltrates that can extend far beyond the main bulk of
the lesion.104, 105 Radiotherapy with wide margins,
however, does not seem to be justified for lesions other than Crosti’s lymphoma, as margins of about 5 cm
usually suffice. Surgical excision is a valuable therapeutic modality for patients with solitary, well circumscribed lesions. In these patients, relapse rates do
not seem to be higher than in patients treated with
more aggressive modalities such as local radiotherapy.
In addition, particularly in patients with PCMZL relapses often occur at cutaneous sites distant or completely unrelated to that of the primary lesion, thus questioning the value of local radiotherapy in these cases
(Figure 15).
In recent years, a few reports have appeared on lowgrade PCBCLs that were treated with systemic antibiotics, achieving a complete resolution in at least a percentage of the patients.100, 106, 107 This type of treatment is conceptually analogous to that adopted for
Helicobacter pylori-associated MALT lymphomas of
the stomach, which in their early stages can be cured
by eradication of H. pylori infection. Complete
response to antibiotic therapy has been observed recently in some patients with Borrelia-associated PCBCL.
Although not yet corroborated by adequate data, antibi-
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Figure 13.—Primary cutaneous follicle center lymphoma. (A) Large tumors on the scalp. (B) Complete resolution after radiotherapy.
Figure 15.—Primary cutaneous marginal zone B-cell lymphoma. Small
recurrence on the arm distant from the surgical scar of the primary excision.
Figure 14.—Primary cutaneous follicle center lymphoma. Recurrent lesions
on the scalp after radiotherapy.
otic treatment of patients with PCBCLs should be considered before more aggressive therapeutic options
are discussed, particularly in countries endemic for
Borrelia infection. It is important to treat patients at
onset of the disease, because in later stages lesions
may no longer be sensitive to systemic antibiotics.
PCR analysis of Borrelia DNA is a rapid test that
should be performed in all patients with PCBCL from
endemic areas, in order to identify those who would
more likely benefit from early antibiotic treatment. A
latency time of 3-4 months between antibiotic treatment
and resolution of skin lesions is usually observed.
Vol. 141 - N. 2
Another treatment modality for low-grade malignant PCBCL is subcutaneous or intralesional administration of interferon, in particular interferon alfa2a.100, 102, 106, 108-114 Interferon alfa has both a direct
antitumor effect and an immunomodulatory activity.
Although some favorable results have been reported,
it seems that treatment with interferon is associated
with a complete response only in about 50% of patients.
Therapy with interferon should be considered for
patients presenting with multiple lesions at different
body sites, such that local radiotherapy becomes difficult to administer. Usually a dose of 3 million units
is administered subcutaneously 3 times per week for
longer periods (at least 6 months). The main side-
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therapy is the treatment of choice for patients with
intravascular large B-cell lymphoma, regardless of
results of staging investigations. Finally, patients with
primary cutaneous B-lymphoblastic lymphoma should
be treated in a hematological setting. Aggressive
chemotherapy (with or without bone marrow transplantation) should be administered, even in patients
with negative staging at presentation.
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effects include leucopenia, nausea, asthenia and a
depressive syndrome.
Intralesional or systemic injection of anti-CD20
monoclonal antibody (rituximab) has been recently
used to manage patients with indolent PCBCL.102, 115125 Systemic treatment is performed by intravenous
administration of 375 mg/m2 of rituximab controlled
by a perfusor. The treatment is given once weekly for
4 consecutive weeks. Intralesional administration
should be considered only in cases presenting with a
few (up to a maximum of 4), localized lesions, and
should be administered as follows: 10 mg of the drug
are injected intralesionally in each single lesion, and
the treatment is repeated 3 times during 1 week. A
new cycle can be repeated after 3 weeks if necessary
(several cycles can be performed). Therapy with antiCD20 monoclonal antibody represents a valid alternative to established treatments, especially in patients
who present relapse after radiotherapy, or who present with disseminated skin lesions. Anti-CD20 monoclonal antibody can also be used in combination with
other treatment modalities, especially in cutaneous Bcell lymphomas with more aggressive behaviour
(PCDLBCLLT).126 The main limitation of this treatment is represented by the high costs. Although patients
experience a depletion of immune-competent CD20+
B lymphocytes, the treatment is usually well tolerated. Circulating B lymphocytes return to the baseline
value after 4 to 6 months. Side-effects are usually mild
and include mainly fever, malaise and nausea, but
severe adverse reactions have been reported rarely
after systemic administration.
Patients with disseminated lesions of PCFCL, diffuse
type or PCDLBCLLT need more aggressive treatment
modalities such as systemic chemotherapy.34, 100, 102,
127-129 The chemotherapeutic regimen used most frequently consists of cyclophosphamide, doxorubicin,
vincristine, and prednisone (CHOP). In the absence of
signs of transformation into high grade lymphoma or
of extracutaneous involvement, systemic chemotherapy is not indicated in patients with PCMZL. Chemotherapy may be used also in patients with relapsing PCFCL
not responding to conventional therapies. Local radiotherapy or systemic chemotherapy are the treatments
of choice for patients with PCDLBCLLT. However,
administration of systemic chemotherapy in these
patients is often complicated by their age and overall
conditions. Therapy with anti-CD20 monoclonal antibody may represent an alternative. Systemic chemo-
150
Conclusions
PCBCLs represent an heterogeneous group of lymphoid malignancies arising in the skin in the absence
of systemic manifestations at presentation. Prognosis
and treatment depend on exact classification into one
of the categories listed in the recent WHO-EORTC
classification for cutaneous lymphomas. Dermatologists should be aware of these disorders that in most
cases are diagnosed and treated in a dermatologic setting.
Riassunto
I linfomi primitivi cutanei a fenotipo B rappresentano un
gruppo eterogeneo di neoplasie linfocitarie con differente
presentazione clinico-patologica e con prognosi variabile.
La definizione di linfoma primitivo cutaneo implica l’assenza di manifestazioni extracutanee documentata da esami
di staging completi effettuati alla presentazione. La classificazione dei linfomi cutanei pubblicata recentemente dalla
“World Health Organization” (WHO) assieme alla “European
Organization for Research and Treatment of Cancer”
(EORTC) – Cutaneous Lymphoma Project Group divide i
linfomi cutanei a fenotipo B in quattro gruppi principali: i primi due gruppi sono composti dai linfomi B follicolari e dai
linfomi B marginali e sono caratterizzati da un andamento
indolente (sopravvivenza ai 5 anni >90%), mentre i linfomi
B a grandi cellule-tipo della gamba ed i linfomi B a grandi
cellule-altri sono caratterizzati da una prognosi intermedia
(sopravvivenza ai 5 anni del 50-60%). Il trattamento dei
pazienti dipende dalla classificazione e dalla presentazione
clinica (lesioni solitarie o multiple, eta’, condizioni generali, ecc.). Le principali strategie terapeutiche includono la
radioterapia locale, l’escissione chirurgica, l’anticorpo monoclonale anti-CD20 (rituximab), l’interferone-alfa e la chemoterapia sistemica (generalmente CHOP). Occorre tuttavia
sottolineare che i pazienti con linfoma primitivo cutaneo B
indolente richiedono solo raramente una chemoterapia. I
casi associati ad infezione da Borrelia burgdorferi possono
essere trattati con terapia antibiotica. Alcuni pazienti si possono giovare per periodi di tempo variabili di una cosiddet-
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ta strategia di “attesa vigile” con controlli regolari ma senza terapia specifica.
19.
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Parole chiave: Cute - Linfomi cutanei a cellule B, diagnosi
- Linfomi cutanei a cellule B, terapia.
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111. Wollina U, Hahnfeld S, Kosmehl H. Primary cutaneous marginal
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113. Wollina U. Complete response of a primary cutaneous T-cell-rich B
cell lymphoma treated with interferon alpha2a. J Cancer Res Clin
Oncol 1998;124:127-9.
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primary cutaneous B cell lymphoma treated with intralesional recombinant interferon alpha-2a. Eur J Cancer 1994;30A:246-7.
115. Heinzerling LM, Urbanek M, Funk JO, Peker S, Bleck O, Neuber K
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et al. Site-specific expression of polycomb-group genes encoding the
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cutaneous large B-cell lymphomas. Am J Pathol 2004;164:533-42.
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Trupiano JK, Bringelsen K, Hsi E. Primary cutaneous lymphoblastic
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Emerging agents for onychomycosis
B. M. PIRACCINI, M. IORIZZO, G. RECH, A. TOSTI
Onychomycosis is the most common nail disease and describes
the invasion of the nail by fungi. In most cases, treatment of onychomycosis requires systemic antifungals, with duration of
administration ranging from 2 to several months. Cure rates
range from 60% to 80%, and relapses are not rare (up to 20%
of patients). New antifungals providing higher cure rates and
less relapses are, therefore, auspicable. A review of onychomycoses and their treatment is made and the new antifungal drugs
that are currently on study or already available are presented.
KEY WORDS: Voriconazole - Ravuconazole - Posaconazole - Antimicotics - Nails.
O
nychomycosis is the most common nail disease
and describes the invasion of the nail by fungi.1,
2 Dermatophytes are the most commonly responsible
agents, nondermatophytic molds (NDM) account for
up to 15% of cases, while yeasts are rare.
In most cases, treatment of onychomycosis requires
systemic antifungals, with duration of administration
ranging from 2 to several months. Cure rates range
from 60% to 80%, and relapses are not rare (up to
20% of patients). New antifungals providing higher
cure rates and less relapses are, therefore, auspicable.
This article reviews onychomycoses and their treatment and presents the new antifungal drugs that are currently on study or already available.
Received: January 17, 2006.
Address reprint requests to: B. M. Piraccini, MD, Dipartimento di Dermatologia, Via Massarenti 1, 40138 Bologna (Italy).
Vol. 141 - N. 2
University of Bologna, Bologna, Italy
Onychomycosis
Onychomycosis affects more frequently toenails
than fingernails and this may be explained by the
growth rate that is 3 times slower for toenails than fingernails.2
Predisposing factors for onychomycosis include old
age, diabetes, HIV infection, peripheral vascular
impairment and peripheral neuropathies, podiatric
abnormalities, sports activities and traumatic nail disorders. It has also been suggested that susceptibility to
dermatophyte nail infection might be inherited as an
autosomal dominant trait.3
Different clinical patterns of onychomycosis result
from the way by which fungi colonize the nail.4 Type
of nail invasion depends on responsable fungus and
host susceptibility. Fungi responsable for onychomicosis are listed in Table I.
Distal subungual onychomycosis
This is the most common type of onychomycosis,
most frequently due to T. rubrum.
Fungi reach the nail unit through the hyponychium
and invade the nail bed spreading proximally. The skin
of the palms and soles is frequently involved, being the
primary site of infection.
155
PIRACCINI
EMERGING AGENTS FOR ONYCHOMYCOSIS
TABLE I.—Agents responsible for onychomycosis.
Common
Epidermophyton floccosum
Microsporum audouinii
Microsporum canis
Microsporum gypseum
Trichophyton mentagrophytes
Trichophyton schoenleinii
Trichophyton soudanense
Trichophyton tonsurans
Trichophyton violaceum
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Dermatophytes
Trichophyton rubrum
Trichophyton interdigitale
Uncommon
PSO due to Aspergillus sp., Fusarium sp. and Scopulariopsis brevicaulis is typically associated with
marked painful inflammation of the periungual tissues. The affected nail shows a deep milky-white or
yellow discoloration that starts from the proximal nail
and often rapidly spreads to involve the whole length
of the nail. Periungual tissues are edematous and red.
Some patients complain of periodical inflammatory
flares with purulent discharge, especially when
Aspergillus is the responsible agent.
Non-dermatophytic molds
Scopulariopsis brevicaulis
Fusarium spp.
Yeasts
Candida albicans
Acremonium spp.
Aspergillus spp.
Onichocola canadensis
Scytalidium spp.
Candida parapsilosis
Clinically the nail shows distal subungual hyperkeratosis and onycholysis. The onycholytic area appears
yellow white in colour. Yellow streaks along the lateral
margin of the nail and/or presence of yellow onycholytic areas in the central portion of the nail (dermathophytoma) are associated with poor response to
systemic antifungals.
The NDM Aspergillus sp., Fusarium sp. and Scopulariopsis brevicaulis may produce a distal subungual
onychomycosis (DSO) that usually involves 1 toenail,
with diffuse nail invasion associated with periungual
inflammation.5 DSO due to Acremonium sp. usually
affects 1 or 2 toenails and presents as one or few longitudinal white streaks extending proximally from the
distal margin. The clinical picture is similar to that of
a dermatophyte onychomycosis.
In DSO due to Scytalidium sp., the periungual tissues
and nail plate show a black pigmentation.
Proximal subungual onychomycosis
Fungi reach the nail unit through the undersurface
of the proximal nail fold and are typically located in
the ventral portion of the nail plate. Clinically, proximal
subungual onychomycosis (PSO) presents as an area
of leukonychia in the proximal portion of the nail plate.
The nail plate surface is normal, being spared by fungi.
This type of onychomycosis is most frequently
caused by molds, but it may also be caused by T.
rubrum, especially in HIV patients where it is a marker of the disease.
156
Superficial white onychomycosis
The infection is on the dorsal surface of the nail
plate. The classical form of superficial white onychomycosis (WSO) 6 is usually caused by T. interdigitale that possesses keratinolytic enzymes able to
metabolize the hard keratins of the superficial nail
plate. Clinically, the nail shows one or more small
white opaque patches that can be easily scraped off
and may coalesce gradually covering the whole nail
plate. Tinea pedis interdigitalis is frequently associated.
In HIV-infected patients, WSO is usually due to T.
rubrum and is not only seen in the toenails but can
also affect the fingernails. Clinically, the affected nail
appears diffusely opaque and white, with the leukonychia often reaching the proximal portion of the nail.
A similar clinical picture of deep WSO is seen in
children with T. rubrum WSO and in WSO due to
NMD.7
The most common species of NDM known to be
able to invade the superficial nail plate are Fusarium
sp., Aspergillus sp. and Acremonium sp. Mold WSO
usually affects a single toenail, mainly the big toe. The
diffuse and deep nail plate involvement makes it difficult to distinguish a deep WSO from a PSO progressed superficially. As seen in the other types of
onychomycosis due to NDM, periungual inflammation may be associated, but usually without pus discharge.
Scytalydium dimidiatum can be responsible for a
rare variety of superficial onychomycosis, black superficial onychomycosis, in which the superficial patches on the nail plate are black in colour.
Endonyx onychomycosis
Fungi invade the nail via the nail plate free margin.
Instead of infecting the nail bed, the fungus immediatelly penetrates the nail plate keratin.
Aprile 2006
antifungals to reduce duration of treatment and increase
cure rate.
DSO, EO, PSO, TDO and deep WSO always require
a systemic treatment.
Systemic treatment with terbinafine, itraconazole
or fluconazole produces mycological cure in more
than 90% of fingernail and in about 60-80% of toenail
dermatophyte infections. Onychomycosis due to Fusarium sp. and Scopulariopsis brevicaulis are very difficult to cure, while Aspergillus sp. responds very well
to antifungals.5, 11
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This rare type of onychomycosis is caused by T.
soudanense and T. violaceum. The nail plate is diffusely opaque and white in the absence of onycholysis and subungual hyperkeratosis. Plantar infection
may be associated.
PIRACCINI
Total dystrophyc onychomycosis
This type of onychomycosis may rarely occur as a
primary condition. Most commonly, in fact, represents the secondary evolution of untreated DSO, PSO,
deep WSO and endonyx onychomycosis (EO).8 Primary total dystrophyc onychomycosis (TDO) is usually due to Candida, and typically affects immunocompromized patients, such as patients with chronic
mucocutaneous candidiasis (CMCC), iatrogenic
immunodepression or HIV infection.9 In CMCC, onychomycosis is associated with inflammation of the
proximal nail fold, nail matrix, nail bed and hyponichium. The nail bed is hyperkeratotic and the nail plate is
extremely thick and dystrophic. Complete destruction
of the nail plate may be observed. Several nails are
generally affected, both fingernails and toenails. Oral
candidiasis is often associated.
In HIV positive patients and in iatrogenic immunocompromised individuals clinical presentation of Candida onychomycosis is less severe, with only one or few
fingernails affected.
Candida albicans has been frequently isolated from
the subungual area of onycholytic nails and from the
proximal nail fold in chronic paronychia. In both these
conditions, however, Candida colonization is a secondary phenomenon and systemic antimycotics do
not cure the nail abnormalities.
Treatment of onychomycosis
Treatment depends on the clinical type of the onychomycosis, the number of affected nails and the severity of nail involvement. The goals of antifungal therapy are mycological cure and a normal looking nail.10
Mycological cure should always be evaluated at the
end of treatment, while clinical cure may require some
more months to be achieved.
Topical nail lacquers containing 5% amorolfine and
8% cyclopiroxolamine are effective as monotherapy in
the treatment of classic WSO and of DSO limited to the
distal nail of a few digits. They are also utilized in
severe onychomycosis in combination with systemic
Vol. 141 - N. 2
New antifungals
New antifungal agents 12-14 are currently studied for
the treatment of systemic infections in immunocompromized patients. Some of them may have a role in
onychomycosis.
Voriconazole
Voriconazole (UK-109,496) is a triazole antifungal
agent, structurally related to fluconazole. It was
approved by the Food and Drug Administration (FDA)
in May 2002 and is indicated for the primary treatment of acute invasive aspergillosis, as salvage therapy for severe systemic infections by Scedosporium
apiospermum and Fusarium sp., and for refractory
Candida infections.
As with all azole antifungal agents, voriconazole
inhibits the fungal cytochrome P450-mediated 14alpha-lanosterol demethylation, an essential step in
fungal ergosterol biosynthesis. The inhibition of P450
14-alpha-demethylase is dose-dependent and, compared to fluconazole, provided with an increased potency. The accumulation of 14 alpha-methyl sterols is
added to the loss of ergosterol in the fungal cell wall
and may be responsable for the antifungal activity of
voriconazole.
Voriconazole is metabolized by the human hepatic
cytochrome P450 enzymes, CYP2C19, CYP2C9 and
CYP3A4, with less than 2% of the dose excreted
unchanged in the urine.The major metabolite of
voriconazole is the N-oxide. It has minimal antifungal
activity and consequently it does not contribute to the
overall efficacy of voriconazole.
Voriconazole is active both in oral and intravenous
administrations. It is available as a lyophilized powder
for solution for intravenous infusion, film-coated tablets
157
PIRACCINI
Microsporum canis. Activity against dermatophytes
is greater than that of itraconazole and fluconazole.
As with all azole antifungal agents, ravuconazole
works principally by inhibition of cytochrome P450 14alpha-demethylase (P45014DM). It’s potency and
binding affinity for P45014DM is similar to that of
itraconazole.
The metabolism is similar to that of voriconazole.
Ravuconazole will be available in both intravenous
an oral formulations.
The most common adverse effects of ravuconazole
are abdominal problems (15%), headache, dizziness
and skin abnormalities (10% of patients).
Gupta et al.16 reported the use of ravuconazole at different dosages for the treatment of distal subungual
onychomycosis. The dose of 200 mg daily for 12 weeks
was the most effective. Percentage of cure (59%) was not
higher than that obtained with terbinafine and itraconazole and, therefore, ravuconazole 200 mg/day does
not appear to be a better option for onychomycosis treatment than the available antifungals. Other clinical trials
on ravuconazole in DSO are currently underway.
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for oral administration, and as a powder for oral suspension. Dosages are: 200 mg twice daily per os and
3 to 6 mg/kg every 12 h intravenously.
Levels of voriconazole are significantly reduced by
the concomitant administration of rifampin, ritonavir,
carbamazepine and long-acting barbiturates.
Coadministration of voriconazole increases levels of:
sirolimus, terfenadine, cisapride and ergot alkaloids.
Coadministration of voriconazole with this drugs
is, therefore, contraindicated.
It is necessary to monitor or adjust the dose of the following drugs when coadministered with voriconazole:
cyclosporine, methadone, tacrolimus, warfarin, oral
coumarin anticoagulants, statins, benzodiazepines and
sulfonylureas.
The interactions of voriconazole with cimetidine,
ranitidine and macrolide antibiotics are minor or no significant, so they do not require dosage adjustment.
The most common side effects of voriconazole are
visual disturbances that affect 40% of patients and
include abnormal vision, color vision change and photophobia, elevations of liver enzymes (20% of patients)
and skin rashes (6%). Side effects often lead to discontinuation of voriconazole therapy. Liver function
tests should be evaluated at the start of and during the
course of the treatment. Acute renal failure has been
observed in severely ill patients.
The mechanisms underlying the dermatologic sideeffects of voriconazole are unknown.
A photosensitivity reaction may occur with longterm treatment. A case of photoaging caused by
voriconazole therapy has been reported in a 15-yearold patient.15
Voriconazole has never been tried for the treatment
of onychomycosis.
Ravuconazole
Ravuconazole (ER-30346 and BMS-207147) is a
second generation triazole derivative related with
voriconazole, currently undergoing Phase II clinical trials.
Ravuconazole has been described in both intravenous and oral formulations. It has broad spectrum in
vitro potency and in vivo efficacy against a wide range
of fungal pathogens.
In vitro ravuconazole is active against important
fungal pathogens, including Candida spp., Aspergillus
fumigatus, Criptococcus neoformans, as well as dermatophytes: Trichophyton mentagrophytes, T. rubrum,
158
Posaconazole
Posaconazole is a new triazole, formerly known as
SCH 56592, that is structurally related to itraconazole. This drug is in Phase I studies to asses safety
and antifungal efficacy.
Posaconazole shows potent broad-spectrum activity against opportunistic fungal pathogens like Candida spp., Cryptococcus neoformans, Aspergillus spp.,
Fusarium spp., dermatophytes and zygomycetes.
Posaconazole works principally by inhibition of
cytochrome P450 14-alpha-demethylase (P45014DM)
and is a significantly more potent inhibitor of sterol C14
demethylation than itraconazole.
SCH 56592 has been formulated in only oral tablet
and suspension preparations.
No data are available about the possible use of
posaconazole for the treatment of onychomycosis.
SCH 56592 has been formulated in only oral tablet
and suspension preparations.
Conclusions
The new antifungals agents ravuconazole, posaconazole, voriconazole are very promising for the treatment of systemic fungal infections. Their possible use
in onychomycosis is still to be assessed.
Aprile 2006
2. Haneke E. Fungal infections of the nail. Semin Dermatol 1991;10:4153.
3. Zaias N, Tosti A, Rebell G, Morelli R, Bardazzi F, Bieley H et al.
Autosomal dominant pattern of distal subungual onychomycosis
caused by Trichophyton rubrum. J Am Acad Dermatol 1996;34 (2 Pt
1):302-4.
4. Baran R, Hay RJ, Tosti A, Haneke E. A new classification of onychomycosis. Br J Dermatol 1998;119:567-71.
5. Tosti A, Piraccini BM, Lorenzi S. Onychomycosis caused by nondermatophytic molds: clinical features and response to treatment of
59 cases. J Am Acad Dermatol 2000;42:217-24.
6. Piraccini BM, Tosti A. White superficial onychomycosis: epidemiological, clinical, and pathological study of 79 patients. Arch Dermatol 2004;140:696-701.
7. Piraccini BM, Lorenzi S, Tosti A. ‘Deep’ white superficial onychomycosis due to molds. J Eur Acad Dermatol Venereol 2002;16:5323.
8. Tosti A, Baran R, Piraccini BM, Fanti PA. Endonyx onychomycosis:
a new modality of nail invasion by dermatophytic fungi. Acta Derm
Venereol 1999;79:52-3.
9. Hay RJ, Baran R, Moore MK, Wilkinson JD. Candida onychomycosis-an evaluation of the role of Candida species in nail disease. Br J
Dermatol 1988;118:47-58.
10. Baran R. Nail fungal infections and treatment. Hand Clin 2002;18:6258.
11. Tosti A, Piraccini BM, Lorenzi S, Iorizzo M. Treatment of nondermatophyte mold and Candida onychomycosis. Dematol Clin
2003;21:491-7.
12. Gupta AK, Tomas E. New antifungal agents. Dermatol Clin
2003;21:565-76.
13. Sheenan DJ, Hitchcock CA, Sibley CM. Current and emerging azole
antifungal agents. Clin Microbiol Rew 1999;12:40-79.
14. Kale P, Johnson LB. Second-deneration azole antifungal agents. Drugs
Today 2005;41:91-105.
15. Racette AJ, Roenigk HH, Hansen R, Mendelson D, Park A. Photoaging and phototoxicity from long-term voriconazole treatment in
a 15-year-old girl. J Am Acad Dermatol 2005;52 (5 Suppl 1):5282-5.
16. Gupta A, Leopardi C, Stolz R, Conetta B, Pierce P. Evaluation of
ravuconazole for the treatment of toenail onychomycosis. Ann Dermatol Venereol 2002;129 (1 Suppl):607-842.
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An optimal systemic antifungal for onychomycosis should posses the following characteristics: easy
way of administration, optimal tolerability, rapid and
long-lasting effect. At the moment, the new antifungals
do not seem to possess these qualities, but further studies are necessary to definitly indicate their role in onychomycosis therapy.
PIRACCINI
Riassunto
Agenti emergenti nell’onicomicosi
L’onimicosi rappresenta la patologia ungueale più comune ed è caratterizzata dall’invasione dell’unghia da parte di
funghi. Nella maggior parte dei casi il trattamento dell’onicomicosi richiede una terapia antifungina sistemica, la cui
durata può variare da 2 a diversi mesi.
Il tasso di guarigione varia dal 60% all’80% e le recidive
non sono rare (possono riguardare sino al 20% dei pazienti).
Sono auspicabili nuovi farmaci antifungini in grado di aumentare il tasso di guarigione e di diminuire quello delle recidive. Questo articolo rivede le onicomicosi e il loro trattamento, presentando inoltre i nuovi farmaci antifungini che
sono attualmente in fase di studio o già disponibili.
PAROLE CHIAVE: Micosi - Farmaci antifungini - Voriconazoleo - Ravuconazolo - Posaconazolo.
References
1. Faergemann J, Baran R. Epidemiology, clinical presentation and diagnosis of onychomycosis. Br J Dermatol 2003;149 Suppl 65:1-4.
Vol. 141 - N. 2
159
GUIDELINES
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Guidelines of the Italian Association
for Non Invasive Diagnosis in Dermatology
Linee guida della Associazione Italiana
di Diagnostica Non Invasiva in Dermatologia
P. CARLI 1, M. GNONE 2, G. L. GIOVENE 3, G. GHIGLIOTTI 4, S. GASPARINI 5, A. CHIARUGI 1, E. DANTI 6,
V. DE GIORGI 1, F. CENCETTI 7, B. MASTRECCHIA 8, P. BUCCINI 9, S. SERRESI 10, F. TANGARI 11
General principles
1) Dermoscopy represents a second level examination aimed at improving the noninvasive diagnosis of
pigmented skin lesions that resulted equivocal by naked
eye observation (I level examination),1 therefore, dermoscopy represents a part of the overall diagnostic
procedure. The dermoscopy report, therefore, supplements the medical report that should be always made
after each dermatological consultation.
2) The prescription of a dermoscopy examination is
appropriate and must be accepted by the specialist that
performs dermoscopy when made by an other physician (general pratictioner, dermatologist or other medical specialist); the prescription must indicate what
lesion/s should be examined.
On the contrary, the prescription of dermoscopy
examination cannot be considered appropriate if sug-
Consensus Meeting held in Florence, December 4, 2004.
The content of the manuscript has been presented and discussed in the
following meetings: Annual Meeting of the Italian Society of Dermatologic
Surgery and Oncology (Rome, April 2005), Dermoscopy Course within the
Annual congress of the Italian Society of Dermatology and Sexualy transmitted Diseases Genova, June 2005). Annual meeting of the AIDNID
Palermo, June 2005).
The content has been approved by the board of the ADINID and that of
the Dermoscopy Forum.
Pervenuto il 21 settembre 2005.
Accettato il 13 aprile 2006.
Address reprint requests to: P. Carli, Dipartimento di Clinica Dermatologica, Università degli Studi di Firenze, Via della Pergola 58, 50121
Firenze. E-mail: [email protected]
Vol. 141 - N. 2
1Department
of Dermatological Sciences
University of Florence, Florence, Italy
2Dermatology Unit, Chiavari Hospital, Genoa, Italy
2Italian Association of
Ambulatory Dermatology, Perugia, Italy
4Dermatology Unit, S. Martino Hospital, Genoa, Italy
5Italian Association of Ambulatory Dermatology, Terni, Italy
6Unit of Forensic Medicine, ASL, Florence, Italy
University of Perugia, Perugia, Italy
La Sapienza University, Rome, Italy
9Dermatology Unit, S.Gallicano Hospital, IRCCS, Rome, Italy
10Dermatology Unit, INRCA, Ancona, Italy
11Private Practice, Rome, Italy
gested by the patient himself that asks the doctor to
examine one or more lesions judged clinically banal by
the specialist and otherwise not selected for the examination.
Furthermore, the prescription of dermoscopy examination cannot considered appropriate if it doesn’t
indicate accurately the lesion/lesions to be examined.
In this case (for example: prescription of a generic
dermoscopy examination for multiple atypical nevi…)
it might be advisable—with the consent of patient—
changing the prescription from dermoscopy (this type
of examination provides a specific sanitary ticket, different from that of the general examination) in a dermatological examination for melanoma screening.
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GUIDELINES FOR DRAFTING A DERMOSCOPY REPORT
tics of the lesion analized regarding dermoscopy as a
step of a wider clinical opinion. Recent literature as
well as clinical experience demonstrate that the combination of dermoscopic and clinical anamnestic data
help in minimizing the risk of incorrect management
of a pigmented lesion.2-4 The existence of the so called
“featureless melanomas”, i.e. melanomas lacking dermoscopic features of malignancy (about 8% of all the
melanomas),5 can hamper the role of dermoscopy as
gatekeeper of decision for removal. In some cases,
excision has to be decided in accordance with lesion’s
history and clinical features. Moreover, the “ugly duckling sign” 6 may seldom help in selecting a lesion to be
removed even if not associated with clear-cut dermoscopy features of malignancy.
8) Even if an evidence-based demonstration remains
to be done, it is opinion of the authors of these guidelines that dermoscopy should be of competence of the
dermatologist more than other medical specialists.
According to the point discussed before, the optimized
use of dermoscopy can be obtained only by means the
integration of dermoscopic features with the most relevant clinical-anamnestic informations. The diagnostic performance achieved by a non dermatologist doctor can be affected by the low experience in examining the skin and, therefore, in taking into account additional points seldom needed to select the appropriate
lesion’s management in those cases difficult to diagnose.
9) Delivery of the report to the patient. From a
medico-legal point of view every instrumental tests
must be communicated to the patient by means of a
written report signed by physician; this report represents the only document juridically valid.
10) Preservation of the report. The law in force
(Ministry of Health Memorandum n. 61 of 19 December 1986) obliges to preservate a copy of the report
in a proper archive at least for 20 years; the suitable
means are: the chemical copying paper, the photocopy
or the print in double copy. If the report is drawn up in
digital file—for example by means of a software
included in the videodermoscope—it is possibile to
preserve a copy of the report in this format. These
data, both in paper and digital format, are submitted to
the regulations provided in the Art. 15 (security of the
data) of the italian law n. 675 of 1996 and in the DPR
n. 445/2000 about the preservation and transmission of
administrative documents; the digital registration must
be made at least on 2 distinct data medium preserved
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This would permit to avoid diagnostic delay in the
case where the patient will eventually show a suspicious lesion; in that case, the specialist will use dermoscopy—if needed—according to his personal judgement.
3) Dermoscopy can be performed in the following
2 cases (a) as a consequence of a specific medical prescription or (b) during an examination aimed to
melanoma screening according to personal judgement
of the examiner. Two different forms for medical report
are enclosed.
4) Informed consent: according to the italian law
by decree n. 196 of 30 June 2003 “Code in the matter
of protection of personal data” that simplifies the previous rule about the Privacy, it is not considered necessary the acquisition of the written consent for the
execution of the diagnostic examination; it is regarded sufficient the verbal consent after adequate information about the modality and the aim of the medical
test (art. 79).
5) Minimal equipment for dermoscopy
a) 10X Minimal magnification.
b) Hand-held dermoscope with diode illumination
(to be preferred to that traditional with incident light).
c) For digital dermoscopy (by means videodermoscope or videocamera) it is not presently possible to
establish the qualitative minimal threshold to consider the image sufficiently informative for the diagnosis.
In our opinion the image quality should not be worse
than that of an analogic image obtained with an handheld dermoscope (standard procedure in the recent literature on dermoscopy) and then digitalized.
6) The examiner is obliged to give a medical report
in the following 2 cases: a) for any dermoscopy examination required by a sending doctor irrespective of
the diagnostic outcome; b) in the case of possible
malignancy identified by dermoscopy that has been
made on the discretion of the dermatologist in the
screening.
To the contrary, the dermoscopy report should’nt
be considered mandatory when dermoscopy did not
reveal neither malignant nor suspicious lesion. In that
case, the report will concern the overall outcome examination (Appendix I).
7) In order to improve the communication with the
patient, it is advisable to base the report more on the
overall clinical-dermoscopic findings than on dermoscopic examination alone. Indeed, we suggest to pay
attention to the main clinical-anamnestic characteris-
162
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13) The problem of the acquisition and preservation of the image in the case of hand-held dermoscopy:
although the authors of these guidelines agree about the
need to record and preserve the image anyhow the
dermoscopic examination is performed, this procedure has to be considered necessary only if a digital
technology (videodermoscopy, video-camera) has
been used, while it is only advisable in the case of
analogical examination. Indeed, in the latter case the
equipment used for hand-held dermoscopy doesn’t
permit the registration of the images. In this case the
dermoscopic examination can be comparable to ophtalmoscopic or otoscopic examination by means of an
optic traditional equipment, that requires a specific
report but usually does not require the acquisition of
the image as diagnostic support.
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in different premises. In the deliberation of the National Center for Informatics in the Public Administration
(Centro Nazionale per l’Informatica nella Pubblica
Amministrazione, CNIPA) n. 11 of 19 February 2004
there are further and more recent instructions about
optical registration and document conservation. The
paper copy registered must be signed by the reporting
physician. It is necessary to designate a person responsible of the data-base that knows the conservation state
of data and the access procedures.
11) Delivery to patient of the print of the dermoscopic images. In spite of the fact that the presence in
the report of the lesion’s image is advisable, the Guarantor for the Privacy pointed out that the Art. 13 of the
law 675/96 don’t provide the necessary delivery to the
patient of the documents or the medium preserving
data, but it obliges, more precisely, the person responsible of the data processing to extract them from the
own archives and documents all the informations in
paper or digital format concerning the petitioner and to
relate them with a manner suitable to easily understand the data. Therefore, it is the written report signed
by the physician the only document with medico-legal
validity. Viceversa the delivery to the patient of the
dermoscopic image has to be regarded as optional. If
given to the patient, the image should have a minimal
qualitative level in order to be representative of the
descripton made on the report. Anyway, if the image is
given to the patient, it can be advisable to specify that
the description and the diagnosis written in the report
have been made on the basis of the in vivo observation.
Furthermore, being dermoscopy a diagnostic procedure that needs to be integrated with the anamnesticclinical data in order to have an optimized management of the lesion, the dermoscopic image cannot be
in itself sufficient to support the conclusions and the
management of the lesion written in the report. The
file copies of the recorded images should be delivered
to the patient if these are required expressly.
12) Storage and preservation of the dermoscopic
images: in accordance with that established by the
Ministry of Health Memorandum n. 61 of 19 December 1986, it can be assumed—on the analogy of what
established for X-ray photographs—that the dermoscopic images must be keeped for 20 years at least;
this is true also for dermoscopic images acquired by
means of analogical technology and recorded on others medium (photographic negative film or photographic paper).
CARLI
Vol. 141 - N. 2
The structure of the report
In order to create an uniformity for drafting among
Italian dermatologists, a standard clinical-dermoscopic
report was made. The clinic-dermoscopic report should
include 2 different parts: a general part and an analytic part (Appendices I, II).
General part
Clinical-dermoscopic screening of the cutaneous
lesions; this has to be filled in every patient. The aim is
to inform the patient and/or the referring doctor about the
present of eventual risk factors for melanoma, to make
education about prevention of skin cancers, to suggest
eventual future medical examination for check-up.
This part can represent the only component of the
medical report when dermoscopy has been performed
on the discretion of the dermatologist performing the
screening and the diagnostic outcome was negative.
Concerning guidelines for skin examination aimed at
skin cancer screening, we suggest to offer to the patient
the chance of a total skin examination including the
anal-genital area. In the case of refusal, it should be
pointed out in the report. The scalp should be examinated in all cases.
Analitical part (Clinical-dermoscopic report of an
index lesion submitted to dermoscopy)
This part must be compiled in all cases of dermoscopic examination specifically asked from another
physician and in all cases where the examination -
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1. Examination aimed to melanoma screening with manual dermoscopy
according to personal judgement of the examiner
No suspicious lesion evidentiated
Suspicious pigmented lesion - according to
dermoscopic parameters evidentiated - to submitted
to excisional biopsy or follow-up
Dermoscopy report not necessary
Dermoscopy report necessary
2. Dermoscopic examination (manual or digital), as consequence
of a specific medical prescription
Dermoscopy report is mandatory irrispective
of the diagnostic outcome
3. Generic prescription of dermoscopy examination that doesn’ t
indicate accurately the lesion/lesions to be examined
The prescription can be changed in dermatological examination
for melanoma screening
The report will concern the overall outcome examination (see point 1)
Figure 1.—Algorythm for the dermoscopy report.
performed on the discretion of the dermatologist during a screening examination - yielded positive results
(i.e. suspicious or clearly malignant lesion to be
removed).
This procedure is summarized by means of the following algorythm (Figure 1):
A) Screening examination (general examination of
all the pigmented lesions with dermoscopy possibly
performed at the discretion of the dermatologist):
164
A) A1) No evidence of pigmented lesions that needs
a diagnostic verification by means excisional biopsy or
careful follow-up.
A) Type of report:
A) — General part: yes
A) — Analytical part: no
A) A2) Evidence of one or more lesions that needs
further investigations.
A) Type of report:
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A) — General part: yes
A) — Analytical part: yes
B) Dermoscopic examination of a specific lesion
following medical request (screening examination not
made).
A) Type of report:
A) — General part: no
A) — Analytical part: yes
Contents of the report
General part
The report must be compiled on the headed paper of
the Physician/ Medical Structure that performed the
examination. The report should include—for educational purpose—a brief explanation about the modal- Figure 2.—Body map for the indication of the lesion localisation.
ities of the skin self-examination and about the rules
for the early diagnosis of melanoma.
Suggested formula:
It must contain:
— We suggest to perform a periodical skin selfA) Patient’s personal data:
examination.
Please not forget to examine also analA) — Name.
genital area and the scalp, this latest possibly with wet
A) — Surname.
hair and with the help of a comb. In the case of modA) — Date of birth.
ification in size, shape or colour of a pre-existent nevus,
A) — Occupation.
or appearance of a new nevus with looks different
A) — Date of the examination.
from the other nevi, it is advisable to seek a timely
dermatological examination.
B) Melanoma risk factors identified:
F) Stamp and sign of the physician on each copies.
A) — Familial history of melanoma (First degree relatives).
A) — Presence of clinically atypical nevi.
Analitical part
A) — Personal history of melanoma.
A compilation of a form for each lesion submitted
A) — Total number of melanocytic nevi >50.
to
dermoscopy is needed. A single form is used for
A) — Repeated sunburns before the adulthood.
every
kind of lesion (melanocyti or not). The form
A) — Intensive and prolonged sunexposure.
will include all dermoscopic parameters both
A) — Phototype I-II according to Fitzpatrick
melanocytic and not melanocytic, and a specific space
C) Outcome of clinical and dermoscopic examina- for the diagnosis.
tion:
Also the analytical part must be compiled on the
A) No suspicious lesions identified:
headed paper of the Physician/ Medical Structure when
A) Possible suggestions:
performing the examination.
The report must be contain:
A) — Periodical skin self-examination
A) Patient personal data
A) — Next examination scheduled after ........months
— Name
A) Lesion/s with suspicious diagnostic features: see
— Surname
enclosed form with specific dermoscopy report
— Date of birth
D) Space for notes
E) Education about the skin self- examination.
— Date of examination
Vol. 141 - N. 2
165
CARLI
include in the report possible factors that may have
hampered an accurate lesion’s examination (presence
of hematic crust, presence of intense diffuse pigmentation, ecc.).
Suggested formula:
The clinical – dermoscopic examination of the lesion
suggest................
E) Indications
The indications must be indicated as necessary.
— Periodical skin self-examination
— Further clinical-dermoscopic examination
— Diagnostic verification by means excisional biopsy
— Surgical excision for treatment
F) Education about the skin self-examination
Suggested formula (see above general part)
G) Stamp and sign of the physician on each copies.
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B) Numbering
The numbering is indipendent for each patient, and
it is represented by progressive number of the examined lesion.
C) Accurate description of the lesion localization in descriptive manner as well as through the indication
of the localization on the figure - (Figure 2).
Moreover, it is advisable to mark directly the lesion
indicated in the report (dermographic pen) on the
patient skin either for the identification at home – also
to make easier the follow-up from relatives or friends
– and for lesion’s identification in case of suggestion
for immediate excision.
D) Measurements o two major diameters of lesion
in mm.
E) Analytical contents:
1) Melanocytic lesions.
— Simmetry-Asymmetry (shape, colour, structure).
— Global pattern.
— Local pattern.
2) No melanocytic lesions.
— Local pattern.
F) Diagnostic conclusions
A qualifying point of the report are the conclusions
that should summarize all the anamnestic, morphologic and dermoscopic data supporting the suggested
lesion’s management. With the purpose of safeguard the
patient from the risk of leaving a melanoma unexcised,
the lesion’s management shoud be regarded as the
greatest point to be addressed. Sometimes, it can be
necessary to suggest the removal of a lesion associated with history of change or high degree of suspicious
on clinical examination even if this lesion cannot be
classified as definitely malignant by dermoscopy.
It is advisable from a medical-legal point of view to
166
References
1. Chimenti S, Argenziano G, Di Stefani A, Andreassi L, Carli P, De
Giorgi V et al. Guidelines in dermoscopy. G Ital Dermatol Venereol
2005;140:329-47.
2. Carli P, De Giorgi V, Giannotti B. Dermoscopy and early diagnosis of
melanoma. The light and the dark. Arch Dermatol 2001;137:1641-4.
3. Carli P, Massi D, De Giorgi V, Giannotti B. Clinically and dermoscopically featureless melanoma. When prevention fails. J Am Acad
Dermatol 2002;46:957-9.
4. Carli P, De Giorgi V, Argenziano G, Palli D, Giannotti B. Preoperative diagnosis of pigmented skin lesions: in vivo dermoscopy performs better than dermoscopy on photographic images. J Eur Acad Dermatol Venereol 2002;16:339-46.
5. Menzies SW, Ingvar C, Crotty KA, McCarthy WH. Frequency and
morphologic characteristics of invasive melanomas lacking specific
surface microscopic features. Arch Dermatol 1996;132:1178-82.
6. Grob JJ, Bonerandi JJ. The “ugly duckling” sign: identification of
the common characteristics of nevi in an individual as a basis for
melanoma screening. Arch Dermatol 1998;134:103-4.
Aprile 2006
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APPENDIX I.
Medical report of a screening examination for melanoma: suggested form
Title and address of the structure
Name……………………………………………………………………. Birth date .…../.…../..…
Address……………………………………………………… Examination date.…../..…./..….
RISK FACTORS FOUND:
— familiarity for melanoma (I grade relatives)
— numerous sunburns in childhood
— personal history for melanoma
— skin type I and II according to Fitzpatrick
— clinically atypical nevi
— number of melanocytic nevi > 50
Dermoscopic examination has been performed
❒ No
❒ Yes
The dermoscopic examination has been performed by means of equipment:
❒ analogical
❒ digital
Outcome of examination
— Absence of suspicious pigmented skin lesions in the examined skin
— — We recommende the skin self-examination
— — We recommende next examination in ………..months
— Presence of suspicious pigmented lesions (specific dermoscopy report enclosed)
Notes:……………………………………………………………………………………………..…………
………………………………………………………………………………………………….............................
............................................................................................................
We recommende you to perform a periodical skin self-examination. Do not forget to esamine also anal-genital area and the scalp with wet hair and withthe help of a comb. In the case of modification in size, shape or
colour of a preexistent nevus, or the appearance of a new nevus looking different than already present nevi,
it is advisable to seek a timely dermatological examination.
Stamp and signature of Physician
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APPENDIX II
Medical report of a dermoscopy examination of a selected lesion: suggested form
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Name………………………………………………………… …. birth date .….…/.…..../.…....
DERMOSCOPIC REPORT no. …………….........................examination date …../…./…./
Lesion site………..………………………………………………………. Dimensions: mm. ____X ____mm.
Referred appearance/growth / changes during the latest months:
❒ No
❒ Yes
Symmetry
Asymmetry
shape
colour
structures
Global pattern
reticular
globular
homogeneous
compound
multicompound
starburst
parallel
lacunar
aspecific
Local pattern
atypical pigment/pseudopigment network ❒
irregular streaks
❒
irregular dots/globules
❒
irregular blotches
❒
blue-whitish veil
❒
regression structures
❒
ipo/depigmentation
❒
maple leaf-like areas
❒
spoke wheel structures
❒
ovoid grey-blu areas
❒
horny pseudocysts
❒
Vascular pattern
pseudofollicolar openings
❒
arborescent
❒
hair-pin like
❒
garland-like
❒
comma-like
❒
dotted
❒
atypical
❒
Diagnostic Method
Pattern analysis ❒ ABCD rule ❒ 7-point checklist ❒ 7-FFM ❒
Dermoscopic examination
analogical ❒ digital ❒ Equipment:..………..……………
Diagnostic conclusions: the clinical-dermoscopic examination of the lesion suggests…………………………
…………………………………………………………………………………………………………………
…………………………………………………………………………………………………………………
Indications: it is needed to submit such neoformation to
— further clinical-dermoscopic examination after …………..months
— diagnostic verification by means excisional biopsy
— surgical excision for treatment
— Periodical skin self-examination
Stamp and signature of the Physician
168
Aprile 2006
CLINICAL CASES
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Familial mediterranean fever
A diagnostic challenge
O. MOURELLOU, F. S. DELLI, G. CHAIDEMENOS, P. GIDAROKOSTA, D. TSATILAS, F. TSATSOU
Familial Mediterranean fever (FMF) is a hereditary disease
that especially affects people living around the Mediterranean
sea. The most serious complication is amyloidosis, which can
lead to terminal renal failure. We report the case of a 48-year
old man who presented in our clinic with recurrent episodes of
erysipelas-like rashes located at the right gluteal area, always
associated with fever and sometimes with orchiepidedymitis,
abdominal pain and arthritis. The clinical diagnosis of FMF was
confirmed by the finding of the mutated marenostrin-encoding
fever (MEFV) gene, using the PCR technique. The attacks
were successfully avoided by continuous administration of
colchicine per os 0.5 mg 3 times daily.
KEY WORDS: Familial Mediterranean fever - Erysipelas-like rash
- Colchicines.
State Hospital for Skin and Venereal Diseases
Thessaloniki, Greece
FMF is characterised by recurrent fever and abdominal pain, often associated with pleuritis, synovitis or
exanthema. The most serious complication is amyloidosis, which can lead to terminal renal failure.3 The
attacks and complications can be avoided by life-long
administration of colchicine.
Case report
F
amilial Mediterranean fever (FMF) is a hereditary
disease that especially affects people living around
the Mediterranean Sea.1 Two independent French and
American teams discovered the gene mutations responsible for the disease in 1997. It encodes for a protein
named pyrin/marenostrin involved in the homeostasis
of the inflammatory mechanisms. The main mutations
have been identified and are, therefore, accessible for
molecular screening.2
This paper was presented as a poster at the European Academy of
Dermatology and Venereology (EADV) 3rd Spring Symposium, 2005,
May 19-22, Sofia, Bulgaria
Received: October 27, 2005.
Accepted for publication: March 15, 2006.
Address reprint requests to: Dr. F. S. Delli, State Hospital for Skin and
Venereal Diseases, 124, Delfon Street, 54643 Thessaloniki, Greece.
Vol. 141 - N. 2
We report the case of a 48-year old greek man who was hospitalised in our clinic for recurrent episodes of fever (3840ºC) and erysipelas-like exanthema of the left lumbar and
gluteal area (Figures 1, 2). Clinical examination also revealed
congenital hemangioma of the left abdomen site and unilateral, erythematous and tender swelling of the scrotum. The
patient mentioned similar attacks several times per year,
monthly or bimonthly, during the last 30 years. He was hospitalised several times for recurrent episodes of scrotal swelling
and aseptic arthritis associated with high fever. Each paroxysm lasted 48-96 h with peak intensity occurring within the
first 12 h. The patient’s family history was negative.
Routine blood tests during the acute attacks were nonspecific. Levels of acute phase reactants (C-reactive protein) and erythrocyte sedimentation rate were elevated and
returned to reference values in about 4-5 days. Histopathological examination of the skin lesions showed nonspecific
features of urticaria. Rectal biopsy excluded the presence
of amyloidosis.
169
FAMILIAL MEDITERRANEAN FEVER
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Figure 1.—Erysipelas-like exanthema of the left lumbar and gluteal area.
Figure 3.—One year after the initiation of colchicine therapy the patient
is free of fever attack, skin exanthema and any other symptom.
Figure 2.—A well-demarcated, erythematous, warm plaque.
The clinical diagnosis of FMF could not be confirmed by
PCR specific test. The patient started therapy with colchicine
0.5 mg 3 times per day (1.5 mg daily). One year after the initiation of the colchicine, he is free of febrile attack, exanthema
or any other symptom (Figure 3).
The diagnosis of FMF is often difficult.
Out of all patients with FMF, 50-60% are younger
than 10 years old, 80-95% are younger than 20 years
old, and 5-10% are older than 20. The disease is rare
in persons older than 40 years old. Our patient is 40
years old, but signs and symptoms have been present
since the age of 10.
As much as 50% of patients report erysipelas-like
170
rashes at the lower extremities, particularly below the
knees.4 A well demarcated, erythematous, warm rash,
ranging from 15 to 50 cm2 may develop and be accompanied by swelling. Several other nonspecific skin
lesions may be seen in FMF. Rash and fever may be the
only manifestations of the attacks.
The diagnostic criteria are short febrile attacks recurring at various intervals and pain in the abdomen, chest
and joints or skin rush.5, 6 Since no specific test for
FMF is available, the diagnosis must be based on precise clinical criteria and genetic tests.7
Nonsense or missense mutations in the MEFV
(Mediterranean fever) gene appear to cause the disease. This gene produces a protein called pyrin (derived
from the association with predominant fever) or
marenostrin (derived from the phrase “our sea”, due to
the Mediterranean origin of most patients).
After the successful cloning of the MEFV gene,
researchers have developed a rapid test for the most
common mutations. The role of E148Q pyrin gene
mutation in the development of FMF remains inconclusive. Some authors believe it causes the disease,
whereas others favour the concept of a noncausative
role. In Greece it seems to be significantly frequent,8
but in our case the test proved to be negative.
The protein is expressed mostly in neutrophils, but
its exact function is not known. The protein may function as an inhibitor of chemotactic factor (C5a) or perhaps of interleukin.8 Patients with normal pyrin/marenostrin levels may have the ability to deactivate the
Aprile 2006
FAMILIAL MEDITERRANEAN FEVER
MOURELLOU
paziente di 48 anni che si è rivolto alla nostra clinica a
seguito di episodi ricorrenti di un’eruzione cutanea similerisipela localizzata a livello del gluteo destro, sempre
associata a febbre e talvolta a orchiepididimite, dolore
addominale a artrite. La diagnosi clinica di febbre familiare
mediterranea è stata confermata dall’identificazione tramite
tecnica PCR del gene mutato codificante per la febbre
mediterranea. La somministrazione continua di colchicina per os (0,5 mg 3 volte al dì) ha consentito di evitare gli
episodi ricorrenti.
PAROLE CHIAVE: Febbre mediterranea - Erisepela - Colchicine.
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target chemotactic factor when it is produced in
response to an inflammatory stimulus. However,
patients with FMF lack this ability, resulting in uninhibited activity of the chemotactic factor and episodes
of inflammation (with associated fever) in the peritoneum, pleura and joints. Presumably, these inflammatory episodes lead to the excess production of amyloid A acute phase protein and reactant serum amyloid
A with subsequent deposition at the kidneys; however, only patients with specific MEFV haplotypes develop amyloidosis.
Colchicine is effective in preventing attacks of FMF
and the development of amyloidosis. The most important aspects of medical care are to make the correct
diagnosis and therapy. In patients who do not respond
to colchicine, the use of interferon-α or the TNF-blocking drug, etanercept may be effective.
Our patient had an immediate and excellent response
to colchicine.
FMF is frequently accompanied by erysipelas-like
exanthem. These should alert the physician to the correct diagnosis of this systemic disease.
Riassunto
Febbre familiare mediterranea. Una sfida diagnostica
La febbre familiare mediterranea è una malattia ereditaria che colpisce particolarmente le popolazioni che vivono nell’area Mediterranea. La complicanza più grave è
rappresentata dall’amiloidosi, che può portare a un’insufficienza renale terminale. Viene descritto il caso di un
Vol. 141 - N. 2
References
1. Sohar E, Gafni J, Pras M, Heller H. Familial Mediterranean fever. A
survey of 470 cases and review of the literature. Am J Med
1967;43:227-53.
2. Samuels J, Aksentijevich I, Torosyan Y, Centola M, Deng Z, Sood R
et al. Familial Mediterranean fever at the millennium. Clinical spectrum, ancient mutations, and a survey of 100 American referrals to the
National Institutes of Health. Medicine (Baltimore) 1998;77:268-97.
3. Meyerhoff J. Familial Mediterranean fever: report of a large family,
review of the literature, and discussion of the frequency of amyloidosis.
Medicine (Baltimore) 1980;59:66-77.
4. Azizi E, Fisher BK. Cutaneous manifestations of familial Mediterranean fever. Arch Dermatol 1976;112:364-6.
5. Livneh A, Langevitz P, Zemer D, Zaks N, Kees S, Lidar T et al. Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum
1997;40:1879-85.
6. Livneh A, Langevitz P, Zemer D, Padeh S, Migdal A, Sohar E et al.
The changing face of familial Mediterranean fever. Semin Arthritis
Rheum 1996;26:612-27.
7. Ben-Chetrit E, Levy M. Familial Mediterranean fever. Lancet
1998;351:659-64.
8. Konstantopoulos K, Kanta A, Lilakos K, Papanikolaou G, Meletis I.
Familial Mediterranean fever and E148Q pyrin gene mutation in
Greece. Int J Hematol 2005;81:26-8.
171
LETTERS TO THE EDITOR
Tinea capitis in an adult woman
masquerading as a worsening
of dermatomyositis
V. BRAZZELLI, O. CIOCCA, A. DI SILVERIO
S. MARTINOLI, G. BORRONI
Department of Human and Hereditary Pathology,
Institute of Dermatology, University of Pavia
IRCCS Policlinico San Matteo, Pavia, Italy
Dear Editor,
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inea capitis (TC) is a common fungal infection, usually
affecting children between 3 and 7 years of age.1 Only 3%
to 5% of TC occurs post puberty. Adult cases of TC are very
uncommon.2 We present a case of TC in a woman affected
by dermatomyositis (DM).
A 66-year-old Caucasian woman was observed at the
Department of Dermatology, University of Pavia. She presented itch, scaling scalp eruption, as well as hair loss of
recent onset.
The previous year, the patient had been diagnosed affected by DM; at that time she had a moderate muscles weakness,
particularly of the proximal ones, and a heliotrope rash involving her face, with eyelid edema and eponichial teleangectases. Muscle enzyme levels were high. Electromyography
revealed an abnormal pattern with myopathic pattern of the
motor unit action, potential myopathic recruitment pattern,
increased insertional and spontaneous activity. DM was diag-
nosed and a treatment with daily 50 mg prednisone and 100
mg azathioprine started. Since then, she could keep DM under
control, tapering prednisone to 25 mg every other day, in
association with daily 50 mg azathioprine.
At the time of the observation the patient showed areas of
scalp alopecia with ill defined margins (Figure 1A), as well
as diffuse scales and crusts (Figure 1A, close-up view). An
interesting fact in her social history was that she owned 5 cats
and 1 dog; some of them presented hairless lesions. On the
basis of the clinical picture and of the patient's social and medical history, the first hypothesis of a worsening of scalp
lesions of DM was excluded, and a fungal infection was suspected. Wood's light examination of the scalp produced a
bright, yellow-green fluorescence of the hair. Microscopic
examination showing an ectothrix infection of the hair shaft
and cultures positivity for Microsporum canis confirmed the
diagnosis of TC. For the photosensitising characteristic of
griseofulvin, an 8-weeks treatment with daily itraconazole
100 mg per os and topical econazole 2% lotion was started.
After 4 weeks we observed a remarkable reduction of erythema and scaling, whereas for the regrowth of hairs 3 months
(Figure 1B) were needed. A moderate hair loss, as a consequence of DM, was, however, persistent.
TC is uncommon in adults and usually accounts for less
than 3% of all TC cases.1 In Italy, during the last century, a
progressive change of the dermatophitic flora causing TC
has been found, with a gradual decrease of anthropophilic fungi and a rapid increase of zoophilic fungi.2 In our case, TC
resulted as inoculation from animals.
As an infection in adults is rare, TC is often not considered
in the case of adults with hair loss. Other different diseases
are erroneously diagnosed: discoid lupus erythematosus,
Brocq pseudo-area, folliculitis decalvans, viral infections,
impetigo, lichen planus pilaris, bacterial folliculitis, pustular psoriasis and DM;3 in particular, in our case, the alopecia was diagnosed as a worsening of scalp lesions of DM.
Microscopic direct exams and fungal cultures represent gold
standard methods for a correct diagnosis.4
The authors have no conflict of interest to disclose.
This case has been presented at the 77th National Congress of the
Società Italiana di Dermatologia e Venereologia (SIDEV). 2002, May 1518, Palermo, Italy.
Figure 1.—Clinical
appearance of tinea
capitis before and
after therapy. (A)
Heliotrope rash on the
face; areas of patchy
alopecia with sharp
margins, severe and
diffuse fine grey-white
scales and crusts on the scalp (close-up view). (B) Complete remission of tinea capitis, with the persistence of moderate
hair loss, due to DM.
Vol. 141 - N. 2
173
acnes.1, 2 The beneficial effect of the zinc component in the
treatment of acne has been related to several mechanisms
including; anti-inflammatory effects, antibacterial effects
(antipropionibacterial) and modulation of epithelial differentiation.2-4
The Leeds revised grading system is a simple useful, rapid
means of assessing and follow-up acne patients, this grading system is based on a 12 colour photographs of facial acne
which are ranked in order of severity. The criteria for severity included extent of inflammation, range and size of inflamed lesions and associated erythema.5
This 12 weeks study was performed to evaluate the efficacy and safety of topical gel containing clindamycin phosphate and zinc acetate (Zindaclin® 1% gel, Straken Ltd.
UK) in the treatment of mild to moderate acne.
Sixty-seven patients with mild to moderate acne vulgaris
according to the Leeds revised grading system, were recruited to this open, noncomparative clinical study. To be included, patient were at least 12 years of age and had to have a
least 15 inflammatory lesions and 10 noninflammatory
lesions without nodules, cysts or deep scars.
No patient had been treated by oral antibiotic before and
topical treatment was stopped within 4 weeks of study entry.
The use of antibiotics or any antiacne agents during the
study was not allowed. Patients were supplied a nonmedicated
soap and were instructed to apply a thin film of the medication once daily before bed time to the entire face after
washing.
Facial lesions (inflammatory; papules and pustules and
noninflammatory, open and closed comedones) were counted at the baseline and after 6 and 12 weeks. At each visit
patients response to treatment was assessed as compared
with baseline using the Leeds revised grading system.
Patients were assessed as excellent response if achieved 75100% of improvement based on the Leeds score before and
after treatment, partial response 50-74%, improvement and
insufficient results in cases of less than 50% improvement.
At each visit, signs and symptoms such as dryness, erythema, peeling, oiliness, itching and burning were evaluated
using a score of 0-3 (0 none, 1 mild, 2 moderate, 3 severe).
The study was approved by the local ethics committee.
The data of 64 patients, 25 male and 39 female, aged 12
to 23, were included in the analyses. Three patients were
excluded from the analyses, 1 patient due to marked facial
irritation and 2 for treatment-unrelated protocol violations.
During the follow-up visits decreased of both inflammatory (papules and pustules) and noninflammatory (open and
closed comedones) lesions was note. Total reduction in both
inflammatory and noninflammatory lesions was noted at
weeks 6 and 12 visits.
At the end of treatment improvement was found in 69%
of patients; 55% of patients showed marked improvement
and in 14% partial improvement was reported. Insufficient
response to treatment was present in 31% of patients. The
treatment was well tolerated.
Side effects were mild and transient and included dry
skin in 17% and mild, transient erythema and itch in 5% of
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DM, together with the therapeutic immunosuppression,
may have impaired the immune defence mechanisms, making our adult patient into a susceptible target and contributing to the development of this unusual and severe dermatophytosis.
Currently, many experts consider griseofulvin to be the
drug of choice for TC, and it is also the only drug Food and
Drug Administration approved for this indication. Griseofulvin is a photosensitising drug, and can make worse the characteristic photosensitivity of DM. The rapid and excellent
results of itraconazole in our patient support the view that this
drug could be a useful alternative to griseofulvin for TC, in particular when associated to photosensitising diseases.5
References
1. Pursley TV, Raimer SS. Tinea capitis in elderly. Int J Dermatol
1980;19:220.
2. Cervetti O, Forte M, Paggio A. Tinea capitis dell'adulto. Descrizione
di tre casi. G Ital Dermatol Venereol 1990;125:27-8.
3. Martin ES, Elewski BE. Tinea capitis in adult women masquerating
as bacterial pyoderma. J Am Acad Dermatol 2003;49(2 Suppl Case
Reports):s177-9.
4. Frieden IJ, Howard R. Tinea capitis: epidemiology, diagnosis, treatment and control. J Am Acad Dermatol 1994;31 (3 Pt 2):s42-6.
5. Chan YC, Frielander SF. New treatments for tinea capitis. Curr Opin
Infect Dis 2004;17:97-103.
Address reprint requests to: V. Brazzelli, Dipartimento di Dermatologia,
IRCCS Policlinico S. Matteo, Piazzale Golgi 2, 27100 Pavia, Italy.
The efficacy and safety of topical gel
containing clindamycin phosphate
and zinc acetate
in the treatment of acne vulgaris
J. SHIRI 1, A. INGBER 2, F. FELDMAN 1,
E. ZFONI 3, A. COHEN 1, T. ZITOV 1, B. AMICHAI 1
1Department of Dermatology,
Clalit Health Services, Tel Aviv, Israel
Hadassah Medical Center, Jerusalem, Israel
Macabi Health Services, Jerusalem, Israel
Dear Editor,
T
opical antibiotics are very effective for the treatment of
mild to moderate acne. Either erythromycin or clindamycin are known to be effective against Propionibacterium
174
Aprile 2006
References
1. Leyden JJ, Shalita AR, Saatjian GD, Sefton J. Erthromycin 2% gel in
comparison with clindamycin phosphate 1% solution in acne vulgaris. J Am Acad Dermatol 1987;16:822-7.
2. Bojar RA, Eady EA, Jones CE, Cunliffe WJ, Holland KT. Inhibition
of erythromycin-resistant propionibacteria on the skin of acne patients
by topical erythromycin with or without zinc. Br J Dermatol
1994;130:329-36.
3. Holland KT, Bojar RA, Cunliffe WJ, Cunliffe AG, Eady EA, Farooq
F et al. The effect of zinc and erythromycin on the growth of erythromycin-resistant and erythromycin-sensitive isolates of Propionibacterium acnes: an in vitro study. Br J Dermatol 1992;126:505-9.
4. Pierard-Franchimont C, Goffin V, Visser JN, Jacoby H, Pierard GE.
A double-blind controlled evaluation of the sebosuppressive activity
of topical erythromycin-zinc complex. Eur J Clin Pharmacol
1995;49:57-60.
5. O’Brien SC, Lewis JB, Cunliffe WJ. The Leeds revised acne grading
system. J Dermatol Treat 1998;8:215-20.
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patients. One patient suffered from marked facial irritation
and left the study.
Zindaclin® 1% gel containing 1.2% clindamycin phosphate and 0.5% zinc acetate in a new topical product for the
treatment of acne vulgaris.
The beneficial effect of Zindaclin® 1% gel in the treatment
of acne may be related to the synergistic effect of clindamycin phosphate and zinc acetate and due to the ResiDerm® technology.
Zindaclin® formulation is based on the ResiDerm® technology which is a drug delivery technology in which topically active agents are complexed with zinc ions to improve dermal penetration and reduce transdermal penetration of
the drug into the systemic circulation.
After 3 months of treatment improvement was found in
69% (55% showed marked improvement) of patients, using
Zindaclin® 1% gel once daily.
The drug was well tolerated and side effects were mild and
transient.
Vol. 141 - N. 2
Address reprint requests to: Dr. B. Amichai, 78 Bialik St. Holon Israel.
175

minerva medica

Transcription

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