Professional Documents
Culture Documents
Guidelines in dermoscopy
A. W. KOPF
Koebner EBS, blistering is generalized with relative gene encoding the subunits of laminin 5 (LAMA3,
sparing of palms and soles. The most severe form is LAMB3, and LAMC2). The Herlitz type is one of the
EBS-Dowling Meara, with generalized blistering pre- most serious types of EB. Patients present with wide-
sent at or shortly after birth, progressive palmoplantar spread blistering at birth. A characteristic feature is
keratoderma, and mucous membrane involvement. exuberant granulation tissue on the face, especially
Blisters often are grouped, resulting in “herpetiform” around the mouth. Enamel hypoplasisa is common,
arrangement. A distinctive feature on electron leading to caries and loss of teeth. Laryngeal involve-
microscopy is clumping of tonofilaments. The mot- ment is a rare but serious complication, and patients
tled pigmentation subtype features hypopigmented who develop stridor will require immediate ENT con-
reticulated macules, and corresponds with an increased sultation to evaluate the airway, and tracheotomy is
number of melanosomes within basal keratinocytes, sometimes required.2 Because of the widespread blis-
dermal macrohages, and Scwann cells.3 It is a very tering, death in the first few years of life is common,
rare type, and was not observed in the data presented often due to combination of factors such as sepsis,
by Tadini et al. This raises the possibility that there severe anemia, and malnutrition. In the non-Herlitz
may be regional variations in its prevalence, although type, patients exhibit a milder phenotype, but gener-
it may simply reflect the extremely uncommon preva- alized blistering is also present at birth, and enamel
lence of this subtype. hypoplasia is also common.1
Tadini et al. reported 1 case of EBS with muscular It is interesting to note that Shabbir syndrome, also
dystrophy, another rare subtype. These patients present known as layrngo-onycho-cutaneous syndrome, is a
with blisters at birth, followed by late onset muscular recessively inherited disorder that features skin fragili-
dystrophy, and abnormalities of the nail and teeth, ty and exuberant granulation tissue around the eyes
sometimes associated with laryngeal webs and ure- and larynx. Investigators have recently uncovered
thral strictures. It is caused by mutations in the gene mutations in LAMA3,3 raising the possibility that this
encoding plectin (PLEC1), an intermediate filament disorder may in fact be related to Herlitz-JEB.
inter-acting protein. Plectin is present not only in the
hemidesmosome, but also in sarcolemma of the mus- Hemidesmosomal EB
cle, findings that may explain the association with
muscular dystrophy. Because of the close association Generalized atrophic benign EB (GABEB) is a form
of plectin with hemidesmosome, it has been proposed of EB originally classified as JEB. In addition to cuta-
that EBS with muscular dystrophy should be reclas- neous fragility, patients have nail dystrophy, scarring
sified into a new type, called hemidesdmosomal type.3 alopecia of the scalp, dental abnormalities, loss of eye-
In contrast to most forms of EBS, EBS with muscular lashes, and patchy hyperpigmentation of the skin. It is
dystrophy is inherited as an autosomal recessive dis- caused by mutations in the gene encoding the 180kDa
order. EBS-Ogna is another rare form of EB, previously BPAG, a transmembrane hemidesmosomal protein
classified as EBS, which has now been shown to be due that is also known as type XVII collagen. Because of
to a missense mutation in PLEC1,3 and which is now the close association of this protein with the
classified as another form of hemidesmosomal EB.3 hemidesmosome, this type of EB has been reclassi-
The plectin mutation has been demonstrated in the fied as a new type, the hemidesmosomal type,3 along
original kindred from the Norwegian village of Ogna, with the types formerly known as EBS-muscular dys-
and also in a German family with similar phenotype.3 trophy and the Ogna variant of EB, discussed previ-
These patients present with hemorrhagic blisters of ously in this review.
the skin, but do not have muscular dystrophy.3 EB with pyloric atresia (EB-PA) is another form of
The vast majority of EBS is transmitted as an auto- EB that was formerly classified as a form of junctional
somal dominant trait, but autosomal recessive muta- EB. It features blistering at birth, in association with
tions have been identified in KRT14 in 7 families.3 pyloric atresia. Often, there is a history of polyhy-
dramnios during the pregnancy, a clue that the newborn
may have some form of gastric outlet obstruction. If this
Junctional EB
is suspected, then an upright abdominal film should be
Junctional EB is transmitted invariably as an auto- done. If pyloric atresia is present, the X-ray will show
somal recessive trait, and is caused by mutations in the single bubble sign, reflecting a large bubble of
swallowed air that is trapped in the stomach. Immediate dystrophy, scarring, and mucosal involvement can also
surgical intervention is then necessary for survival. occur. Some patients present with distinctive white
With early surgical correction of the pyloric stenosis, papules, called albopapuloid lesions.
favourable outcome is possible. EB-PA is caused by
one of the genes encoding the subunit polypeptides
Clinical observations
of the alpha6-beta4 integrin (ITGA6 and ITGB4).
Because of the close association of this integrin with By studying large numbers of EB patients identi-
hemidesmosomes, EB-PA has also been reclassified as fied through a national registry, investigators have
a hemidesmosomal type of EB.3 made important observations about clinical aspects of
EB. These include extracutaneous involvements that
Dystrophic EB have remained poorly understood until recently, includ-
ing involvement of the kidney, eyes, and prevention of
Dystrophic EB (DEB) is caused by mutations in the
skin cancer in the dystrophic types.
gene encoding type VII collagen (COL7A1). Over
100 mutations in this gene have been described in var-
ious forms of dystrophic EB. Type VII collagen is the Ocular involvement
principal constituent of anchoring fibrils, which nor- With its stratified squamous epithelium like the skin,
mally ensure cohesion between the epidermis and der- the cornea is subject to erosions and ulcers in EB. In their
mis. As a result, separation occurs below the lamina study of 3 280 patients enrolled in the American EB
densa, and electron microscopy shows absence or Registry, Fine et al.4 reported an association between
reduced numbers of anchoring fibrils. ocular involvement and disease severity. They found
DEB can be inherited in both autosomal recessive that at least one episode of corneal erosions and blisters
and dominant forms. The recessively inherited Hallo- occurred in 74.1% of patients with RDEB-HS, and in
peau-Siemens form (RDEB-HS) is one of the most dev- 47.5% of patients with JEB-H. Symblepharons and
astating types of EB. Patients present with widespread ectropions were most often seen in the inverse type of
blistering at birth, and soon develop progressive fusion RDEB and JEB-H. Also, blindness resulting from cumu-
of the digits in childhood, resulting in considerable lative corneal scarring was seen in 6.46% of patients
functional disability. Because the esophagus is lined with RDEB-HS. All patients with EB who present with
with stratified squamous epithelium like the skin, patients painful tearing eyes should be assessed by an ophthal-
can also develop esophageal blisters that can lead to mologist to prevent cumulative corneal scarring.
scarring and stenosis. Dysphagia is then a major clini-
cal problem, leading to anemia and malnutrition. Some
Renal disease
patients may require esophageal dilation, but this may
damage the already fragile mucosa and may cause per- Individual case reports have suggested that renal
foration. Bypassing the stenosed portion of the esoph- failure may occur in some patients with EB. The caus-
agus with an isoperistaltic segment of the colon has es of the renal failure have included poststreptococcal
been performed, but this is a major operation. Favourable glomerulonephritis (presumably secondary to frequent
results have been observed with gastrostomy, allowing cutaneous infection), amyloidosis, and chronic mechan-
introduction of nutrients directly into the stomach.2 ical obstruction. Fine et al.5 analyzed data concern-
Patients with the non-Hallopeau Siemens form of ing 3 280 EB patients enrolled with the American EB
RDEB (RDEB-nonHS) have a milder phenotype. They Registry, and found 9 patients who were reported to
still present with generalized blistering at birth, and have died of renal failure. Among these 9 patients,
may also develop partial fusion of the digits. An unusu- clinical and laboratory data permitted classification
al variant is the inverse type, in which blisters devel- in 7 patients. Five of these patients had RDEB-HS,
op mainly at inverse sites such as the axilla and groin, one had RDEB-non HS, and one had JEB-non Herlitz.
and severe oral and esophageal involvement are com- They found that the cumulative risk for death from
mon.2 renal failure among patients with RDEB-HS was
The dominant type of dystrophic EB is also caused 12.3% by age 35 years, and recommended surveil-
by mutations in the gene encoding type VII collagen. lance for early kidney involvement should be part of the
Patients develop relatively minor blistering, but nail routine evaluation of adults with RDEB and JEB.
Squamous cell carcinoma fetal skin biopsy with electron microscopy and/or
immunohistochemistry. However, fetal skin biopsy
Squamous cell carcinoma remains a leading cause
can only be obtained rather late in the pregnancy, often
of death in patients with recessive dystrophic EB. They
after 17 weeks, and is associated with a relatively high
tend to arise in chronically eroded skin, and may pre-
rate of miscarriage. Also, this method requires exam-
sent as heaped up granulation tissue, or thick keratot-
ination of the biopsy specimen by an expert in ultra-
ic plaques. In contrast to squamous cell carcinomas
structure of fetal skin. With identification of the muta-
that arise from actinically damaged skin in patients
tions underlying all major forms of EB, investigators
without EB, these cancers are biologically aggressive,
have made impressive progress towards DNA-based
and metastasize widely. Approximately 85% of all
prenatal diagnosis.
patients with RDEB-HS will have developed at least
Pfendner et al.8 recently reviewed the experience
one cutaneous squamous cell carcinoma by age 45 of DNA-based prenatal diagnosis performed at the
years.6 Furthermore, most patients die of metastatic DeBRA Molecular Diagnostics Laboratory at Jeffer-
squamous cell carcinoma within 5 years of diagnosis son Medical College. Since 1993, investigators at that
of the first tumor.7 In patients with xeroderma pig- center performed 144 DNA-based prenatal diagnoses
mentosum and renal transplants, studies have shown in 121 families at risk for RDEB (63 pregnancies),
that chronic therapy with isotretinoin may prevent JEB (69 pregnancies), EB-PA (6 pregnancies), and
development of squamous cell carcinoma. In 2004, EBS (6 pregnancies). In most cases with DEB, and in
Fine et al.7 performed an open study of 20 patients all cases with JEB and EBS, the diagnosis was con-
with RDEB (5 had RDEB-HS, 15 had RDEB-nonHS) firmed by demonstration of specific mutations. Prenatal
who were aged 15 years or older. Each patient was testing was done on DNA isolated from chorionic vil-
given isotretinoin daily, starting at 0.1 mg/kg/day, and li or amniocytes obtained in the first or second trimester.
the dose was increased monthly by 0.1 mg/kg/day Their overall accuracy was greater than 98% (2 unex-
until either maintenance dose was achieved (0.5 plained discordant results out of 144 samples submit-
mg/kg/day), or the patient became intolerant of the ted), showing that DNA-based prenatal diagnosis is a
next higher dose. Treatment was continued for 8 very accurate and reliable method to assess pregnan-
months in 19 patients. One patient terminated treatment cies at risk.
after 3 months because of hypertriglyceridemia and
transient abdominal pain, consistent with drug-induced
acute pancreatitis, but all symptoms resolved within 3 Gene therapy
days. Other patients experienced side effects that were
mild, including skin dryness and fragility, epistaxis, and One of the most exciting advances in EB research is
pruritus. Interestingly, over half the patients reported the prospect of gene therapy. Research on this has
reduced blister formation while taking low-dosage focused on junctional and recessive dystrophic EB, 2
isotretinoin, but this effect was lost as each patient of the most serious forms.
approached the target maintenance dosage of 0.5
mg/kg/day. This finding may reflect in vitro data sug-
Junctional EB
gesting that isotretinoin may modulate collagenase
synthesis by RDEB fibroblasts.7 These data suggest that Important advances in gene therapy for EB have
isotretinoin is tolerated at the dosage studied in RDEB described in a recent review.9 In early work concern-
patients, and set the stage for this agent to be studied ing junctional EB, investigators have isolated ker-
as a possible chemopreventive agent against squa- atinocytes from a patient with severe Herlitz JEB, and
mous cell carcinoma in RDEB. showed a homozygous mutation of the LAMB3 gene.
These cells were unable to synthesize lamin-5, and
hence were not able to assemble hemidesmosomes.
Prenatal diagnosis Investigators used a retroviral construct expressing
human beta3 cDNA to successfully transduce the JEB
Because EB can be such a devastating disease, fam- keratinocytes, which were then able to synthesize and
ilies with pregnancies at risk often request prenatal secrete mature heteterotrimeric lamin-5.
diagnosis. In the past, this depended on examination of The use of viral vectors, however, is associated with
numerous logistical and biosafety concerns. Investi- gene, giving them the ability to synthesize and secrete
gators have therefore developed non-viral approaches type VII collagen.11 One can theoretically expand these
to JEB gene therapy. Using PhiC31 integrase, inves- cells into large sheets, and transplant them back onto
tigators have successfully integrated a laminin-5 beta3 the patient with RDEB. However, this procedure would
expression plasmid into the genome of primary ker- be technically difficult, and the fragile graft would
atinocytes from four unrelated patients with JEB.9 easily be lost.
Recently, investigators have used another nonviral In a recent report, Woodley et al.12 injected recom-
vector (“Sleeping Beauty” transposable element) to binant human type VII collagen into immunocmpe-
successfully integrate the LAMB3 cDNA into the tent SKH mice. The injected protein was incorporat-
genomes of epidermal holoclones from six unrelated ed onto the basement membrane zone and remained
JEB patients.10 These cells also regenerated human stable for at least 6 weeks. Sera from 10 mice were
JEB skin on SCID mice that was normalized at the evaluated for antibodies to type VII collagen, and these
level of laminin 5 protein expression, hemidesmo- antibodies were found in 6 of the 10 mice. However,
some formation, and blistering. none of the mice lost weight or showed any untoward
effects. Also, the antibodies did not prevent further
Recessive dystrophic EB incorporation of human type VII collagen in the base-
ment membrane zone when later injected into new
Woodley et al.11 have recently reviewed advances areas of the mouse’s skin.
in gene therapy for recessive dystrophic EB. Ker- In the same report, Woodley et al.12 studied RDEB
atinocytes from patients with inherited dystrophic skin tissues regenerated on immunodeficient mice.
EB cannot make type VII collagen, and show various These tissues retained the RDEB phenotype, with
abnormalities when compared with normal ker- histologic evidence of dermal-epidermal separation
atinocytes, For example, they are enlarged, elongat- and absence of human type VII collagen staining.
ed, and attach poorly to extracellular matrix. However, However, intradermal injection of recombinant type
when these cells are transduced with a lentiviral vec- VII collagen into the RDEB skin corrected the blis-
tor encoding human gene for type VII collagen, the tering and restored type VII collagen expression at
cells begin to permanently synthesize and secrete the basement membrane zone. These studies yielded
type VII collagen, and all the abnormal morpholog- important insights to the prospect of protein-based
ic features became normal. They showed normal mor- gene therapy.
phology, attached to extracellular matrix, and migrat-
ed in a normal fashion. Investigators have created
two animal models in which 3 kinds of skin equiva-
lents were transplanted onto mice. The first kind con- References
sisted of cells obtained from patients with severe 1. Fine J-D, Eady RAJ, Bauer EA, Briggaman RA, Bruckner-Tuder-
recessive dystrophic EB, the second consisted of the man L, Christiano A et al. Revised classification system for inherit-
same cells that had been “gene corrected” by stable ed epidermolysis bullosa: Report of the second International Con-
census Meeting on diagnosis and classification of epidermolysis bul-
integration of human type VII collagen and are able losa. J Am Acad Dermatol 2000;42:1051-66.
to synthesize and secrete type VII collagen, and the 2. Lin AN, Carter DM. Epidermolysis Bullosa: Basic and Clinical
third consisted of normal human keratinocytes and Aspects. New York:Springer-Verlag;1993.
3. Uitto J, Richard G. Progress in epidermolysis bullosa: genetic clas-
fibroblasts. The skin equivalents that were not gene sification and clinical implications. Am J Med Genet C Semin Med
corrected showed features of RDEB, with fragile epi- Genet 2004;131C:61-74.
dermal-dermal attachment, and virtually absence of 4. Fine J-D, Johnson LB, Weiner M, Stein A, Cash S, Deleoz J et al.
Eye involvement in inherited epidermolysis bullosa: experience of
anchoring fibrils. However, the skin equivalents made the National Epidermolysis Bullosa Registry. Am J Ophthalmol
with gene-corrected cells showed presence of anchor- 2004;138:254-62.
ing fibrils and type VII collagen at the epidermal der- 5. Fine J-D, Johnson LB, Weiner M, Stein A, Cash S, Deleoz J et al.
Inherited epidermolysis bullosa and the risk of death from renal dis-
mal interface.11 ease: experience of the National Epidermolysis Bullosa Registry. Am
These results suggest that it may be possible to per- J Kidney Dis 2004;44:651-60.
form ex vivo gene therapy, a process in which one 6. Fine J-D, Bauer EA, McGuire J, Moshell A Epidermolysis Bullosa:
clinical epidemiologic, and laboratory advances and the findings of the
takes skin biopsies from patients with RDEB, and then National Epidermolysis Bullosa Registry. Baltimore: Johns Hopkins
stably transfect the cells with the human COL7A1 University Press;1999.
7. Fine J-D, Johnson LB, Weiner M, Stein A, Suchindran C. Chemo- 10. Ortiz-Urda S, Lin Q, Yant SR, Keene D, Kay MA, Khavari PA. Sdus-
prevention of ssquamous cell carcinoma in recessive dystrophic epi- tainable correction of junctional epidermolysis bullosa via transposon-
dermolysis bullosa: results of a phase 1 trial of systemic isotretinoin. mediated nonviral gene transfer. Gene Ther 2003;10:1099-104.
J Am Acad Dermatol 2004;50:563-71. 11. Woodley DT, Chen M. Epidermolysis bullosa: then and now. J Am
8. Pfendner EG, Nakano A, Pulkinen L, Christiano A, Uitto J. Prenatal Acad Dermatol 2004;51:S55-7.
diagnosis for epidermolysis bullosa: a study of 144 consecutive preg- 12. Woodley DT, Keene DR, Atha T, Huang Y, Lipman K, Li W et al.
nancies at risk. Prenat Diagn 2003;23:447-56. Injection of recombinant human type VII collagen restores collagen
9. Bauer JW, Laimer M. Gene therapy of epidermolysis bullosa. Expert function in dystrophic epidermolysis bullosa. Nat Med 2004;10:
Opin Bio Ther 2004;4:1435-43. 693-5.
Given the rarity of some minor EB subtypes even with- allowed us to be able to predict, at any given age of the
in a population as large as the United States, howev- patient, where he or she will likely have each of these
er, it must be stressed that these latter calculated rates, cutaneous findings.
similar to those reported in this issue of the Journal by Fifth, we have been able to determine the frequen-
Tadini et al., can be used only as rough estimates, cy with which different extracutaneous complications
since statistically these numbers are not as firm as occur, as stratified by individual EB subtype.7 This
those derived from the more common EB subtypes. includes quantitation of numerous complications with-
Second, our data have documented that most of the in each of the major organ systems or anatomic sites,
cutaneous features in EB, most notably scarring, mil- to include the external eye, oral cavity, gastrointestinal
ia, and nail dystrophy, can occur not only in dystrophic tract, genitourinary tract, lungs, heart, musculoskele-
EB but also in junctional and simplex patients. For tal system, and bloodstream. A recently published
example, approximately 30%, 11%, and 33% of all example is a summary of the frequency with which
EB simplex patients enrolled in the American registry different complications arise within the genitourinary
had scarring, milia, and nail dystrophy, respectively.4 tract in each of the major EB subtypes.8 It should be
As a practical correlate, this means that the clinician emphasized that the ability to perform detailed analy-
cannot reliably use cutaneous morphological features, ses, especially lifetable ones, is a reflection of the
either singly or in combinations, to accurately assist in power that can be derived from a rare disease registry
the diagnosis and classification of EB patients, in the which has large numbers of well characterized patients,
absence of concurrent laboratory testing. Indeed, we since accurate estimates of such frequencies are depen-
were unable to achieve sensitivities and specificities of dent on the robustness of the size of the study popu-
greater than 90% with any of these findings, singly or lation, its generalizability to an entire population of
in combinations of up to three findings, even for those affected patients, and the length of longitudinal follow-
findings which have previously been believed to be up which was performed. As one derivative of such
good surrogate markers of different EB subtypes. work, we now have quantitative data to demonstrate
Third, we were able to use our extensive database to that most subtypes of EB are prone to develop at least
develop representative diagrams depicting the rela- several of the extracutaneous complications which
tive frequency of cutaneous disease activity in each were previously believed to occur in only the most
of the major EB subtypes.5 These diagrams, for the severe forms of inherited EB.7
first time, clearly demonstrated that considerable over- Analogous to what we did with cutaneous findings,
lap exists among all forms of EB, as relates to both we have been able to use lifetable analyses to predict
sites and relative frequency of skin involvement, fur- the cumulative and conditional risk of an EB patient
ther raising concerns over the use of cutaneous findings developing any of these extracutaneous complications
as surrogate diagnostic markers for the purpose of over time, as stratified by EB type and subtype. This
subclassification. These newer observations will is important, since it provides useful clinical infor-
undoubtedly affect any further revisions of the classi- mation to the physician as to when these patients need
fication system for EB which we proposed in 1999 as to be screened most carefully for early signs of extra-
a result of early data generated on behalf of the Nation- cutaneous complications (i.e., early surveillance should
al EB Registry.6 have a beneficial impact on the success of medical or
Fourth, we have been able to determine the fre- surgical intervention). These types of data also pro-
quency with which specific cutaneous findings arise vide information on the natural history of EB, as per-
over time.4 As a result, we now know that some features tains to extracutaneous disease activity. Several years
commonly used to recognize junctional and dystrophic ago, for example, we reported on the cumulative risk
EB, to include scarring, nail dystrophy, and acral web- of EB subtypes developing esophageal strictures and
bing, may not be present during early infancy, the time upper airway obstruction.9 In the case of esophageal
during which confirmation of diagnosis is the most strictures, about 12% and 80% of all Hallopeau-
emotionally charged. In contrast, other features, such Siemens recessive dystrophic EB (RDEB-HS) patients
as exuberant granulation tissue, may disappear with could be predicted to develop this by ages 2 and 20,
increasing age, making them useful hints for diagno- respectively, as would 25% of all Herlitz JEB (JEB-H)
sis only when they are present. Application of lifetable patients develop tracheolaryngeal stenosis or obstruc-
analysis technique to our extensive dataset has also tion by age 3. Such data argue for meticulous surveil-
lance during infancy for both of these outcomes, since mas arising in patients with Dowling-Meara EB sim-
esophageal strictures will impair nutritional intake plex by mid-adulthood, when compared to observations
and growth if not corrected by dilatation, and upper air- within the overall American population at the same
way obstruction in the setting of JEB may be life- ages (JD Fine, unpublished data, 2005). These col-
threatening. More recently published examples of the lective findings suggest that tumor surveillance for
types of analyses possible from a rare disease registry malignant melanoma in EB patients is of importance
include estimates for the cumulative risk of EB patients only in RDEB-HS, and should be done during early
developing hand and foot deformities,10 and corneal childhood. In contrast, surveillance for SCCs and basal
blisters and scars.11 Not surprisingly, mitten deformi- cell carcinomas is not necessary until at least mid
ties were primarily seen in RDEB-HS, occurring as young adulthood, but must become an integral part of
early as the first year of life, and were present in vir- patient care thereafter, given the risk of mortality from
tually all patients by age 25. In regard to corneal injury, SCCs in the setting of RDEB.
blisters occurred more frequently and earlier than scar- Data collected on behalf of the American EB Reg-
ring, and arose primarily in patients with RDEB-HS istry has also permitted determination within each
and JEB-H.
major EB subtype of the risk of death from a variety
Sixth, and possibly the most important consequence
of causes other than cancer, to include failure-to-thrive
of our database, has been our ability to rigorously
and sepsis (each a risk primarily in infants with junc-
address the issue of skin derived cancers in inherited
tional EB), other infections (pneumonia; other), and
EB. We made this a major goal of this project from the
renal failure.13 For example, we now know that the
onset, since many older case reports and small case
series had suggested that tumors might be prevalent in cumulative risk of death from renal failure in RDEB-
at least some of the EB subtypes. As a result of 16 HS patients is approximately 12%,14 and that such
years of systematic data collection by the American reg- renal disease usually occurs by young to mid adult-
istry, we now know the following about squamous cell hood.
carcinomas (SCCs) and EB.12 First, SCCs are most The collection of such a large patient cohort has
commonly seen in RDEB-HS, but also occur in other also allowed us the opportunity to study several other
forms of RDEB, as well as in junctional EB. In contrast, issues pertinent to inherited EB. For example, we have
there is no increased cumulative risk over lifetime of used a randomly selected subset of our patients to try
SCCs developing in EB simplex or DDEB, when com- to address issues such as: a) the annual cost of care,
pared to the non-EB population, despite suggestions to stratified by age and EB subtype; b) the relative avail-
the contrary in some older publications which were ability of insurance reimbursement for hospitalized
based on case reports. Second, the onset of SCCs is and outpatient services, medications, wound healing
usually first seen within the latter half of the 2nd decade products, and nutritional supplements; c) the psycho-
of life, and by age 40 nearly 80% of all RDEB-HS logical impact of this disease on affected children,
patients will have developed at least one SCC (JD adults, parents and their family units;15 and d) the
Fine, unpublished data , 2005). Third, we now know impact of this disease on basic function (activities of
that multiple primary SCCs are the rule, and that they daily living) and pain.16
usually arise on extremities within areas of chronic Registries also provide the opportunity for the har-
scarring or nonhealing erosions. Fourth, using lifetable vesting and banking of DNA, cells, and blood and tis-
analyses we have demonstrated that about 80% of all sue specimens from a large number of well charac-
of our RDEB-HS patients die of metastatic SCC with- terized patients. These samples can be then used by
in five years of the diagnosis of their first tumors, investigators worldwide as new opportunities arise for
despite having undergone aggressive and presumably basic research. Over the past 10 years, for example, our
successful surgical excision of the primary tumor. patient population has served as a major source for
Fifth, there is no increased risk of EB patients devel- tissues from which many of the molecular defects in
oping internal cancers. Sixth, we have found that there EB have subsequently been detected.
is a small but significant increased cumulative risk Finally, rare disease registries can serve as a major
(about 2%) of malignant melanoma arising by as ear- resource from which patients can be recruited for clin-
ly as age 12 in patients with RDEB-HS, and a higher ical trials. This is invaluable, since it will be other-
than expected cumulative risk of basal cell carcino- wise impossible for any investigator working in one
geographical area to successfully recruit a sufficient very few of these patients survived early infancy,
number of well characterized patients to be able to undoubtedly a reflection of gross differences in the
rigorously test the efficacy of a clinical intervention and availability and quality of care afforded to EB patients
have any hope of achieving statistically interpretable in less industrialized parts of the world.
conclusions. Recently, for example, we used our cohort Fourth, the Italian EB Registry will provide a sub-
to ascertain the clinical efficacy of tetracycline in EB stantial patient population from which patients can be
simplex 17 and to determine whether systemic recruited to participate in basic research or in clinical
isotretinoin might be safe enough to be used as a pos- trials. Given the many regulatory constraints on clin-
sible chemopreventive agent against SCCs in patients ical trials currently imposed by the Food and Drug
with RDEB.17, 18 Administration within the United States, the avail-
How, then, can the Italian EB Registry be used most ability of patients within the Italian EB Registry might
effectively, and what questions can be answered as a provide the opportunity to test some hypotheses more
result of its well defined and growing patient cohort? rapidly in Europe than can be presently done in North
First, it will certainly be very important for the Registry America.
to attempt to collect data on selected extracutaneous The development of a rigorous EB registry in Europe
complications and outcomes of interest, so that their is long overdue. It is therefore wonderful to see that a
findings can be compared with the published experi- vibrant one is now in place in Italy under the direction
ence of its American registry counterpart. This will of Professor Tadini. This registry will serve as a major
allow us to determine whether there are ethnic or reference source for future clinical trials in Europe
immunogenetic differences within these 2 geograph- that require participation of more than only a few
ically distinct populations that might result in signif- patients with EB. From my perspective as head of the
icant differences being observed in the risk for devel- American EB Registry, I look forward to many fruit-
opment of one or more complications across these 2 ful collaborations in the future with my dermatology
different populations. Were such differences noted, counterparts in Italy.
then this would suggest the need to employ different
surveillance strategies in Italy, compared with those
References
proposed by us for implementation within the United
States. 1. Fine JD, Johnson LB and Suchindran CM. The National Epidermol-
Second, the Italian registry can rigorously test ysis Bullosa Registry. J Invest Dermatol 1994;102:54S-56S.
2. Fine JD, Johnson LB, Suchindran C, Moshell A, Gedde-Dahl T. The
whether differences in methods of treatment in Europe epidemiology of inherited EB: findings within American, Canadian,
and the United States significantly impact differen- and European study populations. In: Fine JD, Bauer EA, McGuire J,
Moshell A, editors. Epidermolysis bullosa: clinical, epidemiologic, and
tially on patient morbidity or mortality. As a corre- laboratory advances, and the findings of the National Epidermolysis
late, it is possible that differences in surveillance or Bullosa Registry. Baltimore: Johns Hopkins University Press; 1999.
approach to evaluation and care by physicians in dif- p.101-13.
3. Fine JD, Johnson LB, Suchindran C, Carter DM, Moshell A. The
ferent countries may result in differences in the rela- National Epidermolysis Bullosa Registry: organization, goals, method-
tive severity of some extracutaneous complications ologic approaches, basic demography, and accomplishments. In: Fine
seen within these geographically distinct EB popula- JD, Bauer EA, McGuire J, Moshell A, editors. Epidermolysis bul-
losa: clinical, epidemiologic, and laboratory advances, and the find-
tions. ings of the National Epidermolysis Bullosa Registry. Baltimore: Johns
Third, comparisons may also suggest that inherent Hopkins University Press; 1999.p.79-100.
4. Fine JD, Johnson LB, Suchindran C, Bauer EA, Carter DM, McGuire
differences in the overall nature of the health care sys- J et al. Cutaneous and skin-associated musculoskeletal manifesta-
tems (sources of funding of medical care; relative tions of inherited EB: the National Epidermolysis Bullosa Registry
access to specialists; other) in these 2 countries might experience. In: Fine JD, Bauer EA, McGuire J, Moshell A, editors. Epi-
dermolysis bullosa: clinical, epidemiologic, and laboratory advances,
similarly contribute to differences in clinical outcomes. and the findings of the National Epidermolysis Bullosa Registry. Bal-
Although the latter is less likely to be the case in 2 timore: Johns Hopkins University Press; 1999.p.114-46.
highly industrialized countries, this is clearly a major 5. Devries DT, Johnson LB, Weiner M, Fine J-D. Relative extent of skin
involvement in inherited epidermolysis bullosa (EB): composite
issue elsewhere in the world. For example, when we regional anatomic diagrams based on the findings of the National EB
attempted to recruit young adult RDEB-HS patients in Registry, 1986-2002. J Am Acad Dermatol 2004;50:572-81.
6. Fine J-D, Eady RAJ, Bauer EA, Briggaman RA, Bruckner-Tuder-
South America to participate in an internationally man L, Christiano A et al. Revised classification system for inherit-
based clinical trial, we were surprised to learn that ed epidermolysis bullosa: report of the Second International Con-
sensus Meeting on diagnosis and classification of epidermolysis bul- of the National Epidermolysis Bullosa Registry study population. In:
losa. J Am Acad Dermatol 2000;42:1051-66. Fine JD, Bauer EA, McGuire J, Moshell A, editors. Epidermolysis bul-
7. Fine JD, Johnson LB, Suchindran C, Bauer EA, Carter DM, McGuire losa: clinical, epidemiologic, and laboratory advances, and the find-
J et al. Extracutaneous features of inherited EB: the National Epi- ings of the National Epidermolysis Bullosa Registry. Baltimore: Johns
dermolysis Bullosa Registry experience. In: Fine JD, Bauer EA, Hopkins University Press; 1999.p.175-92.
McGuire J, Moshell A, editors. Epidermolysis bullosa: clinical, epi- 13. Fine JD, Johnson LB, Suchindran C, Bauer EA, Carter DM, McGuire
demiologic, and laboratory advances, and the findings of the Nation- J et al. Premature death and inherited epidermolysis bullosa: contin-
al Epidermolysis Bullosa Registry. Baltimore: Johns Hopkins Uni-
gency table and lifetable analyses of the National Epidermolysis Bul-
versity Press; 1999.p.147-74.
8. Fine J-D, Johnson LB, Weiner M, Stein A, Cash S, DeLeoz J, et al. losa Registry study population. In: Fine JD, Bauer EA, McGuire J,
Genitourinary complications of inherited epidermolysis bullosa (EB): Moshell A, editors. Epidermolysis bullosa: clinical, epidemiologic, and
experience of the National EB Registry and review of the literature. laboratory advances, and the findings of the National Epidermolysis
J Urol 2004;172:2040-44. Bullosa Registry. Baltimore: Johns Hopkins University Press; 1999.
9. Fine JD, Johnson LB, Moshell A, Suchindran C. The risk of selected p.206-24.
major extracutaneous outcomes in inherited epidermolysis bullosa: 14. Fine J-D, Johnson LB, Weiner M, Stein A, Cash S, DeLeoz J et al.
lifetable analyses of the National Epidermolysis Bullosa Registry Inherited epidermolysis bullosa (EB) and the risk of death from renal
study population. In: Fine JD, Bauer EA, McGuire J, Moshell A, edi- disease: experience of the National EB Registry. Am J Kidney Dis
tors. Epidermolysis bullosa: clinical, epidemiologic, and laboratory 2004;44:651-60.
advances, and the findings of the National Epidermolysis Bullosa 15. Fine J-D, Johnson LB, Weiner M, Suchindran C. Impact of inherited
Registry. Baltimore: Johns Hopkins University Press; 1999.p.193- epidermolysis bullosa on parental interpersonal relationships, mari-
205. tal status, and family size. Br J Dermatol 2005;152:1009-14.
10. Fine J-D, Johnson LB, Weiner M, Stein A, Cash S, DeLeoz J, et al. 16. Fine J-D, Johnson LB, Weiner M, Suchindran C. Assessment of mobil-
Pseudosyndactyly and musculoskeletal deformities in inherited epi-
ity, activities and pain in different subtypes of epidermolysis bullosa.
dermolysis bullosa (EB): experience of the National EB Registry,
1986-2002. J Hand Surg (British and European Volume) 2005;30B: Clin Exp Dermatol 2004;29:122-27.
14-22. 17. Weiner M, Stein A, Cash S, DeLeoz J, Fine J-D. Tetracycline and
11. Fine J-D, Johnson LB, Weiner M, Stein A, Cash S, DeLeoz J, et al. Eye epidermolysis bullosa simplex: a double-blind, placebo-controlled,
involvement in inherited epidermolysis bullosa (EB): experience of the crossover randomized clinical trial. Br J Dermatol 2004;150:613-14.
National EB Registry. Am J Ophthalmol 2004;138:254-62. 18. Fine JD, Weiner M, Stein A, Suchindran C, Johnson LB. Systemic
12. Fine JD, Johnson LB, Suchindran C, Bauer EA, Carter DM, McGuire isotretinoin and recessive dystrophic epiderolysis bullosa (RDEB):
J et al. Cancer and inherited epidermolysis bullosa: lifetable analyses results of a Phase 1 clinical trial. J Invest Dermatol 2001;117:543.
melanoma. Disorders such as oculocutaneous albinism, melanoma in an Italian population. A case-control study. Melanoma
Res 2004;14:151-7.
xeroderma pigmentosum and congenital neurocuta- 8. Lefkowitz A, Schwartz RA, Janniger CK. Melanoma precursors in chil-
neous melanosis can serve as important model dis- dren. Cutis 1999;63:321-4.
eases.11-17 Perhaps someday there will be effective 9. Kaszuba A, Schwartz RA, Trznadel-Budzko E, Dobrska-Drobnik G,
Seneczko M. Malignant melanoma. Part I - Epidemiology and
gene therapy, or at least viable options for mending etiopathogenesis. Nowa Klinika 2001;8:769-73.
human genes.18 10. Kaszuba A, Seneczko F, Schwartz RA, Trznadel-Budzko E, Kaszuba
A. Malignant melanoma. Part II - Clinical types, diagnostics and con-
temporary methods of treatment. Nowa Klinika 2001;8:773-9.
References 11. Spicer MS, Stampien TM, Lambert WC, Schwartz RA, Harmon C,
Fitzgerald-Bocarsly P. Severe xeroderma pigmentosum associated
1. Rubegni P, Sbano P, Cevenini G, Risulo M, Stanghellini E, Barbini P with numerous melanomas, no other skin tumors, high natural killer
et al. Methological procedure for evaluation of risk factors for cuta- cell activity, normal interferon production, and a benign course. J
neous malignant melanoma in a representative sample of the Tuscan Cutan Pathol 1997;24:126.
population. G Ital Dermatol Venereol (in press). 12. Leibowitz E, Janniger CK, Schwartz RA, Lambert WC. Xeroderma
2. Dabkowski J, Omulecki A, Zalewska A. Identification of melanoma pigmentosum. Cutis 1997;60:79-84.
risk factors in the Polish population. Dermatol Surg 1997;23:1039-42. 13. Papadopoulos AJ, Schwartz RA, Sarasin A, Lambert WC. Xeroder-
3. Azfar RS, Schwartz RA, Berwick M. Primary melanoma prevention ma pigmentosum variant in a Greek patient. Int J Dermatol
in children. G Ital Dermatol Venereol 2004;139:267-72. 2001;40:442-5.
4. Desmond RA, Soong SJ. Epidemiology of malignant melanoma. Surg 14. Cruz MA, Cho ES, Schwartz RA, Janniger CK. Congenital neurocu-
Clin North Am 2003;83:1-29. taneous melanosis. Cutis 1997;60:178-81.
5. Rokuhara S, Saida T, Oguchi M, Matsumoto K, Murase S, Oguchi S. 15. Okulicz JF, Shah RS, Schwartz RA, Janniger CK. Oculocutaneous
Number of acquired melanocytic nevi in patients with melanoma and albinism. J Eur Acad Dermatol Venereol 2003;17:251-6.
control subjects in Japan: nevus count is a significant risk factor for 16. Centurión SA, Schwartz RA. Oculocutaneous albinism type 2. Acta
nonacral melanoma but not for acral melanoma. J Am Acad Derma- Dermatovenerol Alp Panonica Adriat 2003;12:32-6.
tol 2004;50:695-700. 17. Kraemer KH, Lee MM, Andrews AD, Lambert WC. The role of sun-
6. Youl P, Aitken J, Hayward N, Hogg D, Liu L, Lassam N et al. light and DNA repair in melanoma and nonmelanoma skin cancer. The
Melanoma in adolescents: a case-control study of risk factors in xeroderma pigmentosum paradigm. Arch Dermatol 1994;130:
Queensland, Australia. Int J Cancer 2002;98:92-8. 1018-21.
7. Fargnoli MC, Piccolo D, Altobelli E, Formicone F, Chimenti S, Peris 18. Cleaver JE. Mending human genes: a job for a lifetime. DNA Repair
K. Constitutional and environmental risk factors for cutaneous (Amst) 2005; 4:635-8.
ease, Kaposi sarcoma, port-wine stains, lichen scle- face and scalp. A non-coherent red light source emit-
rosus, scleroderma, Hailey-Hailey disease. ting at 630 nm was employed with light intensity 70-
The literature related to the use of topical ALA- 100 mW/cm2 and light dose of 37 J/cm2, with complete
PDT is extensive for the treatment of actinic keratoses, response rate of 90% in 6 months.
basal cell carcinoma and Bowen’s disease.2 Aminole- Photoexitation of the photosensitizer by light cor-
vulinic acid, a metabolite of the heme biosynthesis responding to its absorption spectrum is a basic require-
was the first agent to receive regulatory approval for the ment in PDT. The light used for PDT can be provided
treatment of AK in conjunction with blue light in der- by incoherent light sources or laser systems. Basic
matology, in 1999 (Levulan, DUSA Pharmaceuticals, considerations for the choice of a light source are the
Inc, Valhalla, NY). following: the emitted wavelength should match an
Several clinical studies report high response rates in absorption peak of the photosensitizer used and the
superficial basal cell carcinoma (BCC) ranging from fact that longer wavelengths penetrate deeper into tis-
79% to 100% and AK from 81% to 100%.2-4 For nodu- sues. The depth of tissue penetration depends on the
lar BCC the results are more disappointing, with report- wavelength, the absorption by endogenous chro-
ed response rates ranging from 10% to 42%. mophores and the absorption by the sensitizing drug
The challenge to the dermatologist remains to opti- (self-shielding), and is limited by optical scattering
mize outcomes following PDT therapy. The efficacy of within the tissue. It might even be of advantage to use
the treatment is dependant on many variables. Small a broad band light source, since photosensitizer’s pho-
modifications of the treatment procedure may have toproducts with other absorption peaks are formed
quite a significant impact on the outcome. Controlled during PDT. Protoporphyrin IX has its maximum
comparative studies or data that sufficiently allow to absorption in the Soret band and additional smaller
compare the different modalities are still missing. peaks in the green and red regions. However, with red
The success of treatment requires an optimal inter- light the interactions with chromophors of the skin
play among different parameters, such as type and (melanin, hemoglobin) are minimized, leading to a
drug dose, selection of light source, depth of light pen- sufficient penetration of light into skin.
etration into tissue and light dose, treatment sched- Regarding the light dose in PDT the fluence and
ules, criteria of tumour and patient selection. the intensity used are different for oncologic and non-
An efficient photodynamic agent should have sev- oncologic indications. For PDT the light source has to
eral properties: selective retention or uptake by the provide sufficient intensity of light, up to 40 mW/cm2
target tissue, high absorbance in the useful wavelength for non-oncologic indications and up to 150 mW/cm2
range for optimal tissue penetration, high quantum for oncologic indications. Basically, the fluence of the
yield of singlet oxygen, fast clearance from serum and light should be less than 150 J/cm2 and the intensity of
healthy tissue, short time interval between drug appli- the light source less than 200 mW/cm2 in order to
cation and its accumulation into lesion, high chemical avoid photothermal effects.
purity, low systemic toxicity and side effects, lack of The time interval between drug administration and
mutagenic potential. sufficient photosensitizer concentration determines
Aminolevulinic acid is the natural precursor of PpIX the optimal time point of light exposure and has been
which is formed endogenously via the biosynthetic estimated for various photosensitizers and route of
pathway of heme. Advantages of ALA-PDT are: local- administration. Irradiation should be performed when
ized and short-term photosensitivity and rapid photo- an optimal ratio of photosensitizer levels in tumor ver-
degradation by light illumination. The induction of a sus normal tissue is reached.
more lipophilic ester-group (ALA- methylester, Some authors emphasized tumour particularities
methyl-aminolevulinate) seems to enhance the selec- that might lead to decreased responsiveness. Thick
tivity and deeper penetration of the photosensitizer. nodular BCC and hypertrophic AK are rather resis-
Discomfort and the intensity of pain may be lower tant, although surgical debulking of nodules and curet-
during PDT with methyl-aminolevulinate than with tage of scales, or repetition of the treatment may
ALA. improve clearance rates. Morpheiform and pigmented
Rossi et al.5 in this issue describe a study of PDT BCC are almost always resistant to the treatment.
using topical methyl-aminolevulinate (Metvix, Pho- However, different photosensitizers and PDT regi-
toCure ASA, Oslo, Norway) to treat 170 AK of the mens may result in different cellular response patterns
even in the same type of tumour, while many specif- ciency) and the correlation of fluorescence spatial dis-
ic responses may be effected only in a narrow win- tribution with the area of the lesion assessed with visu-
dow of time, PDT dose, or both. It becomes clear that al light (photosensitizer localization efficiency).
there is a need to monitor parameters other than deliv- Serial, in vivo and real-time measurements of fluo-
ered light dose and irradiance and to correlate them rescence intensity are of particular advantage when
with ALA-PDT. an endogenous photosensitizer is used, which might be
Prediction of PDT efficacy could be made on the synthesized in various amounts over time in different
basis of indirect data from fluorescence time course tumors of the same type, depending of the metabolic
kinetics and the direct biologic tissue response such as activity of the target cell. Optimal destruction of skin
clinical erythema development after PDT. lesion is therefore achieved while the surrounding skin
The determination of the time course of photosen- is left intact.
sitizer’s fluorescence in skin lesion is crucial for effec- In vivo fluorescence kinetics evaluation over time
tive PDT in order to maximize PDT effectiveness. showed that AK and BCC developed maximum fluo-
Chromophores such as porphyrins have the ability to rescence emission intensity between 4 to 4.5 h after
absorb energy when excited by light of certain wave- application. Despite fluorescence intensity values until
length. The emission of light following absorption of 14 h the irradiation starting is chosen to be early 3.5 to
incident photons is termed “fluorescence”. Blue light 5 h when high localization efficiency was also noted,
is mainly applied for fluorescence detection, due to ensuring the selectivity of the procedure.6
its reparability from the red fluorescence of PpIX gen- Some authors, based on the principle that the inten-
erated. The penetration of blue light is only a few tenth sity of the emitted fluorescence is a function of the
of millimeter and the respective fluorescence is gen- amount of the sensitizer present, claimed that the flu-
erated only in the superficial part of the skin. This flu- orescence of skin lesions after ALA application using
orescence yields hardly any information from deeper a Wood’s lamp or laser-induced fluorescence provid-
structures inside the diseased tissue. The light intensity ed an estimate for prediction of PDT.7 However, no
used for fluorescence excitation is at least twenty-fold direct correlation was found between fluorescence
lower as compared to PDT. intensity and clinical response by other authors.8 On the
Since the PpIX accumulation after ALA-PDT is a other hand, the optimal time for PDT could be deduced
gradual process, fluorescence kinetics could be used to from the time-dependent concentration of PpIX, since
determine the ideal time point application to initiate the fluorescence kinetics is a temporal process. In order to
irradiation. Imaging spectroscopy using digital cam- maximize PDT effectiveness irradiation of the treat-
eras (CCD) can be used to study the time course kinet- ment area should occur at the time of sufficiently
ics and spatial distribution of fluorescence.6 The equip- increased concentration of the endogenous photosen-
ment needed for fluorescence imaging is a light source sitizer within the lesion and of optimal ratio of pho-
for excitation, a digital camera for detection, a sys- tosensitizer levels in tumour: normal tissue. Tope et al.9
tem of optical filters and the software for data pro- studied fluorescence kinetics in BCC after oral admin-
cessing. The fluorescence images are recorded in a istration of ALA and showed a full thickness PpIX
dark room. In our set-up the power density of the light accumulation in all BCC histological subtypes and
source is very low (approximately 0.5 mW/cm2) and maximal tumour: normal skin fluorescence ratios 1
the exposition time very short, in order to avoid pos- to 3 h after ALA ingestion.
sible photobleaching of the photosensitizer. Excita- Based on the cumulative evidence of selective ery-
tion is performed by light of 425±10 nm. For the study thema during ALA-PDT which might be closely cor-
of fluorescence kinetics, serial in vivo fluorescence related with the tissue photo-induced actions, we stud-
images are captured. For any image the medians of ied the in vivo skin color changes, as represented by
fluorescence intensity are calculated after correcting for erythema development by means of a remote machine
background autofluorescence and the sequential inte- vision system in correlation with the clinical and his-
grated fluorescence signals are then plotted versus tological responses of AK and BCC subjected to treat-
time. Two parameters are evaluated: the maximal flu- ment.3 A remarkable correlation of erythema devel-
orescence intensity, as compared with the zero time opment and effective tissue response to PDT was
baseline intensity (photosensitizer accumulation effi- found. The skin erythema imaging is a reliable notable
marker of the phototoxic effect and, thereafter, of the tion of tissue oxygen tension upon illumination during
PDT effectiveness. It is interesting that contrary to the PDT were reported through damage of the vascular
UVB-induced erythema, where higher doses provoke system and through O2 consumption in the oxidative
even stronger reaction, during ALA-PDT the pro- reactions taking place. The rates of singlet oxygen
gressive increase of energy leads the skin erythema generation and therefore tissue oxygen consump-
to a saturation level. This is probably owed to PpIX tion/depletion are high when both tissue photosensitizer
photobleaching due to self reaction with the released levels and the fluence rate of light are high. The fluence
singlet oxygen and free radicals, and this may explain rate must be adjusted downward to slow oxygen con-
why further increase of the light dose has no effect on sumption sufficiently to facilitate the maintenance of
both the tumour response and the erythema develop- tissue pO2 levels during treatment.
ment. The potential for PDT in the treatment of several
Laser Doppler measurements for assessing blood skin conditions is promising, but rigorous trials must
flow were used. By means of the Laser Doppler Per- be performed. Further studies are required to confirm
fusion Imager it is possible to record blood flow in the optimal treatment parameters and reliable predic-
the superficial and reticular dermis over a large surface tors of the therapeutic outcome.
and estimate a representative mean perfusion. Wang et
al. have investigated the perfusion in superficial BCC
and found an increased blood perfusion after topical References
PDT. 1. Stefanaki IM, Georgiou S, Themelis GC, Vazgiouraki EM, Tosca AD.
A full picture of the therapeutic effectiveness of In vivo fluorescence kinetics and photodynamic therapy in condylo-
mata acuminata. Br J Dermatol 2003;149:972-6.
ALA-PDT remains the histological evaluation. Alter- 2. Kalka K, Merk H, Mukhtar H. Photodymamic therapy in deramtology.
native methods allow for control of PDT efficacy. J Am Acad Dermatol 2000;42:389-413.
Techniques to measure photosensitizer concentration 3. Tosca AD, Balas CJ, Stefanidou MP, Katsantonis JC, Georgiou SK,
Tzardi MN. Photodynamic therapy of skin malignancies with aminole-
such as microdialysis and to evaluate light fluence vulinic acid. Emphasis on anatomical observations and in vivo erythema
within tissue, tumour tissue oxygen consumption and visual assessment. Dermatol Surg 1996;22:929-34.
radical generation are being developed to assist PDT 4. Morton CA, MacKie RM, Whitehurst C, Moore JV, McColl JH. Pho-
todynamic therapy for basal cell carcinoma – effect of tumour thick-
treatment. ness and duration of photosensitizer application and response. Arch
Microdialysis is a technique for investigation of Dermatol 1998;134:248-9.
5. Rossi R, Mavilia L, Ghersetich I, Lotti TM. Photodynamic therapy of
drug-penetration. A semipermeable dialysis catheter is actinic keratoses with methyl-aminolevulinate (Metvix). G Ital Der-
placed in the dermis and perfused by a solution. matol Venereol (in press)
Depending on the concentration gradient, molecules in 6. Stefanidou M, Tosca A, Themelis G, Vazgiouraki E, Balas K. in vivo
fluorescence kinetics and photodynamic therapy efficacy of δ-aminole-
the surrounding extracellular space which are at a vulinic acid-induced porphyrins in basal cell carcinomas and actinic
higher concentration diffuse into the dialysis fibre and keratoses; implications for optimization of photodynamic therapy.
the opposite takes place in the case of molecules of Eur J Dermatol 2000;10;351-6.
7. Svanberg K, Andersson T, Killander D, Wang I, Stenram U, Anderson-
lower concentration. Microdialysis samples before Engels S et al. Photodynamic theory of non-melanoma malignant
and after ALA application are analysed with an ion tumors of the skin using topical δ-aminolevulinic acid sensitization and
exchange high performance chromatograph.11 The light irradiation. Br J Dermatol 1994;130:743-51.
8. Fijan S, Hönigsmann H, Ortel B. Photodynamic therapy of epithelial
penetration of ALA in tumour area is rapid and after 15 skin tumours using delta-aminolevulinic acid and desferrioxamine. Br
minutes the concentration is high and stable. On the J Dermatol 1995;133:282-8.
other hand, virtually no ALA penetrates healthy skin. 9. Tope WD, Ross EV, Kollias N, Martin A, Gillies R, Anderson RR. Pro-
toporphyrin IX fluorescence induced in basal cell carcinoma by oral
The availability of oxygen within the tissue under- δ-aminolevulinic acid. Photochem Photobiol 1998;67:249-55.
going PDT treatment is an important parameter that can 10. Wennberg A, Larko O, Lonnroth P, Larson G, Krogstad A. Delta-
aminolevulinic acid in superficial basal cell carcinomas and normal
limit direct tumour kill. Since singlet oxygen arises skin –a microdialysis and perfusion study. Clin Exp Dermatol
from ground state oxygen, rapid and substantial reduc- 2000;25:317-22.
rologic symptoms or arthritis can occur in early or late cia, pseudopelade Brocq, morphoea and lichen scle-
in the course.2 Those could be neurologic (lymphocyt- rosus et atrophicus, cutaneous marginal zone B-cell
ic meningitis, cranial neuritis also with peripheral facial lymphoma, anetoderma, idiopatic atrophoderma Pasi-
nerve palsy, radiculoneuropathy, rarely encephalo- ni-Pierini, progressive facial hemiatrophy, are dis-
myelitis), cardiovascular (carditis), locomotor (arthri- cussed in the literature.4-7
tis, typically in one or both knees, myositis) and others The diagnosis of LB should be based on a presence
(hepatitis, conjunctivitis, incl. general signs and symp- of three factors together: opportunity for a tick exposure,
toms – malaise, headache, fatique etc.). Secondary EM a characteristic clinical manifestation (both local and
follows the primary EM after one week, EM lesions systemic) and a confirmation of B. burgdorferi infec-
are annular and smaller than the primary one. tion, with exception of pathognomic skin manifesta-
Third LB stage of late infection includes involvement tions, i.e. anular erythema migrans (but illness of longer
of the skin, joints, nerves, fatique could be a very than 30 days duration is required for IgG immunoblot
important symptom. Characteristic skin manifestation positivity) and papular BL on the ear lobe in a child.1
is ACA which appears late in the course of LB (months Direct proof of borrelial infection include: 1)
or years after infection). ACA is much less frequent histopathological detection of the microorganisms in
compared to EM, but its diagnostics could be very dif- the tissue by the light or the electron microscope, 2) iso-
ficult. It represents 10% of all cutaneous manifestations lation of B. burgdorferi (sensitivity of isolation of the
of LB. Initial oedema and diffuse dark erythema local- skin samples in non-treated patients is 50 %), 3) con-
ized predominantly on the protrudent parts of the limbs ventional, mainly nested polymerase chain reaction
changes into an atrophy of the skin and the adnexa. Dis- (PCR) or LighCycler real-time PCR or template DNA
tinct clinical types could be recognized in ACA patients hybridization using TaqMan fluorogenic probe. Those
– inflammatory ACA stage is mainly macular (ACA systems are capable to identify 1-10 cultivated
maculare) in 75% of ACA patients, or oedematous spirochaete. Isolation of borrelial DNA from clinical
(ACA oedematosa) in 13% of patients, atrophic stage samples is difficult as they contain abundance of host
of ACA is present in 12 % of our ACA patients and it DNA. Specificity of PCR is evaluated in the Southern
could be of various types: ACA teleangiectatica – blots using specific probes, restriction enzymes or
teleangiectasias predominate, ACA fibromatosa – sequencing of PCR products.8, 9
fibrous nodules above the bone prominences, typical- Indirect laboratory tests include: 1) indirect immuno-
ly localized above elbow joints, ulnar aspects of the fluorescence, 2) ELISA assay, using the whole-cell
forarms and above the interdigital and carpophalangeal sonificated antigen or recombinant borrelial antigens.
joints, and ACA atrophicans sensu stricto – atrophy of Serum specimen with a positive test result is further
the skin and underlying tissue. Histopahology of ACA tested with immunoblotting. However, immunoblotting
lesions varies on the duration of the skin lesions. At the still has many problems. True standardisation of an
beginning, band-like infiltrate of lymphocytes with immunoblotting method for diagnosis of LB would
plasma cells, histiocytes, oesinophils is seen in the require agreement on the strains used for antigen prepa-
upper dermis, later inflammation resolves and is promi- ration. This approach would not be possible in Europe
nent around vessels and adnexa, compact orthoker- due to different local prevalence of species and strains
atosis of the epidermis and epidermis atrophy follows, of Borrelia burgdorferi sensu lato and also hetero-
sometimes dilatation of vessels in the upper dermis genecity within those strains.10
(histopathological background of teleangiectasiae). LB is both underdiagnosed and overdiagnosed, and
After some years, atrophy of the dermis, incl. elastic we believe variability of symptoms is in close relation-
fibres and adnexa is present. In fibromatous ACA type, ship to different Borrelia serotypes. B. burgdorferi sen-
collagen bundles are concentrically composed. Half of su lato which has been subdivided into three
ACA patients suffer also from the joint and peripher- genospecies: B. burgdorferi sensu stricto, B. afzelii and
al nerve involvement.3 The infection heals sponta- B. garinii. Some studies show that B. afzelii represents
neously in some patients, in the others the disease con- a dominant human skin isolate in Europe, B. garinii is
tinues even after the proper treatment. mainly connected to neuroborreliosis and B. burgdore-
Besides those characteristic manifestations some fri sensu stricto appears to be the major pathogen in
authors hesitate, if other signs or symptoms also belong Lyme arthritis. The other Borreliae (e.g. B. valaisiana)
to the clinical picture of LB. Diffuse reversible alope- were not proved to cause the human disease. Further-
more, ACA is connected with B. afzelii OspA serotype not been shown to be effective and no vaccination
2, infection with B. garinii OspA serotype 4 correlates available in Europe until nowadays.
with neuroboreliosis, and B. burgdorferi sensu stricto
appears to play the major role in arthritis.11-13
There are still some unanswered questions con- References
cerning LB. We do not know, if co-infections with the
1. McGinley-Smith DE, Tsao SS. Dermatoses from ticks. J Am Acad Der-
other tick-born pathogens, especially Anaplasma matol 2003;49:363-92.
phagocytophilum are important, and if B. burgdorferi 2. Sood SK. Lyme disease. Pediatr Inf Dis J 1999;18:913-25.
could be terratogenic while the infection is present 3. Hercogová J, Brzonǒvá I. Lyme disease in central Europe. Curr Opin
Infect Dis 2001;14:133-7.
during pregnancy, how to treat and prevent the dis- 4. Hercogová J. Borrelia burgdorferi: a protagonist in Lyme disease, a
ease with its serious consequences. bystander in morphoea? J Eur Acad Dermat Ven 2002;16:98-9.
The agent of human granulocytic ehrlichiosis (HGE), 5. Roggero E, Zucca E, Mainetti C, Bertoni F, Valsangiacomo C, Pedri-
A. phagocytophilum, was identified in the USA in nis E et al. Eradication of Borrelia burgdorferi infection in primary mar-
ginal zone B-cell lymphoma of the skin. Hum Pathol 2000;31:263-8.
1994 and later in Europe. The vectors of HGE are 6. Trevisan G, Rees DHE, Stinco G. Borrelia burgdorferi and localized
nymphs and adults of I. ricinus tick.14, 15 Coinfection scleroderma. Clin Dermatol 1994; 12: 475-9.
may alter the clinical manifestation and response to 7. Weide B, Walz T, Garbe C. Is morphea caused by Borrelia burgdor-
feri? A review. Br J Dermatol 2000;142:636-44.
treatment of LB and therefore they should be consid- 8. Xu Y, Bruno JF, Luft BJ. Detection of genetic diversity in linear plas-
ered in differential diagnosis when evaluating persons mids 28-3 and 36 in Borrelia burgdorferi sensu stricto by subtrac-
who are at the risk for tick-borne diseases. Certain tive hybridization. Mikrob Pathol 2003;25:269-78.
9. Zore A, Ruzic-Sabljic E, Maraspin V, Cimperman J, Lotric-Furlan
clinical features (e.g. trombocytopenia or leukopenia) S, Pikelj A et al. Sensitivity of culture and polymerase chain reaction
which are not typical for LB should suggest these for the etiologic diagnosis of erythema migrans. Wien Klin Wochen-
coinfections. Transmission of the agents of LB and schr 2002;114:606-9.
10. Robertson J, Guy E, Andrews N, Wilske B, Anda P, Granstrom M et
HGE by individual ticks is equally efficient and inde- al. A European multicenter study of immunoblotting in serodiagno-
pendent. Most dually infected ticks are able to trans- sis of Lyme borreliosis. J Clin Microbiol 2000;38:2097-102.
mit both pathogens to a susceptible host.16 11. Manconi RT, Hohenberger S, Jauris-Heipke S. Genetic analysis of
Borrelia infections during pregnancy were consid- Borrelia garinii OspA serotype 4 strains associated with neuroborre-
liosis: evidence for extensive genetic homogeneity. J Clin Microbiol
ered dangerous, more recent studies have refused some 1999;37:3965-70.
of these fears. A causal association with Borrelia infec- 12. Ornstein K, Berglund J, Nilsson I, Norrby R, Bergstrom S. Charac-
tion was not proven in any infant born to 105 mothers terization of Lyme borreliosis isolates from patients with erythema
migrans and neuroborreliosis in southern Sweden. J Clin Microbiol
with EM during pregnancy, however, two abortions 2001;39:1294-8.
and six preterm babies, including one who had car- 13. Luneman JD, Krause A. Heterogenita von Borrelia burgdorferi:
diac abnormalities and two who died shortly after Atiopathogenetische Relevanz und Klinische Implikationen. Z
Rheumatol 2003;62:148-54.
delivery were observed.17 14. Hulínská D, Votýpka J, Plch J, Vlcek E, Valesova M, Bojar M et al.
Problematic effect of LB treatment is based on pos- Molecular and microscopical evidence of Ehrlichia spp. and Borrelia
sible chronic character of infection, non-sufficient burgdorferi sensu lato in patients, animals and ticks in the Czech
Republic. Microbiologica 2002;25:437-48.
knowledge on pharmacodynamic interactions of 15. Santino I, Del Piano M, Sessa R, Favia G, Iori A. Detection of four Bor-
antimicrobial agents with Borreliae, documented fail- relia burgdorferi genospecies and first report of human granulocytic
ure of therapy. Currently, beta-lactams, macrolides ehrlichiosis agent in Ixodes ricicnus ticks collected in central Italy. Epi-
demiol Infect 2002;129:893-97.
and tetracyclines are used. The duration of treatment 16. Levin ML, Fish D. Acquisition of coinfection and simultaneous trans-
(minimum 14 days) and the daily dose depends on the mission of Borrelia burgdorferi and Ehrlichia phagocytophila by
LB stage and the clinical manifestations. New antimi- Ixodes scapularis ticks. Infect Immun 2000;68:2183-6.
crobial agents (fluoroquinolones, ketolids) are under 17. Maraspin V, Cimperman J, Lotric-Furlan S, Pleterski-Rigler D, Str-
le F. Erythema migrans in pregnancy. Wien Klin Wochenschr
evaluation.18 Some studies show that a one dose pro- 1999;111:933-40.
phylaxis with doxycycline (200 mg) could decrease the 18. Hunfeld KP, Kraiczy P, Kekoukh E. Standardised in vitro susceptibililty
risk of LB transmission after a tick-bite.19 Recom- testing of Borrelia burgdorferi aganist well-known and newly devel-
oped antimicrobial agents. Possible implications for new therapeutic
mendations to prevent LB include avoiding exposure approaches to Lyme disease. Int J Med Microbiol 2002;291 Suppl
to tick bites by limiting outdoor activities in tick-infest- 33:125-37.
ed locations, using tick repellents, tucking in cloth- 19. Nadelman RB, Nowakowski J, Fish D, Falco RC, Freeman K, McKen-
na D et al. Prophylaxis with single-dose doxycycline for the preven-
ing and frequent skin inspection for early detection tion of Lyme disease after an Ixodes scapularis tick bite. N Engl J
and correct removal of ticks. Antibiotic prophylaxis has Med 2001;345:79-84.
35 months) and had an overall cure rate of 79% with a décolleté which have clinical signs of seriously sun
recurrence rate of 11% at 35 months and cosmetic out- damaged skin and recurrent AKs, BCCs, and spin-
come excellent or good in 98% of the completely ocellular carcinomas (SCC). These patients have, when
responding lesions.2 Another multicenter study inves- being treated with cryotherapy or surgery, often mul-
tigated MAL-PDT in patients with superficial and/or tiple scars and white spots from previous treatments.
nodular BCCs. Clinical remission rate 3 months after MAL-PDT is very well suited for treating such larger
treatment was 92% for superficial and 87% for nodular areas.
BCCs.3 Compiled data from several trials demonstrat-
ed complete clearance rate of 87% for superficial BCCs
and 71% for nodular BCCs.4 Overall one can conclude Organ transplanted and immunosuppressed
that MAL-PDT is an efficient therapy which can also be patients
repeated if recurrence occurs. In all studies a good to
excellent cosmetic result was reported. These patients demonstrates increased skin cancer
frequency. They should be regularly seen by derma-
tologists and their AKs, BCCs, and SCCs should be
Actinic keratosis treated at an early stage. This is especially important
for the SCCs to prevent metastases. We include all
MAL-PDT of actinic keratosis (AK) has been inves- transplanted patients with immunosuppressive treat-
tigated in several prospective studies and compared ment in a skin care program including surveillance of
with cryotherapy. Randomized multicenter prospective their skin and treatment of their non-melanoma skin
studies of MAL-PDT compared to cryotherapy have cancer lesions.
been performed in Europe and Australia. The com-
plete response rates with PDT in these studies were
69% and 91% as compared to 68% and 75% for Conclusions
cryotherapy. All studies demonstrated an excellent or
good cosmetic outcome of PDT in close to a 100% of PDT is rapidly evolving to become a routine thera-
the patients.5, 6 PDT is especially well suited for larg- py in dermatology. It is well documented through con-
er areas with many AKs, i.e. field cancerization areas. trolled studies and thus evidence based with efficacy
comparable to other commonly used standard treat-
ments. The British Photodermatology Group has
Bowen’s disease and incipient squamous cell already published guidelines for topical PDT.8 The
carcinoma advantages of PDT includes simultaneous treatment of
larger areas with multiple lesions; relatively short heal-
In the largest existing study of treatment of Bowen’s ing period and high patient preference because of the
disease MAL-PDT was compared with cryotherapy excellent cosmetic outcome. PDT can also be repeat-
and 5-fluorouracil (5-FU) in a controlled European ed in the same area if needed.
multicenter study (40 centers). A total of 225 patients
with 275 lesions were included in the study and MAL-
PDT induced a complete response in 93% of lesion References
compared to 86% with cryotherapy and 83% with 5- 1. Szeimies RM, Karrer S, Abels C, Landthaler M, Elmets CA. Photo-
FU. After 12 months the overall lesion cure rate was dynamic therapy in dermatology. In: Krutmann J, Hönigsmann H,
74% with MAL-PDT, 65% with cryotherapy and 62% Elmets CA, Bergstresser PR editors. Dermatological phototherapy
and photodiagnostic methods. Berlin: Springer, 2001. p. 209-47.
with 5-FU.7 2. Solèr AM, Warloe T, Berner A, Giercksky KE. A follow-up study of
recurrence and cosmesis in completely responding superficial and
nodular basal cell carcinomas treated with methyl 5-aminolaevuli-
nate-based photodynamic therapy alone and with prior curettage. Br
Methyl aminolevulinate-photodynamic therapy J Dermatol 2001;145:467-71.
in field cancerization areas 3. Horn M, Wolf P, Wulf HC, Warloe T, Fritsch C, Rhodes LE et al.
Topical methyl aminolevulinate photodynamic therapy in patients
with basal cell carcinoma prone to complications and poor cosmetic
Field cancerization areas are usually sun exposed outcome with conventional treatment. Br J Dermatol 2003;149:
areas, e.g. scalp, face, ears, dorsal aspects of hands, and 1242-9.
4. Zeitouni NC, Oseroff AR, Shieh S. Photodynamic therapy for non- keratosis: a prospective, randomized study. J Dermatol Treat
melanoma skin cancers. Mol Immunol 2003;39:1133-6. 2003;14:99-106.
5. Szeimies RM, Karrer S, Radakovic-Fijan S, Tanew A, Calzavara-Pin- 7. Morton C, Horn M, Leman J, Tack B, Bédane C, Tjioe M et al. A
ton PG, Zane C et al. Photodynamic therapy using topical methyl 5- placebo controlled European study comparing MAL-PDT with
aminolevulinate compared with cryotherapy for actinic keratosis: a cryotherapy and 5-fluorouracil in patients with Bowen’s disease. J
prospective randomized study. J Am Acad Dermatol 2002;47:258- Eur Acad Dermatol Venereol 2004;18 Suppl 2:415.
62. 8. Morton CA, Brown SB, Collins S, Ibbotson S, Jenkinson H, Kurwa
6. Freeman M, Vinciullo C, Francis D, Spelman L, Nguyen R, Fergin P H et al. Guidelines for topical photodynamic therapy: report of a
et al. A comparison of photodynamic therapy using topical methyl workshop of the British Photodermatology Group. Br J Dermatol
aminolevulinate with single cycle cryotherapy in patients with actinic 2002;146:552-67.
Guidelines in dermoscopy
S. CHIMENTI 1, G. ARGENZIANO 2, A. DI STEFANI 1, L. ANDREASSI 3, P. CARLI 4, V. DE GIORGI 4,
G. FERRARA 5, A. FERRARI 6, S. GASPARINI 7, G. L. GIOVENE 8, M. LOMUTO 9, G. MAZZOCCHETTI 10,
G. PELLACANI 11, R. PELLICANO 9, K. PERIS 6, D. PICCOLO 6, M. A. PIZZICHETTA 12, P. RUBEGNI 3,
M. SCALVENZI 13, S. SEIDENARI 11, S. SERRESI 14, I. STANGANELLI 15, B. GIANNOTTI 4
50
40
The role of dermoscopy in the clinical management
30 of pigmented skin lesions (PSL), has been recently
20 evaluated. In order to verify whether this technique
10 may decrease the number of surgical excisions of
benign PSL, a series of lesions consecutively excised
0
Specificity Sensitivity and histologically diagnosed were retrospectively eval-
uated both clinically and dermoscopically.12 The results
Clinical examination Pattern analysis 7-point checklist showed that, although the sensitivity for melanoma
ABCD Combined approach was 90%, all malignant skin neoplasms (melanomas
Figure 1.—Specificity and sensitivity for melanoma diagnosis of clinical and basal cell carcinomas, BCC) were correctly clas-
examination and of the different diagnostic algorithms. sified as equivocal lesions to be excised. In addition,
40% of clinically suspicious (false positives) PSL,
were correctly diagnosed as benign lesions by der-
in teaching programs for residents in dermatology moscopic examination thus avoiding unnecessary
could be recommended. surgery. Therefore, the use of dermoscopy to estab-
lish whether a PSL should be biopsied or not allows us
to significantly improve the clinical diagnosis and
Integration of clinical management of PSL.12 An algorithm for the manage-
and dermoscopic examination ment of PSL showing a combined clinical and der-
moscopic approach is reported in Figure 2. This algo-
Integration of dermoscopy in the context of phys- rithm was designed on the basis of the mean activity
ical examination has been shown to improve the pre- of a reference center for PSL screening and early diag-
operative diagnosis of melanoma (Figure 1). In 1996 nosis of melanoma.
Menzies et al. 9 demonstrated that 9 out of 107 (8%)
melanomas did not have any melanoma-specific der-
moscopic criteria and were reported as featureless Two-step procedure for dermoscopic diagnosis
melanomas. Such lesions were excised only on the
basis of recent changes to the lesions as observed Recently a diagnostic method for the dermoscopic
by the patients. Because the great importance of the diagnosis of PSL was validated and proposed as stan-
clinical evolution of the lesion, the letter E (= evo- dard at the Consensus Net Meeting on Dermoscopy
lution of the lesion) has been added to the ABCD (CNMD). The CNMD, organized in 2000 via the
rule of dermoscopy.10 Moreover, the percentage of Internet between 40 experts from 14 countries, had the
correctly diagnosed melanomas is higher for in vivo objective to investigate some important issues in der-
dermoscopy (face to face with the patient) compared moscopy such as the better definition and standard-
with dermoscopy performed on slide images of the ization of dermoscopic terminology, and the repro-
same cases.11 This also implies that some clinical ducibility and validity of the different criteria and
parameters such as the age and skin phototype of diagnostic algorithms.13 This diagnostic method in
the patient, number and characteristics of the other dermoscopy is based on a two-step procedure. The
nevi, location and history of the lesion, can be cru- first step aims to differentiate melanocytic and non
cial for increasing diagnostic accuracy. In the pres- melanocytic PSL. The criteria to define a specific
ence of any suspicious clinical data the dermatolo- lesion of a melanocytic nature are: pigmented net-
gist may focus attention on slight or less noticeable work, brown globules, streaks, homogeneous blue
PSL
(approximately ~35% clinically
DERMOSCOPY
1 melanoma out EQUIVOCAL (Pattern analysis, ABCD, 7-Point)
of 100 patients lesions
observed)
Follow-up in
EXCISION
selected lesions
Figure 2.—Algorithm for the management of pigmented skin lesions (PLS). Data related to the mean activity of a reference center for melanoma
screening.
pigmentation and parallel pattern.13 If none of those three-point checklist has been proposed to allow non-
criteria can be identified, one should recognize the expert dermoscopists to increase their sensitivity to
presence of criteria for the diagnosis of seborrheic melanoma diagnosis (albeit with a decrease in speci-
keratosis (milia-like cysts, comedo-like openings, fin- ficity).18 The three-point checklist is a simplified
gerprint-like structures, cerebriforme pattern with fis- method based on the evaluation of only 3 dermoscopic
sures and ridges), BCC (arborizing vessels, leaf-like criteria: asymmetry of the lesion, the presence of an
structures, large blue-gray ovoid nests, multiple blue- atypical pigmented network and of blue-white struc-
gray globules, spoke-wheel areas and ulceration), and tures (defined as the presence of any type of blue and/or
vascular lesions (red-blue lacunas, red-bluish to red- white color). The three-point checklist could repre-
dish-black homogeneous areas).14 In the absence of sent a dermoscopic method for melanoma screening
any of the above mentioned criteria, the pattern is also in the hands of non-experts.18
defined as non-specific and should be considered sus-
picious for the diagnosis of melanocytic lesion.13 The
second step is useful for differentiating benign Melanoma-specific dermoscopic criteria
melanocytic lesions from melanoma, and includes dif-
ferent diagnostic algorithms: modified pattern analy- In recent years, several studies have demonstrated
sis,14, 15 ABCD rule,16 Menzies method,9 and seven- the validity and reproducibility of certain dermoscopic
point checklist.17 According to the results of the criteria, significantly associated to melanoma diag-
CNMD, all diagnostic methods exhibited high sensi- nosis, and therefore defined as melanoma-specific
tivity in the diagnosis of melanoma, although pattern criteria 13-15, 19-28 (Table I). Of the various global fea-
analysis has shown a significantly higher specificity as tures, the multicomponent pattern, defined as the com-
compared to the other algorithms. However, it should bination of 3 or more dermoscopic patterns in a giv-
be emphasized that pattern analysis requires a higher en PSL, was the most predictive for the diagnosis of
degree of experience in dermoscopy.13 Recently the melanoma.13 The globular, cobblestone, homoge-
TABLE I.—Melanoma-specific dermoscopic criteria showing a statistically predictive value for melanoma diagnosis, and corresponding histo-
pathologic substrates.13-15, 19-28
Association with
Melanoma-specific Dermoscopic description Histopathologic substrates melanoma diagnosis
dermoscopic criteria (Odds ratio) 13
neous, and starburst pattern were highly predictive The problem of false negatives
of a diagnosis of benign melanocytic lesions.13 Atyp- and equivocal lesions
ical pigment network, irregular streaks and regres-
sion structures were the local features that showed False negatives in dermoscopy mainly include
the highest association with melanoma, followed by melanomas which are misdiagnosed and, therefore,
irregular dots/globules, irregular blotches, and a blue- not referred for surgical excision. False negative
whitish veil.13 In contrast, the typical pigment net- melanomas may essentially simulate a benign
work, regular dots/globules, regular streaks and reg- melanocytic lesion such as Clark nevus and Spitz/Reed
ular blotches were associated with benign melanocyt- nevus, or may lack any distinctive dermoscopic crite-
ic lesions.13 Structural asymmetry of the lesion, as ria (featureless melanoma), or shows hypo- or no pig-
assessed by the ABCD rule or Menzies method, was mentation.9, 14, 29 From a practical point of view, when
also significantly associated with melanoma.13 All a lesion is clinically suspicious and, at first glance, is
melanoma-specific criteria have a well defined dermoscopically benign, it is crucial to perform an
histopathological substrate (Table I) and their presence accurate dermoscopic examination in order to identi-
should always be investigated in a PSL. The obser- fy any subtle atypical features. However, the diagno-
vation of melanoma-specific criteria is almost always sis of melanoma should always be suspected when a
sufficient to decide to surgically excise and histopatho- lesion shows a non-specific pattern. In addition, clin-
logically examine a given lesion. ical history is an essential integration to dermoscopy
when featureless lesions are diagnosed.10 In hypopig- these lesions: surgical excision should be performed for
mented lesions the detection of an atypical vascular pat- any spitzoid lesion occurring in adult patients, while
tern (milky-red areas/globules, linear-irregular ves- in a child, a spitzoid lesion showing typical dermo-
sels or a combination of dotted and linear-irregular scopic features could be dermoscopically monitored
vessels) 29, 30 can be highly suggestive of melanoma, over time.40 Melanocytic skin lesions showing fea-
especially if associated with other criteria such as tures of regression (blue-white structures such as white
irregular blotches, dots/globules, regression structures scar-like depigmentation and blue pepper-like granules)
or a blue-whitish veil.30 In cases of pink or amelanot- may be difficult to classify clinically and dermoscop-
ic lesions, vascular patterns alone may not be suffi- ically. A recent study of dermoscopic-pathologic cor-
cient for the diagnosis of melanoma, and should be relation on clinically equivocal melanocytic lesions
integrated with clinical information such as age, sex, with blue-white structures demonstrated that the major-
personal or family history of melanoma, number and ity of nevi with regression exhibited blue areas with a
sites of lesions, time of onset and description of any central distribution and involving <50% of the lesion
changes over time. A combined approach (dermo- surface, while histopathologic equivocal lesions
scopic examination and clinical data) may help in the revealed a combination of white and blue areas with an
early detection of amelanotic melanoma.30 irregular distribution and involving >50% of the lesion
Moreover, a percentage of lesions that are equivo- surface.41 Based on those results, an algorithm was
cal by clinical and dermoscopic examination, may still proposed that can be applied to the management of
be equivocal after histopathologic examination.31 The lesions exhibiting dermoscopic features of regression:
limit between benign and malignant lesions is not clear lesions showing a low degree (<10%) of blue-white
for lesions such as junctional Clark nevi (and structures can be dermoscopically monitored over
melanoma in situ) or atypical Spitz/Reed nevi (and time; in contrast, lesions with a high degree of regres-
spitzoid melanomas). Skin lesions within this “gray sion (>50%) or with a moderate degree (between 10%
and 50%) of regression along with the presence of a
zone” should be surgically excised or followed up
combination of blue and white areas should be surgi-
closely (1-3 months) by dermoscopy in order to detect
cally excised and histopathologically examined.41
a potential asymmetric enlargement or changes in der-
moscopic features.32, 33 Recently a new dermoscopic
classification of Clark nevi has been proposed to select Dermoscopic follow-up and modification during
specifically those lesions which should be surgically time of pigmented skin lesions
excised.34
An eccentric peripheral hyperpigmentation or the There are 2 main reasons why a patient must be
presence of 3 different structures in a given lesion periodically examined: first, some patients have a high-
(reticular, globular and homogeneous pattern) were er risk of developing a melanoma (i.e. personal or fam-
significantly more frequently found in malignant than ily history of melanoma, total nevus count, skin pho-
in benign melanocytic lesions and this implies the sur- totype I-II); second, to monitor the possible evolution
gical removal of the lesion.35 of single only moderately atypical lesions (not suspi-
A model of possible natural evolution over time has cious for melanoma) over time. In addition, dermo-
been described with sequential dermoscopic exami- scopic follow-up is useful in patients with multiple
nations for spitzoid lesions: from a globular pattern nevi, often clinically atypical, which would be practi-
to a starburst pattern,36 and subsequently the disap- cally impossible to remove simultaneously.1, 42, 43
pearance of streaks at the periphery of the lesion and In a recent study the characteristics of growing
the presence of a central homogeneous pigmenta- melanocytic nevi were described: in a series of 1 612
tion.37, 38 In a percentage of spitzoid lesions the detec- common nevi, 5% showed an enlargement in a mean
tion of a superficial black network (that histopatho- follow-up period of 12 months.44 Dermoscopy revealed
logically corresponds to focal areas of pigmented a peripheral symmetric rim of brown globules in 50%
parakeratosis, producing a black reticulated appear- of enlarging nevi, due to the junctional activity of
ance on the horizontal plane) can be useful for the melanocytes. Although this phenomenon was more
diagnosis of benignancy.39 The age of the patient is common in the under-20s, symmetrical enlargement
an important clinical parameter for the management of alone (without any other atypical feature) did not indi-
TABLE II.—Main dermoscopic features of the most difficult PSL (equivocal lesions and false negatives) with clues for differential diagnosis
and clinical management.
Skin lesions Main dermoscopic features and management recommendations
Equivocal lesions
1) Clark nevus with eccentric hyper- Excision if solitary lesion; short term follow-up (3 months) if multiple lesions with this dermoscopic fea-
pigmentation ture in the same patient 32, 34, 35
2) Clark nevus with regression Excision if regression >50% of the lesion surface; follow-up if regression <10%; excision if regression
10-50% together with the a combination of blue and white areas 41
3) Spitz/Reed nevus Excision in adult patients,40 short term digital follow-up if typical dermoscopic features in children 36, 38
False negatives
1) Melanoma simulating the following
PSL:
— Clark nevus Short term follow-up (3 months) if multiple atypical lesions in the same patient;32, 34, 35 excision if solitary
lesion even if slightly atypical. Excision if simultaneous presence of reticular, globular and homogeneous
structures 35
— Spitz/Reed nevus Excision in adult patients,40 short term digital follow-up if typical dermoscopic features in children 36, 38
— Dermal nevus Differential criteria to evaluate:
— cobblestone pattern, comma-like vessels and hair favor a dermal nevus 14
— asymmetry, blue-whitish veil, irregular dots/globules and atypical vascular pattern favor a melanoma, also
with the presence of a cobblestone pattern 13 Dermoscopic follow-up in nodular lesion should be avoi-
ded.
— Pigmented lesions of the face Diagnostic criteria to evaluate:
— annular-granular structures
— asymmetric pigmented follicular openings
— rhomboidal structures 54 surgical excision or incisional biopsy in suspicious (blue-gray) areas in broad
lesions
— Acral nevus Surgical excision of the lesions showing:70
— parallel-ridge pattern
— atypical or multicomponent pattern
— Ungueal lesions Incisional biopsy if:55-57
— brown background and longitudinal brown to black lines, irregular in shape, coloration, thickness and
parallelism.
— micro-Hutchinson sign
Dermoscopic follow-up in doubtful lesions 56
— Labial and genital melanosis Incisional biopsy in lesions with variegated coloration and irregular distribution of the pigment 58
Excision of nodular lesions
— Blue nevus Excision when dermoscopically atypical or clinical history unclear 59 Rule out a melanoma metastasis 60
— Congenital nevus Dermoscopic follow-up by dermoscopic images of:61, 62
— entire lesion if possible
— representative areas of the architectural pattern
— borders
— special interest areas
Excision or incisional biopsy of suspicious lesions
— Recurrent nevus Atypical dermoscopic features (irregular streaks and dots/globules),63 definite clinical history is essential
if re-excise or not the lesion
— Irritated nevi Close follow-up (1-2 weeks); excision in unsolved cases
— Reticulated lentigo Thickened, dark brown to black pigmented network, with irregular and asymmetric mashes.64 Excision in
equivocal lesions
— Basal cell carcinoma Arborizing vessels, leaf-like areas, large blue-gray ovoid nests, multiple blue-gray globules, spoke wheel areas and
ulceration, with the absence of pigment network 65, 66. Surgical excision is the elective treatment
— Seborrheic keratosis — evaluate the number of milia-like cysts and comedo-like openings: often numerous in seborrheic kera-
tosis, few in melanoma 67
— excision in suspicious lesions, showing false pigment network and/or pseudo-globular structures 67-69
— Vascular lesions — Haemangioma: well circumscribed red lacunas (must be differentiated from milky red areas (less defi-
ned) in melanoma 14
— Pyogenic granuloma: excision and histopathologic exam in adults
2) Melanoma with non-specific pattern Excision of the lesion in the absence of specific dermoscopic criteria 14
3) Amelanotic melanoma Suspicious dermoscopic criteria in pink lesions requiring excision 29, 30
— nodular ulcerated lesion
— pigment remnants, especially if blue-gray in color
— milky red areas
— atypical vascular pattern (dotted and/or linear-irregular vessels)
4) Melanoma metastasis — homogeneous bluish pigmentation
— diffuse non-homogeneous brown-bluish pigmentation
— red-bluish globular pattern 60
ered as a distinctive entity named Reed nevus) can demarked black-reddish areas and by blood spots or
dermoscopically show different dermoscopic patterns: purple-to-black dots. Melanocytic nevi show a brown
starburst, globular, reticular, homogeneous, hypopig- coloration of the background and the presence of reg-
mented and atypical.37 Often these lesions can hardly ular lines in shape and parallelism, and drug-induced
be differentiated from a spitzoid melanoma, either longitudinal melanonychia reveals a grayish col-
dermoscopically or histopathologically. Consequent- oration of the background and the presence of regu-
ly, any spitzoid lesion in adult patients should be sur- lar thin lines.55 When a diagnosis can not be made
gically excised 40 while in childhood, if the spitzoid with certainty, a close dermoscopic follow-up can be
lesion shows typical dermoscopic features, could be useful to establish the final diagnosis.56 Subungueal
closely followed-up over time, avoiding unnecessary melanoma dermoscopically shows a brown back-
excisions of benign lesions.36, 38 ground and longitudinal brown to black lines, irreg-
Dermal nevi (Unna and Miescher nevi) are usually ular in shape, coloration, thickness and parallelism.
characterized by a homogeneous pigmentation (that on Important is the detection of micro-Hutchinson sign
the face appears as a pigment pseudonetwork), by a (pigmentation of the periungueal skin and cuticle,
cobblestone pattern and comma-like vessels.14 In addi- visible only at dermoscopic examination) that,
tion, dermal nevi may show exophytic papillary struc- although rarely detected, is suspicious of melanoma.55,
tures and irregular crypts.14 The detection of asym- 57 In equivocal lesions, an incisional biopsy, includ-
metry, a blue-whitish veil, irregular dots/globules and ing the matrix, is required.
atypical vascular pattern is suspicious of melanoma.13 Labial and genital melanosis are benign pigmented
When a nodular lesion is observed, a follow-up is nev- lesions dermoscopically characterized by a diffuse
er recommended in the presence of even a minimal background pigmentation with a granular or globular
diagnostic suspicion. (often with aligned globules) or linear-curvilinear, fre-
Pigmented lesions of the face show a characteristic quently parallel, intensification of the pigment, light
pigment pseudonetwork, due to the distribution of the brown to brown or grayish in coloration.71 Dermo-
pigment around follicular ostia.14 Criteria to diagnose scopic follow-up of lesions showing even a slightly
a lentigo maligna include: annular-granular structures irregular pigmentation is recommended. In equivocal
(of blue-gray color) and asymmetric pigmented fol- lesions showing variegated coloration and irregular
licular openings.54 Rhomboidal structures and homo- distribution of the pigment, dermoscopy can help to
geneous pigmented areas of follicular invasion are identify the most atypical zone in order to perform an
indeed associated with progression to an invasive incisional biopsy at the diagnostic site.58
melanoma (lentigo maligna melanoma).54 Surgical Blue nevi are easily identified for their typical homo-
excision should always be performed when these fea- geneous blue pigmentation, common locations on the
tures are observed, while an incisional (punch) biop- extremities and without history of changes. In some
sy can be performed in large lesions, preferentially cases, characterized by yellow-whitish areas, related
within the bluish black areas. to the presence of fibrosis, the main differential diag-
Acral nevi (nevi of the palms and soles) show a nosis is melanoma. Because of the important signifi-
characteristic parallel pattern due to the disposition cance of blue structures in dermoscopy, a careful exam-
of the pigment along the sulci. The parallel-furrows pat- ination of these lesions is always recommended and a
tern, the lattice-like pattern and the fibrillar pattern biopsy is suggested when lesions are dermoscopical-
are typical of benign acral melanocytic lesions while ly atypical or the clinical history is unclear.59 Fur-
the parallel-ridge pattern is associated with acral lentig- thermore, melanoma metastasis may simulate a blue
inous melanoma.70 Lesions showing atypical or mul- nevus.60
ticomponent patterns should be surgically excised and Dermoscopy can also be useful to further charac-
histopathologically examined. terize and follow up congenital nevi, although their
Ungueal lesions should be distinguished from sub- dermoscopic features are quite variable. The cobble-
ungueal hemorrhage, melanocytic nevi and drug- stone pattern is the most common, followed by a mul-
induced longitudinal melanonychia. Subungueal ticomponent pattern consisting of multiple colors,
hemorrage is characterized by a clinical history of dots/globules, pigmented network, hypopigmented
trauma and dermoscopically by roundish sharply areas and homogeneous blue areas.61 Recently, other
peculiar features have been described such as target gical excision is suggested in equivocal lesions to rule
network, target globules and target vessels.62 A care- out the possibility, though rare, of a melanoma simu-
ful examination of a sequential digital clinical image lating a seborrheic keratosis.67
of the entire lesion, integrated with a dermoscopic Dermoscopic examination of vascular lesions
image representative of the architectural pattern, bor- allows us to detect specific criteria and to differen-
ders, and areas of special interest, may make it possible tiate with accuracy vascular lesions from melanoma.
to identify the appearance of atypical features.61 In Haemangioma is characterized by a lacunar pattern,
such case, small congenital nevi should be excised, composed of numerous red to red-bluish ovoid,
while in large or giant congenital nevi, an incisional sharply circumscribed areas, called red lacunas.
biopsy in dermoscopically suspicious areas is rec- These structures must be distinguished from the less
ommended. defined milky-red areas, that can be sometimes but
Recurrent nevi (or persistent nevi) usually exhibit specifically seen in melanoma.14 The lacunar pat-
such bizarre and atypical features to be suspicious for tern is hardly recognized in a pyogenic granuloma,
melanoma, including irregular streaks and irregular therefore a biopsy and histopathologic confirmation
dots/globules close to or in the context of the scar.63 are recommended in adult patients. Angiokeratoma
Recurrent nevi following incomplete excision of a exhibits red-bluish to black lacunas, associated with
histopathologically non atypical lesion can be moni- whitish-yellowish keratotic areas.14 Subcorneal hem-
tored over time. When anamnestic data or previous orrhage dermoscopically shows a blackish homoge-
histopathologic diagnosis are not available or not clear, neous area and also a pseudo-parallel or pseudo-
the lesion must be excised. globular pattern.
Another example of the usefulness of a dermoscopic
follow-up is the irritated nevi (mostly by trauma or
infections), also named Meyerson nevi:72 a close dig- Technological standard in dermoscopy
ital monitoring (1-2 weeks) after local treatment can
The hand-held dermatoscope and digital videoder-
solve the diagnostic doubt.
matoscope represent the most widely used instruments
Reticulated lentigo (or ink spot lentigo) is usually
for dermoscopic examination.1-3, 14 In some derma-
located in severe sun damaged skin and may mimic a
tology centers, a stereomicroscope implemented by
melanoma in situ. Dermoscopically it is characterized digital system such as a high resolution digital camera
by a thickened, dark brown to black pigmented net- (3CCD) are employed.3, 52, 53 The current standard tool
work, with irregular and asymmetric mashes which for dermoscopic photographic documentation of PSL
are uniformly distributed throughout the lesion.64 In is the Dermaphot (Heine Optotechnik, Herrsching,
equivocal lesions a biopsy is recommended. Germany), consisting of a special designed lens on a
BCC especially if pigmented, may simulate a camera with high resolution power and optimal image
melanoma. Dermoscopic hallmarks of BCC are: quality.73-75 However, a large number of instruments
arborizing vessels, leaf-like areas, large blue-gray and systems for digital videodermoscopy are current-
ovoid nests, multiple blue-gray globules, spoke wheel ly commercially available, achieving an image quali-
areas and ulceration, in the absence of a pigment net- ty not always comparable to the standard.76, 77 We hope
work.65, 66 that in the near future the companies will conform to
Seborrheic keratosis, mainly the acanthotic and pig- the standard, possibly through the institution of a spe-
mented variants, may mimic a melanoma. Typical der- cific committee for the evaluation and validation of
moscopic features include: milia-like cysts, comedo- videodermoscopy systems.
like openings, fingerprint-like structures and a cere-
briforme pattern with fissures and ridges. Recently
other dermoscopic criteria have been described such as Video-dermoscopic report controversies
sharp demarcation and moth-eaten borders,68 above
all in the early reticulated type of seborrheic keratosis At the moment, there are no precise regulations nor
arising from a solar lentigo. A false pigment network, published papers regarding this topic. In the present
especially of the reticulated type, and pseudo-globu- we would suggest a proposal of standardization of
lar structures can sometimes be observed.68, 69 A sur- the video-dermoscopic report. Considering together
medico-legal and deontological matters, and aiming 12. Argenziano G, Soyer HP, Chimenti S, Ruocco V. Impact of der-
moscopy on the clinical management of pigmented skin lesions. Clin
a full statement of dermoscopy as a second-level Dermatol 2002;20:200-2.
instrumental examination, it is evidently important 13. Argenziano G, Soyer HP, Chimenti S, Talamini R, Corona R, Sera F
to issue a suitable report after providing a specialized et al. Dermoscopy of pigmented skin lesions: results of a consensus
meeting via the Internet. J Am Acad Dermatol 2003;48:679-93.
service. 14. Argenziano G, Soyer HP, De Giorgi V, Piccolo D, Carli P, Delfino M
Hence, in every video-dermoscopic report, we sug- et al. Interactive atlas of dermoscopy. Milan: Edra Medical Publish-
gest including the following points (minimal criteria): ing and New Media; 2000.
15. Pehamberger H, Binder M, Steiner A, Wolff K. In vivo epiluminescence
— Symmetry/asymmetry of the lesion. microscopy: improvement of early diagnosis of melanoma. J Invest
— Global pattern. Dermatol 1993;100:356S-62S.
16. Nachbar F, Stolz W, Merkle T, Cognetta AB, Vogt T, Landthaler M et
— Local features. al. The ABCD rule of dermatoscopy. High prospective value in the
— Diagnostic conclusion. diagnosis of doubtful melanocytic skin lesions. J Am Acad Dermatol
1994;30:551-9.
— Management recommendation. 17. Argenziano G, Fabbrocini G, Carli P, De Giorgi V, Sammarco E,
Although the different video-dermoscopy systems Delfino M. Epiluminescence microscopy for the diagnosis of doubt-
ful melanocytic skin lesions. Comparison of the ABCD rule of der-
have some limits in the standard of image quality and matoscopy and a new 7-point checklist based on pattern analysis.
resolution, printing quality etc., we believe that a print- Arch Dermatol 1998;134:1563-70.
18. Soyer HP, Argenziano G, Zalaudek I, Corona R, Sera F, Talamini R et
ed dermoscopic image of the lesion should be given to al. Three-point checklist of dermoscopy. A new screening method
the patient at the dermatologist’s discretion, specify- for early detection of melanoma. Dermatology 2004;208:27-31.
ing current technological problems. 19. Nilles M, Boedeker RH, Schill WB. Surface microscopy of naevi and
melanomas--clues to melanoma. Br J Dermatol 1994;130:349-55.
20. Soyer HP, Smolle J, Leitinger G, Rieger E, Kerl H. Diagnostic relia-
bility of dermoscopic criteria for detecting malignant melanoma. Der-
References matology 1995;190:25-30.
21. Steiner A, Pehamberger H, Wolff K. In vivo epiluminescence
1. Argenziano G, Soyer HP. Dermoscopy of pigmented skin lesions-a microscopy of pigmented skin lesions. II. Diagnosis of small pig-
valuable tool for early diagnosis of melanoma. Lancet Oncol mented skin lesions and early detection of malignant melanoma. J
2001;2:443-9. Am Acad Dermatol 1987;17:584-91.
2. Wolf IH, Smolle J, Soyer HP, Kerl H. Sensitivity in the clinical diag- 22. Argenziano G, Fabbrocini G, Carli P, De Giorgi V, Delfino M. Epi-
nosis of malignant melanoma. Melanoma Res 1998;8:425-9. luminescence microscopy: criteria of cutaneous melanoma progres-
3. Kittler H, Pehamberger H, Wolff K, Binder M. Diagnostic accuracy sion. J Am Acad Dermatol 1997;37:68-74.
of dermoscopy. Lancet Oncol 2002;3:159-65. 23. Pizzichetta MA, Argenziano G, Talamini R, Piccolo D, Gatti A, Tre-
4. Binder M, Schwarz M, Winkler A, Binder M. Epiluminescence visan G et al. Dermoscopic criteria for melanoma in situ are similar
microscopy. A useful tool for the diagnosis of pigmented skin lesions to those for early invasive melanoma. Cancer 2001;91: 992-7.
for formally trained dermatologists. Arch Dermatol 1995;131:286-91. 24. Soyer HP, Kenet RO, Wolf IH, Kenet BJ, Cerroni L. Clinicopatho-
5. Piccolo D, Smolle J, Argenziano G, Wolf IH, Braun R, Cerroni L et logical correlation of pigmented skin lesions using dermoscopy. Eur
al. Teledermoscopy--results of a multicentre study on 43 pigmented J Dermatol 2000;10:22-8.
skin lesions. J Telemed Telecare 2000;6:132-7. 25. Massi D, De Giorgi V, Soyer HP. Histopathologic correlates of der-
6. Binder M, Puespoeck-Schwarz M, Steiner A, Kittler H, Muellner M, moscopic criteria. Dermatol Clin 2001;19:259-68, vii.
Wolff K et al. Epiluminescence microscopy of small pigmented 26. Argenziano G, Fabbrocini G, Carli P, De Giorgi V, Delfino M. Clin-
skin lesions: short-term formal training improves the diagnostic ical and dermatoscopic criteria for the preoperative evaluation of cuta-
performance of dermatologists. J Am Acad Dermatol 1997;36: neous melanoma thickness. J Am Acad Dermatol 1999;40:61-8.
197-202. 27. De Giorgi V, Carli P. Dermoscopy and preoperative evaluation of
7. Carli P, Quercioli E, Sestini S, Stante M, Ricci L, Brunasso G et al. Pat- melanoma thickness. Clin Dermatol 2002;20:305-8.
tern analysis, not simplified algorithms, is the most reliable method 28. Stante M, Carli P, Massi D, De Giorgi V. Dermoscopic features of
for teaching dermoscopy for melanoma diagnosis to residents in der- naevus-associated melanoma. Clin Exp Dermatol 2003;28:476-80.
matology. Br J Dermatol 2003;148:981-4. 29. Carli P, Massi D, De Giorgi V, Giannotti B. Clinically and dermo-
8. Pagnanelli G, Soyer HP, Argenziano G, Talamini R, Barbati R, Bianchi scopically featureless melanoma: when prevention fails. J Am Acad
L et al. Diagnosis of pigmented skin lesions by dermoscopy: web-based Dermatol 2002;46:957-9.
training improves diagnostic performance of non-experts. Br J Der- 30. Pizzichetta MA, Talamini R, Stanganelli I, Puddu P, Bono R, Argen-
matol 2003;148:698-702. ziano G et al. Amelanotic/hypomelanotic melanoma: clinical and
9. Menzies SW, Ingvar C, Crotty KA, McCarthy WH. Frequency and dermoscopic features. Br J Dermatol 2004;150:1117-24.
morphologic characteristics of invasive melanomas lacking specific 31. Ferrara G, Argenziano G, Soyer HP, Corona R, Sera F, Brunetti B et
surface microscopic features. Arch Dermatol 1996;132:1178-82. al. Dermoscopic and histopathologic diagnosis of equivocal melanocyt-
10. Kittler H, Seltenheim M, Dawid M, Pehamberger H, Wolff K, Binder ic skin lesions: an interdisciplinary study on 107 cases. Cancer
M. Morphologic changes of pigmented skin lesions: a useful exten- 2002;95:1094-100.
sion of the ABCD rule for dermatoscopy. J Am Acad Dermatol 32. Menzies SW, Gutenev A, Avramidis M, Batrac A, McCarthy WH.
1999;40:558-62. Short-term digital surface microscopic monitoring of atypical or
11. Carli P, De Giorgi V, Giannotti B. Dermoscopy as a second step in changing melanocytic lesions. Arch Dermatol 2001;137:1583-9.
the diagnosis of doubtful pigmented skin lesions: how great is the risk 33. Carli P, De Giorgi V, Giannotti B. Dermoscopy and early diagnosis
of missing a melanoma? J Eur Acad Dermatol Venereol 2001;15: of melanoma: the light and the dark. Arch Dermatol 2001;137:
24-6. 1641-4.
34. Hofmann-Wellenhof R, Blum A, Wolf IH, Piccolo D, Kerl H, Garbe 54. Schiffner R, Schiffner-Rohe J, Vogt T, Landthaler M, Wlotzke U,
C et al. Dermoscopic classification of atypical melanocytic nevi (Clark Cognetta AB et al. Improvement of early recognition of lentigo
nevi). Arch Dermatol 2001;137:1575-80. maligna using dermatoscopy. J Am Acad Dermatol 2000;42:
35. Blum A, Soyer HP, Garbe C, Kerl H, Rassner G, Hofmann-Wellenhof 25-32.
R. The dermoscopic classification of atypical melanocytic naevi (Clark 55. Ronger S, Touzet S, Ligeron C, Balme B, Viallard AM, Barrut D et al.
naevi) is useful to discriminate benign from malignant melanocytic Dermoscopic examination of nail pigmentation. Arch Dermatol
lesions. Br J Dermatol 2003;149:1159-64. 2002;138:1327-33.
36. Pizzichetta MA, Argenziano G, Grandi G, De Giacomi C, Trevisan G, 56. Tosti A, Argenziano G. Dermoscopy allows better management of
Soyer HP. Morphologic changes of a pigmented Spitz nevus assessed nail pigmentation. Arch Dermatol 2002;138:1369-70.
by dermoscopy. J Am Acad Dermatol 2002;47:137-9. 57. Baran R, Kechijian P. Hutchinson’s sign: a reappraisal. J Am Acad Der-
37. Peris K, Ferrari A, Argenziano G, Soyer HP, Chimenti S. Dermo- matol 1996;34:87-90.
scopic classification of Spitz/Reed nevi. Clin Dermatol 2002;20: 58. De Giorgi V, Massi D, Carli P. Dermoscopy in the management of pig-
259-62. mented lesions of the oral mucosa. Oral Oncol 2003;39:534-5.
38. Piccolo D, Ferrari A, Peris K. Sequential dermoscopic evolution of pig- 59. Massi D, De Giorgi V, Carli P, Santucci M. Diagnostic significance of
mented Spitz nevus in childhood. J Am Acad Dermatol 2003;49: the blue hue in dermoscopy of melanocytic lesions: a dermoscopic-
556-8. pathologic study. Am J Dermatopathol 2001;23:463-9.
39. Argenziano G, Soyer HP, Ferrara G, Piccolo D, Hofmann-Wellen- 60. Ferrari A, Peris K, Piccolo D, Chimenti S. Dermoscopic features of
hof R, Peris K et al. Superficial black network: an additional dermo- cutaneous local recurrent melanoma. J Am Acad Dermatol
scopic clue for the diagnosis of pigmented spindle and/or epithelioid 2000;43:722-4.
cell nevus. Dermatology 2001;203:333-5. 61. Braun RP, Calza AM, Krischer J, Saurat JH. The use of digital der-
40. Argenziano G, Scalvenzi M, Staibano S, Brunetti B, Piccolo D, moscopy for the follow-up of congenital nevi: a pilot study. Pediatr Der-
Delfino M et al. Dermatoscopic pitfalls in differentiating pigment- matol 2001;18:277-81.
ed Spitz naevi from cutaneous melanomas. Br J Dermatol 1999;141: 62. Seidenari S, Martella A, Pellacani G. Polarized light-surface
788-93. microscopy for description and classification of small and medium-
41. Zalaudek I, Argenziano G, Ferrara G, Soyer HP, Corona R, Sera F et sized congenital melanocytic naevi. Acta Derm Venereol 2003;83:
al. Clinically equivocal melanocytic skin lesions with features of 271-6.
regression: a dermoscopic-pathological study. Br J Dermatol 63. Marghoob AA, Kopf AW. Persistent nevus: an exception to the ABCD
2004;150:64-71. rule of dermoscopy. J Am Acad Dermatol 1997;36:474-5.
42. Malvehy J, Puig S. Follow-up of melanocytic skin lesions with digi- 64. Kaddu S, Soyer HP, Wolf IH, Rieger E, Kerl H. Reticular lentigo.
tal total-body photography and digital dermoscopy: a two-step method. Hautarzt 1997;48:181-5.
Clin Dermatol 2002;20:297-304. 65. Menzies SW. Dermoscopy of pigmented basal cell carcinoma. Clin
43. Robinson JK, Nickoloff BJ. Digital epiluminescence microscopy Dermatol 2002;20:268-9.
monitoring of high-risk patients. Arch Dermatol 2004;140: 49-56. 66. Peris K, Altobelli E, Ferrari A, Fargnoli MC, Piccolo D, Esposito M
44. Kittler H, Seltenheim M, Dawid M, Pehamberger H, Wolff K, Binder et al. Interobserver agreement on dermoscopic features of pigment-
M. Frequency and characteristics of enlarging common melanocytic ed basal cell carcinoma. Dermatol Surg 2002;28:643-5.
nevi. Arch Dermatol 2000;136:316-20. 67. Argenziano G, Rossiello L, Scalvenzi M, Staibano S, Ruocco E,
45. Rhodes AR. Common acquired nevomelanocytic nevi and the fourth Cicale L et al. Melanoma simulating seborrheic keratosis: a major
dimension. Arch Dermatol 2000;136:400-5. dermoscopy pitfall. Arch Dermatol 2003;139:389-91.
46. Braun RP, Lemonnier E, Guillod J, Skaria A, Salomon D, Saurat JH. 68. Braun RP, Rabinovitz HS, Krischer J, Kreusch J, Oliviero M, Naldi
Two types of pattern modification detected on the follow-up of benign L et al. Dermoscopy of pigmented seborrheic keratosis: a morpho-
melanocytic skin lesions by digitized epiluminescence microscopy. logical study. Arch Dermatol 2002;138:1556-60.
Melanoma Res 1998;8:431-7. 69. De Giorgi V, Massi D, Stante M, Carli P. False “melanocytic” para-
47. Kittler H, Pehamberger H, Wolff K, Binder M. Follow-up of meters shown by pigmented seborrheic keratoses: a finding which is
melanocytic skin lesions with digital epiluminescence microscopy: pat- not uncommon in dermoscopy. Dermatol Surg 2002;28:776-9.
terns of modifications observed in early melanoma, atypical nevi, 70. Saida T, Oguchi S, Miyazaki A. Dermoscopy for acral pigmented
and common nevi. J Am Acad Dermatol 2000;43:467-76. skin lesions. Clin Dermatol 2002;20:279-85.
48. Kittler H, Binder M. Risks and benefits of sequential imaging of 71. Gasparini S, Giovene GL, Ferranti G. Trattato di Dermoscopia. Milan:
melanocytic skin lesions in patients with multiple atypical nevi. Arch Spriger-Verlag Italia; 2003.
Dermatol 2001;137:1590-5. 72. Worret WI. Halo eczema and nevus cell nevi (Meyerson nevi). Hau-
49. Carli P, De Giorgi V, Chiarugi A, Nardini P, Weinstock MA, Crocetti tarzt 1990;41:262-4.
E et al. Addition of dermoscopy to conventional naked-eye examination 73. Carli P, de Giorgi V, Salvini C, Mannone F, Chiarugi A. The gold
in melanoma screening: a randomized study. J Am Acad Dermatol standard for photographing pigmented skin lesions for diagnostic
2004;50:683-9. purposes: contact versus distant imaging. Skin Res Technol
50. Hofmann-Wellenhof R, Wolf P, Smolle J, Reimann-Weber A, Soy- 2002;8:255-9.
er HP, Kerl H. Influence of UVB therapy on dermoscopic features 74. Kittler H, Seltenheim M, Pehamberger H, Wolff K, Binder M. Diag-
of acquired melanocytic nevi. J Am Acad Dermatol 1997;37: nostic informativeness of compressed digital epiluminescence
559-63. microscopy images of pigmented skin lesions compared with pho-
51. Hofmann-Wellenhof R, Soyer HP, Wolf Ich, Smolle J, Reischle S, tographs. Melanoma Res 1998;8:255-60.
Rieger E et al. Ultraviolet radiation of melanocytic nevi: a dermo- 75. Bittorf A, Fartasch M, Schuler G, Diepeng TL. Resolution requirements
scopic study. Arch Dermatol 1998;134:845-50. for digital images in dermatology. J Am Acad Dermatol 1997;37:
52. Stanganelli I, Rafanelli S, Bucchi L. Seasonal prevalence of digital epi- 195-8.
luminescence microscopy patterns in acquired melanocytic nevi. J 76. Abramovits W, Stevenson LC. Changing paradigms in dermatology:
Am Acad Dermatol 1996;34:460-4. new ways to examine the skin using noninvasive imaging methods. Clin
53. Stanganelli I, Bauer P, Bucchi L, Serafini M, Cristofolini P, Rafanel- Dermatol 2003;21:353-8.
li S et al. Critical effects of intense sun exposure on the expression of 77. Oliveria SA, Sachs D, Belasco KT, Halpern AC. Adoption of new
epiluminescence microscopy features of acquired melanocytic nevi. technologies for early detection of melanoma in dermatologic prac-
Arch Dermatol 1997;133:979-82. tice. J Am Acad Dermatol 2003;49:955-9.
Significato della dermoscopia L’integrazione della dermoscopia nel contesto della valu-
tazione clinica globale del paziente si è dimostrata capace di
La dermoscopia è una metodica diffusamente utilizzata nel- migliorare ulteriormente la diagnosi preoperatoria del mela-
la pratica clinica per la diagnosi precoce del melanoma 1. noma (Figura 1). Nel 1996, Menzies et al. hanno riscontra-
Studi di valutazione sull’accuratezza diagnostica del solo to che 9 (8%) di 107 melanomi inclusi nel loro studio erano
esame clinico hanno mostrato che il dermatologo è in grado privi dei caratteri diagnostici dermatoscopici specifici e per
di individuare il melanoma nel 65-80% dei casi 2. Una recen- tale motivo erano definiti «featureless». Per tali lesioni, l’a-
te revisione sistematica della letteratura ha dimostrato che la sportazione venne effettuata solo sulla base di un cambia-
dermoscopia è in grado di incrementare la sensibilità dia- mento dell’aspetto clinico riferito dal paziente 9. Proprio in
gnostica del melanoma del 10-35% rispetto alla sola osser- considerazione dell’importanza del criterio clinico evoluti-
vazione clinica 3. È stato, inoltre, riportato che tale miglio- vo, è stato proposto un nuovo sistema ABCD che prevede l’in-
ramento diagnostico può essere ottenuto solo se l’osservatore serimento di un criterio ulteriore, denominato E, relativo
alla storia evolutiva della lesione in esame 10. È stato, inol-
tre, osservato che la percentuale di melanomi diagnosticati
correttamente mediante l’osservazione dermoscopica effet-
100
tuata dal vivo (faccia a faccia con il paziente) risulterebbe
90 maggiore rispetto a quella ottenuta esaminando le immagi-
80
ni dermoscopiche, in diapositiva, dei medesimi casi di mela-
noma 11. Questo significa che esistono dei parametri clinici,
70 quali l’età del paziente, il fototipo, il numero e la tipologia
60 degli altri nevi, la sede della lesione, la storia evolutiva, ecc.,
che sono in grado di aumentare l’accuratezza della diagno-
%
Paziente
(circa 1 ~ 35% lesioni
DERMOSCOPIA
melanoma ogni clinicamente
(Analisi pattern, ABCD, 7-Point)
100 pazienti EQUIVOCHE
osservati)
Follow-up in
ASPORTAZIONE
casi selezionati
Figura 2. — Sistema di gestione integrata delle lesioni pigmentate, elaborato sulla base dell’attività media di un Centro di Riferimento per lo scree-
ning delle lesioni pigmentate cutanee e la diagnosi dermoscopica precoce del melanoma.
valutate dal punto di vista sia clinico che dermoscopico. I zione della terminologia, e verifica della riproducibilità e
risultati hanno mostrato che, pur essendo la sensibilità dia- validità dei diversi criteri e degli algoritmi diagnostici 13. Il
gnostica del melanoma del 90%, tutte le lesioni maligne metodo diagnostico dermoscopico proposto consta di una
(melanomi e carcinomi basocellulari) venivano comunque procedura in 2 fasi. La prima fase consiste nel differenziare
giudicate tali da essere asportate. Inoltre, il 40% delle lesio- la natura melanocitica o non melanocitica della lesione pig-
ni clinicamente classificate come sospette (falsi positivi) mentata in questione. A tale proposito, dovranno, pertanto,
venivano invece diagnosticate come lesioni benigne all’esame essere identificati i criteri che consentono di definire una
dermoscopico e, quindi, da non asportare. Ne consegue che, lesione come melanocitica, quali: reticolo pigmentato, glo-
quando la dermoscopia viene utilizzata per stabilire se la buli marroni, strie, pigmentazione blu omogenea, pattern
lesione debba essere asportata o meno, questa metodica con- parallelo. In assenza di tali aspetti verrà esaminata la presenza
sente di migliorare significativamente in termini di specifi- di criteri per le lesioni non melanocitiche e, in particolare, i
cità la gestione clinica delle lesioni pigmentate 12. Un siste- criteri per la diagnosi di cheratosi seborroica (pseudocisti
ma di gestione di lesioni pigmentate, elaborato sulla base cornee, sbocchi simil-comedonici, strutture a impronta digi-
dell’attività media di un centro di riferimento per lo screening tale, aree con aspetto cerebriforme con giri e solchi), carci-
delle lesioni pigmentate cutanee e la diagnosi precoce del noma basocellulare (vasi arboriformi, aree a foglia d’ace-
melanoma e basato sull’approccio diagnostico integrato, è ro, grandi aree ovoidali grigio-blu, multipli globuli grigio-blu,
schematizzato nella Figura 2. aree a ruota di carro e ulcerazione) o di lesioni vascolari
(lacune rosso-blu, aree omogenee da rosso-bluastre a rosso
nerastre) 14. Nel caso in cui anche questi criteri siano assen-
Procedura in due fasi per la diagnosi dermoscopica ti, il pattern viene definito aspecifico e deve far, comunque,
sospettare una diagnosi di lesione melanocitica 13.
Il metodo diagnostico per l’esame dermoscopico delle La seconda fase diagnostica prevede la differenziazione tra
lesioni pigmentate è stato recentemente standardizzato e le lesioni melanocitarie benigne e il melanoma mediante
proposto come riferimento nel corso del Consensus Net l’applicazione di differenti algoritmi diagnostici: l’analisi
Meeting on Dermoscopy (CNMD). Il CNMD, tenutosi nel di pattern modificata 14, 15, l’ABCD di Stolz 16, il metodo di
2000 via internet tra 40 esperti di 14 diversi Paesi, aveva Menzies 9 e il seven-point check-list 17. In base ai risultati del
come obiettivo stabilire alcune linee guida fondamentali in CNMD è stato osservato che tutti questi metodi assicurano
dermoscopia: definizione, standardizzazione e semplifica- una sensibilità elevata nella diagnosi di melanoma, ma che
TABELLA I. — Criteri dermoscopici melanoma-specifici, che hanno mostrato un valore predittivo significativamente elevato per la diagno-
si di melanoma, e loro correlati istopatologici 13-15, 19-28.
Associazione con la
Criteri dermoscopici Descrizione dermoscopica Correlati istopatologici diagnosi di melanoma
melanoma-specifici (Odds ratio) 13
l’analisi di pattern mostra una più elevata specificità rispet- dermoscopico globale che è risultato avere un valore pre-
to agli algoritmi alternativi semplificati, anche se richiede una dittivo maggiore riguardo al melanoma è stato quello poli-
maggiore esperienza da parte dell’osservatore 13. morfo (o multicomponente), definito come combinazione
Recentemente, è stato proposto il three-point checklist 18 di 3 o più strutture dermoscopiche distinte in una stessa
per consentire anche ai dermoscopisti meno esperti di dia- lesione 13. Al contrario, i pattern globulare, ad acciottolato,
gnosticare il maggior numero di melanomi (anche se con omogeneo e «a stella che esplode», sono risultati maggior-
una diminuzione della specificità). Si tratta di un metodo mente predittivi per la diagnosi di lesioni melanocitiche
semplificato basato sulla valutazione di soli 3 criteri der- benigne 13. Per quanto riguarda i criteri dermoscopici loca-
moscopici: l’asimmetria della lesione, la presenza di reti- li, il reticolo pigmentato atipico, le strie irregolari e le strut-
colo pigmentato atipico e di strutture bianco-blu (definite ture di regressione hanno mostrato il valore predittivo più
come la presenza di qualsiasi struttura di colore blu e/o bian- elevato nei confronti del melanoma, seguite da punti e globuli
co). Il three-point checklist potrebbe rappresentare un effi- irregolari, pigmentazione irregolare e velo blu-biancastro 13.
cace sistema dermoscopico di screening delle lesioni pig- Invece, il reticolo pigmentato tipico, i punti e i globuli rego-
mentate, anche per dermoscopisti non esperti 18. lari, le strie regolari e la pigmentazione regolare, sono risul-
tati maggiormente associati con lesioni melanocitiche beni-
gne 13. Anche l’asimmetria strutturale della lesione (calco-
lata sia con il metodo dell’ABCD che con quello di Menzies)
Criteri dermoscopici melanoma-specifici è risultata statisticamente predittiva di malignità 13. Questi cri-
teri melanoma specifici, espressione di alterazioni istopa-
Negli ultimi anni numerosi studi hanno dimostrato la vali- tologiche ben definite (Tabella I), vanno sempre accurata-
dità e la riproducibilità di criteri dermoscopici che sono più mente ricercati nel contesto di una lesione pigmentata e la loro
frequentemente osservati nel melanoma e, per questo, sono osservazione giustifica il più delle volte l’escissione chirur-
definiti melanoma-specifici 13-15, 19-28 (Tabella I.) Il pattern gica e l’esame istologico.
Il problema dei falsi negativi e delle lesioni equivoche tro in una lesione spitzoide di un reticolo nero superficiale
(che, istopatologicamente, corrisponde a focali aree di para-
In dermoscopia, i falsi negativi comprendono i melanomi cheratosi pigmentata, che producono un aspetto reticolato e
che non vengono diagnosticati e, quindi, non asportati chi- nero sul piano orizzontale) può essere di ausilio nel porre dia-
rurgicamente, e includono essenzialmente i melanomi che gnosi di benignità 39. Per le lesioni con aspetto spitzoide,
mimano lesioni melanocitiche benigne quali il nevo di Clark l’età del paziente risulta, comunque, di fondamentale impor-
e il nevo di Spitz/Reed, oppure i melanomi «featureless», tanza: nei pazienti adulti esse vanno senz’altro asportate;
ossia lesioni che non mostrano criteri dermoscopici specifi- nei pazienti pediatrici, se presentano pattern dermoscopici
ci o sono apigmentate 9, 14, 29. Dal punto di vista pratico, nel tipici, possono essere monitorate nel tempo 40.
caso di lesioni clinicamente sospette ma dermoscopicamente Infine le lesioni melanocitiche che dermoscopicamente
apparentemente benigne, è importante esaminare accurata- possono essere di difficile interpretazione sono quelle che pre-
mente la lesione al fine di individuare possibili aspetti der- sentano strutture di regressione, quali aree bianche simil-
moscopici atipici. La diagnosi di melanoma deve, comunque, cicatriziali e/o aree blu tipo peppering. Un recente studio di
essere sempre sospettata quando la lesione mostra un pattern correlazione dermoscopico-patologica su lesioni melanoci-
aspecifico. In questi casi, è, comunque, fondamentale inte- tiche clinicamente equivoche con caratteristiche di regressione
grare i dati dermoscopici con la storia clinica della lesione 10. ha evidenziato che la maggioranza dei nevi con regressione
In particolare, per le lesioni poco pigmentate, la ricerca di un mostra aree blu che coinvolgono <50% della lesione e han-
pattern vascolare atipico (essenzialmente aree/globuli rosso- no una distribuzione prevalentemente centrale, mentre le
lattescenti, vasi lineari-irregolari o la combinazione vasi lesioni istologicamente equivoche mostrano una combina-
puntiformi e lineari-irregolari) 29, 30 può suggerire la dia- zione di aree bianche e aree blu, irregolarmente distribuite,
gnosi di melanoma se associato ai criteri quali pigmenta- che coinvolgono >50% della lesione 41. In base a tali risul-
zione irregolare, globuli/punti irregolari, strutture di regres- tati, è stato proposto un algoritmo per la gestione clinica
sione e velo bianco-bluastro 30. Per le lesioni «rosa» o nul- delle lesioni che dermoscopicamente presentano regressio-
la pigmentate, i pattern vascolari possono da soli non esse- ne: le lesioni che mostrano un basso grado di strutture di
re sufficienti a porre diagnosi di melanoma e vanno integra- regressione (<10%) potrebbero essere sottoposte a moni-
ti con le informazioni cliniche quali età, sesso, familiarità per toraggio dermoscopico, al contrario, l’escissione andrebbe
melanoma, numero delle lesioni, sede, epoca d’insorgenza sempre effettuata per le lesioni che mostrano un alto grado
e modificazioni nel tempo della lesione. L’approccio integrato di regressione (>50%) o che presentano un grado modera-
(indagine dermoscopica-informazioni cliniche) può con- to di strutture di regressione (compreso tra 10% e 50%) ma
sentire di diagnosticare un melanoma amelanotico in uno con la presenza contemporanea di aree bianche e di aree
stadio più precoce 30. blu 41.
Vi è, infine, una percentuale di lesioni melanocitiche per
le quali è difficile o impossibile stabilire una diagnosi di
benignità o malignità, dal punto di vista sia clinico sia der- Follow-up dermoscopico e modificazioni
moscopico, e, in alcuni casi, anche istopatologico 31. Appar- nel tempo delle lesioni pigmentate
tengono a questo gruppo le lesioni melanocitiche in cui la dia-
gnosi differenziale tra nevo di Clark di tipo giunzionale e La necessità di sottoporre un paziente a esami clinici
melanoma in situ, o tra nevo di Spitz/Reed e melanoma spit- periodici deriva dalla duplice esigenza di monitorare un sog-
zoide è particolarmente difficile. In questi casi, le lesioni getto che presenta significativi fattori di rischio per lo sviluppo
dovrebbero essere asportate chirurgicamente o sottoposte a di un melanoma (e.g. storia personale o familiare di mela-
uno stretto monitoraggio dermoscopico (1-3 mesi) che per- noma, elevato numero totale di nevi ecc.) e di osservare l’e-
mette di apprezzare un eventuale accrescimento asimmetri- voluzione nel tempo di singole lesioni melanocitiche mode-
co della lesione stessa o modificazioni delle strutture der- ratamente atipiche, ma non tali da sospettare un melanoma.
moscopiche 32, 33. Recentemente è stata proposta una nuova Inoltre, il monitoraggio dermoscopico è particolarmente uti-
classificazione dermoscopica dei nevi di Clark, utile nella le nei soggetti che presentano un elevato numero di nevi,
selezione delle lesioni da sottoporre a escissione chirurgica 1. molti dei quali clinicamente atipici, la cui asportazione con-
È stato osservato, infatti, che un’iperpigmentazione eccen- temporanea sarebbe praticamente impossibile 1, 42, 43.
trica (periferica) e la coesistenza di 3 strutture nell’ambito del- In uno studio recente sono state descritte le caratteristiche
la stessa lesione (reticolare, globulare e omogenea) sono dermoscopiche dei nevi in accrescimento: su una casistica di
caratteristiche significativamente più frequenti nel melano- 1 612 nevi melanocitici comuni, il 5% dei nevi ha mostrato
ma; per tale motivo, queste lesioni dovrebbero essere aspor- un aumento delle dimensioni in un periodo di 12 mesi. Nel
tate 35. Per le lesioni con aspetto spitzoide, è stato descritto 50% di queste lesioni era possibile evidenziare un anello di
un modello di possibile evoluzione naturale nel tempo: da un globuli marroni simmetricamente distribuito alla periferia
pattern globulare a un pattern a stella che esplode («star- della lesione, espressione dell’attività proliferativa delle cel-
burst») 36, per poi andare incontro a una graduale scompar- lule neviche 44. Sebbene questo fenomeno fosse riscontrabile
sa delle strie periferiche e a una pigmentazione centrale più più comunemente in soggetti di età inferiore ai 20 anni, l’ac-
diffusa e omogenea 37, 38. In una percentuale di casi, il riscon- crescimento simmetrico di una lesione melanocitaria (in
assenza di altri segni di atipia) non è di per sé indicativo di bile delle cellule neviche 50-53. Risulta necessario, quindi,
malignità, come dimostrato dall’esame istologico condotto esaminare nuovamente queste lesioni 4-6 settimane dopo
su queste lesioni 44. Lesioni in accrescimento in soggetti l’esposizione solare, a causa della loro difficile differenzia-
adulti, soprattutto se in presenza dell’anello globulare peri- zione dal melanoma nel periodo immediatamente successi-
ferico, devono tuttavia essere attentamente seguite attraver- vo alle esposizioni solari stesse 50-53.
so un monitoraggio digitale stretto (3 mesi) o asportate 45. In generale, le lesioni che possono essere sottoposte a un
Altri studi hanno dimostrato l’efficacia del monitoraggio monitoraggio digitale nel tempo sono quelle solo lievemen-
digitale nell’individuare i pattern di modificazione delle te atipiche, piane e non rilevate e non devono avere una sto-
lesioni 46. I nevi atipici hanno mostrato essenzialmente un ria di variazioni morfologiche né presentare criteri melano-
accrescimento focale in assenza di importanti modifiche ma-specifici.
strutturali, mentre nei melanomi è stato rilevato un accre- Il follow-up non dovrebbe mai essere eseguito nelle lesio-
scimento focale, associato a modifiche della forma e com- ni nodulari che presentano caratteri di atipia, data l’impos-
parsa di caratteri dermoscopici quali punti neri irregolari, sibilità di escludere con certezza una diagnosi di melanoma
rete pigmentaria irregolare, strutture di regressione, strie nodulare. In questi casi, infatti, è sempre consigliata l’a-
irregolari, velo blu-biancastro 47. Quando a un esame der- sportazione chirurgica.
moscopico di follow-up si riscontrano modificazioni di cri-
teri dermoscopici, quali espansione o riduzione del reticolo
pigmentato, distribuzione o numero di punti neri, e/o aree di
Aspetti morfologici salienti e indicazioni
ipopigmentazione o di regressione, è sempre consigliabile l’a-
per la gestione clinica delle lesioni pigmentate
sportazione chirurgica. Analogamente, la comparsa di ulte-
di più difficile interpretazione
riori caratteri dermoscopici atipici, quali reticolo pigmen-
tato atipico, punti neri irregolari, strutture di regressione,
strie irregolari, velo blu-biancastro e pattern vascolare atipico, Precedentemente sono stati esaminati in dettaglio i crite-
sono indicativi di lesione sospetta che deve essere escissa ri dermoscopici melanoma specifici, che, quando osservati
chirurgicamente. in una lesione, devono far procedere a un’asportazione chi-
Inoltre Menzies et al. hanno dimostrato che, effettuando rurgica. In Tabella II 13, 14, 32, 34-36, 38, 40, 41, 54-70 sono ripor-
un follow-up a breve termine (in media 3 mesi) su 318 lesio- tati gli aspetti dermoscopici delle lesioni pigmentate che più
ni solo moderatamente atipiche, è stato possibile identifica- comunemente possono costituire dei falsi positivi o dei fal-
re ben 7 melanomi in stadio iniziale dermoscopicamente si negativi, nonché alcuni suggerimenti per un più accurato
«featureless», cioè che non mostravano criteri dermoscopi- inquadramento diagnostico e per una migliore gestione del-
ci atipici ma che la sola modificazione in un intervallo stret- le lesioni che generano problemi di diagnosi differenziale.
to di tempo ha permesso di diagnosticare 32. Per i nevi di Clark, come già accennato, è importante l’in-
Quando si effettua un follow-up di lesioni atipiche, vi dividuazione delle lesioni che presentano un’iperpigmenta-
sono, comunque, alcuni rischi da non sottovalutare. A tale pro- zione eccentrica (periferica) e delle lesioni in cui vi è la coe-
posito è stato recentemente dimostrato che il ricorso indi- sistenza di strutture reticolari, globulari e omogenee. Questi
scriminato al monitoraggio dermoscopico non è raccoman- nevi dovrebbero, infatti, essere asportati chirurgicamente,
dabile, in quanto la sua efficacia clinica dipende dall’espe- in quanto le stesse caratteristiche possono riscontrarsi anche
rienza dell’osservatore e dalla compliance del paziente e, nel melanoma 34, 35. Quando un paziente presenta lesioni
quindi, la sua adesione a un programma di monitoraggio nel multiple con aspetti atipici si può ricorrere all’escissione di
tempo 48. La scelta delle lesioni e dei pazienti da sottoporre quella/e maggiormente sospetta/e ed effettuare un follow-up
a follow-up digitale va, dunque, sempre valutata attenta- dermoscopico stretto (3 mesi) per le altre 32, 34. Un discorso
mente per non rischiare di perdere un melanoma 33. Recen- a parte meritano le lesioni con regressione di cui viene pro-
temente Carli et al. Hanno, infatti, dimostrato, in uno studio posto un modello di gestione in Tabella II 41.
randomizzato effettuato su 938 pazienti, che l’archiviazione I nevi di Spitz/Reed (nevi a cellule epitelioidi e/o fusate,
delle immagini dermoscopiche di lesioni equivoche si asso- compresa la variante pigmentata, prima considerata distin-
cia, da un lato, a una diminuzione di casi sottoposti a escis- ta, detta nevo di Reed), come precedentemente accennato,
sione chirurgica, dall’altro, a un rischio non trascurabile di possono presentarsi dermoscopicamente con una varietà di
melanomi iniziali non asportati 49. pattern: a stella che esplode, globulare, reticolare, omogeneo,
Infine, nel contesto delle variazioni dermoscopiche osser- ipopigmentato e atipico 37. Queste lesioni pongono spesso
vabili nelle lesioni melanocitiche, bisogna tener presenti problemi di diagnosi differenziale con un melanoma spit-
quelle dovute a esposizioni alle radiazioni ultraviolette, che zoide, dal punto di vista sia clinico-dermoscopico sia isto-
consistono in una maggiore pigmentazione e irregolarità logico. Per questo si consiglia l’escissione di qualsiasi lesio-
nella distribuzione del pigmento, un incremento delle dimen- ne che nell’adulto mostri un aspetto spitzoide 40. Nei pazien-
sioni dei globuli marroni, una diminuzione delle aree ipo- ti pediatrici, un nevo di Spitz/Reed che presenta aspetti tipi-
pigmentate e una minore visibilità del reticolo pigmenta- ci può essere sottoposto a uno stretto follow up, in modo da
rio 50-53. Questi cambiamenti morfologici sono, tuttavia, poter monitorare i diversi pattern di modificazione e evita-
transitori e legati presumibilmente a un’attivazione reversi- re inutili asportazioni di lesioni benigne 36, 38.
TABELLA II. — Aspetti dermoscopici salienti delle lesioni pigmentate che più comunemente possono costituire dei falsi positivi o dei falsi nega-
tivi, e suggerimenti per una migliore gestione clinica.
Lesioni pigmentate Aspetti morfologici salienti e indicazioni
Falsi positivi
1) Nevo di Clark con iperpigmentazio- Escissione se unico elemento; follow-up stretto (3 mesi) se più lesioni con aspetto simile nello stesso
ne eccentrica paziente 32, 34, 35
2) Nevo di Clark con regressione Escissione se regressione >50% della superficie lesionale; follow-up se regressione <10% lesione; escis-
sione se regressione 10-50% ma presenza contemporanea di aree bianche e di aree blu 41
3) Nevo di Spitz Escissione nell’adulto 40, nel bambino se aspetti tipici, stretto follow-up dermoscopico 36, 38
Falsi negativi
1) Melanoma che simula una delle
seguenti lesioni pigmentate:
— Nevo di Clark Follow-up a 3 mesi se in paziente con multiple lesioni atipiche 32, 34, 35; escissione se unico elemento
anche se lievemente atipico. Escissione se contemporanea presenza di strutture reticolari, globulari e omo-
genee 35
— Nevo di Spitz Escissione di qualsiasi lesione spitzoide nell’adulto 40 nel bambino stretto follow-up di lesioni con aspetti
tipici 36, 38
— Nevo dermico Criteri differenziali da valutare:
— pattern ad acciottolato, vasi a virgola e peli sono in favore di un nevo dermico 14
— asimmetria, velo blu, punti/globuli irregolari e pattern vascolare atipico sono in favore di un melanoma
anche in presenza di un pattern ad acciottolato 13. Mai follow-up in lesioni nodulari sospette
— Lesioni pigmentate del volto Criteri diagnostici da valutare 54:
— follicoli pigmentati asimmetrici
— strutture anulari-granulari
— strutture romboidali.
Escissione chirurgica o biopsia incisionale in aree sospette (grigio-blu) se lesioni estese
— Lesioni in sede acrale Escissione chirurgica delle lesioni che mostrano 70:
— pattern a creste parallele
— pattern atipici o multicomponenti
— Lesioni in sede ungueale Biopsia incisionale se si rinviene:55-57
— pigmentazione marrone di fondo e linee longitudinali da marroni a nere, irregolari
— micro-segno di Hutchinson
Follow-up negli altri casi meno dubbi 56
— Melanosi delle mucose Biopsia incisionale se lesioni con distribuzione irregolare del pigmento e colore variegato 58
Asportazione delle lesioni nodulari
— Nevo blu Escissione se storia clinica e aspetti dermoscopici dubbi 59, mai follow-up in lesioni nodulari sospette
Escludere una metastasi da melanoma 60
— Nevo congenito Follow-up attraverso immagini dermoscopiche di:61, 62
— intera lesione se possibile
— zone rappresentative del pattern architetturale
— bordi della lesione
— zone di particolare interesse 61, 62
Escissione chirurgica delle lesioni sospette o biopsia incisionale
— Nevo ricorrente Aspetti dermoscopici spesso atipici, fondamentale la storia clinica nel decidere se asportare o monitorare
nel tempo 63
— Nevo irritato Follow-up stretto (anche 1-2 settimane). Escissione chirurgica nei casi che non si risolvono
— Lentigo reticolare Reticolo pigmentato, prominente e molto scuro (anche nerastro) a maglie irregolari 64. Escissione chirur-
gica nelle lesioni sospette
— Carcinoma basocellulare Ricercare la presenza di: vasi arboriformi, aree a foglia d’acero, grandi aree ovoidali grigio-blu, multipli glo-
buli grigio-blu, aree a ruota di carro ed ulcerazione 65, 66 Asportazione chirurgica in ogni caso
— Cheratosi seborroica — valutare il numero di pseudocisti cornee e sbocchi simil-comedonici (numerosi nella cheratosi, pochi nel
melanoma) 67
— escissione delle lesioni sospette che mostrano caratteristiche quali falso reticolo pigmentario e strutture
pseudo-globulari 67-69
— Lesioni vascolari — Emangioma: differenziare le lacune blu-rosse (ben circoscritte nell’angioma) dalle milky red areas (non
ben circoscritte nel melanoma) 14
— Granuloma piogenico: escissione ed esame istologico nell’adulto
2) Melanoma con pattern aspecifico Escissione in assenza di criteri definiti per la diagnosi 14
3) Melanoma amelanotico Criteri diagnostici da valutare nelle lesioni rosa, che devono far propendere per un’escissione 29, 30
— lesione nodulare e/o ulcerata
— residui di pigmento, specialmente se di colore blu-grigio
— milky red areas (aree rosso lattescenti)
— pattern vascolare atipico (vasi punteggiati e/o lineari-irregolari)
4) Metastasi di melanoma — pigmentazione omogenea bluastra
— pigmentazione diffusa non omogenea marrone-bluastra
— pattern a globuli rosso-bluastri 60
I nevi dermici (Unna e Miescher) dermoscopicamente granulare, globulare (con globuli spesso allineati) o lineare-
sono caratterizzati frequentemente da una pigmentazione curvilineo, sovente parallelo, di colore marrone chiaro, bru-
omogenea (che a livello del volto assume l’aspetto di pseu- no o grigiastro 71. Appare, comunque, utile un follow-up di
doreticolo pigmentato), da un pattern ad acciottolato e da queste lesioni e di quelle che mostrano una pigmentazione lie-
vasi disposti a virgola 14. Spesso presentano i caratteri der- vemente irregolare. Nel caso di lesioni sospette, caratterizzate
moscopici tipici delle lesioni esofitiche: strutture papillari eso- da colore variegato e distribuzione irregolare del pigmento,
fitiche e cripte irregolari 14. Tuttavia, il riscontro di asim- la dermoscopia può permettere di identificare la zona più ati-
metria, velo blu-biancastro, punti e globuli irregolari e pat- pica dove praticare una biopsia incisionale 58.
tern vascolare atipico, deve far sospettare un melanoma 13. I nevi blu sono facilmente diagnosticabili quando mostra-
Non è mai consigliabile ricorrere a un follow-up in lesioni no la tipica pigmentazione omogenea bluastra, si riscontra-
nodulari quando si ha anche solo un minimo dubbio dia- no nelle sedi caratteristiche e senza storia di modificazioni.
gnostico. Tuttavia qualche dubbio di diagnosi differenziale con il mela-
Le lesioni pigmentate del volto si presentano all’esame der- noma può insorgere nelle lesioni che presentano aree bian-
moscopico con il caratteristico pseudoreticolo pigmentato, co-giallastre, indice di una fibrosi associata. Data l’importanza
dovuto alla distribuzione del pigmento attorno agli osti fol- delle strutture blu in dermoscopia, è sempre richiesta un’at-
licolari 14. I criteri che permettono di sospettare una lentigo tenta valutazione di tali aspetti, mentre l’asportazione è con-
maligna sono la presenza di strutture anulari-granulari (di sigliabile nei casi in cui la storia clinica di queste lesioni sia
colorito grigio-bluastro) e la pigmentazione asimmetrica dubbia o la dermoscopia anche solo lievemente sospetta 59.
degli sbocchi follicolari 54. Le strutture romboidali e le aree Inoltre, bisogna tenere presente che le metastasi da mela-
omogenee di invasione dei follicoli indicano, invece, una noma possono simulare un nevo blu 60.
fase più avanzata di progressione del melanoma (lentigo La dermoscopia risulta molto utile nello studio e nel fol-
maligna melanoma) 54. Quando si osservano questi caratte- low-up dei nevi congeniti. La presentazione dermoscopica di
ri, è bene procedere all’asportazione chirurgica; in caso di tali lesioni è eterogenea: il pattern più comune è quello ad
lesioni molto estese, si può procedere a una biopsia incisio- acciottolato, ma, frequentemente, è possibile osservare anche
nale, preferibilmente a livello delle zone che mostrano una un pattern multicomponente, per la presenza di colori mul-
pigmentazione bluastra. tipli, punti e globuli marroni, zone di reticolo pigmentato, aree
I nevi in sede acrale (a livello palmo-plantare) mostrano omogenee ipopigmentate e aree omogenee bluastre 61. Sono
un caratteristico pattern parallelo dovuto alla disposizione del stati recentemente descritti anche peculiari aspetti dermo-
pigmento lungo i solchi. In particolare, nei nevi acrali, si scopici come il reticolo a bersaglio, i globuli a bersaglio e i
osservano comunemente il pattern a solchi paralleli, a rete di vasi a bersaglio 62. In ogni caso, un monitoraggio attento
metallo e fibrillare, mentre il pattern a creste parallele è alta- delle immagini cliniche digitali dell’intera lesione, integra-
mente suggestivo di un melanoma acrale-lentigginoso 70. te dalle immagini dermoscopiche rappresentative del pat-
Le lesioni che mostrano dei pattern atipici o multicomponente tern architetturale, dei bordi della lesione e di zone di parti-
vanno comunque sottoposte a escissione chirurgica. colare interesse, può permettere di seguire nel tempo queste
Tra le lesioni a livello ungueale la diagnosi differenziale lesioni congenite e di individuare l’eventuale comparsa di
si pone essenzialmente con l’emorragia subungueale (storia caratteri atipici 61. In questi casi, se la lesione è di piccole
clinica di trauma e aspetto dermoscopico caratterizzato dal- dimensioni è consigliabile l’asportazione chirurgica men-
la presenza di aree tondeggianti ben circoscritte di colore tre in caso di nevi grandi o giganti è possibile effettuare una
nero-rossastro e da «blood spots» o punti di colorito rosso- biopsia incisionale nelle aree dubbie.
nerastro), con i nevi melanocitici (linee longitudinali rego- I nevi ricorrenti (o persistenti), spesso mostrano caratteri-
lari per spessore e parallelismo, su di un fondo marrone stiche dermoscopiche talmente bizzarre e atipiche da far sospet-
omogeneo) e con la melanonichia indotta da farmaci (pig- tare un melanoma, quali strie irregolari, punti e globuli irregolari
mentazione omogenea di colorito grigiastro con linee lon- in prossimità o nel contesto dell’area cicatriziale 63. Se i nevi
gitudinali regolari) 55. Appare utile, in questi casi, il follow- ricorrenti compaiono dopo un’escissione incompleta di un
up dermoscopico a conferma della diagnosi 56. Il melanoma nevo istologicamente non atipico, possono essere monitorati
subungueale, invece, si presenta dermoscopicamente con nel tempo. Quando non vi è certezza sulla precedente diagnosi
pigmentazione marrone di fondo e linee longitudinali da clinico-istopatologica, la lesione deve essere asportata chi-
marroni a nere, irregolari per spessore, parallelismo e colo- rurgicamente.
razione. È importante anche ricercare il micro-segno di Hut- Un altro utile campo di applicazione del monitoraggio
chinson (pigmentazione a livello della cuticola e della cute digitale riguarda i nevi irritati (da traumatismi, infezioni) o
periungueale, visibile solo all’esame dermoscopico) che, nevi di Meyerson 72 in cui un follow-up molto stretto (anche
anche se raro, deve far sospettare un melanoma 55, 57. Nei casi di 1-2 settimane) dopo trattamento locale può permettere di
sospetti si deve ricorrere a una biopsia incisionale che coin- dirimere il dubbio diagnostico.
volga anche la matrice ungueale. Un’altra lesione pigmentata che può mimare un melano-
Le melanosi labiali e genitali sono lesioni pigmentate beni- ma (in situ) è la lentigo reticolare (o «ink spot lentigo»), che
gne che si presentano dermoscopicamente con una pigmen- si riscontra frequentemente su cute intensamente foto-dan-
tazione diffusa di fondo con rinforzi del pigmento di tipo neggiata. Dermoscopicamente la lesione è caratterizzata da
un reticolo pigmentato, prominente e di colore marrone scu- pico 1-3, 14. In alcuni centri si impiega anche lo stereomi-
ro-nerastro, a maglie irregolari e sfrangiate, che tuttavia è croscopio, implementato da sistemi digitali con telecame-
uniformemente distribuito su tutta la lesione 64. Nelle lesio- re ad alta risoluzione (3 CCD) 3, 52, 53. L’attuale standard
ni dubbie è bene ricorrere all’escissione chirurgica. di riferimento, per quanto riguarda la fotografia dermosco-
Il carcinoma basocellulare, specie se pigmentato, può por- pica, è costituito dal sistema di acquisizione Dermaphot
re problemi di diagnosi differenziale con il melanoma. Gli (Heine Optotechnik, Herrsching, Germany) che garantisce
aspetti dermoscopici tipici del BCC sono i vasi arborifor- un ottimo potere risolutivo e un’elevata qualità di immagi-
mi, le aree a foglia d’acero, le grandi aree ovoidali grigio-blu, ne 73-75. Attualmente è disponibile in commercio una serie
i globuli multipli grigio-blu, le aree a ruota di carro e l’ul- di sistemi e strumenti di videodermoscopia digitale, che
cerazione, in assenza di reticolo pigmentato 65, 66. consente di ottenere, in alcuni casi, un’immagine di qualità
La cheratosi seborroica, specie nella sua variante acantoti- sovrapponibile allo standard 76, 77. È auspicabile che, in un
ca e pigmentata, può simulare un melanoma. Tipicamente, le futuro prossimo, le aziende si adeguino a tali standard, even-
caratteristiche dermoscopiche includono le pseudocisti cor- tualmente attraverso l’istituzione di una commissione ad
nee e gli sbocchi simil-comedonici, ma anche strutture a hoc per la valutazione e la validazione dei sistemi di video-
impronta digitale, e aree con aspetto cerebriforme con giri e sol- dermoscopia.
chi. Recentemente sono stati descritti come caratteristici del-
le cheratosi seborroiche i limiti nettamente demarcati e i bor-
di «a morsicatura concava» («moth-eaten borders») 68 osser- Le problematiche della refertazione
vabili soprattutto nelle cheratosi seborroiche in fase iniziale e/o dell’esame videodermoscopico
lentigo solari. Talvolta si possono, però, osservare anche un fal-
so reticolo pigmentato (nelle cheratosi seborroiche di tipo reti- Anche se attualmente non esistono a riguardo né una nor-
colare) e strutture pseudo-globulari 68, 69. Nelle lesioni dubbie mativa precisa né dati in letteratura, vogliamo farci portavoci
è consigliabile l’asportazione, nell’evenienza, sebbene rara, di una proposta di unificazione e standardizzazione del refer-
di un melanoma che simula una cheratosi seborroica 67. to che è opportuno rilasciare a seguito di un esame video-
L’esame dermoscopico delle lesioni di natura vascolare, dermoscopico.
attraverso la ricerca di criteri specifici, consente di esclude-
re il melanoma con elevata accuratezza. Gli emangiomi sono Alla luce delle responsabilità di ordine medico-legale, di
caratterizzati da un pattern lacunare, per la presenza di nume- deontologia professionale e, non ultimo, anche per un rico-
rose aree ovoidali ben circoscritte, di colore dal rosso al ros- noscimento completo della demoscopia quale esame stru-
so bluastro, denominate lacune rosse. Queste strutture vanno mentale di secondo livello, appare fondamentale il rilascio
differenziate dalle aree rosso-lattescenti, meno ben definite, di una refertazione idonea a seguito della prestazione spe-
che possono talvolta, ma in maniera specifica, essere osser- cialistica effettuata. Pertanto, nel referto di un esame video-
vate nel melanoma 14. Nel granuloma piogenico il pattern dermoscopico, suggeriamo di includere sempre i seguenti
lacunare può non essere facilmente riconoscibile, quindi è punti essenziali (criteri minimi):
consigliabile l’escissione con esame istologico nell’adulto. Gli — simmetria/asimmetria della lesione;
angiocheratomi sono caratterizzati da lacune di colore dal — aspetto globale;
rosso-bluastro al nero, associate ad aree cheratosiche bianco- — aspetti locali;
giallastre 14. Infine gli ematomi subcornei mostrano dermo- — conclusione diagnostica;
scopicamente un’area omogenea di colorito nerastro ma anche — indicazione sul trattamento.
un aspetto pseudo-parallelo o pseudo-globulare. Considerando i limiti attuali nella standardizzazione dei
diversi sistemi videodermoscopici (differente qualità del-
l’immagine e diversa risoluzione e qualità di stampa), rite-
Standard tecnologici in dermoscopia niamo per il momento che l’immagine dermoscopica stam-
pata possa essere rilasciata al paziente, a discrezione del
Il dermatoscopio e il videodermatoscopio rappresentano dermatologo, specificando le attuali problematiche tecno-
gli strumenti più utilizzati per eseguire l’esame dermosco- logiche.
play a key role in a better preselection of lesions to TABLE I.—Training set. Clinical features of histologically atypical nevi
be removed. An improvement of specificity of and common nevi (N=114). The two subsets of nevi (common and
atypical on histology) are largely comparable as to clinical cha-
melanoma screening by use of dermoscopy has been racteristics.
recently shown.4
Atypical nevi Common nevi Pearson’s
We investigated the possible role of dermoscopy in Clinical feature (N=68) (N= 46) χ2 test
selecting, within the pool of lesions submitted to ver-
ification biopsy according to their clinical features, Palpability 27/68 (40%) 23/46 (50%) 0.277
Macular-papular aspect 22/68 (32%) 10/46 (22%) 0.216
histologically banal nevi from those with histologic
Asimmetry
atypia. Many studies have demonstrated that clinical N 3/68 (4%) 2/46 (4%)
atypia and histologic atypia in nevi have poor corre- 1 axis 30/68 (44%) 22/46 (48%)
lation.5 This means that a clinically atypical nevi can 2 axis 35/68 (51%) 22/46 (48%) NS
be histologic common and viceversa.5 Since the risk of N Colours
histopathologic misclassification between nevi with 1 colours 14/68 (20.5%) 14/46 (30%)
2 colours 46/68 (68%) 28/46 (61%)
histologic atypia and early melanoma is likely to occur,6 3 colours 8/68 (12%) 4/46 (9%) NS
the exclusion of histologically atypical nevi from ver- Type of predominant colour
ification biopsy, once judged equivocal from a clinical Black 3/68 (4%) 2/46 (4%)
point of view, could be hazardous. Conversely, an Dark brown 34/68 (50%) 25/46 (54%)
Light brown 27/68 (40%) 15/46 (33%)
histopathologic misclassification between early Blue/grey 1/68 (1.5%) 2/46 (4%)
melanoma and common nevi, even if equivocal by Pink/reddish 3/68 (4%) 2/46 (4%) NS
clinical examination, is unlikely. The latter lesions are Border irregularity 51/68 (75%) 31/46 (67%) NS
those who would mostly benefit of a non invasive clas-
sification by dermoscopy in order to be left in place
without risk for the patient. The training set (68 atypical nevi and 46 common
nevi) was aimed to identify dermoscopy features asso-
ciated with histologic atypia. In this study phase the
Materials and methods observers were aware of the histologic diagnosis.
Since the criteria for entry the study was the selection
This study included 264 clinically atypical of the lesion for diagnostic verification, clinical fea-
melanocytic nevi, consecutively excised for diagnos- tures of nevi, either histologically common or atypi-
tic verification in the period January 2001-December cal, were those of clinical atypical lesions, i.e. show-
2002 at the First Dermatology Unit, Florence. ing some or all the ABCD features of melanoma.
A staff of pathologists with experience in diagnosis Table I shows in details clinical features of common
of melanocytic lesions classified the lesions in accor- and atypical nevi included in the training set. No sta-
dance with the criteria of the NIH Consensus Conference tistically significant difference in the frequency of
on Diagnosis and Treatment of Early Melanoma 7 as selected clinical parameters was found. Therefore,
common melanocytic nevi (compound and junctional the two subsets of nevi (common and atypical on his-
nevi, n=133) and melanocytic nevi with histologic tology) were largely comparable as to clinical char-
atypia (architectural disorders and cytological atyp- acteristics.
ia, n=131). Therefore, in this set of lesions, nevi with The training set analysis should enable us in iden-
histologic atypia represented 131/264 (49.6%) of tifying dermoscopic features significantly associated
cases. with histologic atypia.
Before excision, clinical and dermoscopic images The possible role of these features in removing
were obtained using an F50 Nikon camera with objec- nevi without histologic atypia from the pool of lesions
tive AF micro Nikkor 60. For dermoscopy, images were selected for excision on the basis of their clinical
obtained after oil application on the surface of the lesions features will be investigated by means of test set
using a Dermaphot objective (magnification ×10). analysis, with observers blinded as to histologic diag-
We randomly divided the series of lesions in a train- nosis.
ing set and a test set. The same two experienced Test set included 63 nevi with histologic atypia and
observers (AC and PN) examined both training and 87 nevi without histological atypia.
test sets. Dermoscopy terminology adopted in the study was
TABLE II.—Training set. Difference in the frequency of selected dermoscopic features between histologically common and atypical nevi (only
parameters with significant difference are shown).
Atypical nevi Common nevi Pearson’s
Dermoscopic feature (N=68) (N=46) χ2 test
TABLE VI.—Test set. Difference in frequency of selected dermoscopic features between histologically atypical and common nevi.
Atypical nevi Common nevi Pearson’s
Dermoscopic feature (N=63) (N=87) χ2 test NPV
TABLE VII.—Training set. Distribution of the score according to 7 - TABLE VIII.—Test set. Dermoscopic classification of histologically aty-
Point Check List and TDS according to ABCD rule dermoscopy in pical and common nevi according to “Hofmann-Wellenhof”: glo-
histologically atypical and common nevi. bal dermoscopic pattern.
Atypical nevi Common nevi Pearson’s Exact test
(N=63) (N=87) χ2 test NPV Global dermoscopic Atypical nevi Common nevi (Monte-
pattern (N=63) (N=87) carlo)
7-Point check list
<3 46/63 (73%) 76/87 (87.4%) Reticular 360/63 (57.1%) 39/87 (41%)
≥3 17/63 (27%) 11/87 (12.6%) P=0.026 62.2% Globular 1/63 (1.6%) 15/87 (17.2%)
Homogeneous 7/63 (11.1%) 8/87 (9.2%)
<2 27/63 (42.9%) 56/87 (64.4%) Reticular-globular 6/63 (9.5%) 5/87 (6%)
≥2 36/63 (57.1%) 31/87 (35.6%) P=0.009 66.6% Reticular-homogeneous 13/63 (20.6%) 18/87 (21.7%)
ABCD score Unclassified 0/63 (0%) 0/87 (0%)
<4.75 44/63 (69.8%) 71/87 (81.6%) P=0.093 NS
≥4.75 19/63 (30.2%) 16/87 (18.4%) 61.7%
<4 33/63 (52.4%) 58/87 (66.7%) P=0.077
≥4 30/63 (46.6%) 29/87 (33.3%) 59.2%
TABLE IX.—Training set. Dermoscopic classification of histologi-
cally atypical and common nevi according to “Hofmann-Wel-
lenhof”: distribution of pigmentation.
cy of global pattern nor in that of distribution of pig- Exact test
mentation between common and atypical nevi was Distribution Atypical nevi Common nevi (Monte-
of pigmentation (N=63) (N=87) carlo)
found dealing with test set (Table VIII, IX).
Uniform pigmentation 19/63 (30.2%) 28/87 (32.2%)
Central hyperpigmentation 9/63 (14.3%) 12/87 (13.8%)
Central hypopigmentation 7/63 (11.1%) 12/87 (13.8%)
Discussion and conclusions Eccentric peripheral hyper- 15/63 (23.8%) 19/87 (21.8%)
pigmentation
In recent years, dermoscopy proved to be able to Eccentric peripheral hypo- 7/63 (11.1%) 12/87 (13.8%)
pigmentation
increase the accuracy of melanoma diagnosis com- Multifocal hyperpigmenta- 6/63 (9.5%) 4/87 (4.5%) NS
pared to that achieved by visual examination alone.12, 13 tion and hypopigmenta-
Although further studies are still needed, it is con- tion
ceivable that dermoscopy reduce the false positive rate
in melanoma screening.4, 14
Among benign melanocytic lesions, verification diagnostic verification, excluding histologically com-
biopsy to exclude melanoma is currently undertaken mon nevi.
not only for Spitz nevi and nevi with histologic atyp- Since the risk of misclassification between nevi with
ia but also for histologically common nevi.4 As report- atypia and early melanoma by pathologist has been
ed by many studies, clinical features of a nevus do demonstrated by several authors,6, 15 a further reduc-
not correlate with histologic atypia.5 Therefore, even tion of false positives by means of avoid excision of
an histologically common nevus may show some or nevi with histologic atypia, when clinically doubtful,
all the ABCD signs of melanoma sometimes repre- seems to the contrary less desirable.
senting a cause of concern both for patient and physi- According to training set analysis, two dermoscop-
cian. ic features were more frequently found in nevi with his-
We sought to evaluate if dermoscopy may help to tologic atypia than in common nevi: atypical /promi-
achieve—compared to visual examination alone—a nent pigment network and regression features. This
better selection of melanocytic lesions to be excised for finding is in perfect agreement with the data provided
by a previous study of our group conducted on a dif- This scenario has been in part confirmed by test set
ferent series of lesions examined by another group of analysis: only atypical pigment network and seven
observers.16 point score ≥2 or ≥3 confirmed their different distrib-
Also the semiquantitative score assigned in accor- ution between the two subset of nevi with observers
dance with two of the most popular simplified algo- blinded as to histologic diagnosis. Neither regression
rithms for melanoma diagnosis, the ABCD rule of der- features nor the ABCD score were to the contrary
moscopy 9 and the new seven-point check-list,10 sig- longer associated with histologic atypia in the test set
nificantly differed between the two subset of nevi for analysis.
both the threshold values adopted for each method (4 Among the points of strength of this study we men-
and 4.75 for ABCD, 2 and 3 for seven point). This tion the design of the study, with a training set and a test
finding disagree with a previous study where no sig- set; this allows to verify prospectively to what extent
nificant difference between nevi with atypia and those what found in the training set by open observers is
without was found concerning ABCD score.16 Possi- confirmed in a new series of lesions by blinded exam-
ble explainations include a different source of lesions iners. Moreover, this study includes only nevi excised
(clinically equivocal and unequivocal lesion in the for diagnostic verification decided on the basis of clin-
previous study), and a different procedure adopted in ical features, thus approaching as far as possible the
the analysis of the data (comparison of median val- diagnostic setting found in practice. Being in this study
ues in the previous study, comparison among fre- the clinical characteristics of nevi with histologic atyp-
quencies in pre-established categories in the present ia not dissimilar to those without atypia we minimized
study). However, only the seven point score confirmed the risk of lesion’s classification influenced by clini-
a statistically significant difference between the two cal factors acting as confounders. Among the study’s
subsets of nevi according to test set analysis. weaknesses, we mention that fact that this study is
No difference in the frequency of dermoscopic sub- based on lesion’s classification on photographic
types of Clark nevi 11 was found. In this context one images, in a posteriori diagnostic setting
should take into account that our series was small and In order to investigate what consequences this find-
the data have to be interpreted cautiously. Since the ing may have in clinical practice, we calculated the
large number of categories proposed for the classifi- negative predictive value associated with each of the
cation of nevi according to Hofman-Wellenhof et al.,11 above-mentioned feature, i.e. the probability that a
our small series of lesions may not reach a sufficient nevus lacking these features eventually be histologi-
statistical power. Our data strongly cool down the cally common. Unfortunately, the NPV was not high-
expectations of this new classification of Clark’s nevi: er than 60% as average for any of the selected der-
In the opinion of the proposers “this classification moscopic features. This means that when an observ-
should be regarded not just as an academic morpho- er predict that a nevus lacking the above mentioned cri-
logic exercise but as a classification system that will teria of atypia is histologically common, it will be true
lead to a better understanding of the biological char- in 60% only of cases.
acteristics of these melanocytic nevi”.11 The fact that Further prospective, randomized studies should con-
no statistical difference in the frequency of the Hof- firm if the above-mentioned dermoscopic criteria asso-
mann’s classification subtypes has been found between ciated with histologic atypia in nevi, i.e. atypical net-
nevi with atypia and common nevi greatly limits its work, regression features, ABCD score and Seven
validity in the study of biological features of benign point score can help dermatologist in change the
melanocytic lesions. lesion’s management with fewer excision of clinical-
In sum, according to training set, observers may be ly equivocal but histologically common nevi.
able to identify—within a pool of nevi indistiguinsh-
able among them as to clinical features—nevi with
histologic atypia from those without atypia. The “pro- References
totypic” nevus with atypia would therefore be a nevus 1. English DR, Burton RC, del Mar CB, Donovan RJ, Ireland PD, Emery
showing atypical network and/or regression structures, G. Evaluation of aid to diagnosis of pigmented skin lesions in gener-
al practice: controlled trial randomised by practice. BMJ 2003;327:375.
that scores >2 in accordance with seven point check list 2. Carli P, De Giorgi V, Betti R, Vergani R, Catricala C, Mariani G et al.
and >4 in accordance with ABCD rule of dermoscopy. Relationship between cause of referral and diagnostic outcome in
pigmented lesion clinics: a multicenter survey of the Italian Multi- 10. Argenziano G, Fabbrocini G, Carli P, De Giorgi V, Sammarco E,
disciplinary Group on Melanoma (GIPMe). Melanoma Res Delfino M. Epiluminescence microscopy for the diagnosis of doubt-
2003;13:207-11. ful melanocytic skin lesions: comparison of the ABCD rule of der-
3. Gibbon KL. Pigmented lesion clinics – are they a waste of resources? matoscopy and a new 7-point check list based on pattern analysis.
Clin Exper Dermatol 1998;23:3-8. Arch Dermatol 1998;134:1563-70.
4. Carli P, De Giorgi V, Crocetti E, Mannone F, Massi D, Chiarugi A et 11. Hofmann-Wellenhof R, Blum A, Wolf IH, Piccolo D, Kerl H, Garbe
al. Improvement of malignant/benign ratio in excised melanocytic C et al. Dermoscopic classification of atypical melanocytic nevi (Clark
lesions in the “dermoscopy era”: a retrospective study 1997-2001. nevi). Arch Dermatol 2001;137:1575-80.
Br J Dermatol 2004;150:687-92. 12. Pehamberger H, Steiner A, Wolff K. In vivo epiluminescence
5. Annessi G, Cattaruzza MS, Abeni D, Baliva G, Laurenza M, Macchini microscopy of pigmented skin lesions. I. Pattern analysis of pig-
V et al. Correlation between clinical atypia and histologic dysplasia mented skin lesions. J Am Acad Dermatol 1987;17:571-83.
in acquired melanocytic nevi. J Am Acad Dermatol 2001;45:77-85. 13. Carli P, De Giorgi V, Giannotti B. Dermoscopy and early diagnosis of
6. Corona R, Mele A, Amini M, De Rosa G, Coppola G, Piccardi P et al. melanoma. The Light and the Dark. Arch Dermatol 2001;137:1641-4.
Interobserver variability of the histopathologic diagnosis of cuta- 14. Carli P, De Giorgi V, Chiarugi A, Nardini P, Weinstock MA, Crocetti
neous melanoma and other pigmented skin lesions. J Clin Oncol E et al. Addition of dermoscopy to conventional naked-eye examination
1996;14:1218-23. in melanoma screening: a randomized study. J Am Acad Dermatol
7. National Institute of Health Consensus Conference. Diagnosis and 2004;50:683-9.
treatment of early melanoma. JAMA 1992;268:1314-9. 15. Ferrara G, Argenziano G, Soyer HP, Corona R, Sera F, Brunetti B et
8. Argenziano G, Soyer HP, Chimenti S, Talamini R, Corona R, Sera F al. Dermoscopic and histopathologic diagnosis of equivocal melanocyt-
et al. Dermoscopy of pigmented skin lesions: results of a consensus ic skin lesions: an interdisciplinary study on 107 cases. Cancer
meeting via the Internet. J Am Acad Dermatol 2003;48:679-93. 2002;95:1094-100.
9. Stolz W, Riemann A, Cognetta AB, Pillet l, Abmayr W, Holzel D et al. 16. Carli P, De Giorgi V, Massi Giannotti B. The role of pattern analysis
ABCD rule of dermatoscopy: a new practical method for early recog- and the ABCD rule of dermoscopy in the detection of histologic atyp-
nition of melanoma. Eur J Dermatol 1994;4:521-7. ia in melanocytic naevi. Br J Dermatol 2000;143:290-7.
melanocitiche ha classificato le lesioni in accordo con i cri- La 7 – Point Checklist è un metodo basato sull’analisi di
teri della NIH Consensus Conference per la Diagnosi e il pattern semplificata; un punteggio totale ≥3 indica una lesio-
Trattamento del Melanoma Precoce 7 come nevi melanoci- ne maligna. Anche per questo algoritmo abbiamo usato due
tici comuni (nevi giunzionali e composti, n=133) e nevi differenti valori di cut-off: 3 e 2 punti.
melanocitici con atipia istologica (nevi con disordine archi- Infine sia il training set che il test set sono stati classificati
tetturale e atipia citologica, n=131). Quindi, in questo grup- in accordo con la classificazione dei nevi di Clark suggeri-
po di lesioni, i nevi con atipia istologica rappresentavano ta da Hofmann-Wellenhof et al. 11 che comprende i seguen-
131/264 (49,6%) dei casi. ti pattern globali: reticolare, globulare, omogeneo, o retico-
Prima dell’escissione, sono state ottenute le immagini cli- lare-globulare, reticolare-omogeneo, globulare-omogeneo
niche e dermoscopiche utilizzando una macchina fotografi- se ci sono due componenti dominanti. Riguardo la distribu-
ca Nikon F50 con obiettivo micro Nikkor 60. Per la dermo- zione della pigmentazione i nevi sono stati classificati con
scopia, le immagini sono state ottenute, dopo applicazione iperpigmentazione/ipopigmentazione centrale, iperpigmen-
di olio sulla superficie delle lesioni, usando un obiettivo tazione/ipopigmentazione eccentrica periferica, iperpig-
Dermaphot (ingrandimento 10×). mentazione/ipopigmentazione multifocale 11.
Abbiamo suddiviso casualmente la serie delle lesioni in un
training set e in un test set. Gli stessi due osservatori esper- Analisi statistica
ti (AC e PN) hanno esaminato sia il training che il test set.
Il training set (68 nevi atipici e 46 nevi comuni) aveva lo Per l’analisi statistica sono stati utilizzati test non para-
scopo di identificare le caratteristiche dermoscopiche asso- metrici (test del χ2, test esatto di Fisher quando appropria-
ciate con atipia istologica. In questa fase dello studio gli ti). Al fine di valutare il potere dei metodi dermoscopici
osservatori erano a conoscenza della diagnosi istologica. selezionati nell’identificazione dei nevi istologicamente
Poiché il criterio per l’entrata nello studio era la selezione del- comuni (senza atipia istologica), è stato calcolato il valo-
la lesione per verifica diagnostica, le caratteristiche clini- re predittivo negativo (NPV) (vero negativo/vero negati-
che dei nevi, sia istologicamente atipici sia comuni, erano vo+falso negativo). Il NPV rappresenta la probabilità che
quelle di lesioni clinicamente atipiche, quindi che mostravano un nevo definito «senza atipia istologica» mediante la der-
alcuni o tutti i criteri ABCD del melanoma. La Tabella I moscopia, sarà eventualmente confermato tale dall’esame
mostra in dettaglio le caratteristiche cliniche dei nevi comu- istologico.
ni ed atipici inclusi nel training set: non sono state trovate dif-
ferenze statisticamente significative nella frequenza dei para-
metri clinici selezionati. Quindi i due sottogruppi di nevi Risultati
(istologicamente comuni ed atipici) erano ampiamente com-
parabili dal punto di vista delle caratteristiche cliniche. Training set
L’analisi del training set dovrebbe permetterci di identi-
ficare le caratteristiche dermoscopiche significativamente Come atteso, i nevi con e senza atipia istologica non sono
associate all’atipia istologica. risultati differenti dal punto di vista clinico (Tabella I). Al con-
Il possibile ruolo di queste caratteristiche nell’escludere trario, questi due sottogruppi hanno mostrato differenze
i nevi senza atipia istologica dal pool di lesioni selezionate significative per quanto riguarda le caratteristiche dermo-
per l’escissione chirurgica sulla base delle loro caratteristi- scopiche.
che cliniche sarà valutato per mezzo dell’analisi del test set, Riguardo alla frequenza dei maggiori criteri selezionati sul-
in cui gli osservatori non sono a conoscenza della diagnosi la base della Consensus Conference del 2001, è stato evi-
istologica. denziato un reticolo pigmentario irregolare/prominente (per
Il test set comprendeva 63 nevi con atipia istologica e 87 esempio un reticolo con linee scure o spesse e maglie larghe)
nevi senza atipia istologica. nel 59% dei nevi con atipia istologica e nel 39% di quelli sen-
La terminologia dermoscopica adottata nello studio è sta- za atipia (P=0,039). I caratteri dermoscopici di regressione
ta quella dell’Internet Consensus Meeting, svoltosi nel 2000- (per esempio aree blu ed aree bianche) sono stati trovati nel
2001 9. 43% dei nevi con atipia istologica e nel 19,5% di quelli sen-
Sono stati anche testati gli algoritmi diagnostici (regola za atipia (P=0,010) (Tabella II). Nessuna differenza è stata
dell’ABCD della dermoscopia come pubblicata da Stolz et trovata per gli altri caratteri. Le Figure 1 e 2 mostrano le
al. 8) e la 7 – Point Checklist in accordo con Argenziano et maggiori caratteristiche trovate in nevi con atipia istologica.
al. 10. Riguardo agli algoritmi semplificati, i nevi con atipia isto-
Il TDS (Total Dermoscopy Score) ricavato dalla regola logica hanno raggiunto più frequentemente dei nevi comu-
dell’ABCD indica che la lesione è benigna se il valore è ni il valore >4,75 (soglia di sospetto) secondo la regola del-
<4,75, che la lesione è maligna se il valore è >5,45 e che la l’ABCD (43% vs 19,5%) (P=0,02) e il valore ≥3 (soglia di
lesione è dubbia se il valore è intermedio; il TDS per i nevi isto- malignità) in accordo alla 7 – Point Checklist (20,6% vs
logicamente atipici risulta frequentemente compreso fra 4,5 6,5%) (P=0,039) (Tabella III).
e 5,8. Abbiamo testato le nostre serie di lesioni melanocitiche Anche per quanto riguarda la classificazione dei nevi di
usando due differenti valori di cut-off del TDS (4,75 e 4). Clark riportata da Hofmann-Wellenhof è stata trovata una dif-
ferenza statisticamente significativa fra nevi con e senza ati- ca, quando siano dubbi clinicamente, sembra, al contrario,
pia istologica relativa sia ai caratteri globali (Tabella IV) sia meno auspicabile.
alla distribuzione della pigmentazione (Tabella V). Analizzando il training set è stato evidenziato che due
caratteristiche dermoscopiche ricorrono più frequentemen-
Test set te nei nevi con atipia istologica piuttosto che nei nevi comu-
ni: il reticolo pigmentario atipico/prominente e le strutture di
Nel test set la presenza di un reticolo pigmentario atipico regressione. Questa evidenza è in perfetto accordo con i dati
è risultata significativamente associata con l’atipia istologi- forniti da un precedente studio del nostro gruppo condotto su
ca (60,3% vs 42,3%), mentre non lo è stata la presenza del- una serie diversa di lesioni esaminate da un altro gruppo di
le strutture di regressione (Tabella VI). Secondo il NPV asso- osservatori 16.
ciato al reticolo pigmentario atipico (66,6%), l’uso di questo Anche il punteggio semiquantitativo, assegnato in accor-
parametro come marker per l’escissione, potrebbe compor- do con i due più popolari algoritmi semplificati, la regola
tare una diagnosi di falsi negativi in circa il 33%, cioè nevi dell’ABCD della dermoscopia 9 e la nuova 7 – Point Check-
con atipia istologica non asportati. list 10, differiva significativamente fra i due sottogruppi di
Riguardo agli algoritmi semiquantitativi, sia la regola del- nevi per entrambe i valori soglia utilizzati per ciascun meto-
l’ABCD sia la 7 – Point Checklist, hanno confermato il loro do (4 e 4,75 per l’ABCD, 2 e 3 per la 7 – Point Checklist).
possibile ruolo nel selezionare nevi con atipia da quelli comu- Questo risultato è in disaccordo con un precedente studio
ni (Tabella VII). Come si è verificato nel training set, anche dove non è stata rilevata nessuna differenza significativa, uti-
nel test set i nevi con atipia istologica hanno raggiunto più fre- lizzando la regola dell’ABCD, fra nevi con atipia e nevi sen-
quentemente il valore soglia di sospetto se comparati con i za atipia 16. Fra le possibili spiegazioni emerge la differente
nevi comuni. Il NPV oscillava fra il 59% per un valore soglia provenienza delle lesioni (nel precedente studio erano inclu-
di 4 (invece di 4,75) con la regola dell’ABCD ed il 66,6% per se sia lesioni clinicamente equivoche che lesioni non equi-
un valore soglia di 2 (anziché 3) con la 7 – Point Checklist voche), e una diversa procedura adottata nell’analisi dei dati
(Tabella VII). (confronto della mediana nello studio precedente, confronto
Nel test set, seguendo la classificazione dermoscopica dei fra frequenze in categorie prestabilite nel presente studio).
nevi di Clark secondo Hofmann-Wellenhof non sono emer- Tuttavia, analizzando il test set, solamente il punteggio del-
se differenze significative fra i due sottogruppi di nevi né la 7 – Point Checklist ha confermato una differenza statisti-
nella frequenza del tipo di pattern globale né in quella della camente significativa fra i due sottogruppi di nevi.
distribuzione della pigmentazione (Tabella VIII, IX). Analizzando i sottotipi dermoscopici dei nevi di Clark 11
nel test set non è emersa nessuna differenza significativa. In
questo contesto si può pensare che la nostra serie di lesioni fos-
Discussione e conclusioni se troppo piccola e che quindi i dati debbano essere inter-
pretati con cautela. È possibile che la nostra serie di lesioni sia
In anni recenti, la dermoscopia ha dimostrato di poter piccola per poter raggiungere un potere statistico sufficiente
incrementare l’accuratezza della diagnosi del melanoma dato il grande numero di categorie proposte per la classifi-
rispetto a quella ottenuta con il solo esame visivo 12, 13. Seb- cazione dei nevi da Hofmann-Wellenhof et al. 11. I nostri dati
bene ulteriori studi siano ancora necessari, è concepibile che attenuano molto le aspettative di questa classificazione dei nevi
la dermoscopia riduca il tasso di falsi positivi nello screening di Clark: nell’opinione dei proponenti «questa classificazio-
del melanoma 4, 14. ne dovrebbe essere guardata non solo come un esercizio
Nell’ambito delle lesioni melanocitiche, la verifica biop- morfologico accademico ma come un sistema classificativo
tica per escludere il melanoma, viene eseguita correntemente che condurrà ad una miglior conoscenza delle caratteristi-
non solo per i nevi di Spitz e per i nevi con atipia istologica, che biologiche di questi nevi melanocitici» 11. Il fatto che
ma anche per i nevi istologicamente comuni 4. Come ripor- non sia stata trovata nessuna differenza statisticamente signi-
tato da numerosi studi, i caratteri clinici di un nevo non cor- ficativa nella frequenza dei sottotipi della classificazione di
relano con i caratteri istologici 5; quindi anche un nevo isto- Hofmann-Wellenhoff fra nevi con atipia e nevi comuni limi-
logicamente comune può mostrare alcuni o tutti i segni del- ta fortemente la sua validità nello studio delle caratteristiche
l’ABCD del melanoma, rappresentando talvolta una causa di biologiche delle lesioni melanocitiche benigne.
ansietà sia per il paziente sia per il medico. Riassumendo, secondo il training set, gli osservatori pos-
Abbiamo cercato di valutare se la dermoscopia può aiutare sono essere in grado di identificare, all’interno di un pool di
a raggiungere, rispetto al solo esame visivo, una miglior nevi non distinguibili fra loro per le caratteristiche cliniche,
selezione delle lesioni melanocitarie da sottoporre ad escis- nevi con atipia istologica e nevi senza atipia. Il «prototipo»
sione per verifica diagnostica, escludendo i nevi istologica- di nevo con atipia dovrebbe quindi essere un nevo che pre-
mente comuni. senta un reticolo pigmentario atipico e/o strutture di regres-
Poiché il rischio di misclassificazione da parte dei pato- sione, che ha un punteggio >2 secondo la 7 – Point Check-
logi fra nevi con atipia e melanoma iniziale è stato dimo- list e >4 secondo la regola dell’ABCD della dermoscopia.
strato da parecchi Autori 6, 15, una riduzione ulteriore di fal- Questo scenario è stato in parte confermato dall’analisi del
si positivi evitando l’ escissione di nevi con atipia istologi- test set: con i due osservatori non a conoscenza della diagnosi
Figure 1.—Pattern of dermo-epidermal junction and proteins implicated in the pathogenesis of inherited epidermolysis bullosa.
formation after minimal traumatism. The adnexial From a clinical point of view, the bullous manifes-
structures could be involved, resulting sometimes in a tations of epidermolytic EB tend to resolve without
partial or complete absence. any scars or milia, and generally don’t affect extracu-
Depending on the ultrastructural level within which taneous areas with the exception of the oral mucosa
the cleavage plane of the blister occurs, we can clas- (Figure 2-4). Epidermolytic EB is divided into 4 major
sify epidermolytic, junctional and dermolytic EB. This subgroups (Table I), each of them with characteristic
is possible with immunohistochemical assays and with aspects (Table II).
electronic microscopy. In junctional EB blisters resolve with difficulty and
In epidermolytic EB, the molecular defect involves tend to result in atrophic lesions without retractions or
keratins K5 and K14 and plectin, a protein which is also milia; in some subtypes the extracutaneous involvement
present in the neuromuscular plaque, inducing a cleav- (mucosa of the gastroenteric, respiratory and geni-
age at the basal level of the epidermis. tourinary tract) could be impressive and give rise to
In junctional EB the altered molecules are laminin severe complications which could also provoke death.
5 (chain alfa 3, beta 3, gamma 2), collagen XVII and Dermolytic EB types are characterized by scarring,
the integrins alfa 6 and beta 4; the cleavage is at the lev- which in time could cause retractions and contrac-
el of lamina lucida. tures of limbs and sometimes also esophageal stric-
In dermolytic EB the molecular defect involves col- tures.2
lagen VII and the cleavage occurs below lamina den- Until now epidemiological studies about EB have
sa 1 (Figure 1). been mostly incomplete or regard only small samples
Figure 2.—Image showing epidermolysis bullosa of the back. Figure 3.—Infant affected by epidermolysis bullosa.
matoses and the explanation of how to fill in the recruit- — estimate of the incidence of most severe com-
ment cards. plications and study of their management;
— assessment of the causes of deaths.
Prospects The register will help to address the important chal-
The register will give the opportunity to integrate dif- lenges offered by EB in all medical fields; from a
ferent competencies in the study of EB and, on the methodological point of view it would be possible to
other hand, the possibility to build a representative develop new research instruments or to evaluate old
cohort of EB cases. The advantages will be as follows: ones (for example, it would be possible to evaluate
— estimation of genetic heterogeneity within homo- the validity of single patient trials in therapeutic ques-
geneous diagnostic groups, and study of the relation- tions).
ship between specific mutations, phenotypes and clin- The register could also promote, together with patient
ical evolution in a specific diagnostic group. The study associations, information campaigns about EB.
of genetic heterogeneity is important for the develop-
ment of prenatal diagnosis;
Materials and methods
— possibility to organize studies and therapeutic
trials with a large group of patients, which make these
studies and trials statistically significant;
Definition of register
— possibility to estimate the incidence of some In biomedical research “register” means: system-
clinical subgroup in certain geographic areas, studying atic and continuous collection of information regard-
the possible differences between these areas and orga- ing all reported cases of a given disease. There are 2
nizing studies of genetic epidemiology; kinds of registers: population registers and hospital
registers. In population registers the main interests are Regarding this, every center had its own laboratory
descriptive epidemiology (assessment of incidence) or collaborated with a laboratory which could per-
and the organization of medical resources available form histological, immunohistochemical, ultrastruc-
for a specific disease. tural and molecular assays.
Hospital registers (like that of EB), on the other Other hospital divisions and clinics joined these
hand, assess clinical problems such as the descrip- first reference centers in time, and so the collection
tion of the medical evolution of a disease or the def- web over the territory got bigger and wider.
inition of its prognosis. These kinds of registers also In the centers a new figure was created: the mon-
allow the creation of a patient group, which is avail- itor (who already exists in the GISED). This figure is
able for etiological, biological and therapeutic stud- a dermatologist with experience in EB, making it
ies. possible to carry out a widespread targeted survey.
The validity of data obtained from a register depends The 80 monitors, who took part in the registry gave
on the completeness of the information contained: so easily available and prompt information about the
the validity of a hospital register depends on the pos- disease to all ambulatorial dermatologists, called
sibility of containing all the cases observed in the observers, distributed all over Italy. These observers,
structure. who numbered between 350 and 500 per year, rep-
If there are registered cases of disease which are of resented a grassroots web of information over the
good quality and with complete information and if whole territory, which has identified and reported to
they regard all the cases seen in the past, it is possible the nearest monitor all cases compatible with a diag-
to use them for the register although the information nosis of EB.
was collected before the setting up of the registry (ret-
rospective registry). This information is very useful Patient recruitment
if someone wants to reconstruct the natural history of
a disease over a long period. Previous to patient recruitment an informative cam-
paign for dermatologists was carried out: training
Structure of the registry courses in genodermatoses, with an average of 400
participants per year, were organized and informative
The Italian registry of EB, a hospital register, has material about these rare diseases was distributed
been proposed to all Italian centers interested. Dur- (“Project Genodermatoses”).
ing the first stage of the project, all the cases known to Moreover, a promotional campaign for the general
the participant centers until 1993 were collected. Dur- population was organized: gadgets were distributed
ing the second stage, the register continued its activi- in the streets of many cities and articles about this der-
ty by registering all new cases diagnosed. matosis were published in different magazines. All
The structure of the registry envisages a center for this was done with the help of the Italian Lions Club
the coordination of all data. In this center the Derma- organization. Essential both for financial help and for
tological Clinic of Bergamo is responsible for the epi- marketing was the contribution of the TV program
demiological aspects while the CMCE of Milan con- “Telethon”, which has made it possible to collect a
trols the clinical aspects and manages the whole pro- conspicuous amount of money for the creation of many
ject, collecting the data coming from all members tak- scholarships.
ing part in the registry. Four supra-regional centers
refer to this coordination center: CMCE of Milan, Isti- Instruments for data collection
tuto Dermopatico dell’Immacoloata (IDI) of Rome,
Pediatric Dermatology Unit of the Hospital of Bari Report cards were developed where physicians have
and the Dystrophic Epidermolysis Bullosa Recessiva to enter the personal data of the patient, the familiar-
Association (DEBRA) of Catania. Their first task has ity of the disease, the clinical history (symptoms,
been to collect all patients present in the territories of diagnostic procedures and therapies carried out) and,
pertinence, which are respectively the North of Italy, if possible, the supposed type of EB affecting the
the Center, the South and the Islands. These centers also patient.
had to undertake laboratory assessments if necessary These report cards were distributed to all members
to confirm the diagnosis of the different EB sub-types. of the project during the meetings or by mail.
Epidermolytic EB 192 28
— Koebner 75 10.8
— Weber-Cockaine 67 8.5 Junctional EB
— Dowling-Meara 50 8.2 (67, 10%)
— With muscular dystrophy 1 0.2
Junctional EB 67 10
— Non-Herlitz 46 5.8
— Herlitz 12 2.3
— With pyloric atresia 9 1.6
Dermolytic EB 438 62
— Cockaine-Touraine 159 24.5
— Hallopeau-Siemens 182 29
— Non Hallopeau-Siemens 91 8.8
EB unclassifiable 9 —
N.B.: Unclassified EB are not calculated for incidence and prevalence.
Dermol. EB (438, 62%)
Koebner
(38%)
Figure 6.—Table of data concerning epidermolytic EB. These percentages refer Figure 7.—Table of data concerning the junctional EB. These percentages refer
to total number of epidermolytic EB and not to the total of cases picked up. to the total number of junctional EB and not to total cases collected.
Table III shows epidemiologic data using the new In Italy, before the present collection, incidence and
classification. prevalence data were not available and were estimat-
ed on the basis of foreign data.
The Italian Registry enables a widespread sampling
Discussion of patients with EB to be carried out, recruiting also the
highest possible number of milder and paucisympto-
Knowledge of the epidemiology of hereditary EB is matic cases (i.e. familiar mild forms of palmo-plantar
approximate for several reasons: Epidermolytic EB recruited by peripheral- dermatol-
1) Only few countries have worked on this kind of ogists or by the Centers of Military Medicine) that
studies and among these are Japan,3 Finland,6 North- often in this kind of investigation are underestimated
ern Ireland,3 South Africa,7 Sweden and Norway,8 because of the relative paucity of their symptoms.
Scotland and Great Britain 9 and recently the USA.3 Our information reflects the real situation of patients
2) The epidemiologic studies considered parts of with EB in Italy and this is very important for social,
the population or only some regions of a country. Some clinical and scientific purposes.
studies also considered only one subset of EB Knowing the clinical features of EB and how they are
3) In general, data are old and/or not recently revised. spread all over Italy, we are able to organize medical
centers for the management of all these patients with
All these factors don’t allow us to know the situation a chronic disease; that’s why the General Institute of
of all the patients with EB in a country accurately. Health promoted this study and now the Italian Reg-
For example, in Croatia only 56 patients of 50 fam- istry of EB is part of the Register of Rare Diseases of
ilies were considered suggesting an incidence for EBDr the Ministry of Health.
H-S of 19.2/1milion newborns.10 From a scientific point of view all the data are a rich
In Norway, in 1995, the incidence of Epidermolyt- store of knowledge about all the features of this pathol-
ic EB was estimated to be 42 cases/1million without ogy:
considering the different clinical subtypes of Epider-
— clinical features and all their variants in every
molytic EB.
group or subgroup of EB;
In the USA the prevalence was obtained consider-
— traditional and molecular diagnostic trials;
ing the data from the American DEBRA: 327 new-
borns with EB from 1986 to 1991 with an incidence of — study of recurrent or ancestral mutations in the
16.62/1milion newborns,3 these results are not com- Italian population;
plete because they consider only the severe forms of — examination of recurrent pathologies, especial-
EB, excluding milder subtypes. ly cancer, and management of their prevention, ther-
Later, in the USA, methods for recruitment were apy and follow-up.
reinforced and an incidence of 19.60/1milion new- Finally, in perspective, we can hypothesize a sig-
borns was obtained: 10.75 with EBE, 2.86 with EBDd, nificant impact in the strategy of genetic counseling
EBDr and EBJ 2.04 each. which should classify EB patients following the mol-
We note that in Croatia the incidence of EBDr H-S ecular classification in order to find all carriers in the
was 47 times more than in the USA (19.23 vs 0.43) families of EB affected patients and to perform mol-
because of different methods for epidemiologic stud- ecular prenatal diagnosis when requested in lethal or
ies in different countries. very severe forms of EB.
In the USA in 1990 the prevalence was 2 044 patients At this point we remember that 70 mutations were
(8.22/1milion). It is very important to consider that our discovered in Italian patients with EBJ and EBD in the
prevalence data (10.1) are very similar to the data report- 2 main laboratories in Rome (Istituto Dermopatico del-
ed in the USA Registry and underline the relevance of l’Immacolata) and Brescia (Institute of Genetics).
the 2 Registries, even in the presence of a different
socio-sanitary and geographical environment. Never- Mortality rates
theless, the recruitment of patients in the foreign Reg- Until today it was possible to make a rough calcula-
istries does not follow an adequate sampling of the pop- tion of the mortality rate only in patients of the Center
ulation given that the recruitment itself does not refer to of Inherited Diseases of Milan representing 44.7% of
peripheral Centers distributed in the whole territory. all the patients considered in Italy: 18 patients died in
TABELLA V—Mortality of patients at Inherited Cutaneous Disease The rarity of these genodermatoses and their sever-
Center (Milan). ity, considered from the human, medical or social point
Number of deaths of view, forced us to create a structure devoted to the
(period 1992-2002)
on the basis collection of all data regarding EB. From the epi-
of epidermolysis demiological data, we can derive the geographical dis-
bullosa subtypes
tribution of the patients nationally and its relationship
Epidermolytic — with medical and social organizations.
Junctional 8 EBs are genetically determined diseases with genet-
Dermolytic 10
ic variability much greater than clinical and the respec-
Total 18 tive data are available for anyone interested in these
fields at any level.
We can hypothesize a significant impact in the strat-
the 13 years of the survey in a group of 263 patients egy of prevention, especially for the identification of
(mortality rate = 6.8%). Of these, 8 had an EBJ and the mutations in all EB families in order to find carri-
10 an EBD (Table V). Of the patients with EBJ, 2 had ers and avoid consanguineous marriages. Compari-
EBJ with pyloric atresia and 6 had the variant of Her- son with the epidemiological data of other Registries
litz, of these 2 died when they were 6 and11 year-old, may be of great utility. Finally, the medical staff of
and 6 did not pass the first year of life. The most fre- the Italian Registry of EB promotes a European Reg-
quent causes of death were infections, especially in istry of Epidermolyss Bullosa.
EBJ, and metastasis from squamous cell carcinomas of Acknowledgments.—The compilation of the Italian Registry of Hered-
the skin ( 8-10 patients with EBD died in adult age). The itary Epidermolysis has been made possible by the contribution of about
last 2 EBD patients died soon after birth due to sepsis. 600 Italian dermatologists that worked together giving their time and
experience to this project. We thank all contributors, wishing to have them
again as companions in the future projects of other epidemiological stud-
Complications ies on genodermatosis.
Il Registro potrà fungere da catalizzatore per affrontare pro- Ereditarie di Milano, l’Istituto Dermopatico dell’Immacolata
blemi complessi all’interfaccia tra differenti discipline; da un (IDI) di Roma, la Cattedra di Dermatologia Pediatrica del-
punto di vista metodologico potranno essere sviluppati stru- l’Ospedale di Bari e la Dystrophic Epidermolysis Bullosa
menti di ricerca originali o potranno essere valutati stru- Recessiva Association (DEBRA) Italia con sede a Catania.
menti esistenti (ad esempio, valutazione della validità di La loro funzione primaria è stata quella di individuare e rac-
disegni del tipo «single patient trial» in ambito terapeuti- cogliere i pazienti provenienti dalle aree del territorio ita-
co). Il Registro potrà inoltre promuovere, in collaborazione liano di loro competenza, rispettivamente il Nord, il Cen-
con le Associazioni dei pazienti, un’attività di informazione tro, e il Sud peninsulare e insulare. Questi centri dovevano
e documentazione sulle EB. inoltre ricorrere, quando indicato, ad appropriate indagini
di laboratorio per la conferma diagnostica del tipo di EB
incontrata. A questo proposito, si sottolinea che ogni centro
Materiali e metodi di riferimento era in contatto o disponeva di un laboratorio
di analisi per l’esecuzione di indagini istologiche, immu-
noistochimiche, ultrastrutturali e molecolari.
Definizione di registro A queste strutture di riferimento si sono poi affiancati
Si definisce «registro», nella ricerca biomedica, la rac- divisioni ospedaliere e cliniche universitarie, ampliando così
colta sistematica e continua di alcune informazioni su tutti i la rete di arruolamento sul territorio.
casi notificabili di una malattia. Si possono distinguere regi- Nell’ambito di questi centri è stata istituita la figura del
stri di popolazione e registri ospedalieri. Nei registri di popo- «monitor» (già operanti nella rete GISED), cioè quella di
lazione prevalgono gli interessi di epidemiologia descrittiva uno specialista dermatologo, che, dimostrando una cono-
(stime di incidenza nel tempo) e di pianificazione delle risor- scenza specifica di queste patologie, ha permesso di racco-
se sanitarie disponibili per la patologia in esame. I registri gliere una casistica ampia e selezionata. Gli 80 monitor che
ospedalieri, come è quello delle EB, sono invece maggior- hanno preso parte al registro hanno inoltre fornito una con-
mente orientati alla valutazione di problemi clinici come la sulenza pronta e facilmente raggiungibile ai colleghi der-
descrizione della storia evolutiva della malattia e la definizione matologi ambulatoriali, denominati «observers» e distribui-
della prognosi, permettendo inoltre la costituzione di una ti sul territorio italiano. Questi, in numero variabile da 350
base di pazienti per studi eziologici, biologici (banche bio- a 500 per anno, hanno costituito una rete informativa capil-
logiche) o di terapia. L’interesse e la riproducibilità delle lare su tutto il territorio, identificando e segnalando al più vici-
informazioni ottenute in un registro dipendono dalla com- no «monitor» o centro clinico regionale tutti i casi certi o
pletezza della registrazione, per cui la validità di un registro compatibili con diagnosi di EB.
ospedaliero dipende dalla possibilità di segnalare tutti i casi
osservati presso l’istituzione. Reclutamento dei pazienti
Tuttavia, quando sia garantita una buona qualità e com- Il reclutamento dei pazienti è avvenuto mediante una cam-
pletezza delle informazioni retrospettive e sia possibile recu- pagna informativa rivolta ai dermatologi, nell’ambito della
perare informazioni su tutti i casi di malattia, è possibile uti- quale sono state organizzate riunioni di aggiornamento cli-
lizzare anche i casi diagnosticati in un definito periodo pre- nico, che hanno raccolto in media 400 partecipanti per anno,
cedente l’avvio del Registro (registro retrospettivo). L’utilizzo ed è stato stampato materiale didattico in cui erano descrit-
di tali informazioni da tali casi è particolarmente utile quan- te le più importanti caratteristiche di queste rare malattie
do si voglia ricostruire la storia naturale della patologia in esa- (Progetto Genodermatosi).
me su di un lungo periodo di tempo (studi di coorte in par- Inoltre è stata avviata una campagna promozionale anche
te retrospettivi). nei confronti della popolazione generale, mediante la distri-
buzione di gadgets nelle piazze e la pubblicazione di artico-
Struttura del Registro li informativi sui diversi quotidiani, organizzata in coopera-
zione con il Multidistretto Lions Clubs Italia. Fondamenta-
Il Registro Italiano delle EB è stato proposto come regi-
le, sia in termini economici che di risonanza pubblica, è sta-
stro su base ospedaliera a tutti i centri italiani interessati. In to anche il contributo derivato dalla trasmissione televisiva
una prima fase sono stati raccolti tutti i casi noti ai Centri par- «Telethon», che ha permesso di raccogliere una cospicua
tecipanti fino al 1993. Successivamente il Registro ha pro- quota di fondi utilizzati per il finanziamento di borse di ricer-
seguito la sua attività attraverso la segnalazione di tutti i ca.
nuovi casi diagnosticati (casi incidenti).
La struttura del Registro prevede la presenza di un centro
Strumenti per la raccolta dei dati
di coordinamento dei dati, gestito dalla Clinica Dermatolo-
gica di Bergamo per la parte epidemiologica e dal CMCE di Sono state sviluppate delle schede informative in cui veni-
Milano per la parte clinica, col compito di gestire e control- vano richiesti i dati anagrafici del paziente, la familiarità per
lare l’intero progetto e raccogliere tutti i dati forniti dai diver- tali malattie, la storia clinica (sintomi riferiti, indagini dia-
si componenti del progetto stesso. A questo fanno riferi- gnostiche eseguite e terapie intraprese) e, ove possibile, una
mento 4 centri sovraregionali: il Centro Malattie Cutanee diagnosi orientativa per il tipo di EB espressa dal probando.
Le schede sono state distribuite a tutti i collaboratori del Il registro italiano rimane comunque, costantemente ope-
progetto, o durante gli incontri di aggiornamento o median- rativo 4.
te mezzo postale a chi ne facesse richiesta. La distribuzione per tipo e sottotipo di EB, basata sulla più
recente classificazione di tali genodermatosi 5, evidenzia
Dati utilizzati per l’analisi per le forme epidermolitiche 192 casi, circa il 28% del tota-
le; all’interno di questo raggruppamento i valori percentua-
Per stimare la prevalenza e l’incidenza delle EB nel nostro li dei diversi sottotipi di EB oscillano tra 8,2% per la Dow-
paese, le analisi sono state eseguite su tutti i dati disponibi- ling-Meara e 10,8% per la forma generalizzata di Koebner
li del Registro italiano dal 1991 al 2002. (Figura 6). Le EB giunzionali hanno formato una casistica di
Le diagnosi si sono basate sulla concordanza con specifici 67 pazienti, pari al 10% del totale (Figura 7); la variante
criteri clinici e di laboratori descritte in letterature e ampia- non-Herlitz costituisce il 5,8% dei casi. È importante segna-
mente validate dall’utilizzo in tutto il mondo. lare che nei 9 casi (1,6%) di EB giunzionale con atresia pilo-
rica, è stata individuata la mutazione corrispondente.
Approccio all’analisi Le forme dermolitiche costituiscono la parte preponderante
Lo studio di popolazione si è basato su tutti i pazienti della casistica del registro italiano con 438 casi, pari al 62%
affetti da EB facenti parte del Registro, sui quali fossero del totale. In quest’ambito la variante recessiva grave di Hal-
disponibili dati informativi adeguati. lopeau-Siemens con il 29% dei casi sommata a quella domi-
La diagnosi di ciascuna categoria principale di EB è sta- nante di Cockaine-Touraine con il 24,5%, costituiscono ben
ta confermata sulla base della sede di formazione del distac- il 53,5% di tutti i casi (Figura 8).
co dermo-epidermico identificabile a livello ultrastrutturale
con l’immunofluorescenza e la microscopia elettronica, e Incidenza e prevalenza
sulla trasmissione genetica della malattia e, dove effettuata, Nel corso del biennio 1997-98, preso come biennio cam-
anche sulla diagnosi di biologia molecolare (mutazione). pione, sono stati segnalati 21 nuovi casi di bambini nati vivi
I pazienti sono stati progressivamente suddivisi nei prin- e affetti da EB. Nello stesso periodo i nati vivi e sani ammon-
cipali tipi e sottotipi di EB di seguito riportati seguendo la tavano nel nostro paese a 1 044 340. Il valore di incidenza che
nuova classificazione per le EB redatta dalla Consensus Con- ne è derivato è di 20,1 nati affetti per milione di nati vivi. Se
ference di Chicago del 1999: si considerano i principali gruppi di EB, troviamo che le for-
— EB epidermolitiche: Koebner, Weber-Cockaine, Dow- me dermolitiche in questi due anni mostravano un’inciden-
ling-Meara, epidermolitiche con distrofia muscolare associata. za pari a 12,4 nati affetti per 1 000 000 nuovi nati. Per le
— EB giunzionali: non-Herlitz, Herlitz, giunzionale con giunzionali e le epidermolitiche il valore di incidenza è lo stes-
atresia pilorica. so ed è pari a 3,8.
— EB dermolitiche: Cockaine-Touraine, Hallopeau-Sie- La prevalenza, calcolata al 31 dicembre 1998, era pari a
mens, Non-Hallopeau-Siemens. 10,1 pazienti affetti per milione di abitanti (calcolata su una
popolazione di 57 679 855).
L’incidenza viene calcolata in base al numero dei nati vivi
Applicando la nuova classificazione, l’indagine epide-
affetti da EB per 1 000 000 nati in Italia nel biennio 1997-98,
miologica definitiva fornisce i dati raccolti nella Tabella III.
presi come biennio campione.
Il calcolo della prevalenza si è basato sulla determinazio-
ne di tutti pazienti vivi affetti da EB nel corso dell’ ultimo
anno dello studio, preso come anno campione. Discussione
pazienti affetti da EB in quel determinato paese. Per esem- vista medico-sanitario sia per gli aspetti prettamente scien-
pio, in Croazia sono stati esaminati solo 58 pazienti di 50 tifici.
famiglie, suggerendo un’incidenza per la forma dermolitica Nel primo caso, conoscendo le caratteristiche cliniche
recessiva di Hallopeau-Siemens di 19,2 affetti per milione di delle EB, e la loro distribuzione nel territorio si possono
nati vivi 10. In Norvegia, nel 1995, è stata calcolata un’inci- organizzare centri sanitari con strutture congrue alla gestio-
denza delle EB epidermolitiche pari a circa 42 casi per milio- ne di questi malati che sono portatori di una patologia cro-
ne, non considerando però i diversi sottotipi della forma nica. Proprio per questa necessitá l’Istituto Superiore di
stessa. Sanitá, ha stimolato lo sviluppo di tale indagine epidemio-
Negli Stati Uniti la prevalenza è stata calcolata basando- logica e a oggi i dati del Registro Italiano delle EB fanno
si su dati forniti dalla DEBRA americana: è stato infatti parte del Registro Italiano delle Malattie Rare del Ministe-
riportato un totale di 327 nati affetti da EB nel periodo 1986- ro della Salute.
1990, con un’incidenza pari a 16,62 nati per milione di nasci- Da un punto di vista scientifico la casistica raccolta rap-
te 3. In realtà questi dati sono relativi a una maggioranza di presenta un grosso bagaglio informazionale su tutti gli aspet-
casi di pazienti affetti dalle forme più severe, mentre gran par- ti della patologia:
te dei casi meno severi non erano noti al progetto. I redatto- — Aspetti clinici e loro varianti all’interno dello stesso
ri del Registro USA, nel tentativo di fornire una stima più gruppo o sottotipo.
accurata, hanno perciò migliorato negli anni successivi le
metodiche di reclutamento e di sviluppo di centri regionali — Aspetti diagnostici tradizionali e molecolari.
di riferimento. Usando questo approccio, l’incidenza com- — Studio delle mutazioni ricorrenti ed ancestrali della
plessiva di EB è risultata pari a 19,60 nuovi casi per milio- popolazione italiana.
ne di nascite, con una quota maggiore di EB epidermolitiche — Valutazione delle patologie ricorrenti nei pazienti con
(10,75), seguite dalla EB dermolitica dominante (2,86), dal- particolare riguardo ai tumori ed alla loro prevenzione e tera-
la recessiva e dalla EB giunzionale (2,04 ciascuna). È inte- pia.
ressante notare che l’incidenza stimata per la EB dermoliti- Si prospetta infine un impatto significativo nella strategia
ca tipo Hallopeau-Siemens in Croazia sia all’incirca 47 vol- della consulenza genetica la quale prevede di disporre del-
te (19,23 vs 0,43) più alta di quella osservata negli Stati Uni- la classificazione molecolare dei soggetti affetti per indivi-
ti e ciò è spiegato proprio dai differenti sistemi di arruola- duare i portatori fra loro consanguinei e gli incroci a rischio,
mento dei pazienti e della precisione di tale raccolta. e infine per rendere possibile la diagnosi prenatale moleco-
La prevalenza complessiva di EB ereditaria negli Stati lare per ciascuna delle famiglie a rischio per EB letali o gra-
Uniti nel 1990 è stata stimata essere 2 044 pazienti, corri- vemente invalidanti A questo proposito ricordiamo che sono
spondenti ad un tasso di prevalenza di 8,22 casi di EB per state individuate circa 70 mutazioni nei pazienti italiani affet-
milione di abitanti. È importante sottolineare che la nostra ti da epidermolisi bollosa giunzionale e dermolitica, nei 2
casistica e il nostro dato assoluto di prevalenza (10,1) sono laboratori di riferimento italiani di Roma (Istituto Dermo-
molto simili a quelli riferiti dal Registro statunitense e riba- patico dell’Immacolata e di Brescia, Dipartimento di Gene-
disce la validità di entrambi gli approcci fatte salve le diffe- tica Medica dell’Università di Brescia).
renze sociali socio-sanitarie e geografiche. Si fa notare che
comunque la raccolta della casistica finora utilizzata all’estero Dati di mortalità
non segue un campionamento adeguato della popolazione, in
quanto la raccolta dei casi non è stata affidata a centri di Fino ad oggi è stato possibile effettuare una stima dei dati
riferimento periferici ben inseriti in ogni regione del territorio. di mortalità esclusivamente sui pazienti afferenti al Centro
Nel nostro Paese, finora, i dati relativi all’incidenza o pre- Malattie Cutanee Ereditarie di Milano, che costituiscono il
valenza di queste genodermatosi non erano disponibili, ma 44,7% della casistica complessiva: su 263 pazienti, sono
erano desunti in modo proporzionale da quelli degli altri stati registrati 18 decessi (tasso di mortalità = 6,8%), di cui
Paesi. 8 pazienti erano affetti da EB giunzionale e 10 da EB der-
Il Registro Italiano con la sua organizzazione ha permes- molitica (Tabella V); non si sono verificati decessi di pazien-
so un campionamento sul territorio quasi in modo capillare ti con EB epidermolitica. Dei pazienti con EB giunzionale,
dei pazienti affetti da EB, identificando anche un numero 2 erano affetti dalla variante associata ad atresia del piloro e
significativo di casi molto modesti di EB epidermolitiche 6 dalla variante di Herlitz: tra questi ultimi, 2 pazienti sono
(forme familiari fruste di EB epidermolitiche palmo-plantari deceduti tra i 6 e gli 11 anni, mentre 6 non hanno superato
individuate dai dermatologi del SSN a cui i pazienti si rife- l’anno di vita. Tra le più frequenti cause di morte si segna-
rivano per altre patologie oppure diagnosticate nei Centri di lano le complicanze infettive (soprattutto nelle varianti giun-
Medicina Militare) che spesso, in questo tipo di indagini, zionali) e le metastasi a partenza da carcinomi spinocellulari
non riescono a essere individuati proprio per la esiguità del- (presenti in 8 dei 10 soggetti con EB dermolitica, variante
le manifestazioni cliniche. Hallopeau-Siemens, deceduti entrambi in età adulta; gli altri
La disponibilitá di informazioni sufficientemente rappre- 2 pazienti affetti da EB dermolitica sono deceduti poco dopo
sentative della reale situazione dei pazienti affetti da EB nel la nascita per sepsi). I dati che si riferiscono ai decessi rife-
nostro paese è estremamente importante sia da un punto di riti dagli altri Centri di reclutamento saranno elaborati ed
esposti in successive comunicazioni di aggiornamento del una variabilità genetica ben più ampia di quella clinica; dati
Registro. di qualunque natura così ottenuti, sono disponibili a chiun-
que ne sia a qualsiasi titolo interessato. Si prospetta inoltre
Complicanze un impatto significativo nella strategia della prevenzione, la
quale prevede di disporre della classificazione molecolare dei
Sono state descritte numerosissime complicanze nei soggetti affetti per individuare i portatori fra loro consan-
pazienti affetti da EB ereditarie: i dati disponibili sono rela- guinei, per individuare i matrimoni a rischio e, infine, per ren-
tivi a due delle più frequenti e severe (sviluppo di carcinomi, dere possibile la diagnosi molecolare di tutte le famiglie ita-
stenosi esofagea) e rappresentano quindi solo una stima par- liane affette.
ziale rispetto alla loro reale incidenza. In virtù di questa prerogativa, i dati ottenuti potranno esse-
Nella casistica dei pazienti del Centro Malattie Cutanee re confrontati e scambiati con quelli di altri Paesi. Lo staff
Ereditarie di Milano, 7 pazienti su 263 (pari al 2,7%) hanno medico del Registro italiano ha proposto infatti in numero-
sviluppato carcinomi cutanei: tra questi, 2 sono deceduti in si sedi congressuali e istituzionali la creazione di un Registro
seguito allo sviluppo di metastasi. In 6 casi si trattava di car- Europeo delle Epidermolisi Bollose Ereditarie
cinomi spinocellulari; in un solo paziente era presente un
carcinoma basocellulare.
Inoltre, 25 pazienti tra quelli afferenti al CMCE di Mila-
no (N=263) erano affetti da stenosi esofagea, ovvero una Riassunto
percentuale pari al 9,5%.
Anche per le complicanze, i dati di riferimento degli altri Obiettivo. Attualmente in Italia non esiste uno studio epi-
Centri sono in via di rielaborazione. demilogico completo sulle Epidermolisi Bollose (EB) ere-
ditarie: la necessità di avere una stima accurata della casisti-
ca italiana ha favorito la costituzione di un Registro nazionale,
Conclusioni che ha permesso di raccogliere tutti i casi notificabili di malat-
tia, con importanti implicazioni nell’ambito delle conoscen-
ze cliniche dell’EB, per lo sviluppo di strumenti di diagnosi
Le stime di in incidenza e prevalenza sopra riportate sono prenatale e per l’avvio di studi di epidemiologia genetica.
rappresentative della reale situazione italiana per una serie di Metodi. Abbiamo costituito un registro su base ospedaliera
motivi. In primo luogo, si ritiene che tutti i casi più gravi che, in una prima fase, ha raccolto i casi già noti ai centri par-
siano stati raccolti e conteggiati e, in secondo luogo, anche tecipanti dal 1985 al 1993, e, successivamente, ha prose-
i casi relativi alle forme di EB meno gravi sono stati quasi guito con la segnalazione dei nuovi casi incidenti, fino al 31
completamente individuati grazie alla rete informativa capil- Dicembre 2002. Il Registro prevedeva la presenza di un cen-
lare creata sul territorio. Infatti, nessun altro registro ha potu-
tro di coordinamento dati (Clinica Dermatologica di Berga-
to disporre di un campionamento così completo; in questo
mo), di 3 centri sovraregionali (CMCE di Milano, IDI di
modo solo una percentuale minima, non in grado di altera-
Roma, Ospedale di Bari) che hanno raccolto i pazienti pro-
re significativamente il valore di incidenza, sarebbe sfuggi-
venienti rispettivamente dal Nord, Centro e Sud del Paese e
ta alla raccolta.
della DEBRA Italia.
Comunque le cause di questo sia pure modesto «bias»
Risultati. Sono stati notificati in tutto 697 casi e 9 casi
risiedono nel livello socio-culturale dei soggetti affetti e dei
non ulteriormente classificabili, costituiti da un 28% di EB
familiari, dalla esiguità del quadro clinico, dalla inconsape-
epidermolitiche, 10% di EB giunzionali e 62% di EB der-
volezza di essere affetto da EB e da ultimo dalla mancata dia-
gnosi. molitiche. L’incidenza delle EB al 31 Dicembre 2002 era di
La rarità di tali Genodermatosi e la loro gravità, intesa 0,1 pazienti affetti per milione di abitanti; la prevalenza, cal-
sia da un punto di vista umano sia sanitario ed economico, colata al 31 dicembre 2002, era pari a 10,1 pazienti affetti per
rendeva obbligatoria l’istituzione di una struttura atta a rac- milione di abitanti.
cogliere tutte le informazioni possibili su queste materie. Conclusioni. Tali stime epidemiologiche sono rappre-
Dalla disponibilità dei dati epidemiologici sopra esposti sentative della situazione italiana e tracciano una distribuzione
si può evidentemente derivare la distribuzione geografica geografica della malattia sul nostro territorio, con un impat-
della malattia sul territorio nazionale e la sua interferenza nel- to significativo nella strategia della prevenzione.
la organizzazione degli interventi clinici assistenziali. PAROLE CHIAVE: Epidermolisi Bollosa - Registro - Inciden-
Le EB sono malattie geneticamente determinate e con za - Relevanza.
Aim. The incidence of melanoma is rising steadily in countries 1Unit of Dermatology, Department of Clinical Medicine and
with white populations and, despite all attempts at treatment, Immunological Science
a considerable proportion of patients with malignant melanoma University of Siena, Siena, Italy
die of the disease. Primary prevention is, therefore, important 2Department of Surgery and Bioengineering
to reduce mortality at present. Here we report the results of a University of Siena, Siena, Italy
case-control study of melanoma risk factors conducted in Tus-
cany (Italy) in 2002-2003.
Methods. One-hundred-forty Italian subjects who underwent
surgical exeresis of non familial cutaneous malignant melanoma
and 280 age- and gender-matched controls filled in a stan-
dardized questionnaire about occupational and recreational
sun exposure, underwent complete skin examination by a der-
T he incidence of melanoma is rising steadily in
countries with white populations and, despite all
attempts at treatment, a considerable proportion of
matologist to assess the number of nevi and presence of clini- patients with malignant melanoma (MM) die of the
cally atypical nevi, eye color, hair color and Fitzpatrick pho- disease.1-4 Early diagnosis and primary prevention are,
totype. Moreover skin color was measured with a Minolta CR- therefore, the only way to reduce mortality at present.
300 colorimeter. Univariate and stepwise logistic regression
statistical analysis were performed to analyze differences in Many advances in early diagnosis have been made
variables between melanoma patients and control subjects. through innovative non invasive techniques, such as
Results. We demonstrated a highly significant difference digital dermoscopy analysis (DDA), which have shown
between controls and melanoma patients in our study: in nevi the importance of objective numerical parameter mea-
number and presence of atypical nevi, constitutional skin col- surements.5 Less progress seems to have been made
or (Fitzpatrick phototype was completely explained by colori- with primary prevention, despite the fact that instru-
metric variables of skin color) and eye color.
Conclusion. We agree with what was recently proposed by oth- ments for objective numerical evaluation of impor-
ers that objective skin color measurements must be combined tant phenotypic characteristics are now available.
with phenotype parameters and sun exposure history for exact Features known to be correlated with melanoma
assessment of individual risk risk include eye color, hair color, tanning ability, freck-
KEY WORDS: Cutaneous melanoma - Risk factors - Colorimeter - ling, nevus number, skin phototype and skin colour.6,
Skin color. 7 Skin color and phototype characterise skin biotype.8
jective, non reproducible and non quantifiable. The TABLE I.—Frequency counts of categorical risk factors together with
increasing availability of colorimeters now makes it statistical significances (HS=highly significant, P<0.01; S=signifi-
cant, P<0.05; NS=not significant, P>0.05) of χ2 test, Fisher exact test
possible to objectively evaluate skin color in an easy and Spearman correlation analysis applied to contingency tables.
and largely reproducible manner.10, 11
Risk factor Categories Controls Melanomas Totals
Here we report the results of a case-control study of
melanoma risk factors conducted in Tuscany (Italy) Occupational exposure Minor 20 6 26
in 2002-2003. The aim of the study was to assess the χ2 (NS) A few years 16 8 24
Spearman (NS) Part-time 20 8 28
significance of risk factors commonly associated with Most of time 8 10 18
MM in a representative sample of the Tuscan popula- Full-time 216 108 324
Recreational exposure None 40 16 56
tion, combining objective measurement of skin color χ2 (NS) Minor 152 54 206
with other known data acquisition methods (ques- Spearman (NS) Medium 76 70 146
tionnaire and dermatological examination). Strong 12 0 12
Number of nevi and High-risk 76 32 108
presence of atypical nevi Medium-risk 164 44 208
χ2 (NS) Low-risk 40 64 104
Materials and methods Spearman (NS)c
Fitzpatrick phototype I 16 4 20
χ2 (NS) II 88 60 148
Selection of patients and controls Spearman (NS) III 120 74 194
IV 56 2 58
From October 2002 to May 2003 we studied all sub- Eye color Fair (green, blue) 40 46 94
jects (49 men, 91 women, total 140) of native Italian Fisher exact (S) Dark (brown, black) 240 94 326
Spearman (S)
origin from Tuscany who underwent surgical exeresis Hair color Fair (red, blond) 48 26 74
of non familial cutaneous MM and non acral lentigi- Fisher exact (NS) Dark (brown, black) 232 114 346
Spearman (NS)
nous melanoma. Twenty four patients had nodular Freckles No 192 80 272
melanoma and 84 had superficial spreading melanoma. Fisher exact (NS) Yes 88 60 148
Their age and gender distributions were similar to Spearman (NS)
Sunburn No 180 74 254
those of the Tuscan Cancer Registry from 1985 to Fisher exact (NS) Yes 100 66 166
1987. A group of 280 age- and gender-matched con- Spearman (NS)
trols of native Italian origin living in Tuscany was
evaluated in the same period. The control group con-
sisted of subjects chosen by random sampling from strong). Patients were also asked to recall episodes of
the computerized demographic files of Siena, Arezzo sunburn in infancy or adolescence (yes/no). Complete
and Grosseto hospitals. These files contained all the skin examination was performed by a dermatologist to
data required for the present study of subjects attend- assess the number of nevi, distinguishing 3 categories:
ing the dermatology clinics. Subjects with a history less than 10, between 10 and 30, and more than 30. Eye
of phototherapy or skin tumors were excluded from the color was recorded as fair (green-blue) or dark (brown-
control group. The control group may, of course, have black), hair color as fair (red-blond) or dark (brown-
contained subjects who will develop melanoma, how- black), Fitzpatrick phototype as I, II, III or IV and
ever, since the recent mean prevalence of melanoma in freckling (as yes/no). The exact description of cate-
Tuscany is very low (68 cases per million), we regard gories is shown in Table I.
them as normal, though low-risk would be a more
appropriate term. Semi-quantitative risk factors
less than 15 acquired nevi. Clinically atypical nevi used instead of the χ2 test. The Spearman correlation
were defined as acquired macular or slightly palpa- coefficient was also computed to check statistically sig-
ble nevi with a minimum of 3 of the following 5 cri- nificant associations between melanoma and the cate-
teria: diameter 5 mm or more, asymmetrical shape, gories of ordinal variables used. Colorimetric variables
ill-defined border, irregular brown pigmentation, and were described statistically as mean, standard devia-
erythema. Nevi showing only 1 or 2 criteria were tion (SD) and range for all cases and separately for
counted as normal nevi, although histological features melanoma patients and controls. Univariate differences
of dysplasia can sometimes be found in these nevi. between groups were tested by F statistics. Stepwise
logistic regression analysis was then carried out with all
Quantitative risk factors 14 variables (covariates) to identify a statistically sig-
nificant minimum subset of variables with the highest
Six quantitative variables representing objective possible power in discriminating melanoma patients
skin color were also considered. Skin color was mea- from controls and quantifying risk. Logistic discrimi-
sured with a Minolta CR-300 colorimeter consisting of nation is generally preferable to linear discrimination in
a detector and a microcomputer. The detector contains small samples, especially when distributions are sus-
a pulsed xenon arc lamp in a mixing chamber and pro- pected to be non-Gaussian. In logistic regression the
vides diffuse illumination over the sample to be ana- dependent variable is binary, i.e. with only 2 possible val-
lyzed. Six high-sensitivity silicon photocells, filtered ues, in our study melanoma/control. The method
to match the Commission International d’Eclairage assumes that the posterior probabilities P1 and P2 of
standard observer response in a double-beam feed- group membership follow the logistic model:
back system, measure incident and reflected light. The
CR-300 detects any slight deviation in the spectral eV
P1 = 1 + eV
power distribution of the pulsed radiation and corrects 1 + eV
it automatically. The opening of the detector is fitted
with an applicator so that dermal vessels are not com- 1
P2 = 1 - P1 = 1 + eVV
pressed. The CR-300 expresses the results in 5 differ- 1+e
ent color systems. We chose the Yxy system because where V is a linear function of one or more indepen-
it gives parametric color measurements and is widely dent variables, that is:
used in dermatology. After 15 min acclimatization in
a room with air conditioning at 18°C, skin color was V = b0 + b1x1 + b2x2 + ... + +bnxn
measured on the upper medial quarter of the buttock where x1, x2, ..., xn are the n independent variables and
(constitutional color) and on the cheek (facultative b0, b1, b2, ..., bn the corresponding model parameters
color), taking care not to press the detector heavily to be estimated from experimental data.
onto the surface, which could cause ischemia. The The ratio of probabilities
chromameter was calibrated between individuals. The P1 = eV
color measurement was read 3 times and averaged. P1 = eV
Two terns of variables Yxy were, therefore, measured P2 = eV
for each subject, specifically 3 colorimetric values, expresses the risk of group 1 (melanoma patients) with
Yc, xc and yc, for constitutional skin color and 3 more respect to group 2 (healthy subjects). The exponen-
colorimetric values, Yf, xf and yf, for facultative sun- tial quantities ebi (i=1,2, ..., n) are known as odds ratios.
exposed skin color. Supposing the variables (risk factors) to be linearly
uncorrelated, the odds ratio represents the contribution
Statistical analysis of unit variable to relative risk. Therefore, for dichoto-
mous variables binary coded 0 or 1, the odds ratio is
Fourteen variables were analyzed for involvement simply the relative risk of the category coded 1 with
with melanoma risk. Frequency count and contingency respect to the category coded 0. For qualitative vari-
tables were calculated for each categorical variable and ables with n categories, we have n-1 odds ratios relat-
the χ2 test was used to analyze differences in variables ed to the remaining category taken as reference. To
between melanoma patients and control subjects. For interpret odds ratios of quantitative variables it is con-
2×2 tables, the more powerful Fisher exact test was venient to standardize them, that is to transform them
into z-scores with 0 mean and unit SD. Odds ratios TABLE II.—Descriptive statistics for colorimetric variables and Fisher
can then be interpreted as representing an increase of statistics significance of differences between control and melano-
ma cases: HS=highly significant, P<0.01; S=significant, P<0.05;
one SD from the mean value of the variable. NS=not significant, P>0.05.
In the presence of confusing variables which may
Colorimetric Standard
affect the relative risk due to causes not related to the variables
Group Mean
deviation
Min Max
study (for example sample distortions in age or gender),
estimates of odds ratios related to real risk factors can Yc Total 38.27 4.3 22.62 46.93
Fisher (S) Melanoma 39.09 3.3 30.86 46.93
be corrected by including these variables in the analy- Control 37.46 5 22.62 46.55
sis. Their inclusion should be decided on the basis of Xc Total 0.3591 0.0096 0.3354 0.3885
Fisher (HS) Melanoma 0.3557 0.0075 0.3354 0.3822
a preliminary univariate analysis for testing their effec- Control 0.3625 0.010 0.3456 0.3885
tive statistical influence on relative risk. Yc Total 0.3424 0.0066 0.3300 0.3648
In the stepwise process, an independent variable is Fisher (HS) Melanoma 0.3398 0.0059 0.3300 0.3576
Control 0.3449 0.0063 0.3334 0.3648
added to or removed from the model at each step on the YF Total 27.53 4.5 19.08 38.51
basis of a statistical criterion. Many statistical criteria Fisher (S) Melanoma 26.65 4.3 19.42 38.27
for inclusion or exclusion of variables are available Control 28.40 4.5 19.08 38.51
XF Total 0.3826 0.011 0.3539 0.4076
in the following 2 main configurations: Fisher (NS) Melanoma 0.3830 0.011 0.3539 0.4045
— forward, starting (step 0) with all the variables out Control 0.3823 0.0095 0.3619 0.4076
YF Total 0.3440 0.0074 0.3230 0.3643
of the model and adding them stepwise; the removal Fisher (NS) Melanoma 0.3432 0.0061 0.3277 0.3616
process can only begin when at least 2 variables have Control 0.3449 0.0071 0.3230 0.3643
been entered in the model;
— backward, starting with all the variables in the
model and removing them stepwise. Results
The process stops when addition or removal of vari-
ables no longer improves statistical significance. The Frequency counts of categorical variables are shown
subset of variables entered in the model is then consid- in Table I. Univariate statistically significant differ-
ered for interpretation of the multivariate model. We ences between control and melanoma subjects are also
used the criterion of maximum likelihood ratio in the for- reported for each categorical risk factor (P-value of
ward configuration. The Hosmer-Lemeshow test was χ2 or Fisher-exact test). Spearman correlation analy-
used to evaluate the fit of the logistic multivariate mod- sis assessed statistically significant associations
el step by step. An associated value of P=1 indicated per- between risk factors and melanoma. Highly signifi-
fect fit and P < 0.05 indicated 95% statistical significance cant differences between controls and cases were found
of disagreement between model and experimental data. for the 3 classes of number of nevi and presence of
Values of P between 0.05 and 1, therefore, demonstrate atypical nevi and for Fitzpatrick phototype (χ2 test,
a statistically significant fit. A classification matrix was P<0.01). Recreational sun exposure and eye color gave
formed by assigning each case to the group having a less significant differences (χ2 or Fisher exact test,
probability greater than 0.5. The percentage of correct P<0.05). Hair color type, freckles, sunburn and occu-
classification was calculated. Univariate logistic regres- pational sun exposure did not show significant differ-
sion was also obtained from stepwise results at step 0. ences (χ2 or Fisher exact test, P>0.05). A statistically
Any undesired confusing effect of age and gender on significant ordinal association with melanoma was
melanoma risk was also examined by univariate logis- only found for a number of nevi and the presence of
tic regression. Odds ratios and 95% confidence intervals atypical nevi (Spearman, P<0.01) and eye color (Spear-
(CI) were evaluated to establish the relative risk of man, P<0.01).
melanoma by uni- and multivariate models, for statis- Table II shows descriptive statistics for colorimetric
tically significant variables. For this purpose, quantita- variables and Fisher test for statistical comparison of
tive colorimetric variables were standardized, so that melanoma and control cases. Significant differences
odds ratios represented the relative risk associated with were found in constitutional colorimetric variables xc
an increase of one SD from their mean value. and yc (P<0.01) and in constitutional, Yc, and facul-
Statistical analysis was performed using SPSS sta- tative, Yf, reflectances (P<0.05). No statistically sig-
tistical software. nificant differences were found in facultative colori-
metric variables xf and yf (P>0.05). Univariate analy- TABLE III.—Univariate logistic regression. Odds ratios and 95%
sis showed that the major colorimetric factor related to confidence intervals (CI) are only reported for statistically signi-
ficant (P<0.05) variables.
probability of developing melanoma was chromatic-
ity of unexposed skin, followed by reflectance of unex- Reported Odds 95% CI
Risk factors Catogories
posed and chronically exposed skin. Univariate logis- category ratios Lower Upper
tic regression of age and gender failed to reveal sta-
tistical significance, indicating that it is not necessary Eye color Fair Dark 2.4 1.1 5.3
Number of nevi and Medium risk Low risk 0.64 0.27 1.5
to correct for confusing effects of these variables on presence of atypical nevi High risk 3.8 1.4 10
melanoma risk. Fitzpatrick phototype I IV 7 0.50 98
The results of univariate logistic regression applied II 19.1 2.3 156
III 17.3 2.1 139
to the 14 variables investigated are shown in Table III. Yc * 1.5 1 2.1
Only risk factors giving a statistically significant xc * 0.44 0.29 0.66
odds ratio (P>0.05) are reported. It was found that fair yc * 0.39 0.25 0.60
Yf * 0.67 0.47 0.94
eyes are associated with a significantly greater risk of
melanoma than dark eyes (odds ratio 2.4, 95% CI *Odds ratios of quantitative colorimetric variables represent an increase of one stan-
dard deviation with respect to the mean
1.1-5.3). Referring to the class number of nevi and the
presence of atypical nevi, an increased risk differ-
ence was demonstrated for high-risk class in com-
parison with a low-risk class (odds ratio 3.8, 95% CI TABELLA IV.—Multivariate stepwise logistic regression. Odds ratios
and 95% confidence intervals (CI) are only reported for statistically
1.4-10), whereas medium-risk class does not supply significant (P<0.05) variables.
appreciable risk differences. Although odds ratios of
95% CI
Fitzpatrick phototypes had large CI indicating poor Step N. Risk factors Categories
Reported Odds
accuracy in phototype estimation, the risk associat- category ratios Lower Upper
ed with types I-III was much greater than that asso-
1 yc * 0.20 0.088 0.44
ciated with type IV. The fairest constitutional skin 2 Number of nevi Medium risk Low risk 0.83 0.29 2.40
color is also associated with increased risk of and presence of High risk 6.74 1.85 24.60
melanoma: an increase of one SD in reflectance Yc atypical nevi
3 Yf * 0.33 0.18 0.60
leads to a significant increase in risk (odds ratio 1.5, 4 Fitzpatrick I IV 11.3 1.36 92.90
95% CI 1-2.1) and the same increase (one SD) in phototype II 12.1 1.38 105.00
chromaticity xc and yc is associated with a significant III 0.65 0.027 15.70
5 Recreational Minor Null 1.35 0.35 5.20
decrease in risk (odds ratios: xc=0.44, 95% CI 0.29- exposure Medium 7.62 1.65 35.20
0.66; yc=0.39, 95% CI 0.25-0.60). With regard to Strong 0.073 0 1.4×1015
6 yf * 2.05 1.11 3.81
facultative skin color, an increase in reflectance Yf led
to a decrease in risk (odds ratio 0.67, 95% CI 0.47- *Odds ratios of quantitative colorimetric variables represent an increase of one
standard deviation with respect to the mean
0.94). This is in line with the fact that subjects who
expose their skin less to sunlight (and therefore have
paler skin color on the cheek) are at lower risk for
MM. No significant differences were found between or. Once quantitative constitutional and facultative
cases and controls with regard to type of exposure skin color was entered at step 3, the model already
(occupational or facultative), hair color, freckling or has a satisfactory fit and power of discrimination
early history of sunburn. between melanoma and healthy subjects. The Hos-
The multivariate logistic model obtained by step- mer-Lemeshow test gave a P-value of 0.25 indicating
wise regression is shown in Table IV. Some of the a significantly good model fit. Model sensitivity and
results are interesting. When the constitutional skin specificity were 70% and 75.7%, respectively. The
color component yc was entered, at the first step, the Fitzpatrick phototype was entered at step 4. Estimat-
other constitutional skin color components Yc and xc ed odds ratios indicated a risk of melanoma about 11
lose significance, indicating substantial correlation and 12 times greater for phototypes I and II, respec-
among the 3 colorimetric components. One colori- tively, than for phototype IV, though phototypes had
metric component is, therefore, sufficient to account for poor accuracy (large CIs). Recreational exposure
relative melanoma risk due to constitutional skin col- entered at step 5. This furnishes less accurate esti-
mates of odds ratio but towards an increase of risk for With regard to facultative skin color, an increase in
greater exposures. At step 6 yf entered, with a well-esti- reflectance (Yf), i.e. fair skin on the cheek, is associ-
mated odds ratio of about 2 which confirms that high- ated with a decrease in melanoma risk. This finding is
er facultative pigmentation significantly increases the in line with the fact that subjects with lower exposure
risk of melanoma. to sunlight (and hence fairer exposed skin on the cheek)
Finally, the multivariate logistic model gives a good have a lower risk of MM.17 As indicated by all the
fit (Hosmer-Lemeshow test, P=0.42) with apprecia- international literature,1, 12, 15, 16 univariate and multi-
ble sensitivity, specificity and accuracy: 78.6%, 75.7% variate analysis identified fair eyes as a significantly
and 77.1% respectively. greater risk factor than dark eyes, in our study. On the
other hand, no significant differences in type of expo-
sure (occupational or facultative), hair color, freck-
Discussion and conclusions ling or early sunburn history were found between cas-
es and controls by univariate analysis. Some of these
Many environmental and constitutional risk fac- findings disagree with the results of epidemiological
tors have been associated with MM.1 Among consti- studies from other geographical areas,1, 16-18 suggest-
tutional factors, numerous melanocytic nevi or the ing that risk factors on which to base prevention cam-
presence of atypical nevi is the major known risk paigns have to come directly from population sub-
factor.1, 13, 14 The former has also emerged as a risk groups and cannot be based on generalizations from
factor in studies on Caucasian and Mediterranean studies on climatically, geographically and racially
peoples,12, 15 and in Celtic people with fair photo- different peoples. The absence of correlations between
type (northern Europe and Australia). 16 We also risk of melanoma, hair color and freckling, for exam-
encountered a highly significant difference in nevus
ple, may be due to the fact that few Tuscans have red
number and type between controls and melanoma
hair and develop freckles. With regard to early histo-
patients in our study. This finding emerged both with
ry of sunburn, the lack of significance of this factor had
univariate and multivariate statistical analysis. We
already been reported in a population geographically
found that subjects we defined as high risk on the
basis of these 2 factors had a much higher risk of and culturally similar to ours 12 and this could be due
melanoma than those defined as low risk. An inter- to the large percentage of subjects with phototype III
esting new finding, different from those of other stud- or IV, who are unlikely to burn, and to nearness to the
ies, was that subjects defined by us as medium risk sea and temperate climate which permit continuous
actually had a risk of melanoma similar to low risk exposure, so that skin is protected against acute sun-
subjects. We could, therefore, have divided the pop- burn. Indeed, in our study population, only 6% of
ulation into 2 (high and medium-low risk) instead of melanoma patients and 3.8% of controls had a histo-
3 groups on the basis of nevus number. ry of sunburn.
A variable we found highly significant despite an As far as we know, 7 case-control studies have been
odds ratio indicative of high CIs was the Fitzpatrick conducted on melanoma risk factors in the Italian pop-
phototype, and specifically, the risk associated with ulation.12, 15, 19-24 Because these studies differed in aim,
types I-III was much greater than that associated with method (qualitative and/or quantitative) and study
type IV. However, this variable turned out to be cor- population, their results cannot readily be compared.
related and completely explained by colorimetric In particular, northern and southern Italy are charac-
variables of skin color. This means that we could terized by prevalences of fair and Mediterranean pho-
have omitted phototype and studied only skin color. totypes, respectively, and by quite different climates.
The major skin color parameters correlated with risk Moreover, most of these case-control studies were
of MM were chromaticity of unexposed skin (but- based on retrospective assessment of sun exposure
tock y) and reflectance (fairness) of unexposed and and self-reported information on individual sensitiv-
chronically exposed skin (buttock and cheek Y). It is ity to UV radiation. In conclusion, we agree with what
well known that fair subjects are more susceptible was recently proposed by Brenner et al.23 that objec-
to skin cancer because they are more vulnerable to UV tive skin color measurements must be combined with
light, the major environmental risk factor for skin phenotype parameters and sun exposure history for
cancer.17 exact assessment of individual risk.
Aim. Actinic keratoses (AKs) are considered one of the most Unit of Dermatological Physiotherapy
common cutaneous intraepithelial neoplastic disorders. Some Department of Dermatological Sciences
authors have recently proposed to define AK as a keratinocyte University of Florence, Florence, Italy
intraepithelial neoplasia with 3 possible steps of evolution
towards squamous cell carcinoma. According to others, AK is
a true neoplasia from the very beginning. It has been calcu-
lated that 60% of subjects with skin from I to III phototype over grade II lesions. The general response to the first treatment
40s present at least one AK. This diffuse and progressing con- was 77%. We showed 90% of complete healing with excellent
dition requires a prompt diagnosis and an adequate treatment. compliance and cosmetic results.
The prevalence of AKs increases with age, with sun exposure Conclusion. This study has shown that metylaminolevulinate
and is regulated by different factors, including immunosur- PDT is an effective, safe and well tolerated treatment for AKs,
veillance and low phototype. The more risk factors there are, which could probably be considered the treatment of choice
the more diffuse the lesions which required multiple therapies. for this very common and emerging cutaneous disorder. PDT
Up to now both medical (5-FU cream, imiquimod cream, is also a promising treatment modality with a good potential for
retinoids etc.) and surgical (cryosurgery, laser surgery,
future development in different fields, such as T cell lymphoma,
diclofenac gel, etc.) treatments have been used to treat AK with
acne, localized eczema, and human papillomavirus infection.
variable results. Photodynamic therapy (PDT) seems to rep-
resent a new, effective and well tolerated therapy for the treat- KEY WORDS: Skin neoplasms - Actinic keratoses - Photodynamic
ment of AKs with excellent cosmetic results and long term fol- therapy - Methyl-aminolevulinate.
low up in terms of efficacy. In this paper the efficacy of PDT
treatment has been evaluated with special attention to the
employment of methyl-ester of aminolevulinic acid (MAL),
which is a prodrug recently introduced in our country.
Methods. We have treated 100 Caucasian patients (70 males, 30
A ctinic keratoses (AKs) are considered one of the
most common cutaneous intraepithelial neoplastic
disorders. Yantos et al.1 have recently proposed defin-
females) with a skin phototype ranging from 1 to 3 according
to the Fitzpatrick classification, for a total of 170 AKs of the face ing AK as a keratinocyte intraepithelial neoplasia with
and scalp. 3 possible steps in their evolution towards squamous
Results. 15 days after the treatment showed complete healing cell carcinoma. According to others, AK is a true neo-
in 114 lesions of the face (82.4%) and in 44 lesions of the scalp plasia from the very beginning.2, 3 It has been calculated
(78%). 84% of the more superficial and less squamous ker- that 60% of subjects over-40s showing a skin with I to
atosis (grade I) presented a complete response against 80% of III phototype present at least one AK and that this per-
centage increases to 80% in the over-60s.4
Address reprint requests to: Dott. R. Rossi, U.O. Struttura Dermatolo- In patients with diffuse signs of photocarcinogene-
gica Complessa Fisioterapia Dermatologica, Dipartimento di Scienze Der-
matologiche, Via Della Pergola 58, 50121 Firenze. sis AKs may undergo difficult therapeutic manage-
E-mail: r.rossi@med.unifi.it ment, especially if those subjects for professional rea-
sons or life style are chronically photoexposed.5, 6 In TABLE I.—Baseline characteristics of patients.
these cases, lesions are usually widespread and tend to Sex
recur. Available topical treatments usually have bad Male 70 (70%)
compliance, surgical treatments are usually consid- Female 30 (30%)
Age (years)
ered too invasive for patients. Thus a new and less Mean 68
invasive approach has become a hoped-for therapeu- Range (32-93)
tic option. Skin type
(Fitzpatrick skin type)
In cases of patients with diffuse signs of photocar- I 10%
cinogenesis, photodynamic therapy (PDT) is consid- II 30%
III 60%
ered the treatment of choice. Total no. of lesions 170
PDT, a treatment modality involving the use of a Lesion location
photosensitizing agent, oxygen, and light of a specif- Face 114/170 (67%)
Scalp 56/170 (33%)
ic wavelength to produce controlled cell death, has No. of lesions per grade
gained increasing popularity in the treatment of pre- Grade I (AK thin) 119/170 (70%)
malignant and malignant skin lesions.7 This treatment Grade II (AK moderate) 51/170 (30%)
offers the potential advantage of reduced scarring and
improved cosmetic outcome compared with conven-
tional treatments. PDT using topical 5-aminolevulin- Treatment
ic acid (ALA), a precursor of the active endogenous Each lesion was prepared before treatment to facil-
photosensitizer protoporphyrin IX, is effective in the itate access of the cream and to ensure that illumina-
treatment of Aks.8-13 In contrast with systemic photo- tion was not blocked. Scales and crusts were removed
sensitizers, persistent skin photosensitization seems not by a small dermal curette and the surface of the lesion
to be a problem for topical ones. Numerous studies have was scraped gently. The intention of this very gentle
led to the approval of this therapy for dermatological pur- curettage was to remove scales and crusts without
poses, which was obtained in 1999 from the USA FDA bleeding. A thick layer of 160 mg/g MAL cream
for a topical formulation (Levulan® Kerastick, DUSA (Metvix®, Photocure ASA, Oslo, Norway) (approxi-
Pharmaceuticals, Tarrytown, NY) 14, 15 and more recent- mately 1 mm) was applied to each lesion and 5 mm of
ly in Europe and Italy (March 2004) for methy- surrounding tissue and covered with an occlusive
laminolevulinate (MAL) (Metvix®, PhotoCure, Oslo, dressing (Tegaderm, 3M Health care, St Paul, MN,
Norway). USA) and covered with gauze to avoid photo exposure
The aim of the present study was to evaluate the effi- and to prevent the accidental activation of the cream
cacy and tolerability of topical MAL- PDT (recently (photobleaching). After 180 min lesions were exam-
approved in our country) in the treatment of AKs.16-18 ined by fluorescence with a light emitting diode (LED)
lamp (DICAM-UV® - Alpha Strumenti, Milan, Italy)
with UV at 405 nm irradiation to better appreciate
Materials and methods the AKs lesions and the penetration of the cream (Fig-
ure 1).
We evaluated 100 Caucasian patients (70 males and After 3 h (from the beginning) dressings were
30 females) of average age 68 (range 32-93) and Fitz- removed and lesions treated with non-coherent red
patrick skin phototype ranging from 1 to 3 (Table I). light. We employed a device which uses so called LED
These subjects presented one or more AKs, for a light. This lamp (Aktilite PDT - Model CL128- Pho-
total of 170 lesions of the face (114/170, 67%) and/or tocure ASA, Oslo, Norway) has an average wave-
the scalp (56/170, 33%). The lesions were not pig- length of 630 nm, light dose 37J/cm2, light intensity 70-
mented and of grade 1 (119/170, 70%) or moderate 100 mW/cm2. It illuminates areas from 80 to 180 mm
(grade 2) (51/170, 30%). at a distance from 50 to 80 mm (Figure 2).
Lesions was classified as follows:19 After PDT treatment, all lesions were treated with
Grade 1: easily visible, slightly palpable topical antibiotic ointments until complete healing
Grade 2: easily visible, palpable (approximately 1 week).
Grade3: frankly visible and very hyperkeratosic. Some patients requested burning and stinging dur-
Results
Figure 3.—A) Grade I Ak before treatment with MAL-PDT. B) Complete response 6 months after the first MAL-PDT session.
Figure 4.—A) Actinic keratosis of the nose before MAL-PDT treatment. B) Response 15 days after MAL-PDT session.
The pathogenetic role of ultraviolet rays in the induc- tasias, wrinkles and solar lentigos.20 Five percent to
tion and progression of AKs is proved both on exper- 20% of these lesions will progress in 10-25 years into
imental and epidemiologic models. AKs are also squamous cell carcinomas.2
known as solar keratoses. The term solar is more spe- Immunosurveillance can modulate the progression
cific because it refers to a variety of rays. Even among of AKs towards neoplastic lesions in single subjects.
sun rays, action spectrum evaluations indicate that Grafted or immunocompromised patients usually have
ultraviolet B rays (290-320 nm) are the most damag- widespread AKs with a more rapid progression towards
ing, while UVA rays (320-400 nm) can augment the malignancy.
damaging effects of UVB rays. AKs are usually seen as multiple lesions in sun-
AKs are very often associated with other aspects of exposed areas (face, dorsa of the hands, bald portions
photodamage such as actinic elastosis, teleangiec- of the scalp in men). Usually the lesions measure less
TABLE II.—Lesion response rate by lesion grade and location 6 months after the first and the second PDT session.
MAL-PDT After 1 Sessiom After 2 sessions
Lesion location
Face 114/170 (67%) 94/114 (82.4%) 10/20 (104/114) 91%
Scalp 56/170 (33%) 44/56 (78%) 5/12 (49/56) 87.5%
Lesion grade
Grade I (AK thin) 119/170 (70%) 100/119 (84%) 9/19 (109/119) 91.5%
Grade II (AK moderate) 51/170 (30%) 38/51 (80%) 6/13 (44/51) 86%
Complete response 138/170 (77%) 153/170 (90%)
than 1 cm in diameter. They are erythematous, are appears to play a central role in photodynamic cyto-
often covered by adherent scales, and except in their toxicity because of the highly efficient interaction of
hypertrophic form, show little or no infiltration. Some the O2 species with different biomolecules.22, 23 The tis-
solar keratoses are pigmented and show peripheral sue damaging effect is realized via several pathways:
spreading, making clinical differentiation from lenti- i. cell necrosis and apoptosis of dysplastic cells;
go maligna difficult. Occasionally, lesions show ii. microcirculation arrest: damage of endothelial
marked hyperkeratosis and have the clinical appearance cells promotes thrombus formation and consequent
of cutaneous horns. vascular neological stasis which also contributes to
Histologically AKs are squamous cell carcinoma tumor ablation.
in situ. However, biologically, the lesions are still iii. inflammation in the exposed tissue
benign; invasion into the dermis, if present at all, is lim- iv. induction of host immune response.
ited to the most superficial portion of the papillary MAL is a new topical photosensitizer that may offer
dermis. In the typical histological pattern the epider- advantages over ALA in terms of improved skin pen-
mis is thickened and shows irregular downward pro- etration as a result of enhanced lipophilicity and greater
liferation, which is limited to the uppermost dermis selectivity for neoplastic cells than other ALA-induced
and does not represent frank invasion. Most ker- porphyrins.24-27
atinocytes show a loss of polarity and a disorderly In addition, as the cellular uptake mechanisms for
arrangement. Some of these cells show pleomorphism these agents differ, the intensity of pain may be low-
and atypia of their nuclei, which appear large, irregu- er during PDT using MAL than ALA.
lar and hyperchromatic.21 The good cosmetic results which are obtained due
PDT is a treatment modality involving the admin- to selective tissue destruction and mobilization of
istration of a photosensitizing compound and the accu- the organism’s proper immune response is one of the
mulation of the sensitizer molecules in the target cells, main PDT advantages. From the pharmacological
followed by selective irradiation of the lesion with point of view, sensitizers show low toxicity and almost
visible light with wavelength preferentially between no interaction with other medications, making PDT
600 and 700 nm, in order to achieve a deep penetration a safe treatment modality. Many other treatments for
in the tissue. Basically, photodynamic action requires AKs are available, but most of them present side
the presence and interaction of 3 components: photo- effects, and they do not assure the same esthetic
sensitizer, light and oxygen. results.28-30
The initiating step of the photosensitizing mecha- Cryosurgery is generally limited to patients with
nism is the absorption of a light photon by the sensi- only a very limited number of lesions where hypopig-
tizer, causing a promotion of the drug molecule from mentation can resist after treatment. Curettage has
its ground state to the extremely unstable excited sin- potential complications of scarring and infection, and
glet state. The singlet excited photosensitizer either local anesthesia is required before the procedure. Top-
decays back to the ground state, resulting in the emis- ical application of 5-fluorouracil cream has the dis-
sion of light in the form of fluorescence, or undergoes advantages of prolonged erythema and exudation as
intersystem crossover to the longer lived triplet excit- part of the treatment and recovery, lack of patient com-
ed state by electron spin conversion. The in situ gen- pliance, morbidity, only partial effectiveness in remov-
eration of singlet oxygen via the type II pathway ing deep or hyperkeratotic lesions, and the potential for
exacerbation of other cutaneous conditions such as sitano di trattamenti multipli. Le CA devono sempre essere
acne rosacea.6 trattate. Oggi sono disponibili terapie sia mediche (crema al
PDT has gained increasing popularity in the treat- 5-FU, peeling medio-profondi, imiquimod crema, retinoidi
orali, interferone a2b) sia chirurgiche (elettrochirurgia, escis-
ment of premalignant or malignant skin lesions. The sione chirurgica, laser-chirurgia, criochirurgia, dermoabra-
treatment offers the advantages of reduced scarring and sione). La terapia fotodinamica rappresenta una recente effi-
improved cosmetic outcome compared with conven- cace acquisizione per il trattamento delle CA, ben tollerata e
tional treatments. The use of gentle curettage before con eccellenti risultati cosmetici. Può, inoltre, risultare par-
MAL-PDT and the occlusion of the drug before illu- ticolarmente utile per la scarsa invasività e la possibile ripe-
mination probably contribute to the efficacy of the treat- tibilità che la contraddistinguono. In questo lavoro è stata
ment.31 Moreover with this treatment local intralesion- valutata l’efficacia di tale terapia con particolare riguardo
all’utilizzo del metil-estere dell’ALA, profarmaco fotosen-
al anesthesia is not required and the stinging sensation sibilizzante di recentissima introduzione nel nostro Paese.
is usually limited to the treated area and can be easily Metodi. Sono stati trattati 100 pazienti (70 di sesso maschi-
treated with refrigerating devices which are usually pre- le, 30 di sesso femminile) di razza caucasica e fototipo 1 e 2
sent in the most modern and sophisticated PDT lamps. o 3 secondo la scala di Fitzpatrick, per un totale di 170 CA,
The intensity of itching or pain seem to be lower during localizzate al volto e al cuoio capelluto.
PDT using MAL instead of ALA, because of the dif- Risultati. Dopo 15 giorni dal primo trattamento è stata
ferent cellular uptake mechanisms for these agents. evidenziata una risposta completa (completa regressione cli-
nica della lesione) in 114 lesioni del volto (82,4%) e in 44
From a practical perspective, MAL PDT can be use- lesioni del cuoio capelluto (78%). In base al grado di evo-
fully and safely integrated into clinical practice. luzione delle cheratosi, l’84% delle lesioni più superficiali e
In conclusion, in this study we have shown that meno squamose (grado I ) ha presentato risposta completa
MAL PDT is an effective, safe and well tolerated treat- contro l’80% di quelle di grado medio (grado II). La rispo-
ment for AKs, which could be probably considered sta complessiva al primo trattamento è risultata pari al 77%.
the treatment of choice for this very common and Sono state ottenute risposte di guarigione completa nel 90%
dei casi, risultato sovrapponibile o superiore se comparato ai
emerging cutaneous disorder. trattamenti convenzionali.
PDT is also a promising treatment modality with a Conclusioni. In questo studio, la terapia fotodinamica con
good potential for future development in different metil-aminolevulinato si è dimostrata una terapia efficace e
fields, such as T cell lymphoma, acne, localized ben tollerata per il trattamento delle CA; i risultati ottenuti,
eczema, and human papillomavirus infections.32-43 pertanto, sembrano rimarcare il potenziale ruolo della tera-
pia fotodinamica come trattamento di prima scelta per que-
Acknowledgement.—Mrs. S. Lombardi and Mrs. C. Izzap are sta patologia molto comune e in costante aumento. Lo sce-
gratefully acknowledged for their technical assistance. nario è, inoltre, destinato ad arricchirsi rapidamente in quan-
to studi pilota sono in corso per il trattamento fototerapeu-
tico di patologie anche molto diverse tra loro, come il linfo-
Riassunto ma primitivo cutaneo a cellule T e a cellule B, alcune forme
di acne e di eczema, l’ipertricosi, il lichen sclerosus et atrophi-
Terapia fotodinamica con Metil-aminolevulinato (METVIX®) cans e le infezioni da papillomavirus.
nel trattamento delle cheratosi attiniche PAROLE CHIAVE: Cute, carcinoma - Cheratosi attiniche - Tera-
Obiettivo. La cheratosi attinica (CA) o cheratosi solare pia fotodinamica - Metil-aminolevulinato.
rappresenta la più comune neoplasia cutanea circoscritta.
Alcuni Autori hanno recentemente proposto di definire la
CA una “neoplasia intraepiteliale cheratinocitaria” con 3 gra- References
di di evoluzione verso il carcinoma squamocellulare. Secon-
do altri, la CA è una vera e propria neoplasia fin dall’inizio. 1. Yantos VA, Conrad N, Azbawski E, Cockerell CJ. Incipient intraepi-
dermal cutaneous squamous cell carcinoma: a proposal for reclassi-
È stato calcolato, infatti, che il 60% dei soggetti a basso foto- fying and grading solar (actinic) keratosis. Semin Cutan Med Surg
tipo (I-III) oltre i 40 anni di età presenta almeno una cheratosi 1999;1:3-14.
solare. Questa patologia rappresenta, inoltre, la principale 2. Salasche SJ. Epidemiology of actinic keratoses and squamous cell
condizione per lo sviluppo dei carcinomi a cellule squamo- carcinoma. J Am Acad Dermatol 2000;42:8-10.
se e richiede, perciò, una rapida diagnosi e un efficace trat- 3. Cockerell CJ. Histopathology of incipient intraepidermal squamous
tamento. La prevalenza della CA aumenta con l’età e con cell carcinoma (“actinic Keratosis”). J Am Acad Dermatol
2000;115:649-55.
l’esposizione a fattori di rischio (elioesposizione) e varia in 4. Drake LA, Ceilley RI, Cornelison RL, Dobes WL, Corner W, Goltz
presenza di fattori predisponenti (immunosoppressione). In RW et al. Guidelines of care for actinic keratoses. J Am Acad Dermatol
questi casi le lesioni sono spesso diffuse e recidivanti e neces- 1995;32:95-8.
5. Ortonne JP. From actinic keratosis to squamous cell carcinoma. Br J aminolevulinic acid-induced porphyrins in basal cell carcinomas and
Dermatol 2002;146:20-3. actinic keratoses; implications for optimizating of photodynamic ther-
6. Schmook T, Stockfleth E. Current treatment patterns in non melanoma apy. Eur J Dermatol 2000;10:351-6.
skin cancer across Europe. J Derm Treat 2003;14:3-10. 25. Cappugi P, Campolmi P, Mavilia L, Prignano F, Rossi R. Topical 5-
7. Kennedy JC, Pottier RH, Pross DC. Photodynamic therapy with aminolevulinic acid and photodynamic therapy in dermatology: a
endogenous protoprophyrin IX: basic principles and present clinical minireview. J Chemother 2001;13:494-502.
experience. J Photochem Photohiol B 1990;14:275-92. 26. Cappugi P, Rossi R, Mavilia L, Campolmi P. La terapia fotodinami-
8. Jeffes EW, McCullough JL, Weinstein GD, Fergin PE, Nelson JS, ca nella pratica clinica. Manuale pratico e testo-atlante dermatologi-
Shull TF et al. Photodynamic therapy of actinic keratosis with topi- co. 1° ed. Firenze: SEE editrice; 2005.
cal 5-aminolevulinic acid. Arch Dermatol 1997;133:727-32. 27. Cappugi P, Rossi R. Terapia fotodinamica. In: Campolmi P, Bonan P, Can-
9. Kurwa HA, Yong-Gee SA, Seed PT, Markey AC, Barlow RJ. A ran- narozzo G editors. Laser e sorgenti luminose in dermatologia. Manuale
domized paired comparison of photodynamic therapy and topical 5- di applicazioni pratiche. Milano: Masson Editore; 2003. p.138-47.
fluorouracil in the treatment of actinic keratoses. J Am Acad Derma- 28. Szeimies RM, Karrer S, Radakovic-Fijan S, Tanew A, Calzavara-Pinton
tol 1999;41:414-8. PG, Zane C et al. Photodynamic therapy using topical methyl-5-aminole-
10. Pinzi C, Campolmi P, Moretti S, Guasti A, Rossi R, Cappugi P. Ter- vulinate (Metvix) is as efficacious as cryotherapy in actinic keratosis, but
apia fotodinamica di tumori cutanei (non melanoma) primitivi e sec- with superior cosmetic results and high patient satisfaction: a prospec-
ondari con applicazione topica di acido 5-aminolevulinico. G Ital tive, randomised study. J Am Acad Dermatol 2002;47:258-62.
Dermatol Venereol 2000;135:427-31. 29. Freeman M, Vinciullo C, Francis D, Spelman L, Nguyen R, Fergin P
11. Wolf P, Rieger E, Kerl H. Topical photodynamic therapy with endoge- et al. A comparison of photodynamic therapy using topical methyl
nous porphyris after application of 5-aminolevulinic acid: an alternative aminolevulinate (Metvix) with single cycle cryotherapy in patients with
treatment modality for solar keratoses, superficial squamous cell carci- actinic keratosis: a prospective, randomized study. J Dermatol Treat
nomas, and basal cell carcinomas? J Am Acad Dermatol 1993;28:17-21. 2003;14: 99-106.
12. Morton CA, Whitehurst C, Moseley H, Moore JV, MacKie RM. 30. Horn M, Wolf P, Wulf HC, Warloe T, Fritsch C, Rhodes LE et al.
Development of an alternative light source to lasers for photodynamic Topical methyl aminolaevulinate photodynamic therapy in patients with
therapy. 1. Clinical evaluation in the treatment of premalignant and non- basal cell carcinoma prone to complications and poor cosmetic out-
melanoma skin cancer. Lasers Med Sci 1995;10:165-71. come with conventional treatment. Br J Dermatol 2003;149:1242-9.
13. Calzavara-Pinton PG. Repetitive photodynamic therapy with topical 31. Morton CA. Methyl aminolevulinate (Metvix) photodynamic thera-
delta-aminolevulinic acid as an appropriate approach to the routine py-practical pearls. J Dermatol Treat 2003;14:23-6.
treatment of superficial nonmelanoma skin tumors. J Photochem Pho- 32. Coors EA, Von der Driesh P. Topical photodynamic therapy for patients
tobiol B 1995;29:53-7. with therapy-resistant lesions of cutaneous T-cell lymphoma. J Am
14. Jeffes EW. Levulan: the first approved topical photosensitizer for the Acad Dermatol 2004;50:363-7.
treatment of actinic keratosis. J Dermatolog Treat 2002;13 Suppl 1: 33. Orenstein A, Haik J, Tamir J, Winkler E, Trau H, Malik Z et al. Pho-
S19-23. todynamic therapy of cutaneous lymphoma using 5-aminolevulinic acid
15. Lang K, Achulte KW, Ruzicka T, Tritsch C. Aminolevulinic acid topical application. Dermatol Surg 2000;26:765-9.
(Levulan) in photodynamic therapy of actinic keratoses. Skin Thera- 34. Rittenhouse-Diakun K, van Leegoed H, Morgan J, Hryhorenko E,
py Lett 2001;6:1-2, 5. Paszkiewicz G, Whitaker JE et al. The role of trasferrin receptor
16. Uehlinger P, Zellweger M, Wagnieres G Juillerat L, Van Der Bergh H, (CD71) in photodynamic therapy of activated and malignant lym-
Lange N. 5-Aminolevulinic acid and its derivates: physical chemical phocytes using the hem precursor delta-aminolevulinic acid (ALA).
properties and protoporphyrin IX formation in cultured cells. Pho- Photochem Photobiol 1995;61:523-8.
tochem Photobiol 2000;54:72-80. 35. Edstrom DW, Portwit A, Ros AM. Photodynamic therapy with topi-
17. Fritsch C, Homey B, Stahl W, Lehmann P, Ruzicka T, Sies H. Pref- cal 5-aminolevulinic acid for mycosis fungoides: clinical and histo-
erential relative porphyrin enrichment in solar keratoses upon topical logical response. Acta Derm Venereol 2001;81:184-8.
application of 5-aminolevulinic acid methylester. Photochem Photo- 36. Stables GI, Stringer MR, Robinson DJ. The treatment of cutaneous T
biol 2000;71:640-7. cell lymphoma by topical aminolevulinic acid photodynamic therapy.
18. Pariser DM, Lowe NJ, Steward DM, Jarratt MT, Lucky AW, Pariser Br J Dermatol 1997;137(S50):51.
RJ et al. Photodynamic therapy with topical methyl aminolevulinate 37. Markham T, Sheahan K, Collins P. Topical 5-aminolevulinic acid
for actinic keratosis: results of a prospective randomised multicenter photodynamic therapy for tumor-stage mycosis fungoides. Br J Der-
trial. J Am Acad Dermatol 2003;98:227-32. matol 2001;144:1262-3.
19. Olsen EA, Abernethy ML, Kulp-Shorten C, Callen JP, Blazer SD, 38. Mori M, Mavilia L, Rossi R, Campolmi P, Cappugi P, Pimpinelli N.
Huntley A et al. A double-blind, vehicle-controlled study evaluating La terapia fotodinamica nel trattamento dei linfomi primitivi cutanei.
masoprocol cream in the treatment of actinic keratoses on the head and G Ital Dermatol Venereol 2005;140:123-7.
neck. J Am Acad Dermatol 1991;5:738-43. 39. Hongcharu W, Taylor CR, Chang Y, Aghassi D, Suthamjariya K,
20. Touma D, Yaar M, Whitehead S, Konnikov N, Gilchrest B. A trial of Anderson RR. Topical ALA-photodynamic therapy for the treatment
short incubation, broad-area photodynamic therapy of facial keratoses of acne vulgaris. J Invest Dermatol 2002;115:183-92.
and diffuse photodamage. Arch Dermatol 2004;140:33-40. 40. Hillemanns P, Untch M, Prove F, Baumgartner R, Hillemanns M,
21. Petrini N, Massi D, Rossi R, Cappugi P. Patologia precancerosa e Korell M. Photodynamic therapy of vulvar lichen sclerosus with 5-
terapia fotodinamica. In: Cappugi P, Rossi R, Mavilia L, Campolmi aminolevulinic acid. Obstet Gynecol 1999;93:71-4.
P editors. La terapia fotodinamica nella pratica clinica. Manuale prati- 41. Fabbrocini G, Di Costanzo MP, Riccardo AM, Quarto M, Colasanti
co e testo-atlante dermatologico. 1° ed. Firenze: SEE editrice; 2005. A, Roberti G et al. Photodynamic therapy with topical 5-aminolae-
22. Prignano F, Bianchi B, Domenici L, Rossi R, Romagnoli P, Pimpinel- vulinic acid for the treatment of plantar warts. J Photochem Photobi-
li N et al. Early apoptosis plays an important role in the healing mech- ol B Biology 2001;61:30-4.
anism of cutaneous basal cell carcinomas after photodynamic thera- 42. Stender IM, Na R, Fogh H, Gluud C, Wulf HC. Photodynamic ther-
py. Br J Dermatol 2003;149:205-6. apy with 5-aminlaevulinic acid or placebo for recalcitrant foot and hand
23. Nakaseko H, Kobayashi M, Akita Y, Tamada Y, Matsumoto Y. Histo- warts: randomised double-blind trial. Lancet 2000;355:963-6.
logical changes and involvement of apoptosis after photodynamic 43. Ross EV, Romero R, Kollias N, Crum N, Anderson RR. Selectivity of
therapy for actinic keratoses. Br J Dermatol 2003;148:122-7. protoporphyrin IX fluorescence for condylomata after topical appli-
24. Stefanidou M, Tosca A, Themelis G, Vazgiourake E, Balas C. In vivo cation of 5-aminolaevulinic acid: implications for photodynamic treat-
fluorescence kinetics and photodynamic therapy efficacy of delta- ment. Br J Dermatol 1997;137:736-42.
Aim. The instruments to measure the severity of atopic der- 1Epidemiology Unit, Istituto Dermopatico dell'Immacolata
matitis (AD) are time consuming, so their use is limited in IDI-IRCCS, Rome, Italy
routine clinical practice. The self administered eczema area 2Health Service Research Unit, Istituto Dermopatico
severity index (SA-EASI) was developed and validated for dell'Immacolata, IDI-IRCCS, Rome, Italy
a caregiver’s self assessment of the severity of child’s AD. 3Pediatric Unit, Istituto Dermopatico dell'Immacolata, IDI-
The aim of this study was to assess the relationship between IRCCS, Rome, Italy
the SA-EASI and SCORing atopic dermatitis (SCORAD)
tools.
Methods. Thirty-five patients with AD admitted at the Pedi-
atric Unit of a Dermatological Hospital in Rome, Italy, and
their parents, participated in the study. The severity of the dis-
ease has been assessed at admission, by parents using the
SA-EASI, and by dermatologists using the SCORAD, inde-
A topic dermatitis (AD) is a chronic skin condition
with a significant quality of life (QoL) impact.
Psychological stress, quality of family life, financial
pendently. problems and social well-being are related to the sever-
Results. Evidence of convergent validity was provided by ity of AD in children.1-4
high correlation between SA-EASI and SCORAD (Rank Essential to the study of the impact of AD on QoL
Spearman rs=0.71; P<0.001). is the measurement of disease severity.
Conclusion. Both instruments are useful in daily clinical
practice and in the research on outcomes. The parents
Different scoring systems have been developed to
received no training in the measurement of eczema and no determine the severity of AD.5-11 Recently, more objec-
training in the use of the SA-EASI instrument itself. SA- tive scores like that using permeability barrier function
EASI, moreover promotes the involvement of families with an and stratum corneum hydratation with computer-assist-
affected child. ed estimates for extent disease,12 or the specific soft-
KEY WORDS: Atopic dermatitis - Child - Measures. ware to evaluate automatically the extension of the
involved area 13 have been developed.
This report is part of a broader study examining the effects of a
patient/parental education programme on medical and psychosocial out- Despite better precision and reproducibility of objec-
comes. tive measures are known, clinicians and researchers use
This study was supported by a grant from the Italian Ministry of more classical instruments.14-16
Health.
The SCORing atopic dermatitis (SCORAD),17 one
Received: September 15, 2004.
Accepted for publication: July 6, 2005. of the best validated systems,18-20 is based on objective
signs (e.g. extension) and subjective symptoms (e.g.
pruritus and sleep loss). The instrument is suited for
Address reprint requests to: Dott.ssa E. Mazzotti, Istituto Dermopatico
dell'Immacolata, IDI-IRCCS, Via dei monti di Creta 104, Rome, Italy. clinical trials, but is too time consuming for routine
E-mail: e.mazzotti@idi.it. clinical use.
Generally, the use of self-assessed severity indices for children aged above 7 years, roughly consistent
in dermatology is restricted to adult patients.21, 22 with the “rule of nines”.24 For children <7 years old, a
Recently, an instrument for a caregiver’s self-assess- modification was used: BSAs were 20% for the head,
ment of the severity of his/her child’s AD, the self- 20% for the upper extremities, 30% for the trunk and
administered eczema area and severity index (SA- 30% for the lower extremities.24 Finally the 4 products
EASI) has been developed.23 The original study evi- were summed to obtain the total area score. The sec-
denced that “caregivers can accurately assess their ond part of the one-page SA-EASI instrument con-
child’s cutaneous disease severity in a valid fashion sisted of five 100-mm visual analogue scales (VASs).
using the SA-EASI”.23 The VAS consists of a continuous line on which the
Aims of our study are to assess the performance of caregivers make a mark to show the average severity
the SA-EASI italian version and to measure the rela- of the AD lesions. The VASs enabled caregivers to
tionship between parental and dermatologist assess- describe the redness, thickness, dryness, number of
ment of AD severity. scratches and itchness of an average AD lesion. On
each VAS, extremes and intermediate levels were
labelled with anchor marks at equivalent intervals
Materials and methods along the VAS line. For example, the VAS for redness
contains the following word descriptions: no redness,
Subjects
slightly pink, pink, red, and dark red. Severity scoring
A total of 35 inpatients, 16 males and 19 females, was calculated from an equation.23 The percentual val-
aged 2 months to 17 years, were recruited from the ue, no proportional score, of BSAs were used in this
Pediatric Unit of a dermatological hospital in Rome, study. Translation and adaptation were authorized by
Italy. Only patients with a diagnosis of AD were the author. In the Italian version we changed the figure
enrolled in the study. The exclusion criteria were: oth- from adult to child, and the intermediate levels on
er concomitant severe diseases; parents not available each VAS were marked by signs of 3-mm (heigh) at
to complete the SA-EASI. intervals of 10-mm.
The SCORAD is a scoring system based on the
Instruments assessment of severity by dermatologists. The complete
system is called SCORAD index 17 and also includes
The SA-EASI is a one-page instrument allowing
caregivers of children with AD to measure disease the assessment of subjective symptoms (pruritus, sleep
severity. To estimate the surface area involved a line- loss) on a VAS. The extent of lesions is scored by
drawing silhouette of the body (front and back) was applying the rule of nine after drawing the lesions on
presented to the caregivers and they have to shade the an evaluation form like that of SA-EASI. The intensity
areas currently affected by AD. Based on the silhou- is determined by grading each of the 6 items on a scale
ette shading, an investigator not directly involved in from 0 to 3 (erythema, edema/papulation, oozing/crust,
patient evaluation assigned a value, corresponding to excoriation, lichenification, and dryness). Each item
0-100% body surface area (BSA) involvement, for should be scored on the most representative area for a
each of the following 4 areas: head, upper extremi- given intensity item. Finally the total score is the sum
ties, trunk, and lower extremities. To the BSA involved of extent/5+7*intensity/2 in a standardized way. Owing
for each of the 4 body regions was assigned a propor- to this formula extent accounts for about 25% and
tional score as defined on a seven-point ordinal scale: intensity for about 75% of the total score. The range of
0, no eruption; 1, ≤9%; 2, 10-29%; 3, 30-49%; 4, 50- the objective SCORAD lies between 0 and 83. Based
69%; 5, 70-89%; 6, 90-100%. Each area score was on the objective SCORAD, the severity of AD can be
then multiplied by a factor assigned to the corre- classified into mild (<15), moderate (between 15 to
sponding body area on the SA-EASI scoring sheet. 40), and severe (>40). In this study we adopted the
The multiplier varied according to body region and version without the assessment of subjective symp-
the child’s age. SA-EASI weights the involvement of toms (pruritus, sleep loss).17
the head, upper extremities, trunk, and legs as 10%, Both instruments were completed immediatly after
20%, 30%, and 40% of the total BSA, respectively, the admission.
In clinical practice it should be useful to adopt both 11. Abrams BB. Atopic dermatitis: elements in clinical study design and
analysis. Acta Derm Venereol Suppl 1989;144:15-9.
tools in a hospital setting, in day-hospital or in ambu- 12. Sugarman JL, Fluhr JW, Fowler AJ, Bruckner T, Diepgen TL, Williams
latory setting, and, for patient/caregiver, at home. ML. The objective severity assessment of atopic dermatitis score: an
SA-EASI moreover participate in the empowerment objective measure using permeability barrier function and stratum
corneum hydration with computer assisted estimates for extent of
of families with an affected child. disease. Arch Dermatol 2003;139:1417-22.
However, other studies with more patients are nec- 13. Tripodi S, Panetta V, Pelosi S, Pelosi U, Boner AL. Measurement of
essary to confirm the tools capability to monitor body surface area in atopic dermatitis using specific software (Sco-
radCard(c)). Pediatr Allergy Immunol 2004;15:89-92.
changes in the disease during the follow up. 14. Frederiksson AJ, Peterssonn DC. Severe psoriasis: oral therapy with
a new retinoid. Dermatologica 1978;157:238-44.
Acknowledgments.—The authors thank all the families for par- 15. Bahmer FA, Schafer J, Schubert HJ. Quantification of the extent and
ticipating in the study and their perseverance in completing the the severity of atopic dermatitis: the ADASI score. Arch Dermatol
tools. 1991;127:1239-40.
16. Kezawa Z, Ikebe T, Ogura H, Odajima H, Kurosaka F, Sase K et al.
Clinical effect of hypoallergenic rice HRS-1 in a atopic dermatitis. Jpn
J Allergol 1991;40:633-42.
References 17. European Task Force on Atopic Dermatitis. Severity scoring of atopic
dermatitis: the SCORAD index. Consensus report of the European task
1. Aziah MS, Rosnah T, Mardziah A, Norzila M. Childhood atopic der- force on atopic dermatitis. Dermatology 1993;186:23-31.
matitis: a measurement of quality of life and family impact. Med J 18. Kunz B, Oranje AP, Labreze L, Stalder JF, Ring J, Taieb A. Clinical
Malaysia 2002;57:329-39. validation and guidelines for the SCORAD index: consensus report of
2. Ben-Gashir MA, Seed PT, Hay RJ. Are quality of family life and dis- the European Task Force on Atopic Dermatitis. Dermatology
ease severity related in childhood atopic dermatitis? J Eur Acad Der- 1997;195:10-9.
matol Venereol 2002;16:455-62. 19. Oranje AP, Stalder JF, Taieb A, Tasset C, de Longueville M. Scoring
3. Warschburger P, Buchholz HTH, Petermann F. Psychological adjust- of atopic dermatitis by SCORAD using a training atlas by investiga-
ment in parents of young children with atopic dermatitis: which tors from different disciplines. ETAC Study Group. Early Treatment
factors predict parental quality of life? Br J Dermatol 2004;150:304- of the Atopic Child. Pediatr Allergy Immunol 1997;8:28-34.
11. 20. Wolkerstorfer A, De Waard Van Der Spek FB, Glazenburg EJ, Mul-
4. Ben-Gashir MA, Seed PT, Hay RJ. Quality of life and disease sever- der PGH, Oranje AP. Scoring the severity of atopic dermatitis: three
ity are correlated in children with atopic dermatitis. Br J Dermatol item severity score as a rough system for daily practice and as a pre-
2004;150:284-90. screening tool for studies. Acta Derm Venereol 1999;79:356-9.
5. Clendenning WE, Clack WE, Ogawa M, Ishizaka K. Serum IgE stud- 21. Feldman SR, Fleischer AB Jr, Reboussin DM, Rapp SR, Exum ML,
ies in atopic dermatitis. J Invest Dermatol 1973;61:233-6. Clark AR et al. The self-administered psoriasis area and severity
6. Ring J, Senter T, Cornell RC, Arroyave CM, Tan EM. Plasma com- index is valid and reliable. J Invest Dermatol 1996;106:183-6.
plement and histamine changes in atopic dermatitis. Br J Dermatol 22. Fleischer AB Jr, Rapp SR, Reboussin DM, Vanarthos JC, Feldman SR.
1979;100:521-30. Patient measurement of psoriasis disease severity with a structured
7. Zachary CB, MacDonald DM. Quantitative analysis of T lympho- instrument. J Invest Dermatol 1994;102:967-9.
cytes subsets in atopic eczema, using monoclonal antibodies and flow 23. Housman TS, Patel MJ, Camacho F, Feldman SR, Fleischer AB jr,
cytometry. Br J Dermatol 1983;108:411-22. Balkrishnan R. Use of the Self Administered Eczema Area and Sever-
8. Queille-Roussel C, Raynaud F, Saurat JH. A prospective computerized ity Index by parent caregivers: results of a validation study. Br J Der-
study of 500 cases of atopic dermatitis in childhood. Acta Derm matol 2002;147:1192-8.
Venereol Suppl 1985;114:87-92. 24. Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M,
9. Costa C, Rilliet A, Nicolet M, Saraut JH. Scoring atopic dermatitis: the EASI Evaluator group. The eczema area and severuty index
the simpler the better? Acta Derm Venereol 1989;69:41-5. (EASI): assessment of reliability in atopic dermatitis. Exp Dermatol
10. Hanifin J. Standardized grading of subjects for clinical research stud- 2001;10:11-8.
ies in atopic dermatitis: workshop report. Acta Derm Venereol Sup- 25. StataCorp. 1999. Statistical Software: Release 6.0. College Station, TX:
pl 1989;144:13-4. Stata Corporation.
Sono stati proposti diversi metodi per la misura della gra- deve tratteggiare con una penna le aree della silhouette cor-
vità della DA 5-11. Tra i contributi più recenti ci sono la misu- rispondenti all’eczema sul corpo del proprio figlio.
ra del funzionamento della permeabilità della barriera e del- La stima dell’area della superficie corporea (body surface
l’idratazione dello strato corneo che si avvalgono di algoritmi area, BSA) coinvolta è ottenuta applicando un algoritmo a par-
computerizzati per la stima dell’estensione del problema 12, tire dalla valutazione percentuale (0-100) che un ricercatore,
o la valutazione automatica, con software dedicati, dell’e- che non ha visto il paziente, fa dell’area indicata dal genito-
stensione delle lesioni cutanee 13. Sebbene sia nota la mag- re, separatamente per la rappresentazione anteriore e poste-
gior precisione e la riproducibilità di misure oggettive, i cli- riore e per 4 distinti distretti corporei: testa, arti superiori,
nici e i ricercatori utilizzano strumenti più classici 14-16. tronco, arti inferiori. I valori percentuali vengono trasforma-
L’introduzione dello SCORing atopic dermatitis (SCO- ti in punteggi proporzionali, definiti su una scala ordinale a 7
RAD, European Task Force on Atopic Dermatitis) 17, uno dei punti, dove 0 corrisponde a “nessun eczema”, 1 corrisponde
sistemi meglio validati che combina insieme la valutazione a una superficie coinvolta del ≤9%, 2 equivale a 10-29%, 3 a
di alcuni criteri oggettivi (ad esempio l’estensione delle 30-49%, 4 a 50-69%, 5 a 70-89%, e 6 a 90-100%. Ogni pun-
lesioni) e soggettivi (ad esempio prurito, sonno perso), ha rap- teggio di area viene moltiplicato per uno specifico peso (0,1
presentato un valido criterio di riferimento per la misura del- per la testa, 0,2 per gli arti superiori, 0,3 per il tronco, 0,4
la gravità della DA 18-20. Benché utilizzato nella ricerca cli- per gli arti inferiori) e i prodotti sono poi sommati per ottenere
nica, richiede, tuttavia, tempi troppo lunghi per la compila- il punteggio totale (BSA). Per i soggetti con età inferiore ai
zione e ciò ne limita l’utilizzo nella pratica clinica di routi- 7 anni di età viene applicato un algoritmo modificato in cui
ne. Inoltre gli strumenti di valutazione di gravità in derma- i pesi corrispondenti ai distretti corporei sono rispettivamen-
tologia sono stati generalmente rivolti a pazienti adulti 21, te 0,2 per la testa, 0,2 per gli arti superiori, 0,3 per il tronco,
22. Solo recentemente è stato sviluppato il self administe- 0,4 per gli arti inferiori. In entrambi i casi la funzione appli-
red eczema area and severity index (SA-EASI) 23 che con- cata è consistente con la “regola del nove” 24.
sente ai genitori la valutazione della gravità della DA dei La seconda sezione è costituita da 5 scale analogo visive
figli. I risultati riportati nello studio originale 23 hanno evi- (visual analogue scales, VAS) di 100-mm. La VAS è costi-
denziato che “i genitori, utilizzando il SA-EASI, possono tuita da una linea continua su cui il genitore deve segnare il
valutare in modo accurato la gravità della patologia cutanea punto che corrisponde alla gravità media di una lesione del-
dei figli”. la DA. Sulla linea i livelli estremi e intermedi sono posti a
Scopo di questo contributo è stato valutare la performan- distanze equivalenti. Le scale VAS consentono al genitore di
ce della versione in italiano del SA-EASI, confrontando la descrivere l’intensità media di arrossamento (nessun rosso-
misura della gravità della DA effettuata dal genitore con re, lievemente rosa, rosa, rossa, rosso scuro), di ispessimento
quella effettuata dal dermatologo. (da non ispessita a molto), di secchezza (da non secca a
estremamente secca), di lesioni da graffiamento (da nessun
graffio a molti graffi), di prurito (da nessun prurito a pruri-
to severo).
Materiali e metodi
Il punteggio di gravità è ottenuto applicando un’equazio-
ne che combina i punteggi derivati dalle 2 sezioni 23.
Soggetti In questo studio è stata utilizzata una versione in cui i
Hanno partecipato allo studio 35 pazienti, 16 di sesso pesi specifici per distretto corporeo sono moltiplicati diret-
maschile e 19 di sesso femminile, di età compresa tra 2 mesi tamente per i punteggi percentuali di area.
e 17 anni, ricoverati presso la divisione di dermatologia L’autorizzazione per tradurre, adattare e utilizzare lo stru-
pediatrica dell’IDI-IRCCS di Roma, e almeno uno dei loro mento in lingua italiana è stata gentilmente concessa dal-
genitori. Sono stati inclusi pazienti con diagnosi di DA con- l’Autore. Dal riferimento originale l’immagine di un uomo
fermata da un dermatologo esperto. Sono stati esclusi i è stata modificata in quella di un bambino e le 5 scale, esat-
pazienti con patologie concomitanti gravi e/o i cui genitori tamente di 100 mm, sono state graduate con linee di mede-
non erano disponibili o non erano in grado di compilare il SA- sima altezza, di 3 mm, collocate a una distanza di 10 mm l’u-
EASI. na dall’altra. È stata effettuata una retro traduzione per veri-
ficare la congruità della versione italiana con quella in ingle-
se.
Strumenti Lo SCORAD 17 è uno strumento per la valutazione della
Il SA-EASI è uno strumento di una pagina che consente gravità clinica della DA completato dal dermatologo. È arti-
al genitore del bambino affetto da DA di misurare la gra- colato in 3 sezioni. La prima è inerente alla valutazione del-
vità della patologia del figlio. È articolato in 2 sezioni, la l’estensione e alla localizzazione della dermatite. La secon-
prima relativa alla localizzazione e all’estensione della der- da è relativa alla valutazione dell’intensità di: eritema, ede-
matite, la seconda relativa alle caratteristiche cliniche, ogget- ma/papule, siero/crosta, escoriazioni, lichenificazione e sec-
tive e soggettive, della dermatite stessa. Nella prima sezio- chezza; quest’ultima è valutata sulle aree non coinvolte dal-
ne sono rappresentate 2 silhouette di un bambino ideale, una la dermatite, mentre le altre caratteristiche sono valutate sul-
vista da una prospettiva frontale, l’altra posteriore. Il genitore l’area maggiormente interessata dall’eritema. La terza sezio-
ne è relativa ai sintomi soggettivi di prurito e perdita di son- na= 8) hanno partecipato allo studio. Il 61,6% sono risulta-
no negli ultimi 3 giorni. ti affetti da DA moderata (SCORAD tra 15 e 40) e il 38,4%
Nella prima sezione sono rappresentate 2 silhouette di un da DA grave (SCORAD >40). Il range di variazione del pun-
bambino ideale, una vista da una prospettiva frontale, l’altra teggio totale SCORAD al momento del ricovero è compre-
posteriore. Il dermatologo deve tratteggiare con una penna le so tra 15,2 e 70,3, con un punteggio medio di 38,8 (ds=13,03)
aree della silhouette corrispondenti all’eczema sul corpo del e mediano di 36,1.
bambino. Per valutare le caratteristiche del SA-EASI, come misu-
La stima della BSA coinvolta è ottenuta applicando un ra della gravità della DA, sono stati confrontati i punteggi otte-
algoritmo a partire dalla valutazione percentuale (0-100) nuti con quelli derivati dallo SCORAD.
che un ricercatore, che non ha visto il paziente, fa dell’area Sono stati calcolati gli indici di correlazione tra i 2 pun-
indicata dal clinico, separatamente per la rappresentazione teggi totali, tra i punteggi relativi alle misure di BSA e tra i
anteriore e posteriore e per 4 distinti distretti corporei: testa, punteggi relativi ai 4 distretti corporei. Tutti gli indici sono
arti superiori, tronco, arti inferiori. risultati soddisfacenti. Tra i punteggi totali la correlazione è
Successivamente i punteggi di area sono moltiplicati per risultata 0,71 (P<0,0001), e solo leggermente inferiore tra le
uno specifico peso (9 per la testa, 18 per gli arti superiori, 36 2 misure di BSA (rs=0,68; P<0,0001). Le correlazioni tra
per il tronco, 37 per gli arti inferiori). Valori diversi sono ogni coppia dei 4 distretti corporei variano tra 0,59 e 0,70
proposti per i soggetti con meno di 2 anni di età 17. Infine i (superficie testa rs=0,61; superficie estremità superiori
prodotti sono sommati per ottenere il punteggio BSA. rs=0,61; superficie tronco rs=0,59; superficie estremità infe-
Il punteggio totale è derivato dall’applicazione della for- riori rs=0,70; P<0,0001).
mula estensione/5+7intensità/2 in cui l’estensione pesa per Dal confronto delle caratteristiche specifiche delle lesio-
il 25% e l’intensità per il 75% del punteggio totale. Il range ni emergono relazioni basse che suggeriscono una limitata
teorico del punteggio è compreso tra 0 e 83. La gravità del- concordanza tra le misure; tra arrossamento ed eritema l’in-
la DA è classificata in lieve (<15), moderata (tra 15 e 40) e dice di relazione è rs=0,42 (P=0,0013), tra graffi e escoria-
grave (>40). zione rs=0,43 (P=0,0010), tra secchezza rs=0,29. Per le carat-
In questo studio è stata utilizzata la versione che esclude teristiche di ispessimento e prurito, considerate dal SA-
il conteggio dei criteri soggettivi relativi al prurito e al son- EASI, e quelle di lichenificazione, presenza di crosta/siero
no perso 17. e infiammazione o formazione di papule dello SCORAD,
Entrambe le valutazioni sono state effettuate al ricovero. per le quali non vi è corrispondenza tra i 2 strumenti, le cor-
Il dermatologo (AP), dopo aver visitato il bambino e com- relazioni sono inferiori a 0,10.
pilato lo SCORAD, consegnava al genitore il SA-EASI. Per valutare la capacità dei 2 strumenti di registrare un
cambiamento nello stato clinico del paziente è stato propo-
Analisi statistica sto al dermatologo e ai genitori di un gruppo di 23 soggetti,
13 di sesso femminile e 10 di sesso maschile, di età compresa
Le correlazioni sono state calcolate tra i punteggi totali SA- tra 3 mesi e 17 anni (media 8,03, ds 5,22, mediana 8,11), di
EASI e SCORAD, e separatamente tra estensione, distretti compilare il SA-EASI e lo SCORAD al momento del rico-
corporei e gravità. Come indice di correlazione è stato cal- vero e a distanza di 48 h o più. La durata dell’intervallo mini-
colato il coefficiente ρ di Spearman (rs). mo è stata scelta per bilanciare l’effetto della possibile distor-
La stabilità è stata misurata, separatamente per i 2 stru- sione dovuta al ricordo della prova precedente che può veri-
menti, in 23 soggetti con una seconda somministrazione a ficarsi quando l’intervallo tra le 2 è troppo breve.
distanza di 48 h. Nella Tabella I sono riportate le caratteristiche dei punteggi
Le valutazioni, riportate in percentuale, sono state fatte totali dei 2 strumenti al tempo 1 e al tempo 2. Nella Tabella
separatamente per distretto corporeo (testa, arti superiori, I, la differenza, delta, tra il punteggio al momento del rico-
tronco, arti inferiori) e piano d’osservazione (frontale, dor- vero e quello successivo evidenzia un miglioramento della
sale). Sono stati, quindi, applicati gli specifici algoritmi per sintomatologia durante il ricovero, sia nei punteggi SCO-
la misura delle BSA: RAD sia in quelli SA-EASI. Il punteggio differenziale nega-
BSASA-EASI=(0,1*Ah)+(0,2*Au)+(0,3*At)+(0,4*Al) tivo nel range dello SCORAD identifica un soggetto che tra
BSASCORAD=(9*Ah)+(18*Au)+(37*At)+(36*Al) i 2 momenti della misura ha avuto un aggravamento dell’a-
(Ah= area testa, Au= area arti superiori, At= area tronco, rea interessata dalla patologia. Il 52,4% dei soggetti pre-
Al= area arti inferiori( sentano a distanza di pochi giorni dal ricovero un quadro di
Per l’analisi statistica è stato utilizzato il software PC- gravità lieve (SCORAD<15), il 42,9% ancora moderata, e il
STATA 25. 4,8% grave.
Risultati Discussione
Trentacinque soggetti (51% di sesso femminile) di età Il SA-EASI si è dimostrato uno strumento equivalente
compresa tra 2 mesi e 17 anni (media= 7,7; ds= 5,07; media- allo SCORAD per misurare la gravità della DA infantile.
La versione italiana adattata è risultata facilmente e imme- se presentazioni cliniche della patologia. Tuttavia il SA-
diatamente comprensibile a tutti i genitori coinvolti. I risul- EASI presenta il vantaggio secondario di coinvolgere atti-
tati di questo studio rappresentano un importante contribu- vamente, nella valutazione e nel monitoraggio, la famiglia del
to preliminare in quanto evidenziano la capacità del genito- bambino affetto da patologia cronica.
re di valutare in modo accurato, e sufficientemente sovrap- I punteggi di entrambi gli strumenti riflettono il diverso sta-
ponibile a quello del dermatologo, l’estensione e la gravità to clinico del paziente anche se saranno necessari altri stu-
della DA del proprio figlio utilizzando uno strumento strut- di, su campioni più numerosi, per confermare la capacità di
turato. La valutazione fatta dal genitore non si discosta da registrare cambiamenti nella patologia, sia nel tempo, sia
quella fatta dal dermatologo, tutte le correlazioni indicano una come risposta ai trattamenti.
sostanziale convergenza e sono del medesimo ordine di gran-
dezza.
Come atteso i 2 strumenti mostrano delle differenze per Riassunto
quanto riguarda le caratteristiche specifiche delle lesioni
peculiari di ogni strumento, tuttavia quest’assenza di paral- Obiettivo. Gli strumenti per misurare la gravità della der-
lelismo non sembra influenzare i punteggi totali. matite atopica (DA) richiedono tempo sia per la compila-
zione, sia per l’attribuzione del punteggio e sono, quindi,
poco utilizzati nella pratica clinica abituale. Il self admini-
Conclusioni stered eczema area severity index (SA-EASI) è stato svi-
luppato e validato per la valutazione, da parte dei genitori, del-
In conclusione, sembra che i risultati di questo studio la gravità della DA dei figli. Lo scopo di questo studio era ana-
indirizzino verso l’individuazione di uno strumento, il SA- lizzare la relazione tra SA-EASI e SCORing atopic derma-
EASI, che ha il vantaggio - comune a molti strumenti auto- titis (SCORAD).
somministrati - di non richiedere l’intervento di personale spe- Metodi. Hanno partecipato allo studio 35 pazienti, rico-
cializzato, che non necessita di addestramento, che consen- verati presso la divisione pediatrica di un ospedale derma-
te, attraverso una rapida e facile compilazione, di valutare le tologico di Roma, e almeno uno dei loro genitori. La gravità
manifestazioni di intensità ed estensione della patologia. Il della patologia è stata valutata, al momento del ricovero in
SA-EASI potrebbe essere lo strumento di comunicazione, sul- ospedale, separatamente dal genitore, con il SA-EASI, e dal
la patologia, tra paziente (o genitore) e medico curante, e dermatologo, con lo SCORAD.
rappresentare, per quest’ultimo, il mezzo per seguire l’an- Risultati. La validità concorrente è espressa dalla corre-
damento della patologia. lazione tra i punteggi totali dello SCORAD e del SA-EASI
L’altro strumento, lo SCORAD, presenta caratteristiche (ρ di Spearman=0,71; P<0,001).
analoghe, e il suo impiego nella routine consentirebbe al cli- Conclusioni. Entrambi gli strumenti sono utili nella pra-
nico una valutazione più puntuale e oggettiva, non soltanto tica clinica quotidiana e nella ricerca sugli outcome. Il SA-
in quei contesti nei quali il tempo a disposizione del medi- EASI ha il vantaggio di non richiedere l’intervento di per-
co è poco, ad esempio le visite ambulatoriali, ma anche nel sonale specializzato e non necessita di addestramento; favo-
rapporto con il paziente cronico, seguito nel tempo. risce, inoltre, un maggior coinvolgimento dei familiari.
Rispetto al SA-EASI, lo SCORAD si caratterizza come Parole chiave: Dermatite atopica - Estensione - Gravità -
una misura più accurata in quanto il dermatologo con la sua Misura dell’accordo - SA-EASI - SCORAD - Validità con-
esperienza professionale è in grado di differenziare le diver- corrente.
Extracellular matrix protein 1 (ECM1) is a glycoprotein found 1Genetic Skin Disease Group
in many tissues, including skin. First discovered in 1994, its St John’s Institute of Dermatology
function in skin biology was largely unknown until 2002 when Division of Skin Sciences
it was identified as the candidate gene/protein for the autoso- Guy’s, King’s College
mal recessive disease, lipoid proteinosis. This inherited disor- and St Thomas’ Hospitals’ Medical School,
der is characterised clinically by skin and mucosal infiltra- St Thomas’ Hospital, London, UK
2Department of Dermatology
tion and scarring, and histologically by disruption or dupli-
cation of basement membrane, as well as widespread deposi- Kurume University School of Medicine, Kurume, Japan
3Department of Dermatology
tion of hyaline material in the dermis. Over 30 pathogenic
mutations in the ECM1 gene have been characterised, with Fukushima Medical University School of Medicine
recurrent mutations, ancestral alleles, genotype-phenotype Fukushima, Japan
correlation and new diagnostic techniques now established
for this rare genodermatosis. Further insight into the role of
ECM1 in human skin was revealed in 2003 with the discovery
of circulating autoantibodies against the ECM1 protein in the
sera of most patients with lichen sclerosus, a common chron-
ic inflammatory condition that shares some clinicopatholog- ly discovered glycoprotein ECM1 has an important function
ical features with lipoid proteinosis. These autoantibodies have in skin biology.
been characterised and the immunodominant epitope isolat- KEY WORDS: Gene mutation - Autoantibodies - Lipoid proteinosis
ed, and a new ELISA test for lichen sclerosus is currently - Lichen sclerosus - Epidermis - Dermis - Basement membrane.
being evaluated. Protein-protein interaction studies have iden-
tified that ECM1 binds to the major heparan sulphate pro-
teoglycan, perlecan, as well as to matrix metalloproteinase 9,
The discovery of extracellular matrix protein 1
epidermal growth factor, and legumain. These findings, in
combination with the lipoid proteinosis and lichen sclerosus
data, suggest that ECM1 has a key role in several aspects of epi-
dermal differentiation, maintaining dermal architecture, and
regulating basement membrane composition. Clearly, the new-
E xtracellular matrix protein 1 (ECM1) is a glyco-
protein that was first discovered in 1994. In a
study relevant to bone matrix biology, Mathieu et al.
analysed the proteins secreted by a clonal osteogenic
Funding from the Charitable Foundation of Guy’s and St Thomas’ stromal cell line, MN7, derived from mouse bone mar-
Hospitals and the British Skin Foundation for several of the original stu-
dies referred to in this review is gratefully acknowledged. row, using two-dimensional polyacrylamide gel elec-
trophoresis, Western blotting and microsequencing.1
Amongst several proteins identified, a novel glycosy-
Address reprint requests to: J. McGrath, Genetic Skin Disease Group,
St John’s Institute of Dermatology, St Thomas’ Hospital, Lambeth Pala- lated 85-kDa protein with an average isoelectric point
ce Road, London SE1 7EH, UK. E-mail: john.mcgrath@kcl.ac.uk of 5.7 was isolated.1 This protein was initially desig-
nated p85 based on its size, but was also named ECM1 ety of biological ligands.12 The CC-(X7-10)C motif is
because it was discovered amidst various other con- also present in the serum albumin family of proteins
nective tissue proteins including type I collagen, and shows structural similarities to the Endo 16 cal-
osteonectin, cathepsin and sialo bone protein.1, 2 The cium-binding protein of sea urchin.2, 13 The specific
human homologue was later identified in 1997.3, 4 motif may enable ECM1 to serve as a transporter pro-
Most of the early functional studies on ECM1 con- tein or to be involved in binding growth or differenti-
centrated on its role in tissues other than skin, and ation factors.10 Indeed, yeast-two-hybrid studies have
involvement of ECM1 in bone and cartilage develop- shown that ECM1 can bind to several other proteins,
ment, angiogenesis and certain malignancies, was including the major heparan sulphate proteoglycan,
demonstrated. For example, ECM1 was found to be a perlecan, matrix metalloproteinase 9 (MMP-9, type
negative regulator of endochondral bone formation, IV collagenase), epidermal growth factor (EGF), and
inhibiting alkaline phosphatase activity and mineral- legumain.11, 14 The ECM1 protein also contains 3 N-
isation.5 ECM1 was also shown to be able to stimulate glycosylation sites for protein kinase C and several
blood vessel endothelial cell proliferation (in culture), phosphorylation sites for casein kinase II.3 ECM1 also
and to promote angiogenesis (in chicken embryos).6 contains a calcium-binding domain, which is present
Presence of ECM1 was also demonstrated in the stro- in the ECM1a and ECM1c isoforms but not in
ma of 2 human breast cancer cell lines, MDA-435 and ECM1b.2, 10
LCC15.6 Additionally, increased ECM1 expression,
revealed by microarray experiments, has been report-
ed in cartilage formation, dendritic cell differentia- Gene structure and expression
tion and maturation, and in grade I, II and IV glioblas- of extracellular matrix protein 1
toma multiformes.7-9 Some experimental data for a
potential role for ECM1 in the skin, notably in epi- The ECM1 gene has been mapped to chromosome
dermal differentiation, were also postulated,2, 10 but 1q21.2 3, 4 and it has 3 known splice variants, ECM1a,
the key role of ECM1 in multiple aspects of cutaneous ECM1b and ECM1c.3, 11 ECM1a is encoded by a 10-
biology was not immediately apparent. exon gene, whereas ECM1b lacks exon 7 and ECM1c
contains an additional exon 5a within intron 5. Exon
5a is homologous to the sixth mouse exon that was
Protein structure initially thought to be absent in the human gene.11
of extracellular matrix protein 1 ECM1a is the most widely expressed splice variant. It
is found in various tissues including skin, liver, small
The ECM1 protein consists of 3 isoforms, ECM1a, intestines, lung, ovary, prostate, testis, skeletal muscle,
ECM1b and ECM1c, of 540, 415 and 559 amino acids, pancreas and kidney, but gene expression is greatest in
respectively. ECM1 contains a signal peptide of 19 placenta and heart. By contrast, ECM1b has a much
amino acids followed by 4 functional domains: a cys- more restricted expression pattern, being detectable
teine-free N-terminus, 2 tandem repeats and a C-ter- only in tonsils and keratinocytes.3 The full pattern of
minus.2, 3, 11 The latter 3 domains contain numerous cys- ECM1c expression has yet to be determined, but in
teine residues, arranged in a specific manner. The cys- skin it accounts for approximately 15% of total ECM1
teine distribution and structure in humans is almost RNA.11 Apart from the functions identified for the
identical to its mouse counterpart, containing 28 cys- ECM1 protein, sequence analysis also predicts that
teine residues, although there is just one amino acid less ECM1 is a positive regulator of the I-κB kinase/NF-κB
in the human protein.3 Significantly, the cysteine-con- cascade. The precise localisation of the ECM1 gene
taining domains all have the typical CC-(X7-10)C maps just centromeric to the epidermal differentiation
arrangement that is capable of forming protein double complex region,10 a locus that contains a cluster of 3
loops involved in protein-protein interactions.2, 3 ECM1 families of genes involved in epidermal differentia-
contains 1 double-loop domain within each of the 2 tan- tion.3 Nevertheless, ECM1 may have a role in termi-
dem-repeats and 1 in the C-terminal domain.11 Dif- nal keratinocyte differentiation, as suggested by stud-
ferent double loops can have varying binding affinities, ies demonstrating expression of ECM1a within basal
increasing the potential for interactions with a vari- keratinocytes and ECM1b in suprabasal cells.10
Figure 1.—Skin and mucous membrane features of lipoid proteinosis in (A) a 36-year-old man with severe inflammation, erosions and thickening of
the oral mucosa and skin infiltration and scarring on his face, and (B) a 10-year-old boy with infiltration of the lips and tethering of the tongue with a
thickened frenulum and reduced tongue movement. There is also papular infiltration of his facial skin.
Extracellular matrix protein 1 gene mutations patients world-wide and 31 different pathogenic muta-
in lipoid proteinosis tions (including unpublished data) have been identified
(Figure 2).18-22 Mutations have been identified in every
Lipoid proteinosis (OMIM 247100), also known as exon, apart from exon 5a. The majority of mutations
Urbach-Wiethe disease or hyalinosis cutis et mucosae, occur in exons 6 and 7, with 9 mutations occurring in
is a rare autosomal recessive disorder typified by gen- exon 7, and 10 mutations occurring in exon 6. Most of
eralised thickening and scarring of the skin and the mutations are nonsense or frameshift mutations,
mucosae (Figure 1).15, 16 Other characteristic clinical presumably resulting in truncation of the ECM1 pro-
features include beaded eyelid papules, waxy yellow tein, and/or low levels of the corresponding mRNA
skin papules and nodules, and most notably, a hoarse through nonsense-mediated mRNA decay mecha-
voice from infancy.16 Increased skin scaling and thick- nisms. In addition, there are 4 missense mutations:
ening occurs in regions exposed to mechanical friction V10G in exon 1 and F167I,18 F167L and L210P in
including elbows, hands and knees. In 2002, genome- exon 6 (including unpublished data). All 4 of these
wide linkage analysis using genomic DNA from con- amino acid changes represent substitution of one
sanguineous families with lipoid proteinosis, was hydrophobic neutral amino acid by another, but the
reported.17 Screening mapped lipoid proteinosis to a relative sizes of the amino acids are different and there-
2.3-cM interval on the long arm of chromosome 1, at fore the functional conformation of ECM1 may be
1q21.2.17 A candidate gene approach was then used, altered. All these missense changes have been exclud-
presupposing that, as in many other recessive geno- ed as rare polymorphisms and the substituted amino
dermatoses, the lipoid proteinosis gene product would acids are highly conserved residues. The missense
show reduced expression in dermal fibroblasts com- mutation V10G occurs at the start of the ECM1 gene
pared to normal control fibroblasts. Following this in the region coding for the signal peptide, whereas
rationale, the gene for lipoid proteinosis was identified F167I, F167L and L210P all occur in the first tandem-
as ECM1. Sequencing of genomic DNA from 6 con- ly-duplicated domain of ECM1. A donor splice site
sanguineous families disclosed the presence of mutation, 80+1G>A, has also been identified (unpub-
homozygous loss-of-function mutations (nonsense, lished data).
frameshift or internal deletions) in all cases.17 Reduced Initial genotype-phenotype correlation suggested
ECM1 protein expression in lipoid proteinosis skin that mutations occurring outside exon 7 were associ-
was also noted.17 Thereafter, the molecular basis of ated with a slightly more severe mucocutaneous phe-
lipoid proteinosis has been determined in over 50 notype, but this has not been borne out in more detailed
Q95X/1432delA
F167L
1019delA C220G/R476X
501insC Q276X Q346X
Q32X Q114X 541 735delTG W359X 1253delC
80+1G>A del3 R243X
V10G ins16
R243X
5a
1 2 3 4 5 6 7 8 9 10
L210P
Q197X
542insAA/R243X
R53X W160X/F167I 1163-bp deletion
735delTG
243delG 507delT H1190insC
E248X
785delA
892delC
Figure 2.—Schematic representation of all known pathogenic mutations in the ECM1 gene in lipoid proteinosis. Double arrows indicate homozygous
mutations; joined arrows depict compound heterozygosity.
analyses.18 Specifically, considerable inter-individ- be time-consuming and not readily available in many
ual variability has been shown, for example in 29 diagnostic laboratories. Alternatively, one comple-
South African subjects, all with the same homozy- mentary approach to the diagnosis of many recently
gous mutation, Q276X, in exon 7.20 This mutant allele characterised genodermatoses has involved skin
was thought to have been propagated by a German immunohistochemistry. Indeed, many of the severe,
settler (from Cologne) to the Northern Cape in the usually autosomal recessive, single gene disorders
1650s.20, 23-25 Other mutated ancestral ECM1 alleles typically involve loss-of-function mutations leading
have also been identified, for example 501insC in to reduced or absent expression of the encoded protein.
Northern Europe and W359X in Scotland. The muta- Such changes can often be detected through dimin-
tion 507delT, however, appears to be a hotspot muta- ished immunohistochemical labelling of skin sections
tion, having occurred on different genetic backgrounds using an antibody to the corresponding protein. This
in 2 Thai brothers, a Canadian Iranian family, a Japan- approach has proved to be very useful in the rapid
ese individual, and an Indian girl with lipoid pro- diagnosis of other genodermatoses such as epider-
teinosis.18, 21 molysis bullosa, lamellar ichthyosis, Netherton’s syn-
drome and Kindler syndrome.26, 27 To develop an
immunohistochemical test for lipoid proteinosis, a
New diagnostic test for lipoid proteinosis rabbit polyclonal antibody to human ECM1 was raised
against the oligopeptide SGDTENAKGQGEQGSTG,
Lipoid proteinosis can be difficult to diagnose in encoding the carboxyl-terminal of the human ECM1
early life. With time, it can usually be diagnosed clin- protein.28 Immunolabelling with this antibody was
ically but the early manifestations of lipoid proteinosis reduced in lipoid proteinosis skin, confirming its use-
are protean and may overlap with other diseases, fulness as a diagnostic probe (Figure 3). However, the
including subtypes of porphyria. Having identified pattern of labelling was also able to provide clues as to
ECM1 as the lipoid proteinosis gene, however, it is where the pathogenic mutation might lie.28 Specifi-
now possible to screen DNA in suspected cases to cally, attenuated but not absent labelling suggested
establish the diagnosis, notwithstanding that this may that the pathogenic mutation was in exon 7, whereas
Figure 3.—Immunohistochemical labelling of (A) normal control skin (B) skin from a patient with lipoid proteinosis caused by the homozygous muta-
tion Q276X in exon 7 of the ECM1 gene, using a polyclonal anti-ECM1 antibody. In (A), there is intracellular and cell-surface labelling in the lower
epidermis, particularly in basal keratinocytes and to lesser extent, in suprabasal keratinocytes. (B) shows attenuated, though still detectable, immunos-
taining. (Bar = 50 µm).
Figure 4.—Atrophic shiny, pale white plaques of extragenital lichen sclerosus on the trunk of (A) a 38-year old man and (B) a 65-year-old woman.
amino acids 359 and 559 within the distal second tan- might be any correlation between anti-ECM1 anti-
dem repeat and the carboxyl-terminus of ECM1.33, 34 body titres and disease parameters in lichen sclerosus,
The anti-ECM1 IgG subclass is predominantly IgG2, a diagnostic ELISA was recently reported.34 The pro-
with almost 90% of sera containing IgG2 anti-ECM1 tein for the ELISA in this study was based on the
autoantibodies, either alone or in combination with immunodominant epitope, i.e. the distal second tan-
other subclasses.33 These antibodies are not just an dem repeat and carboxyl-terminus of ECM1. This
epiphenomenon since they are not observed in other ELISA test exhibited a high sensitivity of 80% (76
sclerosing or basement membrane diseases.32 Fur- of 95 sera were positive) and a high specificity of
thermore, passive transfer studies with affinity-purified 93.7% in discriminating lichen sclerosus from nor-
lichen sclerosus IgG autoantibodies injected intrader- mal controls and other autoimmune basement mem-
mally into the ears of neonatal mice have shown that, brane or sclerosing diseases, thus establishing this
compared to control injected sites, lichen sclerosus ELISA as a useful diagnostic test (Figure 5).34 Clin-
IgG injection causes the mice to scratch their ears. ically, higher ELISA titres correlated with more long-
Macroscopically, at 28 days, there is swelling and ery- standing disease, with cases that were refractory to
thema, and microscopically there is oedema, a patchy treatment, and with cases complicated by squamous
mononuclear inflammatory cell infiltrate in the dermis, cell carcinoma.34 This ELISA, therefore, may be use-
focal pigmentary incontinence in the superficial der- ful in detecting individuals with lichen sclerosus who
mis and dilatation of some superficial blood vessels.34 need more aggressive immunosuppressive therapy or
These changes do not fully recapitulate the full histo- who may be at risk for disease complications, such as
logical features of lichen sclerosus (i.e. no hyalinosis) malignancy or extensive scarring. Detection of the
but are fully consistent with early histological changes antibodies by ELISA may also provide a means of
seen in this disease. assessing the potential benefits of new treatments for
lichen sclerosus, such as immunoadsorption thera-
New ELISA test for lichen sclerosus pies in which recombinant ECM1 protein might be
used to remove circulating anti-ECM1 antibodies
High throughput diagnostic ELISA measurement of from the sera of patients with lichen sclerosus. Cur-
serum autoantibodies has become an established part rently, however, no prospective studies examining
of the investigation of several autoimmune skin dis- how the anti-ECM1 antibody fluctuates with disease
orders, such as pemphigus and bullous pemphigoid.35 activity and time in individual patients have been
Moreover, the antibody titres determined by ELISA reported, and these will be extremely important in
in these diseases may have clinical implications for establishing the potential usefulness of the ECM1
optimal patient management. To assess whether there antibody ELISA in clinical practice.
1.2
EPIDERMAL
Arbitrary unit of ELISA (405 nm)
1.0 DIFFERENTIATION
0.8
0.6
0.0
Normal LS SLE BP SSc
(n=161) (n=95) (n=70) (n=72) (n=15) MMP-9
Figure 5.—ELISA for anti-ECM1 antibodies assessed in 95 patients with
lichen sclerosus (LS), as well as 318 control subjects, comprising 161
normal volunteers, and 70 systemic lupus erythematosus (SLE), 72 bul-
lous pemphigoid (BP), and 15 systemic sclerosis (SSc) individuals. These
data show that the assay is highly sensitive and specific for lichen sclero- ECM1 ECM1 PERLECAN
sus.
BINDING
The function of extracellular matrix protein 1 TO
in human skin COLLAGENS
ELASTIC
The discovery that loss-of-function mutations in
FIBRES
ECM1 result in lipoid proteinosis provided the first
GROWTH
clinical indication of the possible relevance of the BLOOD FACTORS
ECM1 protein to skin adhesion, epidermal differenti- VESSEL
ation, wound healing, scarring, angiogenesis and base- ENDOTHELIAL CELL
ment membrane integrity. Histologically, skin from PROLIFERATION
patients with lipoid proteinosis shows hyperkeratosis,
basement membrane thickening at the dermal-epider- Figure 6.—Illustration of the possible functions of ECM1 in human skin
mal junction and around blood vessels and adnexal biology.
epithelia, as well as presence of hyaline material in
the dermis.16 This suggests that a lack of ECM1 may
influence the normal pattern of epidermal differenti- ation and, therefore, the epidermal atrophy seen in
ation, as well as disrupting dermal physiology. It is lichen sclerosus may be due to changes in the dynam-
plausible that one of the main functions of ECM1 in the ics of normal keratinocyte maturation.10, 32 In the der-
dermis is to act as some form of biological glue, help- mis, the basement membrane thickening and hyaline
ing to regulate basement membrane and interstitial appearance to collagen could reflect perturbations in
collagen fibril macro-assembly and growth factor bind- the normal binding of ECM1 to proteoglycans, such as
ing.19 In lipoid proteinosis, the glue is defective or perlecan.11, 32 Notably, co-localisation between ECM1
simply missing, leading to dysregulation of dermal and perlecan has been demonstrated in skin basement
homoeostasis and clinical features of skin infiltration membranes, in dermal blood vessels, and surround-
and scarring.19 The clinical features seen in lichen ing adnexal epithelia and it has been shown that the car-
sclerosus may also help illustrate the function of ECM1 boxy-terminus of ECM1 interacts with the EGF-like
in human skin, i.e. antibodies to ECM1 disrupt the modules flanking the LG2 subdomain of perlecan
normal function of the protein and thereby illustrate domain V.11 Perlecan is also known to bind to
what the ECM1 protein normally protects against or fibronectin, laminin, type IV collagen, fibulin 2, dys-
prevents. ECM1 has a role in keratinocyte differenti- troglycan, platelet-derived growth factor 7 and fibrob-
Conclusion
Riassunto
Figure 7.—Illustration of the ECM1 gene and protein and the corre-
sponding disease associations. Loss-of-function mutations in the ECM1
gene result in lipoid proteinosis whereas autoantibodies to ECM1 are Proteina 1 della matrice extracellulare: una nuova glico-
found in the sera of most patients with lichen sclerosus. In both these dis- proteina fondamentale nella biologia cutanea
orders, light microscopy reveals a hyaline appearance to the papillary der-
mis with dilated superficial blood vessels. La proteina 1 della matrice extracellulare (ECM1) è una
glicoproteine presente in molti tessuti, compresa la cute.
Scoperta nel 1994, il suo ruolo nella biologia della cute è
stato in gran parte sconosciuto fino al 2002 quando è stato
last-growth factor binding protein.11, 36 Disruption to
identificato il gene/proteina responsabile della proteinosi
these normal associations could account for the hya- lipode, malattia a carattere autosomico recessivo. Dal pun-
line abnormalities seen in lichen sclerosus.32 Perhaps to di vista clinico è caratterizzata da infiltrazioni e lesioni cica-
disruption of normal expression of ECM1 in blood triziali a livello della cute e delle mucose, e da un punto di
vessels could also explain the ecchymoses seen in vista istopatologico, da distruzione e duplicazione della
lichen sclerosus. Moreover, the link between ECM1 membrana basale con numerosi depositi di sostanza ialina nel
derma. Sono state identificate più di 30 mutazioni del gene
expression and certain malignant tumours might pro-
di ECM1, mutazioni ricorrenti, alleli ancestrali, correlazio-
vide a partial explanation for the increased incidence ni fra genotipi e fenotipi; sono state pertanto messe a punto
of squamous cell carcinoma in lichen sclerosus.25 nuove strategie diagnostiche. Un nuovo passo avanti nelle
ECM1 also interacts with legumain, MMP-9, and conoscenze del ruolo di ECM1 nella biologia cutanea è sta-
EGF.14 Legumain is a protease linked to aspects of to fatto nel 2003 con la scoperta di autoanticorpi circolanti
epidermal differentiation;37 EGF is a critical compo- contro ECM1 nel siero di pazienti affetti da lichen sclerosus,
una malattia infiammatoria cronica che condivide molti
nent of several signalling cascades, including calci-
aspetti anatomopatologici e clinici con la proteinosi lipoide.
um response pathways;38 and MMP-9 is a metallo- Sono stati caratterizzati gli autoanticorpi e isolati gli epito-
proteinase with a key role in basement membrane and pi immunomodulanti; attualmente viene utilizzato un nuovo
interstitial collagen remodelling as well as vasculari- test ELISA per la diagnosi del lichen sclerosus. Studi di
valutazione dell’interazione proteine/proteine hanno dimo- 12. Kragh-Hansen U. Structure and ligand binding properties of human
strato che ECM1 lega a perlecan, proteglicano eparan solfato, serum albumin. Dan Med Bull 1990;37:57-84.
alle proteine della matrice metalloproteinasi 9, fattori di cre- 13. Godin RE, Urry LA, Ernst SG. Alternative splicing of the Endo16
transcript produces differentially expressed mRNAs during sea urchin
scita dell’epidermide e legumain. Questi risultati, insieme ai gastrulation. Dev Biol 1996;179:148-59.
dati di correlazione fra la proteinosi lipoide e il lichen scle- 14. Terlizzi J, Li K, Aho A, Fujimoto N, Oyama N, Hamada T et al. Char-
rosus, suggeriscono che ECM1 gioca un ruolo fondamenta- acterization of ECM1 protein interactions by yeast-two-hydrid system.
le in molti aspetti della differenziazione dell’epidermide, J Invest Dermatol 2004;22:A38.
nel mantenimento dell’architettura del derma e nel regolare 15. Urbach E, Wiethe C. Lipoidosis cutis et mucosae. Virchows Arch
Path Anat 1929;273:285-319.
la composizione della membrana basale. Pertanto la glico- 16. Hamada T. Lipoid proteinosis. Clin Exp Dermatol 2002;27:624-9.
proteina ECM1 ha un ruolo fondamentale nella biologia 17. Hamada T, McLean WHI, Ramsay M, Ashton GH, Nanda A, Jenkins
cutanea. T et al. Lipoid proteinosis maps to 1q21 and is caused by mutations
in the extracellular matrix protein 1 gene (ECM1). Hum Mol Genet
PAROLE CHIAVE: Geni, mutazioni - Autoanticorpi - Proteino- 2002;11:833-40.
si lipoide - lichen sclerosus - Epidermide - Derma - Mem- 18. Hamada T, Wessagowit V, South AP, Ashton GH, Chan I, Oyama N
brana basale. et al. Extracellular matrix protein 1 gene (ECM1) mutations in lipoid
proteinosis and genotype-phenotype correlation. J Invest Dermatol
2003;120:345-50.
19. Chan I, El-Zurghany A, Zendah B, Benghazil M, Oyama N, Hamada
References T et al. Molecular basis of lipoid proteinosis in a Libyan family. Clin
Exp Dermatol 2003;28:545-8.
1. Mathieu E, Meheus L, Raymackers J, Merregaert J. Characterization 20. van Hougenhouck-Tulleken W, Chan I, Hamada T, Thornton H, Jenk-
of the stromal osteogenic cell line MN7: identification of secreted ins T, McLean WH et al. Clinical and molecular chracterization of
MN7 proteins using two-dimensional polyacrylamide gel elec- lipoid proteinosis in Namaqualand, South Africa. Br J Dermatol
trophoresis, western blotting and microsequencing. J Bone Miner 2004;151:413-23.
Res 1994;9:903-13. 21. Chan I, Sethuraman G, Sharma VK, Bruning E, Hamada T, McGrath
2. Bhalerao J, Tylzanowski P, Filie JD, Kozak CA, Merregaert J. Mol- JA. Molecular basis of lipoid proteinosis in two Indian siblings. J
ecular cloning, characterization and genetic mapping of the cDNA cod- Dermatol 2004;31:764-6.
ing for a novel secretory protein of mouse. Demonstration of alternative 22. Chan I, Bingewar G, Patil K, Nayak C, Wadhwa SL, McGrath JA.
splicing in skin and cartilage. J Biol Chem 1995;270:16385-94. An Indian child with lipoid proteinosis resulting from a recurrent
3. Smits P, Ni J, Feng P, Wauters J, van Hul W, Boutaibi ME et al. The frameshift mutation (507delT) in the extracellular matrix protein 1
human extracellular matrix gene 1 (ECM1): genomic structure, cDNA (ECM1) gene. Br J Dermatol 2004;151:726-7.
cloning, expression pattern and chromosomal localization. Genomics 23. Heyl T. Genealogical study of lipoid proteinosis in South Africa. Br
1997;45:487-95. J Dermatol 1970;83:338-40.
4. Johnson MR, Wilkin DJ, Vos HL, de Ortiz Luna RI, Dehejia AM, 24. Gordon H, Gordon W, Botha V. Lipoid proteinosis in an inbred
Polymeropoulos MH et al. Characterization of the human extracellular Namaqualand community. Lancet 1969;1:1032-5.
matrix protein 1 gene on chromosome 1q21. Matrix Biol 1997;16: 25. Strassberger E. The Rhenish Mission Society in South Africa 1830-
289-92. 1950. South Africa: C. Struik (Pty) LTD; 1969.
5. Deckers MM, Smits P, Karperien M, Ni J, Tylzanowski P, Feng P et 26. McGrath JA, Eady RA. The role of immunohistochemistry in the
al. Recombinant extracellular matrix protein 1 inhibits alkaline phos- diagnosis of the non-lethal forms of junctional epidermolysis bul-
phatase activity and mineralization of mouse embryonic metatarsals losa. J Dermatol Sci 1997;14:68-75.
in vitro. Bone 2001;28:14-20. 27. Ashton GHS, McLean WHI, South AP, Oyama N, Smith, FJD, Al-
6. Han Z, Ni J, Smits P, Underhill CB, Xie B, Chen Y et al. Extracellu- Suwaid R et al. Recurrent mutations in Kindlin-1, a novel keratinocyte
lar matix protein 1 (ECM1) has angiogenic properties and is expressed focal contact protein, in the autosomal recessive skin fragility and
by breast tumor cells. FASEB J 2001;15:988-94. photosensitivity disorder, Kindler syndrome. J Invest Dermatol
7. Sekiya I, Vuoristo J, Larson B, Prockop DJ. In vitro cartilage forma- 2004;122:78-83.
tion by human adult stem cells from bone marrow defines the sequence 28. Chan I, Oyama N, Hamada T, Bhogal BS, Black MM, Hamada T et
of cellular and molecular events during chondrogenesis. Proc Natl al. Rapid diagnosis of lipoid proteinosis using an anti-extracellu-
Acad Sci USA 2002;99:4397-402. lar matrix protein 1 (ECM1) antibody. J Dermatol Sci 2004;35:
8. Le Naour F, Hohenkirk L, Grolleau A, Misek DE, Lescure P, Geiger 151-3.
JD et al. Profiling changes in gene expression during differentiation 29. Powell J, Wojnarowska F. lichen sclerosus. Lancet 1999;353:1777-83.
and maturation of monocyte-derived dendritic cells using both oligonu- 30. Tasker GL, Wojnarowska F. lichen sclerosus. Clin Exp Dermatol
cleotide microarrays and proteomics. J Biol Chem 2001;276: 2003;28:28-33.
17920-31. 31. Neill SM, Tatnall FM, Cox NH. Guidelines for the management of
9. Rickman D, Bobek M, Misek D, Kuick R, Blaivas M, Kurnit DM et lichen sclerosus. Br J Dermatol 2002;147:640-9.
al. Distinctive molecular profiles of high-grade and low-grade gli- 32. Oyama N, Chan I, Neill SM, Hamada T, South AP, Wessagowit V et
nomas based on oligonucleotide microarray analysis. Cancer Res al. Autoantibodies to extracellular matrix protein 1 in lichen sclero-
2001;61:6885-91. sus. Lancet 2003;362:118-23.
10. Smits P, Poumay Y, Karperien M, Tylzanowski P, Wauters J, Huyle- 33. Chan I, Oyama N, Neill S, Wojnarowska F, Black MM, McGrath JA.
broeck D et al. Differentiation-dependent alternative splicing and Characterization of autoantibodies to extracellular matrix protein
expression of the extracellular matrix protein 1 gene in human ker- 1 (ECM1) in lichen sclerosus. Clin Exp Dermatol 2004;29:
atinocytes. J Invest Dermatol 2000;114:718-24. 499-504.
11. Mongiat M, Fu J, Oldershaw R, Greenhalgh R, Gown AM, Iozzo RV. 34. Oyama N, Chan I, Neill S, South AP, Wojnarowska F, Kawakami Y et
Perlecan protein core interacts with extracellular matrix protein 1 al. Development of antigen-specific ELISA for circulating autoanti-
(ECM1), a glycoprotein involved in bone formation and angiogene- bodies to extracellular matrix protein 1 (ECM1) in lichen sclerosus.
sis. J Biol Chem 2003;278:17491-9. J Clin Invest 2004;113:1550-9.
35. Ishii K, Amagai M, Hall RP, Hashimoto T, Takayanagi A, Gamou S 38. Uyemura T, Takagi H, Yanagida T, Sako Y. Single-molecule analysis
et al. Characterization of autoantibodies in pemphigus using antigen- of epidermal growth factor signaling that leads to ultrasensitive cal-
specific enzyme-linked immunosorbent assays with baculovirus- cium response. Biophys J 2005;88:3720-30. Epub 2005 Mar 4.
expressed recombinant desmogleins. J Immunol 1997;159:2010-7. 39. Sung HJ, Johnson CE, Lessner SM, Magid R, Drury DN, Galis ZS.
36. Dunlevy JR, Hassell JR. Heparan sulphate proteoglycans in base- Matrix metalloproteinase 9 facilitates collagen remodeling and angio-
ment membranes: perlecans, agrin and collagen XVIII. In: Iozzo RV genesis for vascular constructs. Tissue Eng 2005;11:267-76.
editor. Proteoglycans; structure, biology and molecular interactions. 40. Kowalewski C, Kozlowska A, Chan I, Gorska M, Wozniak K, Jablon-
New York: Marcel Dekker Inc; 2000.p.275-336. ska S et al. Three-dimensional imaging reveals major changes in skin
37. Zeeuwen PL. Epidermal differentiation: the role of proteases and microvasculature in lipoid proteinosis and lichen sclerosus. J Der-
their inhibitors. Eur J Cell Biol 2004;83:761-73. matol Sci 2005;38:215-24.
Recent advances in the diagnosis of mycosis fungoides, includ- Department of Pathology and Dermatology
ing T cell receptor gene rearrangement studies, have improved Yale University School of Medicine, New Haven, CT, USA
our ability to diagnose this challenging condition. However, it
is clear that clonality alone does not equate with malignancy.
Despite the aide of ancillary studies, mycosis fungoides remains
one of the most difficult dermatologic diagnoses to establish. The studies performed by members of European Organi-
histopathologic diagnosis of mycosis fungoides remains with-
in the realm of clinical/histologic/molecular correlation. As
zation for Research and Treatment of Cancer (EORTC)
such, histologic analysis of early mycosis fungoides remains a demonstrated accuracy in the diagnosis in MF likened
key factor in the diagnosis of this challenging condition. It is well to a coin toss.1 Three expert pathologists reviewed 73
known that mycosis fungoides can mimic and be mimicked by MF biopsies admixed with controls on 2 different
a variety of other dermatologic conditions, most of which are occasions. MF was identified correctly on both occa-
inflammatory. A wide variety of studies have well characterized sions 50% of the time.1 Forty percent of control cas-
the histologic findings of mycosis fungoides, however, we know es were identified correctly on both occasions. Other
much less about which histologic criteria are most specific for
this disorder. This article will address myriad of difficulties
studies seemed to appear more optimistic but, on clos-
encountered in the histopathologic diagnosis of mycosis fun- er review, were equally disheartening. In a study sim-
goides and then review individual criteria used to establish ilar to that of the EORTC, Olerud et al.2 were able to
this disorder, with emphasis on criterion specificity. correctly diagnose or suggest MF 92% of the time
KEY WORDS: Mycosis fungoides, diagnosis - Mycosis fungoides, (60% of MF biopsies diagnostic of MF; 32% consis-
histology - Mycosis fungoides, classification. tent with or suspicious for MF). Review of the control
group in this study revealed significant problems, how-
ever. Fifty two percent of control biopsies were called
What is the most difficult diagnosis to establish in suspicious for MF, and 6% were called MF outright.
dermatopathology? These results suggest that if we lower our threshold for
the diagnosis of MF, we will significantly over-diag-
nose this condition. Given the implications of over-
P atch Stage mycosis fungoides (MF) is arguably
the most difficult dermatopathologic diagnosis to
establish histopathologically. There is literature to sub-
treatment, insurance coverage issues, psychological
well being of patients, and a variety of other matters,
stantiate this impression. Approximately a decade ago, it is arguably more important not to over-diagnose MF
than to under-diagnose it.
Some authors who have addressed discordance in the
Address reprint requests to: E. J. Glusac, MD, Yale University School
of Medicine, Dermatopathology Laboratory, 5031 LMP, P.O. Box 208059, diagnosis of MF have argued that similar inaccura-
New Haven, CT 06520-8059. E-mail: Earl.Glusac@yale.edu cies are seen in most diseases and in most organ sys-
tems.3 A variety of references are typically cited in 5) Mycosis fungoides very often looks like a rash
support of this premise. One frequently cited refer- histologically as well. As such, a clinical misdiagnosis
ence, authored by Rosai, addressed diagnostic dis- may be supported by a congruous if inaccurate histo-
crepancies in the histopathology of the intraductal logic impression. This can readily occur, as the cells of
breast carcinoma.4 However, a careful review of this early MF often do not show significant morphologic dif-
manuscript reveals disagreement between benign and ferences from those of inflammatory conditions.11, 14
malignant diagnoses (the type of discrepancy we see 6) Mycosis fungoides does not resemble merely a
in MF studies) in less than 1/4 of cases. Frequently few different inflammatory processes under the micro-
cited papers in pulmonary and in gynecologic pathol- scope; it resembles many. Shapiro et al., in an analy-
ogy demonstrate even less significant discrepancies sis of 222 MF biopsies, demonstrated that virtually
when compared with MF.5, 6 And, for all the difficul- every inflammatory pattern developed by Wallace
ties encountered in histopathologic interpretation of Clark and A. Bernard Ackerman can be seen in MF.8
melanocytic lesions, interrelator agreement is still The most common patterns encountered are psoriasi-
much better with these lesions than with MF.7 form, lichenoid and psoriasiform/lichenoid. Less com-
mon patterns include superficial perivascular, super-
ficial perivascular and interstitial, vacuolar, psoriasi-
Why so difficult? form/spongiotic, spongiotic/psoriasiform/lichenoid,
nodular, superficial and deep perivascular and inter-
There are at least 8 important reasons why MF is so stitial, diffuse and folliculitic. Rare patterns include
difficult to diagnose. spongiotic, vasculitic, vesicular and panniculitic. With
1) MF is a clinicopathologic diagnosis.8-10 The his- this in mind, I am sometimes asked how one becomes
tory we often receive is rule out MF. It is often unclear good at diagnosing MF. My answer is “by becoming
in such cases whether the clinician believes the patient good at everything in the differential diagnosis”
likely has MF or, rather, an inflammatory disease, with (inflammatory skin disorders mostly). Often, one can
MF at the bottom of the differential diagnosis. A vari- only rule out MF by making another diagnosis.
ety of other conclusions are also possible. 7) MF resembles inflammatory disorders not to a
2) Treatment alters the histopathologic features of small degree but, frequently, to a large degree. Lym-
MF. At the time of biopsy, patients have often failed phocytes typically infiltrate the basal layer in MF,
standard treatments for a presumed exanthem, includ- interacting with Langerhans cells.11, 14, 15 This feature
ing topical steroids. It should be noted that topical is seen in a wide variety of other inflammatory con-
steroids appear to diminish or erase the epidermotropic ditions and is, in fact, typical of some of them, includ-
ing lichen sclerosis et atrophicus.16, 17
features of MF.11
8) There is no agreed upon absolute criteria for the
3) MF has a wide variety of clinical and histopatho-
diagnosis of early MF. The concept of MF underwent
logic variants, granulomatous, folliculotropic, verru-
a paradigm shift in the late 1970’s.11, 14, 18 Previously
cous, bullous, hyperpigmented and hypopigmented to
thought of as a rare, relentless, fatal lymphoma, MF
name a few.12 While the diagnosis of standard patch
became accepted as a lymphoma which usually
stage MF is difficult enough, the existence of a variety behaves in an indolent fashion, marked by patches,
of challenging variants complicates the matter. with progression to tumor stage disease or fatal disease
4) Clinically, early MF often looks more like a rash in a minority of patients. It is really a tale of 2 dis-
than a neoplasm.13 Certainly, other neoplasms can eases. In fact, were a particular British author able to
occasionally resemble exanthems; sporadic examples write about this disorder he might have said (my
of Bowen’s disease (squamous cell carcinoma in situ) changes in italics): “It was the best of diseases, it was
show an appearance that resembles eczema. Fortu- the worst of diseases, it was the diagnosis of wisdom,
nately, these 2 diseases do not resemble one another it was the diagnosis of foolishness... we has all crite-
under a microscope. Most neoplasms are mimicked ria before us, we had nothing before us, we were all
by other neoplasms, e.g. malignant melanoma and going direct to Heaven, we were all going direct the
pigmented basal cell carcinoma. Fortunately, these 2, other way”.19
at least, do not resemble each other microscopically. Histopathologists generally demonstrate a high
degree of accuracy in the diagnosis of tumor stage important to bear in mind that immunohistochemical
MF. Clinically and histopathologically, the presence of analysis of T cell infiltrates relies upon identifying
a neoplasm is evident at this stage. And whether these antigen loss. It must be kept in mind that, even with
tumors retain their epidermotropic capacity or whether adequate controls, it is more difficult to be certain
they lose it, as they often do, a diagnosis of tumor about absence of staining than positive staining. At
stage MF can generally be made. And whether the Yale University and at some other MF centers,
tumor is comprised of small to medium size convoluted immunohistochemistry is generally reserved until after
lymphocytes or large transformed ones, a diagnosis a diagnosis of cutaneous T cell lymphoma has been
of the tumor stage of this lymphoma can usually be established. It is then employed to identify aggressive
established.18 Plaque stage disease, though not as sim- subsets of cutaneous T cell lymphoma, such as gam-
ple, is generally not so laden with difficulties as patch ma/delta lymphoma or aggressive variants of CD8
stage disease.20 One sees, by definition, involvement positive lymphoma.
of the reticular dermis in plaque stage disease. This Less controversial is investigation for T cell recep-
is usually accompanied by the epidermal and papillary tor gene rearrangements (TCR) via polymerase chain
dermal changes typical of MF. In difficult examples of reaction (PCR). It is important to keep a variety of
plaque stage disease, ancillary studies, including caveats in mind, however, in the interpretation of TCR
immunohistochemistry and gene rearrangement stud- results. It should be noted that a significant percentage
ies, are often helpful.21-23 of patients with indubitable patch stage MF will not
The diagnosis of patch stage disease, as mentioned, demonstrate a clone via PCR.23, 26-28 Furthermore,
is entirely a different matter. Regarding the literature investigation of patients without indubitable MF is
on histopathologic diagnosis of early MF, it is fair to fraught with even greater difficulty. Patients described
say that there is good news and bad news. The good as having parapsoriasis,29 pre-MF 26 or as borderline 26
news is that some studies have conveyed that accura- can show clonality rates of significantly less than 50%.
cy in the diagnosis of MF does increase with experi- It is also important be aware that clones can be iden-
ence.2, 3 The bad news is that most studies suggest that
tified in disorders that we do not categorize as malig-
we have not yet established adequate criteria to diag-
nant. A few of these include cutaneous lymphoid hyper-
nose or dismiss MF consistently.1-3
plasia,29, 30 pityriasis lichenoides et varioliformis acu-
ta,31-33 pigmented purpuric eruption,34 lichen sclero-
Magic bullet? sis,35 and even lichen planus.36
As such, it is fair to say that there is no magic bul-
The next logical question to ask is “If histopathol- let. It is also likely fair to say that the gold standard for
ogy is inadequate to diagnose early MF, what ancillary the diagnosis of MF remains in the realm of clini-
studies can identify this challenging condition?” The cal/histologic/molecular correlation. As such,
first to come to mind is immunophenotyping. It is histopathology remains a key factor.
readily accessible and commonly used, but how use- With this in mind, and given the coin toss like sta-
ful is it? Early hopes centered on increased CD4:CD8 tus of histopathologic diagnosis of MF, it is fair to ask:
ratio, but it has been subsequently demonstrated that “Do we know the histologic criteria for MF?” I think
most inflammatory disorders are CD4 predominant, that we do. There have been many excellent descrip-
and, of course, some examples of cutaneous T cell tive studies regarding MF.8, 14, 37, 38 From such studies
lymphoma are CD8 positive. Immunophenotyping is we know a great deal about histologic features of MF,
clearly helpful in plaque and tumor stage MF, where but we know less regarding which criteria are most
loss of the common T cell antigens CD2, CD3 and/or specific. To be more accurate in the diagnosis of MF,
CD5 may be seen.21, 22 Such losses are not seen, how- we must know the relative specificity of various criteria
ever, in patch stage disease. Loss of Leu-8 was origi- employed. We can only establish specificity with con-
nally thought to be helpful in patch stage disease, but trolled, blinded studies of MF versus controls. Impor-
its value has now been dismissed.21, 22, 24 Loss of CD7 tantly, there must also be a gold standard against which
(Leu-9) is sometimes still touted as useful,25 but loss the histopathologic features of MF can be analyzed
of CD7 can be seen as frequently in inflammatory as independent variables. Given that the current gold
conditions as in early MF.21, 22, 24 Additionally, it is standard remains within the realm of clinical/histo-
7-9 µ Convoluted
Lymphocytes __ __ 100%** 8% __ __
LargeER
Interepidermal Lymphocytes 20%* 0% __ __ 17% 3%
Convoluted lymphocytes 67%* 32% __ __ 53% 12%
Haloed lymphocytes 59%* 13% __ __ 13% 0%
Pautrier’s
Microabscesses 37%* 2% 4%** 0% 17% 7%
Disproportionate
Exocytosis 58%* 28% __ __ 37% 6%
Basilar***
Lymphocytes 67%* 23% 46%** 0% 17% 3%
Pagetoid
Dystribution — — 33%** 0% 0% 0%
Papillary dermal fibrosis 61%* 49% 33%** 100% 67% 63%
* 2+ or greater (of 4)
** tiny collections of 4 cells in 42%
*** Defined variously, see text
Stanford = Stanford University study
ISCL = International Society for Cutaneous Lymphoma study
EORTC = European Society for Research and Treatment of Cancer study
MF = Mycosis Fungoides
CTL = Control Cases
Figure 4.—Disproportionate exocytosis (lymphocytes in the epidermis Figure 6.—Lymphocytes at all levels of the epidermis (pagetoid distribu-
associated with relative paucity of spongiosis) is a subjective finding tion) is indicative of MF but is rarely seen in early biopsies of this condi-
indicative of MF. tion.
Basilar lymphocytes
Basilar lymphocytes have been likened to strings
of pearls or toy soldiers. Neoplastic lymphocytes in MF
typically infiltrate the basal layer, in contiguity with
Langerhans cells.11 When basilar lymphocytes are
florid, a diagnosis of MF is likely.14 But how much is
enough? In the Stanford study, 1-5 lymphocytes in the
basal layer per 20X field was a statistically signifi-
cant and relatively sensitive if poorly specific dis-
criminator.15 In the ISCL study 4 contiguous lym-
phocytes within the basal layer (Figure 5) was an insen-
Figure 5.—Four or more contiguous lymphocytes within the basal layer
has been shown to be a feature indicative of MF. sitive criterion (17% of MF cases), but it was almost
perfectly specific (Burg et al. study submitted). The
EORTC study found that several contiguous rete (not
dermal surface 40 (Figure 3). Such collections will further specified) involved by basilar lymphocytes
label with CD1a and S100.41 They are typical of spon- was seen in approximately half of MF cases and, sur-
giotic processes but can also be seen in MF.41 prisingly, in no control specimens.39
Figure 7.—Medium-large convoluted lymphocytes that approximate the Figure 8.—Lymphocytes with halos or vacuoles around them are a partially
width of basilar keratinocytes are features strongly supportive of MF. artifactual feature that is supportive of MF.
dermis of that case. This data is very striking, and it ford study, performed on biopsies processed in the
is curious. It would appear to imply that a diagnosis Stanford University histopathology laboratory, it was
of MF can be made routinely and reliably. Other stud- the strongest histologic discriminator between MF
ies performed by members of this same group1 and and control cases.15 In the ISCL study (Burg et al.
other groups 2 do not appear to support that suppo- study submitted), performed on biopsies from a vari-
sition. Nonetheless, medium-large convoluted lym- ety of European laboratories, it was an insensitive
phocytes is an important criterion. Its combination of (13%) but completely specific discriminator.
size and convolution has crystalized existing ele-
ments in the literature and provided a useful histologic Papillary dermal fibrosis
benchmark (width of basilar keratinocyte nuclei) for
comparison. While papillary dermal fibrosis (Figure 9) has been
The Stanford 15 and ISCL studies (Burg et al. sub- touted as a key feature of patch stage MF, none of the
mitted) did not evaluate for the above criterion, but, 3 studies in question found it to be a useful discrimi-
rather, for convoluted nuclei alone. Each found con- nator between MF and control cases. It may be a mark-
voluted nuclei to be a significant, if imperfect dis- er simply of disease chronicity. In fact, the EORTC
criminator. It should be noted that the evaluation study found papillary dermal fibrosis much more fre-
of nuclear convolutions is a highly subjective quently in control cases than early MF biopsies.39 It
endeavor 43 and requires excellent histopathologic should be noted that the criterion assessed in each of
sections. these studies was simply papillary dermal fibrosis, as
opposed to lymphocytes splayed between thickened ity and specificity of various criterion in MF, in order
papillary dermal collagen bundles. The latter criterion to integrate this knowledge into the necessarily gestalt
may still be a useful discriminator, especially in late fashion in which we must all establish a diagnosis.
patch stage MF. The gold standard for the diagnosis of MF arguably
remains within the realm of clinical/histologic/mole-
Criteria clusters? cular correlation. Familiarity with sensitivity and speci-
ficity of criteria for MF, in conjunction with extensive
It is well known that no single histologic criterion can knowledge of disorders within the differential diagnosis
establish a diagnosis of MF. It is poorly known at this of MF (inflammatory dermatopathology), should help
time whether specific criteria clusters can be useful us improve our accuracy in the histopathologic diag-
in the evaluation of MF. The Stanford study did find nosis of early biopsies of this condition.
that moderate disproportionate exocytosis in combi-
nation with at least one haloed lymphocyte for 20X
field was specific for MF.15 While I doubt that this Riassunto
feature is specific for MF, it is likely a criteria cluster
that merits attention. Diagnosi istopatologica della micosi fungoide: frequenti i
problemi, rare le soluzioni
Sézary syndrome Recenti studi sulla diagnosi della micosi fungoide, compresi
quelli riguardanti il riarrangiamento del gene del recettore
Regarding the leukemic variant of cutaneous T cell delle cellule T, hanno migliorato le possibilità diagnostiche di
lymphoma, Sézary syndrome it is fair to say that his- questa patologia che ancora oggigiorno lancia numerose sfi-
de al dermatologo. Tuttavia è chiaro il concetto che clonalità
tologic diagnosis goes from difficult to more difficult. non significa necessariamente neoplasia maligna. Attual-
Buechner and Winkelmann’s classic treatise on this mente la micosi fungoide costituisce una delle patologie più
condition showed that only 15% of cases showed an difficili da diagnosticare. L’analisi istopatologica permette
epidermotropic pattern.45 Shapiro et al. demonstrated di eseguire studi e correlazioni da un punto di vista clinico,
increased spongiosis and diminished epidermotropism istologico e molecolare e come tale rimane fondamentale
as compared to standard MF.8 Other studies have nella diagnosi di questa patologia. La micosi fungoide si può
manifestare con caratteristiche simili ad altre patologie der-
demonstrated diminished disproportionate exocyto- matologiche generalmente di tipo infiammatorio. Molti stu-
sis,46 diminished basilar lymphocytes,46 fewer convo- di hanno riportato le caratteristiche istologiche della micosi
luted lymphocytes,46 increased acanthosis 47 and dimin- fungoide, tuttavia non sappiamo ancora quali siano i criteri
ished Pautrier’s microabscesses 47 as compared to MF. istologici più specifici per poter fare diagnosi.
Questa review prenderà in considerazione tutte le diffi- Attempts to enhance light microscopic diagnosis of cutaneous T-cell
coltà incontrate nella diagnosi istopatologica della malat- lymphoma (Mycosis Fungoides). Arch Dermatol 1981;117:408-11.
tia e i criteri individuali utilizzati, siano essi più specifici o 21. Ralfkiaer E. Immunohistological markers for the diagnosis of cuta-
neous lymphomas. Semin Diagn Pathol 1991;8:62-72.
meno. 22. Ralfkiaer E. Controversies and discussion on early diagnosis of cuta-
PAROLE CHIAVE: Micosi fungoide, diagnosi - Micosi fungoi- neous T-cell lymphoma. Phenotyping. Dermatol Clin 1994;12:329-34.
de, anatomia patologica, Micosi fungoide, classificazione. 23. Bachelez H, Bioul L, Flageul B, Baccard M, Moulonguet-Michar I,
Verola O et al. Detection of clonal T-cell receptor gamma gene
rearrangements with the use of the polymerase chain reaction in cuta-
neous lesions of mycosis fungoides and Sezary syndrome. Arch Der-
References matol 1995;131:1027-31.
24. Payne CM, Spier CM, Grogan TM, Richter LC, Bjore CG, Cromey
1. Santucci M, Burg G, Feller AC. Interrater and intrarater reliability of DW et al. Nuclear contour irregularity correlates with Leu-9-, Leu-8-
histologic criteria in early cutaneous T-cell lymphoma. Dermatol Clin cells in benign lymphoid infiltrates of skin. An ultrastructural mor-
1994;12:323-7. phometric and quantitative immunophenotypic analysis suggesting the
2. Olerud JE, Kulin PA, Chew DE, Carlsen RA, Hammar SP, Weir TW normal T-cell counterpart to the malignant mycosis fungoides/Ã(c)zary
et al. Cutaneous T-cell lymphoma. Evaluation of pretreatment skin cell. Am J Dermatopathol 1988;10:377-89.
biopsy specimens by a panel of pathologists. Arch Dermatol 25. Ormsby A, Bergfeld WF, Tubbs RR, Hsi ED. Evaluation of a new
1992;128:501-7. paraffin-reactive CD7 T-cell deletion marker and a polymerase chain
3. Santucci M, Biggeri A, Feller AC, Burg G. Accuracy, concordance, and reaction-based T-cell receptor gene rearrangement assay: implica-
reproducibility of histologic diagnosis in cutaneous T-cell lymphomaan tions for diagnosis of mycosis fungoides in community clinical prac-
EORTC Cutaneous Lymphoma Project Group Study. European Orga- tice. J Am Acad Dermatol 2001;45:405-13.
nization for Research and Treatment of Cancer. Arch Dermatol 26. Aston-Key M, Diss TC, Du MQ. The value of the polymerase chain
2000;136:497-502. reaction in the diagnosis of cutaneous T-cell infiltrates. Am J Surg
4. Rosai J. Borderline epithelial lesions of the breast. Am J Surg Pathol Pathol 1997;21:743-7.
1991;15:209-21. 27. Tok J, Szabolcs J, Silvers DN, Zhong J, Matsushima AY. Detection of
5. Feinstein AR, Gelfman NA, Yesner R. Observer variability in the clonal T-cell receptor gamma chain gene rearrangements by poly-
histopathologic diagnosis of lung cancer. Am Rev Respir Dis merase chain reaction and denaturing gradient gel electrophoresis
1970;101:671-84. (PCR/DGGE) in archival specimens from patients with early cutaneous
6. Ismail SM, Colclough AB, Dinnen JS, Eakins D, Evans DM, Gradwell T-cell lymphoma: correlation of histologic findings with PCR/DGGE.
E et al. Observer variation in histopathological diagnosis and grading J Am Acad Dermatol 1998;38:453-60.
of cervical intraepithelial neoplasia. BMJ 1989;298:1030-1. 28. Bergman R, Faclieru D, Sahar D, Sander CA, Kerner H, Ben-Aryeh
7. Weinstock MA, Barnhill RL, Rhodes AR, Brodsky GL. Reliability of Y et al. Immunophenotyping and T-cell receptor gamma gene
the histopathologic diagnosis of melanocytic dysplasia. The dys- rearrangement analysis as an adjunct to the histopathologic diagno-
plastic nevus panel. Arch Dermatol 1997;133:953-8. sis of mycosis fungoides. J Am Acad Dermatol 1998;39:554-9.
8. Shapiro PE, Pinto FJ. The histologic spectrum of mycosis fun- 29. Staib G, Sterry W. Use of polymerase chain reaction in the detection
goides/Sezary syndrome (cutaneous T-cell lymphoma). A review of of clones in lymphoproliferative diseases of the skin. Cancer Res
222 biopsies, including newly described patterns and the earliest 1995;139:239-47.
pathologic changes. Am J Surg Pathol 1994;18:645-67. 30. Wood GS, Tung RM, Haeffner AC, Crooks CF, Liao S, Orozco R et
9. Glusac EJ, Shapiro PE, McNiff JM. Cutaneous T-cell lymphoma. al. Detection of clonal T-cell receptor gamma gene rearrangements in
Refinement in the application of controversial histologic criteria. Der- early mycosis fungoides/Sezary syndrome by polymerase chain reac-
matol Clin 1999;17:601-14. tion and denaturing gradient gel electrophoresis(PCR/DGGE). J Invest
10. Glusac EJ. Criterion by criterion, mycosis fungoides. Am J Der- Dermatol 1994;103:34-41.
matopathol 2003;25:264-9. 31. Weiss LM, Wood GS, Ellisen LW, Reynolds TC, Sklar J. Clonal T-cell
11. Ming M, LeBoit PE. Can dermatopathologists reliably make the diag- populations in pityriasis lichenoides et varioliformis acuta (Mucha-
nosis of mycosis fungoides? If not, who can? Arch Dermatol Habermann disease). Am J Pathol 1987;126:417-21.
2000;136:543-6. 32. Dereure O, Levi E, Kadin ME. T-Cell clonality in pityriasis lichenoides
12. LeBoit PE. Variants of mycosis fungoides and related cutaneous T-cell et varioliformis acuta. Arch Dermatol 2000;136:1483-6.
lymphomas. Semin Diagn Pathol 1991;8:773-81. 33. Weinberg JM, Kristal L, Chooback L, Honig PJ, Kramer EM, Lessin
13. Zackheim HS, McCalmont TH. Mycosis fungoides: the great imita- SR. The clonal nature of pityriasis lichenoides. Arch Dermatol
tor. J Am Acad Dermatol 2002;47:914-8. 2002;138:1063-67.
14. Sanchez JL, Ackerman AB. The patch stage of mycosis fungoides. Am 34. Toro JR, Sander CA, LeBoit PE. Persistent pigmented purpuric der-
J Dermatopathol 1979;1:5-26. matitis and mycosis fungoides: simulant, precursor, or both? A study
15. Smoller BR, Bishop K, Glusac EJ, Kim YH, Hendrickson M. Reassess- by light microscopy and molecular methods. Am J Dermatopathol
ment of histologic parameters in the diagnosis of mycosis fungoides. 1997;19:108-18.
Am J Surg Pathol 1995;19:1423-30. 35. Lukowsky A, Munche JM, Sterry W, Audring H. Detection of expand-
16. Fung MA, LeBoit PE. Light microscopic criteria for the diagnosis ed T cell clones in skin biopsy samples of patients with lichen scle-
of early vulvar lichen sclerosus. A comparison with lichen planus. rosus et atrophicus by T cell receptor-y. J Invest Dermatol
Am J Surg Pathol 1998;22:473-8. 2000;115:254-9.
17. Citarella L, Massone C, Kerl H, Cerroni L. Lichen sclerosus with 36. Schiller PI, Flaig MJ, Puchta U, Kind P, Sander CA. Detection of
histopathologic features simulating early mycosis fungoides. Am J Der- clonal T cells in lichen planus. Arch Dermatol 2000;292:568-9.
matopathol 2003;25:463-5. 37. Nickoloff BJ. Light-microscopic assessment of 100 patients with
18. Glusac EJ. Of cells and architecture: new approaches to old criteria in patch/plaque-stage mycosis fungoides. Am J Dermatopathol
mycosis fungoides. J Cutan Pathol 2001;28:169-3. 1988;10:469-77.
19. Dickens CA. A tale of two cities. Reader’s Digest ed. Pleasantville, NY: 38. Smith NP. Histologic criteria for early diagnosis of cutaneous T-cell
The Readers Digest Association, Inc; 1859. lymphoma. Dermatol Clin 1994;12:315-22.
20. Lefeber WP, Robinson JK, Clendenning WE, Dunn JL, Colton T. 39. Santucci M, Biggeri A, Feller AC, Massi D, Burg G. Efficacy of his-
tologic criteria for diagnosing early mycosis fungoides. An EORTC 46. Kohler S, Kim YH, Smoller BR. Histologic criteria for the diagnosis
Cutaneous Lymphoma Study Group Investigation. Am J Surg Pathol of erythrodermic mycosis fungoides and Sezary syndrome: a critical
2000;24:40-50. reappraisal. J Cutan Pathol 1997;24:292-7.
40. LeBoit PE, Epstein BA. A vase-like shape characterizes the epidermal- 47. Kamarashev J, Burg G, Kempf M, Hess Smid M, Dummer R. Compar-
mononuclear cell collections seen in spongiotic dermatitis. Am J Der- ative analysis of histological and immunohistological features in myco-
matopathol 1990;12:612-6. sis fungoides and Sezary syndrome. J Cutan Pathol 1998;25:407-12.
41. Candiago E, Marocolo D, Manganoni MA, Leali C, Facchetti F. Non- 48. Trotter MJ, Whittaker SJ, Orchard GE, Smith NP. Cutaneous
lymphoid intraepidermal mononuclear cell collections (Pseudo-Pautri- histopathology of Sezary syndrome: a study of 41 cases with a proven
er Abscesses) A morphologic and immunophenotypical characteri- circulating T-cell clone. J Cutan Pathol 1997;24:286-91.
zation. Am J Dermatol 2000;22:1-6. 49. Cooper KD. A scoring system based on differentially weighted criteria
42. Burkert KL, Huhn K, Menezes DW, Murphy GF. Langerhans cell for establishing a standardized threshold for the diagnosis of early
microgranulomas (pseudo-pautrier abscesses): morphologic diversi- mycosis fungoides. In: Lambert WC, Giannotti B, van Vloten WA
ty, diagnostic implications and pathogenetic mechanisms. J Cutan editors. Basic mechanisms of physiologic and aberrant lymphopro-
Pathol 2002;29:511-6. liferation in the skin. NATO ASI series A. New York: Plenum Press;
43. Yeh YA, Hudson AR, Prieto VG, Shea CR, Smoller BR. Reassessment 1994. p. 291.
of lymphocytic atypia in the diagnosis of mycosis fungoides. Mod 50. Hoppe RT, Wood GS, Abel EA. Mycosis fungoides and Sézary syn-
Pathol 2001;14:285-8. drome: pathology, staging, and treatment. Curr Probl Cancer
44. El Darouti M, Marzouk SA, Horn TD. Failure of detection of mucin 1990;14:293-71.
in the clear halos around the epidermotropic lymphocytes in mycosis 51. Guitart J, Kennedy J, Ronan S, Chimiel JS, Hsiegh YC, Variakojs D.
fungoides. J Cutan Pathol 2000;27:183-5. Histologic criteria for the diagnosis of early mycosis fungoides: pro-
45. Buechner SA, Winkelmann RK. Sezary syndrome: a clinicopatho- posal for a grading system to standardize the pathology reporting. J
logic study of 39 cases. Arch Dermatol 1983;119: 979-86. Cutan Pathol 2001;28:174-83.
symptoms can persist also in absence of live spiro- dermia, linear scleroderma, idiopathic atrophoderma
chetes and thus do not respond to antibiotics. of Pierini-Pasini, Parry-Romberg syndrome, Busckhe
In the last years the attention is focused on several scleredema and eosinophil fasciitis of Schulmann has
clinical features related to LB. These clinical mani- been reported as late Lyme disease manifestations,
festations could be similar to LB but also non-specif- although the associations have not yet been estab-
ic complaints and could be associated to the spiro- lished satisfactorily. In some cases of ACA borrelial iso-
chete characteristics or to the immune response to it. lation was recovered from skin biopsy specimens of
These syndromes are: ACA lesion of more than 10 years duration.
— late Lyme disease; In particular, morphea has been related several times
— chronic Lyme disease; to late stages of LB. Morphea, also known as localised
— treatment-resistant Lyme disease; scleroderma, is characterised by the induration of cutis
— post-Lyme disease; and subcutis due to collagen deposition.16 Morphea
— chronic fatigue syndrome. is classified according to clinical characteristics and the
depth of cutaneous tissue involved. Some of these are
plaque, generalised, linear and morphea profunda.
Late Lyme disease Contrary to systemic sclerosis, in the localised scle-
roderma there is no involvement of internal organs,
Late Lyme disease occurs in 7 months or more after digital sclerosis or the presence of Raynaud's phe-
the bite of the infected thick. Cutaneous manifesta- nomenon. Bb DNA was detected by PCR amplification
tions are mainly atrophosclerodermia, while extracu- in skin biopsies of some morphea patients.9
taneous manifestations involve mainly joints and ner-
vous systems.13
Musculoskeletal system:chronic arthritis
(duration > 1 year)
Skin manifestations
Lyme arthritis is often regarded as a onset manifes-
Acrodermatitis chronica atrophicans (Pick-Herxheimer tation of LB in North America. In Europe it is less fre-
disease) quent, but the clinical features of Lyme arthritis are
Acrodermatitis chronica atrophicans (ACA) is a rel- similar both in Europe and North America. The onset
atively frequent chronic skin manifestation of LB. could appear from few weeks to years after the thick
ACA develops insidiously. It occurs from few months bite. The course of Lyme arthritis is very variable, it is
up to 1 year after the thick bite. Initially it is charac- usually recurrent and can last for several years. The
terised by red-bluish discolourations, usually on exten- arthritis could become chronic or maintain intermittent
sor surface of extremities. The lesion could be uni or attacks lasting from a few weeks to months.3 In the
bilateral.14 The disease evolution is chronic. The lesions beginning the attacks of arthritis are frequent and short,
enlarge very slowly over months to years, after which then they may be longer. Patients present usually gen-
the edema slowly vanishes and atrophy become grad- eral tiredness.15
ually prominent. The skin becomes thin and wrinkled Features:15
and the discoluration becomes violet. Sometimes the — mono or oligoarthritis;
atrophy lesions develop and dermis, subcutis and mus- — asymmetric;
cles are affected. It has been also reported the presence — frequent and intermittent attacks.
of chronic ulcers and malignant transformation of the Localization:15
atrophic skin. Lesions can occur with itching or burn-
ing sensation, but also without any symptoms.14, 15 — large joints are predominantly affected, most
Other cutaneous manifestations are: lichen sclero- often the knee.
sus et atrophicus,16, 17 general sclerodermia, atropho- Clinical features:15
dermia of Pierini-Pasini, of nodular panniculitis of — swelling;
Pfeifer-Weber- Christian.15, 18 — cutaneous nodules;
Atrophosclerodermic dermatitis such as lichen scle- — loss of functionality;
rosus et atrophicus, morphea, circumscribed sclero- — no rigidity in the morning.
gias, fibromyalgias and other alteration of the nervous ic neuroborreliosis in 30-50% of patients developing
system (neurocognitive and neuropsychiatric), are fibromyalgia and chronic fatigue.29 Chronic LB may
related to chronic Lyme disease.27, 28 However, case be present not only in different organs but also in dif-
reports of patients have reported several non-specific ferent patterns. The pathophysiology of the chronic
complaints such as paresthesia, tremor, palpitation, symptoms is not well understood, hypothesis are rang-
tachycardia, equilibrium alteration, sweating, visual and ing from persisting infection to autoimmunity or a
gastrointestinal (irritable colon) disorders, frequent combination of the 2.
urination.25 Some investigators believe that Bb per- Chronic Lyme disease is not fatal, but debilitating,
sistence could be the causative agent. The pathogen- characterised by persistent symptoms with cyclic
ic mechanism of the chronic Lyme disease is not yet recrudement of the disease. The variety of symptoms
understood. could be related to genetic factors that can contribute
There are controversial opinions about chronic and to the development of chronic disease. The incidence
late Lyme disease. Some authors, in fact, consider of asymptomatic patients has not been reported but
them the same clinical event, while others describe there are evidences that some individuals, asympto-
them as 2 distinct clinical aspect of the disease.25 matic for months or years after the infection, can man-
To support the second theory there is the presence in ifest chronic symptoms of the disease owing to pro-
patients with late LB arthritis of characteristic fea- voking events such as trauma, pregnancy or psycho-
tures (swelling, cutaneous nodules,...), while in chron- logical stress.25 There are many theories about the
ic LB these signs are absent. Moreover, patients with mechanism leading to chronic LB, it is known that
chronic LB are mostly not responsive to antibiotic viable Bb can persist for decades and cause late skin
treatment. Patients with late LB and high IgG present manifestation of ACA. Thus, the immunopathogenet-
a better response to treatment in comparison with ic findings in ACA can serve as a model for studying
patients with lower IgG and symptoms of chronic LB. the chronic course of LB. Recent findings indicate
Typically, chronic LB patients are characterised by that the most important cells for antigen presentation,
high IgM value and low IgG.6 Several reports support the epidermal Langherans cells, are invaded by Bb in
the increasing evidence that IgM reactivity is com- early LB. Therefore, Langherans cells were stained
mon in chronic, active disease. It is known that IgM immunohisochemically with different markers to inves-
reactivity may represent reactivation of latent disease tigate their functional activity. The number of Langher-
or persistent infections in other chronic infections (e.g. ans cells CD1a positive was reduced in erythema
cytomegalovirus and toxoplasma) and it is likely the migrans but was normal or slightly elevated in ACA.
case of LB.6 On the other side, the detection of IgM and In both diseases there was also a marked downregu-
IgG antibodies to individual Bb antigens (24kDa, 31 lation of major hisocompatibility complex class II
kDa, 34 kDa, but mainly 41 kDa) can provide a sup- molecules on Langherans cells. This phenomenon
porting evidence of an active phase of LB, but IgM might be a mechanism that protects against the pre-
response could also be induced by several condition of sentation of autoantigens and may be the cause of
cross reactivity, including ehrlichial, cytomegalovirus impaired capacity of Langherans cells to eliminate Bb
and toxoplasma infections leading to false positive antigens, thus explaining the chronicity of LB.30
results. Some patients with chronic Lyme disease who Other authors have postulated the autoimmune the-
responded to treatment, decreased the level of IgM ory 31 for chronic LB. T cell recognition of self antigens
and increased the level of IgG. The mechanism that is a key event in the pathogenesis of autoimmune dis-
leads to IgM persistence and lower IgG production eases.32 To date, the initial events that trigger autore-
remains unclear.6 active T cells are unknown. The molecular mimicry
The entity of chronic Lyme disease has been the hypothesis predicts that during an infection T cells
subject of great controversy. Some authors have not that recognize both a microbial antigen and a related
approved the chronic form of Lyme disease assuming self peptide become activated and cause autoimmune
that the ongoing long-lasting symptoms could be relat- disease. The hypothesis that the T cell response to one
ed to psychiatric problems. The fact that a chronic LB or more antigens of Bb is different in patients with
exists is supported by published reports of epidemio- treatment-responsive or treatment-resistant Lyme
logic studies that are related to the incidence of chron- arthritis was tested. Results from this study demon-
strated that treatment resistant patients presented some Some risk factors to develop PLS have been report-
alterations in T cell antigen recognition associated ed, such as delayed treatment (over 1 year), high lev-
with an up-regulation of HLA molecules. els of serum immunoglobulin G antibodies and the
Other theories have been made on the pathogenesis presence of multiple bands in Western blots that seems
of chronic LB ranging from the intacellular infection to be related to aphasia.
persistence to coinfection with other microorganisms Athralgias, mostly persistent knee synovitis, in some
(e.g. Babesia microti) or the existence of Bb species cases is possibly related to the triggering of intrasyn-
resistant to antibiotic treatment.33 Most of the clini- ovial autoimmunity. For these patients, there is no evi-
cal manifestations of LB are due to the local presence dence of Borrelia infection by culture or detection of
of the causative agent, Bb in the affected tissue. How- Bb DNA in blood or spinal and synovial fluids. The
ever, the precise means of tissue damage are not well IgG positivity is a common feature with chronic LB,
understood and there is not proof that the organism, live so serological analysis is not a good tool to distin-
or dead, is always present. An understanding of the guish PLS from chronic LB.38 Different studies have
complex interactions between the organism and the reported on the antibiotic treatment failure in patients
host can explain manifestations of the disease and the with PLS.36 In these cases hydroxychloroquine treat-
persistence of symptoms and signs after antibiotic ment seems to be effective.6, 39
treatment.34 Another clinical syndrome associated to LB is the
Whether chronic LB represents continual infection treatment-resistant Lyme arthritis. In about 10% of
or it is a post-Lyme disorder is currently unknown. patients with Lyme arthritis joint inflammation per-
Some authors have reported about post-Lyme syn- sists for months or even several years after the appar-
drome (PLS) in patients who have developed persistent ent eradication of the spirochete, Bb, from the joint
symptoms after antibiotic treatment. They include with antibiotic treatment.5, 12, 40 A model of molecular
physic and mental fatigue, myalgias, athralgias, pares- mimicry has been proposed affecting genetically sus-
thesias or dysesthesias or memory and mood distur- ceptible individuals to explain this treatment-resistant
bances.8, 35 Related symptoms have been detected both course. The majority of patients with treatment-resis-
in seropositive and seronegative patients. Even for PLS tant Lyme arthritis have HLA-DRB1*0401 or related
the mechanism of symptoms persistence is not under- alleles, and the severity and duration of their arthritis
stood. There are also limited informations regarding correlate with cellular and humoral immune respons-
to the utility of extended antibiotic treatments for this es to outer-surface protein A (OspA) of the spirochete.
disorder. Some authors reported that treatment over Using an algorithm, the immunodominant epitope of
several months appears to be required to achieve sig-
OspA presented by the DRB1*0401 molecule was
nificant improvement in most patients, but other results
predicted to be located at aa 165-173. In a search of the
have shown that treatment with long course of antibi-
Genetics Computer Group gene bank, only one human
otics did not improve symptoms more than placebo.36
protein was identified, lymphocyte function associat-
Patients with PLS report the following features, as
ed antigen-1 (hLFA-1), that had sequence homology
summarised by the Centers for disease control and
with OspA(165-173)and predicted binding in the
prevention (CDC):36
DRB1*0401 molecule. Synovial fluid T cells from
— diagnosis of LB in the past; most patients with treatment-resistant arthritis respond-
— treatment with standard courses of antibiotics ed to both OspA and hLFA-1, whereas those from
for established acute LB;37 patients with other forms of chronic inflammatory
— long-lasting symptoms (for months or even arthritis did not. Molecular mimicry between a dom-
years). inant T cell epitope of OspA and hLFA-1 may be an
In particular, PLS is characterised by: important factor in the persistence of joint inflamma-
— encephalopathy with memory or mood distur- tion in genetically susceptible patients with treatment-
bances (at a short date); resistant Lyme arthritis.12, 40, 41
— athralgias; Several studies have been performed to identify pos-
— musculoskeletal pain localised in the back and sible sites of bacterial persistence in patient with treat-
cervicalgias; ment resistant Lyme arthritis. Among them, PCR analy-
— chronic fatigue. sis in DNA obtained from urine, synovial fluid and
membrane demonstrated that Bb DNA was not TABLE II.—Chronic fatigue syndrome: differential diagnosis.
detectable in synovial fluid after antibiotic treatment. Autoimmune diseases
However, in patients with ongoing or recurring Lyme Localised infections
arthritis after antibiotic treatment a negative Bb PCR Chronic inflammatory diseases (Sarcoidosis)
in synovial fluid or urine does not exclude a persisting Malignant tumors
infection. In these patients, in fact synovial membrane Chronic or sub-acute infections (Lyme)
Neuromuscular diseases
could be positive for Bb PCR detection.11 Endocrine diseases
It has also been reported in literature about B garinii Parasitosis
seronegative arthritis.42 Mycosis
Psychiatric disturbances
HIV infection
Side effects of long-lasting therapies
Chronic fatigue syndrome
patients with PLS show greater cognitive deficits than frequent IgM bands were of 24 kDa (OspC) and 41
patients with CFS compared with healthy controls. kDa. No IgG is typically detected in this phase of the
This is particularly apparent among patients with PLS disease. IgM to antigens of 60 and 66 kDa could be
who lack premorbid psychiatric illness.48 revealed with the further sero-conversion to IgG anti-
bodies against 24 and 41 kDa antigens. With clinical
manifestation of LB the presence of antibodies against
Diagnosis 24 and 41 kDa antigens may be of assistance in con-
firming the diagnosis.6, 29, 51 The antigen of 41 kDa is
Diagnosis of LB is mainly based on clinical and not a characteristic only of Bb, but 24 kDa. Other anti-
epidemiological criteria, supported by laboratory gens are characteristic of Bb such as 39, 83 or 93 kDa,
tests.3, 15 In routine patient management with typical The immune response to the recombinant outer sur-
early skin lesion the diagnosis of LB in endemic area face protein A (OspA- 31 kDa) occurs about 1 year
is purely clinical. In these cases laboratory testing is not after the infection. With the resolution of symptoms the
necessary. For the other manifestations of LB labora- IgM level usually disappears or decreases but some-
tory support is essential to confirm the infection. In times IgG can persist.6, 29.
more complicated cases it is necessary to evaluate Some patients could be symptomatic despite nega-
more aspects. They include the clinical picture, other tive western blot.52 The absence of immune response
preceding or concomitant diseases of the Lyme bor- could be explained by the intracellular localisation of
reliosis complex, serodiagnostic results, CSF find- Bb, that in this way evades the immune system.25, 53, 54
ings, demonstration of intrathecal specific antibody Recently, a sensitive and specific ELISA was intro-
synthesis, results of PCR analysis, response to ade- duced in which the antigen is a 26-mer peptide with-
quate antibiotic therapy and exclusion of other dis- in the sixth invariant region (IR6) of the Vlse (Variable
eases. The significance of each of these criteria depends major protein like sequence Expressed) outer-surface
on the clinical involvement and on the stage of Lyme lipoprotein of Bb.55 The outer cell membrane of Bb
borreliosis. Laboratory diagnosis is possible with direct contains many polypeptides, the most extensively stud-
or indirect methods. Indirect methods to assess Bb ied are the outer surface proteins Osp. OspA and B
antibodies in serum, synovial and cerebral fluids are proteins are expressed in vector, but not in vertebrate
serological tests. These comprise ELISA, immuno- host. OspC and VlsE are expressed in vivo in vertebrate
fluorescence assays (IFA) and Western blotting. A host.56 VlsE is an outer surface lipoprotein of Bb that
two-step serological approach has been proposed to undergoes antigenic variation through an elaborate
increase specificity. A positive or equivocal first test gene conversion mechanism and is thought to play a
(ELISA or IFA) is followed on the same serum sam- major role in the immune response to Borellia in Lyme
ple by an immunoblot test which can detect IgM and disease. The surface localization of the variable amino
IgG antibodies to individual Bb antigens. acid segments appears to protect the conserved regions
Direct laboratory diagnosis is related to histological from interaction with antibodies and hence may con-
and immunohistochemical techniques, cultivation and tribute to immune evasion.57, 58
hybridiastion using fresh tissues and biological flu- VlsE has a predicted molecular mass of 34. Two
ids.15 Routine laboratory tests, including VES are usu- invariable domains, one at the amino terminus and the
ally normal. VES value is an important aspect for the other at the carboxyl terminus, encompass together
differential diagnosis with LES and rheumatoid arthri- approximately one-half of this molecule's length. The
tis. Seronegativity does not exclude LB diagnosis,49 as remainder is composed of a central variable domain
reported for Lyme arthritis.41 In suspected cases for that contains 6 variable regions (VRs) and 6 invari-
late LB, a positive serology is fundamental.50 In about able regions (IRs). These 2 types of regions are inter-
75% of patients a negative ELISA and a positive West- spersed with each other, and each constitutes about
ern blot was reported. Most patients with Lyme arthri- one-half of the variable domain's length.
tis are IgG positive both in ELISA and Western blot. The coding sequence of VlsE contains 1 vls cas-
The appearance and evolution of IgM and IgG anti- sette region in the middle and 2 noncassette regions.
bodies to Bb was investigated in patients with erythe- Most sequence differences among the vls cassettes
ma migrans. The first immune response resulted against are confined within 6 highly variable regions.57, 58 DNA
flagellin (41kDa) and OspC (24 kDa) in fact the most segments of the silent cassettes are able to recombine
in an apparently random manner into the vlsE cassette including the choice of antibiotic, dosage, duration of
region throughout the course of infection. Sequence treatment, potential or adverse effects and compli-
results are consistent, with roughly 6 to 11 recombi- ance.15 Amoxicillin and doxycycline are the treatment
nation events with multiple silent vls cassettes during of first intention in early LB,3 but not for late disease.
the first 28 days of infection. The promiscuous recom- Some patients treated with standard courses of these
bination events at the vlsE site lead to extensive genet- antibiotics recover only partly. For other patients symp-
ic and antigenic variation in VlsE variants.57, 58 toms persist during and after treatment. In these cas-
Recombination events between the expressed and es longer duration of treatment has been proposed.36
silent vmp genes lead to antigenic variation and thus Lyme arthritis could be treated with oral or par-
evasion of the host immune response during the course enteral antibiotic therapy (amoxicillin and doxycy-
of mammalian infection. Unlike the invariable regions cline).4, 61 Treatment with these 2 antibiotics lasting
of variable major protein, which are not antigenic in even 28 days was reported with positive response.
natural infections, the most conserved of the IRs, IR6, Nervous system involvement and Lyme carditis are
is immunodominant in Lyme disease patients. IR6 is usually treated with ceftriaxone and penicillin G or
exposed on the surface of VlsE, as assessed by cefuroxime intravenously.
immunoprecipitation experiments, but is inaccessible Treatment for children consists of conventional
to Ab on the spirochete's outer membrane.58 VlsE thus antimicrobial therapy - either orally administered
significantly departs from the antigenic variation par- amoxicillin, doxycycline (major than 12 years old),
adigm, whereby immunodominance is only manifest erythromycin, or penicillin or intravenously adminis-
in variable portions. IR6 may contribute to divert the tered ceftriaxone, better if children are older than 8
Ab response from other, perhaps protective regions years.3, 4
of VlsE. In most patients with Lyme arthritis, antibiotic ther-
The major limitation in serologic tests is that they do apy is curative, but patients with persistent symptoms
not reliably distinguish between active and past infec- after the first cycle of antibiotic treatment could be
tion. With these tests the IgG and sometimes IgM
retreated for 4 weeks with the previous oral therapy,
response may persist for years after successful antibi-
otherwise for 2 weeks intravenously with ceftriaxone
otic treatment. A recent study reported that IgG anti-
or cefotaxime. For patients treatment-resistant arthri-
VlsE antibody titres wane rapidly after successful
tis, in which antibiotic therapy is ineffective; arthro-
antibiotic treatment in both humans and experimental
animal.59 However, other authors reported that the scopic synovectomy may be considered to reduce artic-
Anti-VlsE response persisted for months or years after ular inflammation.4
antibiotic treatment so their presence cannot be equat- In cases of neuroborreliosis with central nervous
ed with spirochetal persistence in LB.60 system involvement a lumbar puncture is recommended
Direct methods of laboratory diagnosis are particu- before antibiotic treatment with ceftriaxone and peni-
larly useful in the early phases of the disease when cillin G or cefuroxime intravenously (2 g/die for 2-4
antibody titre is absent or low. Ideally, the detection of weeks).3, 4
Bb by cultivation is the standard goal to prove the The appropriate treatment of patients with chronic
infection, but the sensitivity of this method is inade- Lyme disese is a controversial clinical issue. With the
quate for diagnosis. Positive Bb colture results some- possibility that chronic LB is due to persistent infec-
times from skin biopsies, serum, synovial and cerebral tion, the use of antibiotics with intracellular penetra-
fluids.15 PCR is a good tool for Bb detection espe- tion capability such as macrolides and tetracycline is
cially for differential diagnosis of suspected LB.15 proposed.6, 39 The location of Bb in vivo is unknown,
but increasing number of microbes with reactivation
potential are located in lysosomes or other acidic endo-
Therapy somes. Macrolide alone has limited activity in acid
environment. Usually, macrolides have not been used
Antibiotic therapy is more effective in the early in the treatment of LB. A recent study reported the
phases of the disease. The results of treatment depends use of macrolides in conjunction with lysosomotrop-
not only on the location, extent, and duration of clin- ic agents which can alter the pH of acidic intacellular
ical manifestations but also on several other factors compartements such as lysosome. With this assum-
tion, patients were treated with hydroxychloroquine as 14. Trevisan G, Cattonar P, Nobile C, Perkan V. Dermatological mani-
festations of Lyme borreliosis. Acta Dermatovenereologica APA
lysosomotropic agent.39, 62 Treatment over several 1996;5:101.
months appears to be required to achieve significant 15. Trevisan G, Stinco G. Dermatologia di importazione. In: Veraldi S,
improvement in most patients with chronic LB. In Rizzitelli G, Caputo R editors. Infezione da batteri: Borreliosi. Milano:
Poletto; 2000. p. 2-21.
recent observations the duration of treatment appears 16. Kaya G, Berset M, Prins C, Chavaz P, Saurat JH. Chronic Borrelio-
to be closer to 12-18 months. However, some patients sis presenting with morphea and lichen sclerosus et atrophicus - like
with chronic LB have no benefits from the use of this cutaneous lesions. A case report. Dermatology. 2001;202:373-5.
17. Trevisan G, Menni S, Stinco G, Nobile C, Pistritto G, Perin R. Lichen
therapy. slerosus et atrophicus and Borrelia burgdorferi infection. Eur J Pedi-
Even if late, chronic and post manifestations of at Dermatol 1994;4:159.
Lyme disease have been identified, difficulties in diag- 18. Trevisan G. Atypical dermatological manifestations of Lyme borre-
liosis. Acta Dermatovenereologica 2001;10.
nosis of late stages of Lyme disease persist due to low 19. Kristoferistsch W, Mayr WR, Partsch H, Neumann R, Stanek G. HLA-
sensitivity of serological testing and late inclusion of DR in Lyme borreliosis. Lancet 1986;2:278.
Lyme disease in the differential diagnosis. A special 20. Steere AC, Dwyer E, Winchester R. Association of chronic Lyme dis-
ease with HLA-DR4 and HLA-DR2 alleles. N Engl J Med
attention to clinical spectrum and laboratory criteria is 1990;323:219.
required in these cases. Based on experimental evi- 21. Duray PH. Clinical pathologic correlations of Lyme disease. Rev
Infect Dis 1989; 11 Suppl 6: S1487-93.
dence and experience more additional work is needed 22. Ogrinc K, Lotric-Furlan S, Maraspin V, Cimperman J, Ruzic- Sabljio,
to improve the understanding of the underlying patho- Strle F et al. Cerebrospinal fluid findings in patients with symptoms
physiology of the disease, its diagnosis and treatment. suggesting chronic Lyme borrliosis. Ien Klin Wochenschr
2002;114:535-8.
23. Cox J, Krajden M. Cardiovascular manifestations of Lyme disease. Am
Acknowledgements.—The authors wish to thank Dr. S. Mier- Heart J 1991;122:1449-55.
tusova for the English revision of the manuscript. 24. Bertuch AW, Rocco E, Schwartz EG. Lyme disease: ocular manifes-
tations. Ann Ophtalmol 1988;20:376-8.
25. Donta S. Late and chronic Lyme disease. Med Clin N Am 2002;86:
341-9.
References 26. Vrethem M, Hellblom L, Widlund M, Ahl M, Danielsson O, Ernerud
J et al. Chronic symptoms are common in patients with neuroborre-
1. Trevisan G, Cinco M. Lyme disease: a general survey. Int J Dermatol liosis: a questionnaire follow- up study. Acta Neurol Scand
1990;29:1-8. 2002;106:205-8.
2. Steere AC. Lyme disease. N Engl J Med 2001;345:115-25. 27. Elkins LE, Pollina DA, Scheffer SR, Krupp LB. Psychological states
3. Hengge UR, Tannapfei A, Tyring SK. Lyme borreliosis. Lancet and neuropsychological performances in chronic Lyme disease. Appl
2003;3:489-500. Neuropsychol 1999;6:19-26.
4. Wormser GP, Nadelman RB, Dattwyler RJ, Dennis DT, Shapiro ED, 28. Westervel HJ, McCaffrey RJ. Neuropsychological functioning in
Steere AC et al. Practice guidelines for the treatment of Lyme disease. chronic Lyme disease. Neuropsychol Rev 2002;12:153-77.
Clin Infect Dis 2000;31 Suppl 1:1-14. 29. Seltzer EG, Gerber MA, Cartter ML, Freudigman K, Shapiro ED.
5. Carlson D, Hernandez J, Bloom BJ, Coburn J, Aversa JM, Steere AC. Long-term outcomes of persons with Lyme disease. JAMA 2000;
Lack of Borrelia burgdorferi DNA in synovial samples from patients 283:609-16.
with antibiotic treatment - resistant Lyme arthritis. Arthritis Rheum 30. Silberer M, Koszik F, Stingl G, Aberer E. Downregulation of class II
1999;42:2705-9. molecules on epidermal Langerhans cells in Lyme borreliosis. Br J
6. Donta S. The existence of chronic Lyme disease. Curr Treat Options Derm 2000;143;786-94.
Inf Dis 2001;3:261-2. 31. Behar SM, Porcelli SA. Mechanisms of autoimmune disease induc-
7. Preac-Mursic V, Weber K, Pfister HW, Wilske B, Gross B, Baumann tion: the role of the immune response to microbial pathogens. Arthri-
A et al. Survival of Borrelia burgdorferi in antibiotically treated tis Rheum 1995;38:458-76.
patients with Lyme borreliosis. J Infection 1989;17:355-9. 32. Hemmer B, Gran B, Zhao Y, Marques A, Pascal J, Tzou A et al. Iden-
8. Steiner I. Treating post Lyme disease. Neurology 2003;60:1888-9. tification of candidate T - cell epitopes and molecular mimicry in
9. Trevisan G, Stinco G, Nobile C, Bonin S, Stanta G. Detection of Bor- chronic Lyme disease. Nat Med 1999;5:1346-7.
relia burgdorferi in skin biopsies from patients with morphea by poly- 33. Sweeney CJ, Ghassemi M, Agger WA, Persing DH. Coinfection with
merase chain reaction. J Eur Acad Dermatol Venereol 1996;6:15. Babesia microti and Borrelia burgdorferi in a western Wisconsin res-
10. Keller TL, Halperin JJ, Whitman M. PCR detection of Borrelia ident. Mayo Clin Proc 1998;73:338-41.
burgdorferi DNA in cerebrospinal fluid of Lyme neuroborreliosis 34. Sigal LH. Immunologic mechanisms in Lyme neuroborreliosis: the
patients. Neurology 1992;42:32-42. potential role of autoimmunity and molecular mimicry. Semin Neu-
11. Priem S, Burmester GR, Kamradt T, Wolbart K, Rittig MG, Krause A. rol 1997;17:63-8.
Detection of Borrelia burgdorferi by polymerase chain reaction in 35. Klempner MS. Controlled trials of antibiotic tratment in patients with
synovial membrane, but not in synovial fluid from patients with per- post- treatment chronic lyme disease. Vector Borne Zoonotic Dis
sisting lyme arthritis after antibiotic theraphy. Ann Rheum Dis 2002;2:255-63.
1998;57:118-21. 36. Krupp LB, Hyman LG, Grimson R, Coyle PK, Melville P, Ahnn S et
12. Steere AC, Gross D, Meyer AL. Autoimmune mechanisms in antibiot- al. Study and treatment of post Lyme disease (STOP - LD). Neurol-
ic treatment - resistant Lyme arthritis. J Autoimmun 2001;16:263-8. ogy 2003;60:1923-30.
13. Wahlberg P, Granlund H, Nyman D, Panelius J, Seppala I. Late Lyme 37. Datttwyler RJ, Halperin JJ, Volkman DJ, Luft BJ. Treatment of late
borreliosis: epidemiology, diagnosis and clinical features. Ann Med Lyme boreliosis-randomized comparison of ceftriaxone vs Penicillin.
1993;25:349-52. Lancet 1988;2:1191-4.
38. Weinstein A, Britchkov M. Lyme arthritis and post - Lyme disease syn- 52. Donta S. Tetracycline therapy for chronic Lyme disease. Clin Infect
drome. Curr Opin Rheumatol 2002;14:383-7. Dis 1997;25 Suppl 1:S52- 6.
39. Donta S. Macrolide therapy of chronic Lyme disease. Med Sci Monit 53. Nanagara R, Duray PH, Schumacher HR Jr. Ultrastructural demon-
2003;9:PI136-42. stration of spirochetal antigens in synovial fluid and synovial mem-
40. Guerau de Arellano M, Huber BT. Development of autoimmunity in brane in chronic Lyme disease: possible factors contributing to per-
Lyme arthritis. Curr Opinion Rheumatol 2002;14:388-93. sistence of organisms. Hum Pathol 1996;27:1025-34.
41. Akin E, Aversa J, Steere A. Expression of adhesion molecules in syn- 54. Donta St. Treatment of chronic Lyme disease with macrolide antibi-
ovia of patients with treatment-resistant lyme arthritis. Infect Immun otics. 8th International Conference on Lyme Borreliosis, 1999, June
2001;69:1774-80. 20-24, Munich, Germany.
42. Dejmkova H, Hulinska D, Tezgova D, Pavelka K, Gatterova J, Vavrik 55. Liang FT, Steere AC, Marques AR, Johnson BJ, Miller JN, Philipp MT.
P. Seronegative Lyme arthritis caused by Borrelia garinii. Clin Sensitive and specific serodiagnosis of Lyme disease by enzime-
Rheumatol 2002;21:330-4. linked immunosorbent assay with a peptide based on an immun-
43. Craig T, Kakumanu S. Chronic fatigue syndrome: evaluation and odominant conserved region of Borrelia burgdorferi VlsE. J Clin
treatment. Am Fam Physician 2002;65:1083-90. Microbiol 1995;37:3990-6.
44. Fukuda K, Staus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A. 56. Ohnishi J, Piesman J, De Silva AM. Antigenic and genetic hetero-
The chronic fatigue syndrome: a comprehensive approach to its def- geneity of Borrelia burgdorferi populations transmitted by icks. Proc
inition and study. International chronic fatigue syndrome study group. Natl Acad Sci 2001;98:670-5.
Ann Intern Med 1994;121:953-9. 57. Lawrenz MB, Hardham JM, Owens RT, Nowakowski J, Steere AC,
45. Abbey S, Garfinkel P. Chronic fatigue syndrome and depression: Wormser GP et al. Human antibody responses to VlsE antigenic vari-
cause, effect or covariate. Rev Infect Dis 1991;13 Suppl 1: S73-83. ation protein of Borrelia burgdorferi. J Clin Microbiol 1999;37:3997-
46. Hsu VM, Patella SJ, Sigal LH: Chronic Lyme disease as the incorrect 4004.
diagnosis in patients with fibromyalgia. Arthritis Rheum 1993;36: 58. Eicken C, Sharma V, Klabunde T, Lawrenz MB, Hardham JM, Nor-
1493-500. ris SJ et al. Crystal structure of Lyme disease variable surface antigen
47. Fallon BF. Differential diagnosis in Lyme disease. 12th Internation- VlsE of Borrelia burgdorferi. J Biol Chem 2002;277:21691-6.
al Conference on Lyme disease and other spirochetal and tick-borne 59. Philipp MT, Bowers LC, Fawcett PT, Jacobs MB, Liang FT, Mar-
disorders, 1999, 2-10 April, New York, NY. ques AR et al. Antibody response to IR6, a conserved immunodom-
48. Gaudino EA, Coyle PK, Krupp LB. Post-Lyme disease syndrome inant region of the VlsE lipoprotein, wanes rapidly after antibiotic
and chronic fatigue syndrome. Neuropsychiatric similarities and dif- treatment of Borrelia burgdorferi infection in experimental animals
ferences. Arch Neurol 1997;54:1372-6. and in humans. J Infect Dis 2001;184:870-8. Epub 2001 Aug 30.
49. Dattwyler RJ, Volkman DJ, Luft BJ, Halperin JJ, Thomas J, Golight- 60. Peltoma M, McHugh G, Steere AC. Persistence of the antibody
ly MG. Seronegative Lyme disease. Dissociation of specific T- and B- response to the VlsE sixth invariant region( IR6) peptide of Borrelia
lymphocyte responses to Borrelia burgdorferi. N Engl J Med burgdorferi after successful antibiotic treatment of Lyme disease. J
1988;319:1441-6. Infect Dis 2003;187:1178-86.
50. Dorward DW, Schwan TG, Garon CF. Immune capture and detection 61. Cimmino MA, Accardo S. Long term treatment of chronic Lyme
of Borrelia burgdorferi antigens in urine, blood, or tissues from infect- arthritis with benzathine penicillin. Ann Rheum Dis 1992;51:1007-8.
ed ticks, mice, dogs, and humans. J Clin Microbiol 1991;29:1162-70. 62. Maurin M, Benoliel AM, Bongrand P, Raoult D. Phagolysosolal alka-
51. Karlsson M. Aspects of the diagnosis of Lyme borreliosis. Scand J linization and the bactericidal effect of antibiotics: the Coxiella bur-
Infect Dis Suppl 1990;67:1-59. netii paradigm. J Infect Dis 1992;166:1097-102.
sistere in siti privilegiati (cute 9, liquor 10, liquido sinovia- ni-Pasini, l’emiatrofia facciale di Parry-Romberg, lo scle-
le 11) ed eludere la risposta immunitaria. Una piccola per- redema di Busckhe e la fascite eosinofila di Schulmann sono
centuale di pazienti geneticamente predisposti, poi, si presenta state ripetutamente segnalate, quali manifestazioni tardive del-
resistente al trattamento, manifestando un’infiammazione la BL, ma, mentre per l’ACA il rapporto con l’infezione da
articolare persistente nonostante l’apparente eradicazione Bb sembra costante, con, in alcuni casi, l’isolamento della Bb
della spirocheta 3, 12. da biopsie cutanee anche a 10 anni dall’insorgere della BL,
Negli ultimi anni si è posta l’attenzione, quindi, su un per gli altri quadri atrofo-sclerodermici la correlazione con
complesso di sindromi cliniche correlate alla BL che pre- la BL è molto discussa 18.
sentano varie similitudini e sulla cui patogenesi sono state for- La morfea, in particolare, è stata più volte associata alla
mulate e vagliate varie ipotesi, legate ora alle caratteristi- forma tardiva della BL; conosciuta anche come sclerodermia
che proprie della spirocheta ora alla risposta immunitaria localizzata, è caratterizzata da un indurimento localizzato del-
nei confronti della stessa. la cute e del tessuto sottocutaneo dovuto a un’eccessiva depo-
Tali sindromi sono: sizione di collagene 16. I vari tipi di morfea si classificano in
— malattia di Lyme tardiva; base alle caratteristiche cliniche e al grado di profondità del tes-
— malattia di Lyme cronica; suto coinvolto. Essi includono forme a placca, generalizzate,
— artrite di Lyme resistente al trattamento; lineari e forme più profonde. A differenza della sclerosi siste-
— post malattia di Lyme; mica, nella forma localizzata non si hanno mai sclerodattilia,
— sindrome della stanchezza cronica. il fenomeno di Raynaud o coinvolgimento di organi interni. In
alcuni pazienti, è stato possibile individuare tramite metodi-
che di polymerase chain reaction (PCR) il DNA della Bb in bio-
Malattia di Lyme tardiva psie cutanee di pazienti con morfea 9.
Se non viene trattata, può portare a una irreversibile ero- Lyme cronico e diagnosi differenziale
sione della cartilagine e dell’osso con conseguente danno
permanente. Nella Tabella I viene mostrato uno schema riassunto del-
Durata della malattia: se non è trattata, persiste per alme- le diagnosi differenziali.
no 4 anni, fattori di tipo genetico influenzerebbero la dura- Mentre può essere relativamente semplice riconoscere
ta e la severità dell’artrite. Soggetti con HLA-DR4 e/o DR disturbi associati alla malattia di Lyme quali l’eritema cro-
15, 19, 20 sembrano sviluppare con maggiore frequenza un’ar-
nico migrante, la paralisi di Bell o l’artrite (specie se
trite cronica erosiva scarsamente responsiva alla terapia anti- monoarticolare o oligoarticolare), può essere piuttosto dif-
biotica e gli stessi possono avere una PCR negativa per la ficoltoso riconoscere sintomi cronici associati alla malat-
ricerca del DNA della Bb nel liquido sinoviale, nonostante tia di Lyme 25, 26.
la persistenza dell’infiammazione 4, per motivi che saranno Si definisce malattia di Lyme cronica un complesso di
descritti successivamente. sintomi cronici correlati alla malattia di Lyme che consisto-
L’artrite cronica viene considerata l’espressione più fre- no in senso di affaticamento generale con artralgie (senza
quente di Lyme nei bambini (fino al 33%). alcun segno obiettivo), fibromialgie e altre disfunzioni del
sistema nervoso (neurocognitive e neuropsichiatriche) 27,
28. Possono essere presenti, ma più raramente, sintomi asso-
Sistema nervoso ciati, di tipo neurologico, quali parestesie, tremori, palpita-
zioni, tachicardia, alterazioni dell’equilibrio, sudorazione
Encefalopatia con soli difetti cognitivi. Manifestazioni (a volte intensa), disturbi visivi, disturbi gastro-intestinali
tipiche sono disturbi della memoria (a breve termine) e del- (sindrome del colon irritabile) e aumento della frequenza
le funzioni intellettive. È presente irritabilità e sonnolenza 15. urinaria 25.
Encefalomielite cronica oscillante. Può simulare una scle- Responsabile del corteo sintomatologico sarebbe la per-
rosi a placche per l’interessamento multifocale del sistema sistenza dell’infezione da Bb.
nervoso centrale (cervello, nervi ottici, tronco encefalico e cer- Rimane ancora da distinguere, soprattutto per ciò che
velletto) il decorso e l’aspetto alla risonanza magnetica (mul- riguarda il processo patogenetico, tale forma dalla cosid-
tipli focolai nella sostanza bianca periventricolare). È carat- detta “late Lyme disease” descritta in precedenza; le 2 sin-
terizzata da improvvisi deficit focali, transitori o perma- dromi, infatti, non sono ancora perfettamente differenziate,
nenti, quali emiparesi, paraparesi, atassia e afasia 15. anzi, spesso considerate sinonimi, costituirebbero, in realtà,
Encefalopatia multi-infartuale: possono essere presenti 2 entità cliniche diverse 25.
difetti neurologici focali 16 acuti transitori (tipo attacco ische- Le differenze principali consisterebbero nel fatto che la
mico transitorio) o permanenti (tipo ictus). malattia di Lyme tardiva è caratterizzata, contrariamente alla
Polineuropatia assonale 21: molti pazienti affetti da bor- forma cronica, da segni obiettivi di artrite (tumefazione,
reliosi tardiva (di solito in associazione con l’artrite) pre- noduli cutanei...) che non sono presenti nell’altra forma e
sentano una lieve neuropatia sensitiva, che si manifesta cli- che la forma tardiva, oltre a essere più facile da diagnosticare,
nicamente con parestesie intermittenti agli arti. Gli studi risulta molto più responsiva al trattamento rispetto alla cro-
elettromiografici rivelano un quadro multinevritico con velo- nica.
cità di conduzione nervosa generalmente nella norma. Si è constatato, infatti, che pazienti affetti da malattia di
Esami effettuati sul liquido cerebrospinale mostrano nel- Lyme tardiva con un’importante risposta anticorpale di tipo
la neuroborreliosi cronica un liquor generalmente normale o IgG rispondevano meglio alla terapia se confrontati con
con pleiocitosi 10, 22, con presenza di anticorpi anti Bb risul- pazienti con sintomi cronici e con bassa risposta anticorpa-
tanti da una sintesi intratecale. Metodiche di PCR possono le IgG che necessitavano di terapia più prolungata. In gene-
consentire l’isolamento genomico della spirocheta. re, in molti pazienti affetti dalla forma cronica si possono ritro-
vare valori alti e persistenti di IgM associati a un titolo anti-
corpale IgG piuttosto limitato 6.
Cuore La risposta anticorpale di tipo IgM contro le proteine spe-
cifiche di Bb (23Kd, 31Kd, 34Kd e soprattutto 41Kd) è indi-
La miocardiopatia dilatativa 23, considerata una compli- cativa di una fase attiva della malattia di Lyme. L’elevata
canza molto rara, potrebbe essere la sola ragione di un out- presenza di titoli IgM nella forma cronica della malattia non
come fatale nei pazienti con LB. è caratteristica solo della malattia di Lyme; ci sono esempi
di altre infezioni che possono presentare un nuovo innalza-
mento delle IgM dopo l’infezione primaria in caso, ad esem-
Occhio pio, di riattivazione della malattia (toxoplasmosi, citome-
galovirus) 6. Nei casi di malattia di Lyme cronica che rispon-
Come conseguenza di una neuroborreliosi o di una con- de al trattamento, si può assistere a un progressivo calo del
dizione infiammatoria dell’occhio possono manifestarsi: titolo IgM a favore delle IgG. Rimane, tuttavia, ancora da sta-
cheratiti, episcleriti, iridocicliti, neurite ottica 3, 24. L’in- bilire il meccanismo che determina la persistente reattività
fiammazione intraoculare di lunga durata può portare a cecità. delle IgM e la limitata reattività delle IgG, è molto probabi-
le che sia coinvolto il processo di “switch” dalla risposta malattia di Lyme cronica citano l’esistenza di forme parti-
immunitaria di tipo IgM a quella di tipo IgG 6. colarmente attive di Bb che sfuggono al controllo degli anti-
Alcuni Autori negano l’esistenza di una forma cronica di biotici o suggeriscono che la forma cronica sia espressione
malattia di Lyme, asserendo, piuttosto, che tali pazienti sof- di un danno causato dalla risposta dell’ospite nei confronti
frano di disturbi psichiatrici; in realtà, studi epidemiologici della spirocheta, o ancora che essa sia dovuta a una confezione
confermano l’esistenza di una forma cronica di neuroborre- di Bb con un altro microrganismo trasmesso dalla zecca Ixo-
liosi che si sviluppa dal 30% al 50% di pazienti che svilup- des (Babesia microti, specie di Erlichia) 33.
pano una serie di disturbi spesso difficilmente distinguibili È noto che le manifestazioni cliniche della malattia di
dalla fibromialgia e dalla sindrome della fatica cronica, con- Lyme sono dovute alla presenza, a livello locale, dell’agen-
siderando anche il fatto che entrambi questi disturbi posso- te causale ma, a tutt’oggi, non è perfettamente noto il mec-
no essere conseguenti alla malattia di Lyme 29. canismo di danno tissutale che deriva da un’interazione mol-
I sintomi della malattia di Lyme cronica sono in genere per- to complessa tra il batterio in questione e il sistema immu-
sistenti con delle fasi di peggioramento che si verificano nitario dell’ospite 34.
ciclicamente. Alcuni pazienti sono più sintomatici di altri, par- Alcuni pazienti mostrano una persistenza di sintomi, qua-
ticolare che fa pensare a una differenza geneticamente deter- li stanchezza fisica e mentale, mialgie, artralgie senza artri-
minata nella risposta all’infezione e al suo coinvolgimento te, disestesie/parestesie, cefalea, vertigini, disturbi della
sistemico. memoria nonostante l’adeguato trattamento antibiotico 8, 35.
Si può, quindi, affermare che la malattia di Lyme cronica Si parla, in questo caso, di “post-Lyme syndrome” (PLS).
non è di certo una malattia distruttiva o fatale ma può esse- La persistenza di tali sintomi è stata riportata sia in pazien-
re fortemente debilitante. ti privi di anticorpi IgG anti Borrelia sia in pazienti con tito-
L’incidenza dell’infezione asintomatica non è stata valu- lo anticorpale positivo.
tata, ma è importante precisare che molti pazienti, sebbene Il meccanismo patogenetico che causa la persistenza di
asintomatici per lungo tempo, possono andare incontro a tali sintomi non è stato ancora chiarito e, anzi, la questione rima-
una riaccensione dell’infezione e, quindi, a una comparsa ne piuttosto controversa. A causa dell’associazione di tali sin-
di sintomi della malattia di Lyme cronica mesi o anni dopo tomi con l’infezione borreliosica alcuni pazienti sono stati
aver contratto l’infezione e ciò a causa di eventi scatenanti sottoposti a terapie antibiotiche prolungate, spesso con il risul-
quali trauma, gravidanza, o stress di tipo psicologico 25. tato che, alla sospensione del trattamento, avveniva la ricom-
Non è noto il meccanismo responsabile della riattivazio- parsa della sintomatologia precedentemente descritta 36.
ne della malattia e numerose sono le teorie sulla patogene- Un paziente si definisce affetto da PLS quando sono
si della malattia di Lyme cronica. Le caratteristiche immu- rispettati i seguenti criteri definiti dai Centers for disease Con-
nopatogenetiche presenti nell’ACA forniscono un modello trol and Prevention (CDC) 36:
di studio interessante per meglio comprendere la patogene-
— documentata infezione di Lyme in passato;
si di tale disturbo.
Recenti studi indicano che le cellule di Langherans del- — ciclo completo di terapia antibiotica adeguata 37;
l’epidermide sono invase dalla Bb già nelle forme precoci di — persistenza per mesi o anni dei sintomi precedente-
malattia di Lyme. Tali cellule sono state studiate immunoi- mente descritti.
stochimicamente con differenti marker per valutare la loro In particolare, la PLS si presenta con:
attività funzionale. Si è visto che le cellule di Langherans atti- — encefalopatia con disturbi della memoria a breve ter-
ve sono ridotte nell’eritema migrante ma sono normali o mine;
addirittura elevate nell’ACA. In entrambe le manifestazioni — dolore muscolare con particolare coinvolgimento del
cliniche, c’è, inoltre, una downregulation di molecole di dorso e della regione cervicale;
classe II del complesso maggiore di istocompatibilità sulle — artralgie.
cellule di Langherans. Questo fenomeno di downregulation Probabilmente i sintomi articolari, soprattutto alle ginoc-
potrebbe essere una sorta di meccanismo protettivo che evi- chia, sono causati dall’instaurarsi di un meccanismo autoim-
ta la presentazione di autoantigeni ma impedisce alle cellu- munitario intrasinoviale. È importante considerare che, in tale
le di Langherans di eliminare Bb, da qui deriverebbe l’in- forma, i sintomi non si associano ad alcun segno obiettivo né,
sorgenza della forma cronica 30. tantomeno, a qualsiasi marker biologico. La ricerca della Bor-
Secondo la teoria dell’autoimmunità 31, che è descritta relia nel sangue o nel liquor cerebri o sinoviae, tramite esa-
meglio successivamente, esisterebbero dei linfociti T, nati dal- me culturale o tecniche di amplificazione del DNA (PCR) del-
l’interazione con Bb, che mostrano un’alterazione nella loro la Borrelia risulta, infatti, negativa, mentre la sierologia può
capacità di riconoscimento dell’antigene 32 e potrebbero mantenersi positiva per alcuni anni dopo la guarigione del-
essere coinvolti nei sintomi neurologici e muscolo-scheletrici l’infezione borreliosica e, quindi, non consente di distin-
nelle varie fasi della malattia. Ci sarebbe, infatti, una dele- guere accuratamente tra la forma cronica e la PLS 38.
zione incompleta di tali linfociti autoreattivi nel timo e ciò, Da vari studi descritti in letteratura emerge che, nella PLS,
aggiunto alla up-regulation di molecole HLA, di co-stimo- il trattamento antibiotico sistemico per via sia endovenosa che
latori, di co-recettori provocherebbe il danno. orale è inefficace 36 e, quindi, non necessario, mentre può
Altre ipotesi che tentano di spiegare la patogenesi della essere efficace la terapia con idrossi-clorochina 6, 39.
Un’altra sindrome clinica associata alla malattia di Lyme za cronica che limita le attività precedenti la malattia del
è la cosiddetta “treatment-resistant Lyme arthritis”, un’artrite 50% per un periodo di almeno 6 mesi. La malattia può esse-
di Lyme che si manifesta nel 10% dei pazienti ed è caratte- re persistente o recidivante 44.
rizzata da un’infiammazione articolare persistente che non Inoltre possono essere presenti altri sintomi (almeno 4):
risponde alla terapia antibiotica 12, 40. — compromissione della memoria e della concentrazio-
Tale infiammazione persiste per mesi o anni dopo l’ap- ne;
parente eradicazione della spirocheta 5. — faringite;
Studi di biologia molecolare hanno mostrato che tali — dolorabilità dei linfonodi (cervicali o ascellari);
pazienti hanno una predisposizione genetica dovuta a un — febbricola (o sensazione di febbre/brividi);
aplotipo HLA - DRB1* 0401 e relativi alleli e che la seve- — dolori muscolari (mialgia);
rità e la durata di tale artrite sarebbe altamente correlata alla — dolori articolari multipli (artralgia);
risposta immunitaria sia di tipo umorale sia cellulo-media- — cefalee di nuovo esordio;
ta nei confronti della proteina di superficie della Bb (Osp — disturbi del sonno (ipersonnia o insonnia);
A). Ciò deriva dal fatto che, in questi pazienti, tale proteina, — stanchezza successiva all’esercizio fisico.
in particolare la sequenza di amminoacidi OspA165 - 173,
ha una sequenza altamente omologa a un peptide contenuto Criteri di esclusione: altra causa o diagnosi responsabile
in una proteina presente normalmente nell’uomo, la hLFA - della stanchezza o dei sintomi accusati.
1α (lymphocyte function associated antigen - 1alpha). I In molti casi la valutazione della CFS si concentra sulla
linfociti T del liquido sinoviale di questi pazienti con artri- ricerca di una causa infettiva o di un’altra causa specifica
te resistente al trattamento e geneticamente predisposti deter- per questa malattia.
minano una risposta immunitaria nei confronti sia di OspA Molto importante è la diagnosi differenziale della malat-
sia di hLFA - 1, ciò suggerisce che hLFA - 1α possa agire tia, che spesso è molto laboriosa, in quanto la stanchezza e
da parziale agonista e che abbia un ruolo importante per la gli altri sintomi generali si manifestano in molte altre malat-
persistenza dell’infiammazione articolare 12, 40, 41. tie; in generale, si tratta di una diagnosi di esclusione, dopo
Sono stati effettuati vari studi per individuare i possibili siti aver effettuato un’anamnesi completa, un’attenta visita medi-
di persistenza della Bb in pazienti con forme resistenti al ca e, soprattutto, una serie di test laboratoristici che escludano
trattamento, comprese analisi di PCR per il DNA della spi- altre cause 43. Nel caso della diagnosi differenziale con la
rocheta effettuate sulla membrana sinoviale in pazienti che malattia di Lyme esami sierologici e test diretti (PCR) ci
mostravano risultati negativi per la PCR condotta su liquido permettono di porre diagnosi di esclusione.
sinoviale dopo il trattamento antibiotico. Ebbene, in alcuni
casi, la PCR condotta sulla membrana sinoviale dava esito
positivo suggerendo che, in forme di artrite di Lyme resi- Diagnosi differenziale nella sindrome da stanchezza
stenti al trattamento antibiotico, la PCR negativa su liquido cronica
sinoviale non esclude la presenza intrarticolare della Bb 11.
In letteratura sono state descritte anche forme di artrite Nella Tabella II è mostrata la diagnosi differenziale del-
sieronegativa da B. garinii 42. la CFS 444, 45.
Soltanto sulla base clinica è arduo distinguere la malattia
di Lyme cronica e la CFS o fibromialgia 46, questa difficoltà
La sindrome da stanchezza cronica è dovuta al fatto che una piccola percentuale di pazienti in
effetti sviluppa dolore cronico o la sindrome di affatica-
La sindrome da stanchezza cronica (chronic fatigue syn- mento in associazione con o subito dopo la malattia di Lyme.
drome, CFS), nota anche come sindrome da stanchezza cro- Rispetto alla malattia di Lyme, la sindrome da fatica croni-
nica e immunodeficienza, è una malattia caratterizzata da ca o la fibromialgia tendono a produrre sintomi più genera-
una persistente fatica cronica accompagnata da una serie di lizzati e disabilitanti, comprendenti notevole fatica, forte
sintomi sistemici di tipo reumatologico, cognitivo e simil- mal di testa, dolore muscolare scheletrico diffuso, punti
infettivo 43. dolorosi simmetrici in siti caratteristici, dolore e rigidità in
Non è nota ancora la causa di tale sindrome, varie ricer- molte articolazioni, disestesia diffusa, difficoltà di concen-
che hanno confermato un possibile ruolo eziologico di alcu- trazione e disturbi del sonno 47. I pazienti con la CFS o la
ne infezioni virali (compresi il virus dell’Epstein barr, ente- fibromialgia non presentano evidenza di infiammazione arti-
rovirus, virus poliomielitico), funghi (in particolare Candi- colare; hanno risultati normali nei test neurologici e hanno
da albicans), batteri (Chlamydia pneumoniae), ma non c’è un grado di ansietà e depressione maggiore rispetto ai pazien-
evidenza che essa possa essere provocata da un determina- ti con neuroborreliosi cronica, non hanno storia di infezio-
to e specifico agente eziologico. ne di Lyme.
Colpisce tutte le razze, le etnie, senza distinzione di clas- La CFS mostra anche sintomi molto simili alla post-Lyme
se sociale; si rileva, comunque, una maggiore prevalenza disease e, in alcuni studi, effettuati per valutare le differen-
per il sesso femminile tra la terza e la quarta decade di vita. ze di ordine neuropsichiatrico, si è visto che i pazienti con
La principale caratteristica della malattia è una stanchez- PLS mostrano una deficienza cognitiva maggiore rispetto
ai pazienti con CFS, e ciò avviene soprattutto e ovviamente nitaria contro la 23-Kd e la 41-Kd è considerata diagnosti-
in pazienti con PLS e con pregressi disordini di tipo psi- ca della malattia di Lyme 6, 29, 51.
chiatrico 48. La proteina 41 Kd non è caratteristica solo delle Bb, a
differenza della 23-Kd. Altre proteine caratteristiche sono 35-
Kd, 37-Kd, 39-Kd, 83-Kd, e 93-Kd.
Diagnosi Reazioni immunitarie contro la 31-Kd non compaiono
fino a un anno o più dopo aver contratto l’infezione. Con la
La diagnosi della malattia di Lyme si basa principalmen- risoluzione dei sintomi, scompare o si attenua la reazione
te su criteri clinici ed epidemiologici con il supporto di inda- di tipo IgM, mentre la risposta di tipo IgG può persistere
gini sierologiche, istologiche e colturali 3, 15. dopo la scomparsa dei sintomi, ma, comunque, in genere, si
Quando l’affezione segue il suo decorso tipico, l’accer- attenua o scompare dopo un adeguato trattamento antibioti-
tamento diagnostico risulta solitamente agevole; le indagi- co 6, 29.
ni laboratoristiche non fanno altro che confermare l’ipotesi Alcuni pazienti possono manifestare i sintomi nonostan-
del clinico. Tuttavia, come nelle forme precedentemente te il Western blot risulti negativo 52. Questo fatto si spiega con-
descritte, la diagnosi può risultare estremamente difficile e siderando che, a volte, la Borrelia rimane all’interno delle cel-
raramente certa. Essa potrà essere il risultato della somma di lule, senza avere una fase extracellulare e ciò impedisce che
molti indizi, quali provenienza da zona endemica, dato anam- si generi la risposta immunitaria dell’organismo nei con-
nestico positivo per puntura di zecca, sintomatologia clini- fronti della spirocheta 25, 53, 54.
ca, che cercano di cogliere i criteri di diagnosi differenziale I test serologici di ultima generazione sono volti a sem-
delle forme prima descritte, correlazione clinico temporale plificare la serologia, pur mantenendo elevato il valore pre-
delle manifestazioni patologiche, sfumature del quadro cli- dittivo in termini di sensibilità e specificità al punto da poter
nico, esclusione di altre affezioni, positività, tecniche di sostituire, da solo, la procedura a 2 test (ELISA e Western
amplificazione genica. blot) finora ritenuta la più predittiva.
Nella diagnostica di laboratorio della malattia di Lyme Recentemente si è utilizzato, infatti, un nuovo antigene, in
ci si avvale di metodiche dirette o indirette. metodologia immuno enzimatica, rappresentato da un cor-
La diagnosi indiretta si basa sulla ricerca degli anticorpi to peptide, detto VlsE 55.
anti Borrelia nel siero, nel liquido cefalorachidiano e nel È noto che la Bb presenta sulla membrana esterna una
liquido sinoviale di soggetti affetti, con test di primo livello serie di lipoproteine, le Osps, che vengono espresse in manie-
(ELISA o test immunoenzimatico) e test di secondo livello ra differenziale nell’ospite mammifero e nel vettore. Le pro-
(Western-Blot); la diagnosi diretta si avvale di metodiche teine OspA e OspB sono espresse nel vettore ma non nel
istologiche, immunoistochimiche, colturali e di ibridazione mammifero, le OspC e le Vlse sono espresse in vivo nel
genetica, effettuate su tessuti e liquidi biologici 15. mammifero 56.
I test laboratoristici di routine sono in genere normali, la VlsE (variable major protein-like sequence, expressed) è
VES è normale (questo è un importante elemento per la dia- una proteina di superficie della Bb che riveste un importan-
gnosi differenziale con l’artrite reumatoide e il lupus erite- te ruolo nella diagnosi sierologica della malattia di Lyme in
matoso sistemico). quanto gioca un ruolo fondamentale nella sopravvivenza
La negatività dei test sierologici non esclude la BL 49 e della spirocheta nell’uomo.
sono riportate, come descritto precedentemente, segnala- Dopo la penetrazione nell’organismo ospite la Bb subisce
zioni di artrite di Lyme sieronegativa 41. Tuttavia, quando importanti modificazioni a livello della VlsE, che le per-
si sospetta che una manifestazione clinica sia espressione mettono di sfuggire al riconoscimento e all’attivazione del
di una malattia di Lyme in fase tardiva, la positività sierolo- sistema immunitario 57, 58.
gica è un elemento fondamentale 50. La VlsE è divisa in varie parti: regioni conservate, che
Più del 75% dei pazienti con malattia cronica di Lyme ha formano il dominio transmembrana e ancorano la proteina alla
un test ELISA negativo e un Western blot positivo. In gene- membrana batterica, e regioni variabili, che subiscono costan-
re, i pazienti con artrite oligoarticolare possono presentare temente delle ricombinazioni. Per la produzione della Vlse
un’intensa e positiva risposta IgG sia con l’ELISA che con il DNA di Bb contiene da 15 a 20 sequenze (cosiddette varia-
il Western blot. ble major protein-like sequenze [vls]) che contengono un
Da analisi di Western blot risulta che, nella malattia di gran numero di informazioni genetiche 57, 58.
Lyme, la prima reazione immunologica si ha nei confronti del- Ognuna è composta da 12 sezioni: 6 costanti e 6 variabi-
la proteina flagellare 41-Kd e la proteina OspC 23. In gene- li. Dalla ricombinazione di elementi differenti nascono pro-
re, nella fase dell’eritema cronico migrante, si ha un’inten- teine di superficie che differiscono nella loro regione varia-
sa reazione IgM contro le proteine 23-Kd e 41-Kd e nessu- bile. Il DNA che si assembla e che si usa per la sintesi delle
na reazione di tipo IgG. Nelle settimane successive persiste proteine è detto vlsE (E = expressed). Esso contiene anche
la reazione IgM, a volte accompagnata da reazioni minori i domini transmembrana della VlsE.
contro le proteine 60-Kd e la 66 Kd, e perciò segue un innal- VlsE è esclusivamente espressa in vivo nei mammiferi,
zamento delle IgG contro le proteine 23-Kd e 41-Kd. In pre- quindi non è presente nelle colture di Bb 58.
senza di un caratteristico quadro clinico, la reazione immu- Le regioni costanti sono mascherate da quelle variabili e sono
protette dal diretto attacco del sistema immunitario. Quando sono di utilità nelle forme croniche il cui trattamento è anco-
la Bb viene processata dalle cellule che presentano l’antige- ra dibattuto.
ne, l’intera VlsE viene presentata al sistema immune con la for- Alcuni individui non rispondono alla terapia, cioè, dopo
mazione di anticorpi sia contro le regioni conservate che con- la terapia, hanno una fase di remissione completa dei sinto-
tro quelle variabili. Questi anticorpi in vivo non possono lega- mi generali, che riappaiono dopo un periodo più o meno
re la Bb a causa dell’effetto maschera, ma sono particolar- lungo, talora con maggiore intensità.
mente importanti nella diagnosi in quanto agenti contro una Altri, nonostante la terapia antibiotica, continuano a mani-
regione fortemente conservata della proteina 58. festare la sintomatologia; perciò si preferisce, in tal caso, soli-
Il limite maggiore dei test sierologici è che non consento- tamente somministrare terapie antibiotiche prolungate 36.
no di distinguere tra infezioni recenti e passate, soprattutto In generale, l’artrite di Lyme viene trattata con terapia
perché, spesso, il titolo delle IgG, e talvolta delle IgM, può man- antibiotica sistemica orale o parenterale 4, 61.
tenersi elevato anche in seguito al trattamento antibiotico. Doxiciclina o amoxicillina, entrambe somministrate anche
Un recente studio ha dimostrato che il titolo degli anticorpi fino a 28 giorni di trattamento, hanno mostrato buoni risul-
della classe IgG anti- VlsE cala rapidamente dopo la terapia tati e sono raccomandate se non vi sono segni clinici di un
antibiotica; ciò suggerisce che una diminuzione di tale tito- coinvolgimento di tipo neurologico, eventualità in cui sarà
lo anticorpale entro 6 mesi dall’infezione e dopo terapia necessaria una terapia per via parenterale con cefotaxime o
antibiotica possa essere considerato come un marker indi- penicillina G.
cativo dell’eradicazione della spirocheta (con una funzione Per i pazienti pediatrici più piccoli si utilizza l’amoxicil-
assai simile al VDRL nella sifilide) 59. lina, per quelli di età superiore agli 8 anni la doxiciclina 3, 4.
Altri studi che valutano la risposta anticorpale al peptide Per pazienti che manifestano disturbi articolari persistenti
VlsE dopo terapia antibiotica, sia 6 mesi che anni dopo, nel dopo un ciclo completo di terapia antibiotica, si preferisce
siero di pazienti con manifestazioni cliniche di Lyme precoce ripetere il trattamento per altre 4 settimane con antibiotici per
o cronica, mostrano che la persistenza di titoli anticorpali via orale o, alternativamente, con 2 settimane di cefotaxime
anti Vlse per mesi o anni dopo la terapia antibiotica non può endovena. Alcuni Autori sono concordi nel ritenere di atten-
essere considerata una persistenza dell’infezione da Bb 60. dere qualche mese prima di iniziare il nuovo ciclo di terapia
Le metodiche dirette si rivelano particolarmente utili nel- antibiotica, essendo il processo di risoluzione dell’infiam-
le fasi iniziali della malattia di Lyme, quando il movimento mazione a livello articolare estremamente lento. Se, nono-
anticorpale non è ancora rilevante, o nei casi in cui la siero- stante i ripetuti cicli di terapia antibiotica non si evidenzia
logia è negativa. L’isolamento colturale resta il gold stan- alcun beneficio, si può ricorrere alla sinoviectomia in artro-
dard e, in alcuni casi, la Bb si può coltivare da lesioni cuta- scopia che riduce il periodo di infiammazione dell’articola-
nee, siero, liquido cerebrospinale e sinoviale 15. zione 4.
La PCR è una metodica diretta che ricerca la presenza Nei pazienti che presentano disturbi di tipo neurologico con
del DNA di Bb nei tessuti e nei liquidi biologici, ed è un interessamento del sistema nervoso centrale o periferico,
esame di grande importanza per porre una diagnosi diffe- dopo un’attenta valutazione neurologica e l’esecuzione di
renziale tra le varie sindromi associate al Lyme 15. una puntura lombare, la raccomandazione è somministrare
il cefotaxime per via parenterale (2 g/die per 2-4 settimane)
o la penicillina G 3, 4.
Terapia Il trattamento della forma cronica non è a tutt’oggi ben
definito.
Per ciò che riguarda il trattamento delle forme precoci di L’obiettivo principale sarebbe utilizzare antibiotici capa-
Lyme c’è un accordo generale tra i vari studi pubblicati; la ci di penetrare all’interno delle cellule, quali i macrolidi e le
terapia è essenzialmente di tipo antibiotico e altri farmaci tetracicline 6, 39.
sintomatici possono essere di volta in volta usati a seconda In realtà, macrolidi non sono di norma utilizzati nel trat-
dei quadri clinici associati. La scelta deve essere effettuata tamento della malattia di Lyme, ma alcuni studi conferma-
in base a quadro clinico, stadio, sintomatologia, età del no la loro efficacia nel trattamento delle forme croniche se
paziente, sesso e fattori concomitanti, quali una gravidanza. associati a un agente lisosomotropico che alcalinizza l’aci-
La BL è un’infezione multisistemica e tutti i distretti del- dità intracellulare dei lisosomi, l’idrossiclorochina, appun-
l’organismo sono interessati, perciò è necessario tenere con- to 62. L’attività della clorochina incrementerebbe di molto l’at-
to della capacità del farmaco di raggiungere le spirochete tività dei macrolidi che sono inattivati normalmente dal pH
per svolgere l’effetto terapeutico. Inoltre, il farmaco deve acido 6, 39.
essere in grado di diffondersi nei tessuti e nei liquidi biolo- Il razionale di tale terapia si basa sul fatto che i sintomi del-
gici, di attraversare la barriera ematoencefalica, di penetra- la malattia di Lyme cronica sarebbero provocati da una per-
re all’interno delle cellule, di legarsi in maniera stabile alle sistenza intracellulare della Bb e, in questo caso, i macroli-
strutture vitali del germe ed esplicare in questa sede l’attività di agirebbero nel distretto intracellulare 39, dove penicilline
antimicrobica 15. e cefalosporine non arrivano.
L’amoxicillina e la doxiciclina costituiscono i farmaci di Si è concordi nel ritenere che il trattamento di tali forme
prima scelta nella malattia di Lyme3 recente, mentre non deve essere piuttosto prolungato, da 12 a 18 mesi. Una pic-
cola percentuale di pazienti risulta, comunque, non rispon- mente la cute, le articolazioni, il sistema nervoso, il cuo-
dere nemmeno dopo terapie prolungate. re e l’occhio.
Sebbene in parte definite e confermate, le varie sindro- La valutazione clinica, supportata da dati epidemiologici,
mi correlate alla malattia di Lyme richiedono ancora un indagini sierologiche, istologiche e colturali, costituisce il fon-
maggiore inquadramento nell’ambito di uno spettro clini- damento per porre una diagnosi certa della malattia di Lyme.
co associato al Lyme e una diagnosi di certezza, che, rela- Le manifestazioni cutanee, nervose, osteoarticolari si possono
tivamente semplice nelle forme precoci, spesso è difficile manifestare, in alcuni casi, anche a distanza di tempo dalla
se non improbabile; sta al clinico, quindi, cercare di coglie- puntura della zecca o, addirittura, in seguito a un’apparente
re quegli elementi di diagnosi differenziale, sia clinici sia eradicazione della stessa.
laboratoristici, tuttora oggetto di discussione tra vari Auto- In questo lavoro vengono descritte alcune sindromi clini-
ri, per riconoscere e diagnosticare le varie forme cliniche, che correlate alla malattia di Lyme che presentano varie
escludere sindromi simili e poter scegliere efficienti strategie similitudini e sulla cui patogenesi sono state formulate e
terapeutiche. vagliate varie ipotesi; l’individuazione dei principali ele-
menti di diagnosi differenziale, clinici e laboratoristici, costi-
tuisce il primum movens per riconoscere e diagnosticare le
Riassunto varie forme cliniche e scegliere un opportuno trattamento.
PAROLE CHIAVE: Borreliosi di Lyme - Malattia di Lyme tar-
La borreliosi di Lyme è un’infezione multisistemica diva - Malattia di Lyme cronica - Artrite di Lyme resistente
causata da Borrelia burgdorferi che interessa principal- al trattamento - Post-malattia di Lyme.
Chronic urticaria
A review
B. WEDI, A. KAPP
Chronic urticaria remains a major problem in terms of patho- Department of Dermatology and Allergology
genesis, diagnostic work-up and management. During the last Hannover Medical University, Hannover Germany
years several new concepts regarding the disease have been
developed. Some of these aspects resulted in a different man-
agement of patients with chronic urticaria whereas others still
need research activities for confirmation or clarification of details.
Symptoms are the result of the degranulation of mast cells and
basophils. Possible mechanisms include autoimmune mecha-
nisms, infectious diseases, pseudoallergic mechanisms and oth-
C hronic urticaria remains a major problem in terms
of pathogenesis, diagnostic work-up and man-
agement. During the last years several new concepts
ers such as internal diseases/malignancies. A detailed history
plays a main role in the diagnostic program. Further diagnostic regarding the disease have been developed. Some of
procedures depend on the urticaria subtype. Whereas in acute these aspects resulted in a different management of
urticaria routine diagnostic is not recommended, in chronic patients with chronic urticaria whereas others still
urticaria a diagnostic programm considering associated infections
(particularly with Helicobacter pylori, staphylococci, streptococ- need research activities for confirmation or clarifica-
ci, yersinia), autoreactivity and non-allergic hypersensitivity tion of details. This review summarizes the current
reactions is reliable and successful. Special considerations are concepts of classification and definition, pathogenesis
indicated in the case of recurrent angioedema without whealing and management of chronic urticaria.
and in childhood urticaria. In most cases a targeted diagnostic
program leads to the identification of potential triggering factors
and after their adequate treatment long-lasting and life quality
impairing urticaria disappears or improves within several weeks. Classification and definition
With regard to treatment non-sedating H1 antihistamines should
be given regularly and daily, most often increased dosage is need- The 4 main subtypes of urticaria should be clearly
ed. Data on alternatives are insufficient but in selected cases differentiated: acute, chronic, physical urticaria and
cyclosporin A, leukotriene receptor antagonists, or hydroxy-
chloroquine may be useful. Several questions have to be addressed a heterogeneous group of other types that do not fit
in the future and there is hope that during the next years new in these scheme such as urticaria pigmentosa/masto-
therapeutic strategies will be developed to facilitate the man- cytosis, urticaria vasculitis, familiar cold urticaria and
agement of this long-lasting and life-quality restricting disease. hereditary or acquired angioedema with C1-INH defi-
KEY WORDS: Chronic urticaria - Autoreactivity - Infections - Heli- ciency.1-3
cobacter pylori. The cardinal clinical feature of urticaria is the occur-
rence of itchy wheals anywhere on the skin (Figure 1).
Address reprint requests to: B. Wedi, MD, Associate Professor, Depart- Wheals are short-lived elevated erythematous lesions
ment of Dermatology and Allergology, Hannover Medical University,
Ricklinger Str. 5, D-30449 Hannover, Germany. ranging from a few millimeters to several centimeters in
E-mail: Bettina_Wedi@t-online.de. diameter and can become confluent. Sometimes the
Laboratory findings
In the last years some interesting laboratory findings
showed differences between patients with chronic
urticaria and healthy controls although a specific mark-
er is still not available.
Figure 1.—Typical wheal and flare reaction in chronic urticaria.
It has been shown that the number of basophil
granulocytes is significantly decreased in chronic
urticaria 7, 8 and is negatively correlated with disease
wheals are paler than the surrounding skin because of activity.9 This led to the hypothesis that basophils may
the compressing effect of the edema on the postcapillary be actively recruited, for example by chemokine
venules. The itching can be pricking or burning and is induced adhesion molecules on endothelial cells, from
usually worse in the evening or nighttime. Typically the circulation to the wheals. Interestingly, not only
the lesions are rubbed and not scratched, therefore, basophils, but also eosinophils and lymphocytes are
excoriated skin is usually not a consequence of urticaria. decreased in chronic urticaria.9 Moreover, in autoim-
Acute urticaria generally disappears within 2 to 4 mune urticaria basophil counts are significantly low-
weeks. By definition urticaria is chronic if wheal and er compare to non-autoimmune urticaria.7 Additional
flare reactions persist daily or nearly daily for at least data demonstrated that basophils and mast cells appear
6 weeks. At least half of the patients suffer from con- to be activated. In this aspect, Ferrer et al. have shown
comitant and sometimes life threatening angioedema that serum IL-4 levels are significantly increased in
most typically involving the face, lips, tongue, pharynx, chronic urticaria compared to healthy controls.10 In
genitalia, and extremities.1 Systemic symptoms such addition, intracellular Il-4 and IFN-γ were signifi-
as fatigue, respiratory, gastrointestinal and arthralgic cantly increased in peripheral CD4+ lymphocytes, but
symptoms are rare. not in CD8+-lymphocytes. Moreover, if urticaria was
Quality of life is significantly impaired like in associated with angioedema, leukotriene levels
patients with severe atopic dermatitis, psoriasis or appeared to be increased.10 Others showed that serum
coronary artery disease.2-4 IL-2 receptor levels and tryptase are significantly high-
Chronic urticaria usually persists for long time since er in chronic urticaria pointing to T-cell and mast cell
not even 50% of patients that consulted a university der- activation.11 In the subgroup with positive autologous
matology department were symptomfree within 10 serum skin test (ASST) and FcεRIα autoantibodies
years.5 tryptase levels were highest. Moreover, CD40L expres-
It is important to know that 2 or rarely more subtypes sion on activated T-cells and bcl2 expression in acti-
of urticaria can occur in the same patient such as chron- vated T- and B-lymphocytes were increased in severe
ic urticaria and dermographism or delayed pressure chronic urticaria.12
urticaria.1 In these cases urticaria is more worst.6 In contrast, ASST positive patients with chronic
urticaria did not demonstrate increased stem cell fac-
tor (SCF) serum levels compared to controls.13
Pathogenesis
a physical examination including a test for dermo- TABLE I.—Urticaria-Score according to Zuberbier T, Bindslev-Jen-
graphism, laboratory investigations and, if needed, sen C, Canonica W, Grattan CEH, Greaves MW, Henz BM et al.
EAACI/GA_LEN guideline: definition, classification, and dia-
additional specific procedures. gnosis of urticaria. Submitted to Allergy and Zuberbier et al.19
According to an international consensus 14 patient
Score Wheals Pruritus
history should include at least the following items
to define the subtype of urticaria and to identify 0 None None
potential related causes: 1) first manifestation, fre- 1 Mild Mild
quency, duration and daily variability; 2) border, size (<20 wheals/24 h)
and distribution of wheals; 3) association with 2 Moderate Moderate
(21- 50 wheals/24 h)
angioedema; 4) subjective symptoms like pruritus,
3 Severe Severe
pain; 5) family history for urticaria, atopy; 6) prior or (>50 wheals/24 h
current allergies, infections, internal diseases or oth- or large confluent
er related causes; 7) exacerbation by physical fac- areas of wheals)
tors or exercise; 8) drug intake (particularly NSAID Sum of score: (0-6).
and angiotensin converting enzyme inhibitors); 9)
relation to food/food additives; 10) nicotine; 11)
occupation, hobbies; 12) relation to weekends, hol-
numbered the following parameters as useful in
idays, holidays abroad; 13) surgical implants; 14)
chronic urticaria: serology for helicobacter, gas-
reactions to insect stings; 15) association with men-
troscopy, anti-streptolysin titre, serology for hepati-
struation; 16) response to prior treatment; 17) stress
tis, pseudoallergen-low diet for 3 weeks, ASST, anti-
and 18) quality of life impairment (Zuberbier T, Bind-
nucleare antibodies, thyroid antibodies, oral provo-
slev-Jensen C, Canonica W, Grattan CEH, Greaves
cation tests, specific IgE, ova/parasites and other
MW, Henz BM et al. EAACI/GA_LEN guideline:
investigations.19, 21
definition, classification, and diagnosis of urticaria.
However, it should be noted, that this consens was
Submitted to Allergy).
established by simple hand voting and regionally, the
Patient diaries are very helpful to become aware of
the fluctuating intensity of the disease. optimal diagnostic schedule may differ, e.g. in Ger-
Physical examination should determine number and many investigation for hepatitis and parasites is not
size of wheals, angioedema and should include der- very useful.
mographism. Our research results during the last years revealed a
If physical triggering is suspected, appropriate and reliable and successful diagnostic program based on the
standardized physical tests should be performed such following 3 parameters:1, 22-27
as pressure test with defined weights,15-18 but physical 1) infections;
urticaria will not be discussed in this review. 2) autoreactivity;
Activity of the disease should be evaluated using a 3) non-allergic hypersensivity reactions (pseudoal-
standardized score (Table I).19 This is of particular lergies).
importance for treatment trials. In addition, impair- Therefore, the determination of the parameters pre-
ment of daily life, occupational and psychosocial sented is used routinely in our department (Figure 2).
aspects should be considered. Standardized instru-
ments for dermatologic diseases have been used,3, 4
Infections
however, instruments adapted for chronic urticaria
may be more useful.2 Recently, we reviewed the published literature
If single wheals persist for longer than 24 h biopsies regarding “chronic urticaria and infections.” 23 It was
should be taken to exclude vasculitis by histology and found that studies investigating this topic were difficult
immunofluorescence that may indicate systemic dis- to compare, evidence-based criteria were not applic-
ease like lupus erythematodes.20 able and a meta-analysis was impossible. Most stud-
Routinely only differential count and general ies did not consider the multiplicity of triggering fac-
inflammatory parameters such as C-reactive protein tors. Further complicating factors are for example geo-
(CRP) should be determined. An international con- graphic variations in the frequency of infections (e.g.
sensus established by hand voting in the year 2001 for parasitosis).
Non-allergic
Infections Autoreactivity hypersensitivity
Figure 2.—Recommended diagnostic schedule in chronic urticaria. In children, serology for Epstein-Barr-virus and cytomegalovirus should be includ-
ed; 1) urea breath test or gastroscopy with biopsies; 2) antiDNAseB-, antistreptolysin-titre; 3) antistaphylolysin-titre; 4) Yersinia-IgA, -IgG and
immunoblot; 5) autologous serum skin test; 6) BHR = basophil histamine release, BasoAT = basophil activation test (CD63 expression), CAST = cel-
lular antigen stimulation test (production of sulfidoleukotrienes); 7) basal TSH, microsomal Abs, thyroglobulin Abs, TSH receptor Abs; 8) in select-
ed patients for at least 3 weeks; 9) general parameter for inflammation/malignancy.
From the literature it can be seen that the preva- dence interval 1.4-6.8; P= 0.005). The authors con-
lence of infections, either bacterial, viral, parasitic or cluded that clinicians, after considering other caus-
fungal appears not to differ compared to the general es of urticaria, should constitute 1) testing for Heli-
population (for yersinia this has to be demonstrated). cobacter pylori; 2) treating with appropriate antibi-
However, there is a very large amount of reports otics if Helicobacter pylori is present; and 3) con-
demonstrating benefit after eradication of infectious firming successful eradication of infection.28 We are
processes and it is hardly to believe that all these are recommending this approach for several years.22-24, 26,
due to spontaneous remissions. Nevertheless, avail- 27, 29, 30
able studies have common flaws and cannot be However, Helicobacter is not the only triggering
reviewed as a meta-analysis or according to evidence- factor. Other persistent, chronic, in most cases sub-
based medicine rules. Best evidence exists for Heli- clinical infections, for example, with streptococci,
cobacter pylori infection.23 staphylococci and yersinia can also be found.23
Systematically reviewing existing studies address- In the case of an identified infection, targeted erad-
ing the effect of antibiotic therapy for chronic urticaria ication should be performed and it should be careful-
patients infected with Helicobacter pylori revealed ly looked whether eradication was successful.
that resolution of urticaria was more likely when It should be borne in mind that often urticaria does
antibiotic therapy was successful in eradication of not disappear until all triggering factors have been
Helicobacter.28 Ten studies met the inclusion criteria carefully addressed, e.g. Helicobacter pylori asso-
and when data from these studies were combined, ciated gastritis, persistent yersiniosis, elevated anti-
eradication of Helicobacter pylori was both quanti- streptococcal titres with chronic sinusitis plus posi-
tatively and statistically associated with remission tive ASST plus exacerbation through regular aspirin
of urticaria, with an odds ratio of 2.9 (95% confi- intake.
Autoreactivity
Details of the autoimmune pathogenesis of chron-
ic urticaria have been recently reviewed.31, 32
Evidence for autoreactive mechanisms in chronic
urticaria is provided by a positive ASST (Figure 3).
However, the clinical relevance is far from being clear
because the presence of functional autoantibodies
against FcεRI and/or IgE itself does not correlate with
a positive ASST. Moreover, ASST can be still positive
although urticarial symptomatology disappeared.
Therefore, several authors recommed a functional
cellular activity assay such as basophil histamine
release for confirmation. In addition, the determina-
tion of sulfidoleukotriene de novo production in leuko-
cyte suspensions (cellular antigen stimulation test,
CAST) and flow cytometric CD63 surface expres-
sion on basophils are possible 33-35 although hista-
mine release appears to be more specific. Nevertheless, Figure 3.—Positive autologous serum skin test in chronic urticaria, read-
ing after 30 min.
these functional assays are difficult to perform and
to interpret due to their dependence on the releasabil-
ity of the donor cells used. Up to the present, the direct chronic urticaria.37 After exclusion of other causes, in
measurement of the autoantibodies is not available single cases a standardized pseudoallergen-low diet
for routine purposes since a satisfactory ELISA has not might be indicated for at least 3 weeks.38 However,
been developed. controlled provocation test often are not able to iden-
Patients with positive ASST more often have thyroid tify causal substances.39
autoantibodies. Thus, their determination is recom-
mended at least in women with chronic urticaria. It is
debated whether therapeutic implications are given SPECIAL DIAGNOSTIC ISSUE: CHILDHOOD CHRONIC
when—as it is most often the case—thyroid function URTICARIA
is normal. In selected cases assessment of antinuclear Recently, it has been shown that 20-30% of chil-
antibodies may be advisable to exclude systemic lupus dren with acute urticaria progressed into chronic
erythematosus. urticaria. In almost all (91%) acute urticaria was con-
sidered to be induced by acute infection.40 Similarly,
Non-allergic hypersensitivity (pseudoallergic reac- assocation with infections also plays a major role in
tions) chronic urticaria.23 Persistent chronic often bacterial
infections (e.g. with streptococci, staphylococci, but
NSAID, particularly aspirin, are a common exac-
also with Helicobacter pylori and yersinia) are most
erbating factor in chronic urticaria and should be avoid-
common in chronic urticaria.40, 41 Furthermore, posi-
ed. However, as single causal factor they are rare. If sus-
tive ASST indicating autoreactivity can also be found
pected a placebo-controlled provocation test should
in about 30% of children with chronic urticaria.41, 42 In
be envisaged.
children and young adults serology for Epstein-Barr
In this aspect, recently an interesting publication
virus and cytomegalovirus should be included in the
demonstrated that 33% of patients with acute urticaria
diagnostic program.
due to NSAID intake developed chronic urticaria 1 to
10 years later in contrast to 1% of an atopic control pop-
RECURRENT ANGIOEDEMA
ulation.36 The authors concluded that NSAID intoler-
ance may predispose to later development of chronic Recurrent angioedema without wheals may be
urticaria. caused by hereditary or acquired C1-esterase inhibitor
In addition, food additives are suggested to trigger deficiency or dysfunction, drugs (particularly
angiotensin converting enzyme inhibitiors, angiotensin studies with several flaws, so that their level of evidence
II receptor antagonists),43, 44 and perhaps also persis- is very low.
tent infections (e.g. Helicobacter pylori-associated In MEDLINE and EMBASE there is no study
gastritis, yersiniosis).45-47 addressing the efficacy of corticosteroids in chronic
If angioedema are described principally at least the urticaria although they are widely used. Sometimes
functional activity of the C1-esterase inhibitor should corticosteroids are needed for example to achieve rapid
be assessed to exclude deficiency or dysfunction.48 control to cover social or occupational events but it is
ACE-inhibitors and perhaps also AT II receptor antag- consent that prolonged daily treatment should be clear-
onists should be avoided. It has to be considered that ly avoided due to severe side effects.
angioedema which often are located in the oropharynx In the treatment of chronic urticaria best evidence
occur within several weeks after initiation of treat- exists for non-sedating H1-antihistamines such as aze-
ment but can also occur first after several years of lastine, cetirizine, desloratadine, ebastine, fexofenadine,
intake.49 levocetirizine, loratadine and mizolastine (alphabeti-
cal order). The quality of these RCTs is high and tak-
en together non-sedating H1 antihistamines can be
Treatment recommended with highest Grade A. However, we
should bear in mind that most of these studies includ-
Henderson et al.50 addressed the question what ed only patients with mild to moderate urticaria. High
agents are commonly used to treat urticaria in 9.2 mil- quality RCTs that compared non-sedating H1-anti-
lion visits in office-based practices between 1990 and histamines are not available and from the existing evi-
1997 in the USA. They found that H1-antihistamines dence it appears that differences are rather small if
were prescribed in 56% of consultations, systemic
ever existing. However, from clinical experience it is
corticosteroids in 14% and other drugs in 12%. Inter-
well known that non-responders with one non-sedat-
estingly, allergists were the least likely to prescribe
ing antihistamines may respond favourably to anoth-
corticosteroids whereas internists were the most like-
er. Urticaria experts often use increased dosage and
ly.51 Looking at alternatives, H2-antihistamines, β-
agonists, doxepin, nifedipine and, interestingly enough they are clearly needed in most patients with chronic
methotrexate were prescribed. These drugs are not urticaria. However, RCTs addressing this point in
prescribed in our clinic. chronic urticaria are missing.
An italian study described prescription of antihist- Several drugs, such as cyclosporin A, LT receptor
amines in 351 patients with chronic urticaria, with a antagonists and stanazolol have been combined with
good response in only 40%.51 In this study 221 patients non-sedating H1 antihistamines. However, from an
were treated with other drugs such as steroids, evidence based view the grade of recommendation is
cyclosporine A, cromolyn, LT receptor antagonists low. The situation is even more bad looking at other
and adrenaline. alternatives such as doxepin, oxatomide, nifedipin,
It is undeniable that we do not have a standard treat- montelukast, and warfarin. For several drugs such as
ment of chronic urticaria. corticosteroids, dapsone, sulfasalazine, methotrexate,
To make preparations for the recent international interferon, for plasmapheresis and intravenous
urticaria consensus conference in Berlin 2004 we per- immunoglobulins (IVIGs) we do not have RCTs. Evi-
formed a systematic review of randomised controlled dence is based on case series, uncontrolled trials or
trials (RCTs) in chronic urticaria (Zuberbier T, Bind- expert opinion.
slev-Jensen C, Canonica W, Grattan CEH, Greaves Nevertheless, cyclosporin A may be a valuable alter-
MW, Henz BM et al. EAACI/GA_LEN guideline: native in severely affected patients although potential
definition, classification, and diagnosis of urticaria. side effects have to be considered. Grattan et al. 52
Submitted to Allergy). A literature search using MED- investigated a dose of 4 mg/kg per day in combination
LINE and EMBASE, in part also by hand-searching with a doubled dose of cetirizine in ASST+ patients.
was done. In chronic urticaria RCTs demonstrated An unblinded study by Baskan et al. 53 also included
ineffective treatment with sedating H1-antihistamines ASST+ patients and used the same dose but their aim
plus cimetidine or terbutaline and also with tranex- was to compare 4 weeks versus 12 weeks treatment.
amic acid or cromolyn. However, these were single The unblinded and uncontrolled study by Toubi 54
investigated the effect of low-dose cyclosporine. They delle mast cell e dei basofili attraverso possibili meccanismi
stated that efficacy of cyclosporine was independent of di tipo autoimmune, infettivo, pseudoallergico, e altri (con-
ASST reactivity. However, all these studies included nessi a malattie internistiche e a neoplasie).
Un’accurata anamnesi della malattia gioca un ruolo fon-
very few patients. damentale nel programma diagnostico. Ulteriori indagini
Available data for leukotriene receptor antagonists sono indicate in base al sottotipo di patologia. Nell’orticaria
are inconsistent and difficult to compare.55-60 These acuta, il classico iter diagnostico non viene generalmente
drugs may be of benefit in subgroups of patients with raccomandato, mentre nella forma cronica si consiglia viva-
chronic urticaria that have a positive ASST and/or suf- mente di eseguire un programma mirato alla valutazione di
fer from ASA and/or food intolerance. It may be also infezioni (in particolar modo da Helicobacter pilori, stafi-
lococchi, streptococchi, Yersinia), test di autoreattività e test
worthwhile to compare patients with and without di ipersensibilità non allergologici. Particolare considera-
angioedema. zione deve essere posta all’angioedema e all’orticaria del-
In our hands hydroxychloroquine is effective in l’infanzia. Nella maggior parte dei casi l’iter diagnostico
patients with autoimmune urticaria. Several years ago porta alla identificazione dei fattori trigger della malattia; è
in vitro we found significant inhibitory effects of stato visto che il trattamento a lungo termine dei fattori trig-
chloroquine on serum activity of ASST positive ger migliora la qualità di vita dei pazienti e le manifestazio-
ni cliniche della malattia possono scomparire o manifestar-
patients.35 Chloroquine inhibited histamine release, si nuovamente, ma dopo parecchi anni.
basophil CD63 expression and leukotriene de novo Vengono consigliati gli antistaminici H1 (pochi effetti
production that was induced by ASST positive chron- collaterali) che devono essere somministrati quotidiana-
ic urticaria sera. mente e regolarmente; a volte è necessario aumentare la
This benefit may be also confirmed by an australian posologia. Altri trattamenti sono risultati non soddisfacenti
open label study 61 and a recent randomised placebo- anche se la ciclosprina A, gli antagonisti leucotrienici e l’i-
controlled controlled trial 62 although both studies droclorochina possono essere efficaci in casi selezionati.
Ci sono ancora molte domande a cui rispondere in futuro
have several flaws. con la speranza che nei prossimi anni le strategie terapeuti-
Taken together non-sedating H1 antihistamines che possano facilitare il management e la qualità di vita di
remain the key treatment of chronic urticaria although questa patologia cronica e limitante le attività quotidiane.
these drugs are insufficient in several patients even in Parole chiave: Orticaria cronica - Autoreattività - Infezioni
increased dosage. Thus, more and well designed RCTs - Helicobacter pylori.
are clearly needed to recommend or refuse potential
alternative drugs. Although difficult to perform these
RCTs should include best characterised patients and References
should try to minimise bias by carefully addressing
1. Wedi B. Acute, chronic or physical urticaria. What causes the hives?
critical points of internal validity. MMW Fortschr Med 2002;144:28-32. German.
Several questions have to be addressed in the future 2. Baiardini I, Giardini A, Pasquali M, Dignetti P, Guerra L, Specchia C
and there is hope that during the next years new ther- et al. Quality of life and patients’ satisfaction in chronic urticaria and
respiratory allergy. Allergy 2003;58:621-3.
apeutic strategies will be developed to facilitate the 3. Poon E, Seed PT, Greaves MW, Kobza-Black A. The extent and nature
management of this long-lasting and life-quality of disability in different urticarial conditions. Br J Dermatol
restricting disease. 1999;140:667-71.
4. O’Donnell BF, Lawlor F, Simpson J, Morgan M, Greaves MW. The
impact of chronic urticaria on the quality of life. Br J Dermatol
1997;136:197-201.
Riassunto 5. Van der Valk PG, Moret G, Kiemeney LA. The natural history of
chronic urticaria and angioedema in patients visiting a tertiary refer-
ral centre. Br J Dermatol 2002;146:110-3.
Orticaria cronica: una review 6. Kozel MMA, Mekkes JR, Bossuyt PM, Bos JD. Natural course of
physical and chronic urticaria and angioedema in 220 patients. J Am
L’orticaria cronica rimane una delle patologie maggior- Acad Dermatol 2001;45:387-91.
mente problematiche in tema di eziopatogenesi, work-up dia- 7. Bakos N, Hillander M. Comparison of chronic autoimmune urticaria
gnostico e trattamento. Negli ultimi anni sono stati portati with chronic idiopathic urticaria. Int J Dermatol 2003;42:613-5.
avanti nuovi concetti riguardanti questa patologia. Alcuni di 8. Grattan CE, Walpole D, Francis DM, Niimi N, Dootson G, Edler S et
questi aspetti hanno portato a modificare il management del- al. Flow cytometric analysis of basophil numbers in chronic urticaria:
basopenia is related to serum histamine releasing activity. Clin Exp
la malattia, mentre i risultati di altri studi di ricerca devono Allergy 1997;27:1417-24.
ancora essere confermati e validati. I sintomi dell’orticaria deri- 9. Grattan CE, Dawn G, Gibbs S, Francis DM. Blood basophil num-
vano, da un punto di vista fisiopatologico, dalla degranulazione bers in chronic ordinary urticaria and healthy controls: diurnal vari-
ation, influence of loratadine and prednisolone and relationship to induces histamine release, leukotriene production and basophil CD63
disease activity. Clin Exp Allergy 2003;33:337-41. surface expression – inhibitory effects of anti-inflammatory drugs. J
10. Ferrer M, Luquin E, Sanchez-Ibarrola A, Moreno C, Sanz ML, Kaplan Allergy Clin Immunol 2000;105:552-60.
AP. Secretion of cytokines, histamine and leukotrienes in chronic 36. Asero R. Intolerance to nonsteroidal anti-inflammatory drugs might
urticaria. Int Arch Allergy Immunol 2002;129:254-60. precede by years the onset of chronic urticaria. J Allergy Clin Immunol
11. Hidvegi B, Nagy E, Szabo T, Temesvari E, Marschalko M, Karpati S 2003;111:1095-18.
et al. Correlation between T-cell and mast cell activity in patients 37. Zuberbier T. Pseudoallergens and chronic urticaria. Allergologie
with chronic urticaria. Int Arch Allergy Immunol 2003;132:177-82. 2001;24:457-62. German.
12. Toubi E, Adir-Shani A, Kessel A, Shmuel Z, Sabo E, Hacham H. 38. Zuberbier T, Chantraine-Hess S, Hartmann K, Czarnetzki BM.
Immune abberations in B and T lymphocytes derived from chronic Pseudoallergen-free diet in the treatment of chronic urticaria. A
urticaria patients. J Clin Immunol 2000;20:371-8. prospective study. Acta Derm Venereol 1995;75:484-7.
13. Asero R, Tedeschi A, Lorini M, Gerosa M, Meroni P, Riboldi P. Cir- 39. Werfel T, Wedi B, Kleine-Tebbe J, Niggemann B, Saloga J, Sen-
culating stem cell factor in patients with chronic idiopathic urticaria. nekamp J et al. Vorgehen bei Verdacht auf eine pseudo-allergische
Ann Allergy Asthma Immunol 2003;91:79-81. Reaktion durch Nahrungsmittelinhaltsstoffe. Allergo J 1999;8:
14. Zuberbier T, Greaves MW, Juhlin L, Merk H, Stingl G, Henz BM. Man- 135-141.
agement of urticaria: a consensus report. J Investig Dermatol Symp 40. Sackesen C, Sekerel BE, Orhan F, Kocabas CN, Tuncer A, Adalioglu
Proc 2001;6:128-31. G. The etiology of different forms of urticaria in childhood. Pediatr Der-
15. Fleischer M, Grabbe J. Physical urticaria. Hautarzt 2004;55:344-9. matol 2004;21:102-8.
16. Muller BA. A comprehensive review of physical urticaria. Compr 41. Wieczorek D, Raap U, Liekenbrocker T, Kapp A, Wedi B. Chronic
Ther 2002;28:214-21. urticaria in childhood. Hautarzt 2004;55:357-60. German.
17. Kontou-Fili K, Borici-Mazi R, Kapp A, Matjevic LJ, Mitchel FB. 42. Brunetti L, Francavilla R, Miniello VL, Platzer MH, Rizzi D, Lospal-
Physical urticaria: classification and diagnostic guidelines. An EAACI luti ML et al. High prevalence of autoimmune urticaria in children with
position paper. Allergy 1997;52:504-13. chronic urticaria. J Allergy Clin Immunol 2004;114:922-7.
18. Black AK, Lawlor F, Greaves MW. Consensus meeting on the defin- 43. Bowen T, Cicardi M, Farkas H, Bork K, Kreuz W, Zingale L et al.
ition of physical urticarias and urticarial vasculitis. Clin Exp Derma- Canadian 2003 International Consensus Algorithm for the Diagnosis,
tol 1996;21:424-6. Therapy, and Management of Hereditary Angioedema. J Allergy Clin
19. Zuberbier T, Aberer W, Grabbe J, Hartmann K, Merk H, Ollert M et Immunol 2004;114:629-37.
al. Diagnostik und Therapie der Urtikaria. JDDG 2003;1:655-64. 44. Bork K, Hardt J, Schicketanz KH, Ressel N. Clinical studies of sud-
20. Mehregan DR, Hail MJ, Gibson LE. Urticarial vasculitis: a histopatho- den upper airway obstruction in patients with hereditary angioedema
logic and clinical review of 72 cases. J Am Acad Dermatol due to C1 esterase inhibitor deficiency. Arch Intern Med 2003;
1992;26:441-8. 163:1229-35.
21. Zuberbier T. Urticaria. Allergy 2003;58:1224-34. 45. Heymann WR. Acquired angioedema. J Am Acad Dermatol
22. Wedi B, Kapp A. Helicobacter pylori infection in skin diseases: a 1997;36:611-5.
critical appraisal. Am J Clin Dermatol 2002;3:273-82. 46. Sabroe RA, Kobza Black A. Angiotensin-converting enzyme (ACE)
23. Wedi B, Raap U, Kapp A. Chronic urticaria and infections. Curr Opin inhibitors and angio-oedema. Br J Dermatol 1997;136:153-8.
Allergy Clin Immunol 2004;4:387-96. 47. Varvarovska J, Sykora J, Stozicky F, Chytra I. Acquired angioedema
24. Wedi B, Liekenbröcker T, Kapp A. Persistent bacterial infection and and Helicobacter pylori infection in a child. Eur J Pediatr 2003;162:
serum activity in chronic urticaria - role of molecular mimikry? Aller- 707-9.
gologie 2001;24:480-90. German. 48. Charlesworth EN. Differential diagnosis of angioedema. Allergy
25. Wedi B, Novacovic V, Koerner M, Kapp A. Chronic urticaria is fre- Asthma Proc 2002;23:337-9.
quently triggered by focal, particularly gastrointestinal infection: 49. Wedi B, Raap U, Wieczorek D, Kapp A. Urticaria - an update. Aller-
analysis of 325 cases. J Investig Dermatol Symp Proc 2001;6:163. gologie 2004;27:435-43. German.
26. Wedi B, Wagner S, Werfel T, Körner M, Manns MP, Kapp A. 50. Henderson RL, Fleischer AB, Feldman SR. Allergists and dermatol-
Rationelles diagnostisches Vorgehen bei der chronischen Urtikaria. Z ogists have far more expertise in caring for patients with urticaria
Hautkr H + G 2000;75:78-84. than other specialists. J Am Acad Dermatol 2000;43:1084-91.
27. Wedi B, Wagner S, Werfel T, Manns MP, Kapp A. Prevalence of Heli- 51. Nettis E, Pannofino A, D’Aprile C, Ferrannini A, Tursi A. Clinical and
cobacter pylori associated gastritis in chronic urticaria. Int Arch Aller- aetiological aspects in urticaria and angio-oedema. Br J Dermatol
gy Immunol 1998;116:288-94. 2003;148:501-6.
28. Federman DG, Kirsner RS, Moriarty JP, Concato J. The effect of 52. Grattan CE, O’Donnell BF, Francis DM, Niimi N, Barlow RJ, Seed
antibiotic therapy for patients infected with Helicobacter pylori who PT et al. Randomized double-blind study of cyclosporin in chronic
have chronic urticaria. J Am Acad Dermatol 2003;49:861-4. ‘idiopathic’ urticaria. Br J Dermatol 2000;143:365-72.
29. Raap U, Liekenbrocker T, Wieczorek D, Kapp A, Wedi B. New ther- 53. Baskan EB, Tunali S, Turker T, Saricaoglu H. Comparison of short-
apeutic strategies for the different subtypes of urticaria. Hautarzt and long-term cyclosporine A therapy in chronic idiopathic urticaria.
2004;55:361-6. German. J Dermatolog Treat 2004;15:164-8.
30. Wedi B, Kapp A. Helicobacter pylori infection and skin diseases. J 54. Toubi E, Blant A, Kessel A, Golan TD. Low-dose cyclosporin A in the
Physiol Pharmacol 1999;50:753-76. treatment of severe chronic idiopathic urticaria. Allergy 1997;52:
31. Kaplan AP. Chronic urticaria: pathogenesis and treatment. J Allergy 312-6.
Clin Immunol 2004;114:465-74. 55. Bagenstose SE, Levin L, Bernstein JA. The addition of zafirlukast to
32. Grattan CE, Sabroe RA, Greaves MW. Chronic urticaria. J Am Acad cetirizine improves the treatment of chronic urticaria in patients with
Dermatol 2002;46:645-57. positive autologous serum skin test results. J Allergy Clin Immunol
33. Kikuchi Y, Kaplan AP. Mechanisms of autoimmune activation of basophils 2004;113:134-40.
in chronic urticaria. J Allergy Clin Immunol 2001;107:1056-62. 56. Di Lorenzo G, Pacor ML, Mansueto P, Pellitteri ME, Lo Bianco C, Dit-
34. Sabroe RA, Francis DM, Barr RM, Black AK, Greaves MW. Anti- ta V et al. Randomized placebo-controlled trial comparing deslo-
Fc(epsilon)RI auto antibodies and basophil histamine releasability ratadine and montelukast in monotherapy and desloratadine plus
in chronic idiopathic urticaria. J Allergy Clin Immunol 1998;102 (4 montelukast in combined therapy for chronic idiopathic urticaria. J
Pt 1):651-8. Allergy Clin Immunol 2004;114:619-25.
35. Wedi B, Novacovic V, Koerner M, Kapp A. Chronic urticaria serum 57. Nettis E, Colanardi MC, Paradiso MT, Ferrannini A. Desloratadine in
combination with montelukast in the treatment of chronic urticaria: a 60. Pacor ML, Di Lorenzo G, Corrocher R. Efficacy of leukotriene recep-
randomized, double-blind, placebo-controlled study. Clin Exp Aller- tor antagonist in chronic urticaria. A double-blind, placebo-controlled
gy 2004;34:1401-7. comparison of treatment with montelukast and cetirizine in patients
58. Erbagci Z. The leukotriene receptor antagonist montelukast in the with chronic urticaria with intolerance to food additive and/or acetyl-
treatment of chronic idiopathic urticaria: a single-blind, placebo-con- salicylic acid. Clin Exp Allergy 2001;31:1607-14.
trolled, crossover clinical study. J Allergy Clin Immunol 2002;110: 61. Baumgart KW, Mullins R. Use of hydroxychloroquine in refractory
484-8. urticaria. J Allergy Clin Immunol 2000;105:795-6.
59. Reimers A, Pichler C, Helbling A, Pichler WJ, Yawalkar N. Zafir- 62. Reeves GEM, Boyle MJ, Bonfield J, Dobson P. Impact of hydroxy-
lukast has no beneficial effects in the treatment of chronic urticaria. chloroquine therapy on chronic urticaria: chronic autoimmune urticaria
Clin Exp Allergy 2002;32:1763-8. study and evaluation. Int Med J 2004;34:182-6.
Granular parakeratosis
C. TOMASINI, Z. SEIA
Granular parakeratosis is an acquired disorder of keratiniza- Division of Dermatology, University of Turin, Turin, Italy
tion of unknown origin affecting mainly flexures of adults. A 48-
year-old woman presented a 1-year history of keratotic papules
on the infra- and submammary regions. A skin biopsy revealed
granular parakeratosis confined to epidermal foci. The patient's
eruption resolved completely with topical steroid therapy. Herein, we report and discuss a case of GP in inter-
Etiopathogenesis and differential diagnosis are discussed.
and submammary regions.
KEY WORDS: Granular parakeratosis - Keratinization disorder -
Skin.
Case report
Figure 1.—Reddish hyperkeratotic papules in the inter-and submamma- Figure 2.—The horny layer is parakeratotic with granular appearance.
ry regions.
Discussion and conclusions Figure 3.—The corneocytes are nucleated and replete with keratohyaline
granules.
GP is an acquired disorder of keratinization that
affects flexures, initially described in 1991 in 4 patients
who had an erythematous eruption in the axillae.1 spirant,1, 4, 12, 13 but this could not explain the fre-
Since then, to the best of our knowledge, 42 addition- quent unilateral involvement, 4 the inconsistent
al cases - including the present case - have been report- response to discontinuation of the suspected irritant,
ed. Thirteen of these cases occurred in sites other than the negative patch tests, and the localization in non-
the axillae, including the groin, infra- e submammary axillary intertriginous folds.1 The absence of spon-
areas, perianal area, trunk and the knee.2-7 Eight cas- giosis on histology also militates against contact
es occurred in infants with ages at presentation rang- dermatitis as an etiologic factor. Conversely, the ten-
ing from 9 to 22 months.8-11 Interestingly, in this small dency to localize to intertriginous or occluded regions
series of cases, 2 clinical patterns could be identified: would implicate that heat, moisture, friction, and
bilateral linear plaques in the inguinal folds and ery- obesity are contributing factors.1, 4, 12, 13 Furthermore,
thematous, geometric plaques underlying pressure the well-demarcated, geometric distribution under-
points from the diaper.8 lying pressure points of disposable diapers would
The etiology of GP was initially thought to be an also suggest that diapers play a role in GP of the
unusual contact reaction to a deodorant or antiper- infancy.8-11
A possible role of fungal/yeast infections in the Approaches to treatment of GP have been largely
development of GP has been suggested by finding of empirical. Although many cases have a self resolu-
positive cultures for Candida albicans from lesions tion,4-12, 17 a variable response has been observed
of GP and histologic observation of hyphal elements with oral and topical corticosteroid, antimicrobials,
within granular parakeratotic corneocytes.12-14 antifungals, and keratolytics. 18-21 Whilst topical
In adults, the putative pathophysiological mecha- retinoids do not appear to be effective, the use of vit-
nism of GP involves a defective pathway of kera- amin D analogues was noted to be effective in some
tinization in which profilaggrin is unable to form cases, supporting the theory of abnormal differenti-
filaggrin, the protein component of keratohyaline ation.1, 6, 17-19
granule. 12 The function of filaggrin has not been
completely elucidated, but in the cornified cells it
is thought to serve as the matrix protein that embeds References
and promotes the aggregation and disulphide bind- 1. Northcutt AD, Nelson DM, Tschen JA. Axillary granular paraker-
ing of keratin filaments producing the keratin pattern atosis. J Am Acad Dermatol 1991;24:541-4.
structure of the lower cornified cells. The conver- 2. Wallace CA, Pichardo RO, Yosipovitch G, Hancox J, Sangueza OP.
Granular parakeratosis: a case report and literature review. J Cutan
sion of profilaggrin into its monomeric subunits must Pathol 2003;30:332-5.
be carefully controlled to prevent premature aggre- 3. English JC, Derdeyn AS, Wilson WM, Patterson JW. Axillary gran-
gation. Patients with GP exhibit a lack of degradation ular parakeratosis. J Cutan Med Surg 2003;7:330-2.
4. Meheregan DA, Thomas JE, Meheregan DR. Intertriginous granular
of keratohyaline granules and aggregation of ker- parakeratosis. J Am Acad Dermatol 1998;29:495-6.
atin filaments.2 5. Meheregan DA, Vandersteen P, Sikorski L, Meheregan DR. Axillary
granular parakeratosis. J Am Acad Dermatol 1995;33:373-5.
The clinical differential diagnosis of GP involving 6. Wohlrab J, Juftul M, Wolter M, Marsch WC. Submammary granular
the flexures includes a wide spectrum of disorders parakeratosis: an acquired punctate hyperkeratosis of exogenic origin.
characterized by erythemato-keratotic papules, such J Am Acad Dermatol 1999;40:813-4.
7. Resnik KS, DiLeonardo M. Follicular granular parakeratosis. Am J
as Hailey-Hailey disease, Darier disease, pemphi- Dermatopathol 2003;25: 428-9.
gus vegetans, plane warts, acanthosis nigricans, pso- 8. Chang MW, Kaufmann JM, Orlow SJ, Cohen DE, Mobini N, Kamino
riasis, tinea infection, seborrheic dermatitis, inter- H. Infantile granular parakeratosis: recognition of two clinical patterns.
J Am Acad Dermatol 2004;50 (5 Suppl):S93-6.
trigo, candidiasis, Langerhans cell histiocytosis, 9. Trowers AB, Assaf R, Jaworsky C. Granular parakeratosis in a child.
nummular eczema and seborrheic keratosis in early Pediatr Dermatol 2002;19:146-7.
10. Patrizi A, Neri I, Misciali C, Fanti PA. Granular parakeratosis: four
stage. The diagnosis is confirmed by examination pediatric cases. Br J Dermatol 2002;147:1003-6.
of a biopsy specimen showing characteristic find- 11. Pimentel DR, Michalany N, Morgado de Abreu MA, Petlik B, Mota
ings of parakeratotic corneocytes containing kera- de Avelar Alchorne M. Granular parakeratosis in children: case report
and review of the literature. Pediatr Dermatol 2003;20:215-20.
tohyaline granules situated usually over a hyper- 12. Metze D, Rutten A. Granular parakeratosis:a unique acquired disor-
plastic epidermis, although occasionally granular der of keratinization. J Cutan Pathol 1999;26:339-52.
parakeratotic changes are confined only to follicular 13. Barnes CJ, Lesher JL, Sangueza OP. Axillary granular parakerato-
sis. Int J Dermatol 2001;40:439-41.
infundibulum.7 14. Resnik KS, Kantor GR, DiLeonardo M. Dermatophyte-related gran-
Interestingly, in newborns GP shows striking clin- ular parakeratosis. Am J Dermatopathol 2004;26:70-1.
15. Gartmann H, Steigleder GK. [Inguinal "pomade" crust of infants] Z
ical and pathological resemblance to a disorder first- Hautkr 1975;50:667-9. German.
ly described in German literature in 1975 by Gart- 16. Patrizi A, Neri I, Marzaduri S, Fiorillo L. Pigmented and hyperkera-
mann et al. as pomaden Kruste 15 and later reported in totic napkin dermatitis: a liquid detergent irritant dermatitis. Derma-
tology 1996;193:36-40.
English literature under the name "pigmented and 17. Sceppa J, Mowad C, Elenitsas R. Crusted plaques in the axillae. Arch
hyperkeratotic napkin dermatitis",16 attributed to Dermatol 2001;137:1241-6.
overtreatment of the groins of babies with ointments 18. Brown SK, Heilman ER. Granular parakeratosis: resolution with top-
ical tretinoin. J Am Acad Dermatol 2002;47(5 Suppl):S279-80
and oils. It is likely that these diseases actually repre- 19. Webster CG, Resnik KS, Webster GF. Axillary granular paraker-
sent examples of GP. atosis: response to isotretinoin. J Am Acad Dermatol 1997;37:
In conclusion, GP represents a pattern of altered 789-90.
20. Chamberlain AJ, Tam MM. Intertriginous parakeratosis respon-
keratinization in which multiple etiologies may be sive to potent topical corticosteroids. Clin Exper Dermatol 2003;
operative, one of them is microbic, and this might also 28:50-2.
21. Contreras ME, Gottfried LC, Bang RH, Palmer CH. Axillary intert-
explain why GA has a propensity for intertriginous riginous granular parakeratosis responsive to topical calcipotriene
sites. and ammonium lactate. Int J Dermatol 2003;42:382-3.
Paracheratosi granulare
corretta diagnosi evidenziando la caratteristica parachera- loghi della vitamina D ha sortito risultati incoraggianti, avva-
tosi granulare a livello dell’ epidermide, sebbene in qualche lonando l’ ipotesi di un’ anomalia della differenziazione che-
caso tale fenomeno sia limitato all’ infundibulo follicolare 7. ratinocitaria alla base di questa dermatosi 1, 6, 17-19.
Nei neonati, la GP presenta notevoli similarità a una par-
ticolare dermatosi descritta per la prima volta da Gartmann
et al. nel 1975 con il nome di “Pomaden Kruste” 15 nella Riassunto
letteratura tedesca e poi riportata da quella anglosassone
come “pigmented and hyperkeratotic napkin dermatitis” 16,
La paracheratosi granulare (GP) è un disordine acquisito
attribuita a un trattamento eccessivo della cute genitale dei
della cheratinizzazione a eziologia sconosciuta che colpi-
neonati con creme e olii. È verosimile che questi quadri, in
sce prevalentemente le pieghe di soggetti adulti. In questo
realtà, rappresentino esempi di GP.
In conclusione, la GP rappresenta un disordine della che- lavoro è riportato il caso di una paziente di 48 anni che pre-
ratinizzazione a eziologia verosimilmente multifattoriale. sentava da circa un anno papule cheratosiche alle pieghe
Ciò potrebbe spiegare la particolare predisposizione per le infra e sottomammarie. Una biopsia cutanea evidenziava il
aree intertriginose. quadro della paracheratosi granulare. L’ eruzione regrediva
Il trattamento della GP non è codificato. Sebbene molti casi rapidamente con terapia steroidea topica. Vengono, inoltre,
mostrino una risoluzione spontanea 4,12, 17, si è notata una discusse le problematiche eziopatogenetiche e di diagnosi dif-
risposta variabile agli steroidi topici e per os, agli antimi- ferenziale.
crobici, agli antifungini e ai cheratolitici 18-21. Sebbene i PAROLE CHIAVE: Paracheratosi granulare - Disordini della
retinoidi topici non appaiano efficaci, l’ uso di retinoidi ana- cheratinizzazione - Cute.
Dear Sir,
Figure 1.—Large oedematous and erythematous lesion on the right knee.
Figure 3.—EE-10×. Acanthosis and focal hyperkeratosis. Presence of der- Figure 5.—EE-40×. Flame figure. Histiocytes surrounding focal deposi-
mal perivascular lymphocytic infiltration. tion of eosinophilic material.
The FF associated with EC are not pathognomonic, as they cemente in placche che tendono alla risoluzione spontanea,
can be seen in other unrelated dermatoses. FF may be seen dopo settimane o mesi, senza residuare cicatrici.
incidentally in bullous pemphigoid, pemphigoid gestation- Segnaliamo il caso di una paziente di 23 anni che si pre-
is, tinea, spider and insect bite reactions and other inflam- sentava alla nostra attenzione per la comparsa, da circa 15
matory conditions in which numerous eosinophils are pre- giorni, di una placca anulare eritemato-edematosa, con ampio
sent.6 Diagnosis is, therefore, the result of the matching of all bordo periferico edematoso e violaceo, localizzata dapprima
anamnestic, clinical and histologic findings. sulla superficie estensoria del ginocchio destro e, in seguito,
anche alla superficie estensoria del ginocchio sinistro (Figu-
re 1, 2). La paziente veniva inizialmente trattata con un anti-
References istaminico per os (cetirizina 10 mg/die per 10 giorni) che
sortiva solo modesti effetti clinici. Al momento della prima
1. Wells GC. Recurrent granulomatous dermatitis with eosinophilia. visita dermatologica la paziente lamentava una sintomatologia
Trans St Johns Hosp Dermatol Soc 1971;57:46-56. locale fortemente pruriginosa. Risultavano assenti febbre e
2. Weiss G, Shemer A, Confino Y, Kaplan B, Trau H. Wells’ syndrome: malessere generale. Le placche, calde al tatto, apparivano
report of a case and review of the literature. Int J Dermatol 2001;40:
148-52. di grandi dimensioni, di colore rosso-rosa, con area centra-
3. Stam-Westerveld EB, Daenen S, Van der Meer Jb, Jonkman MF. le color camoscio e bordo periferico rosso-violaceo ed ede-
Eosinophilic cellulitis (Wells’ syndrome): treatment with minocy- matoso in espansione. Nell’ipotesi di una forma di cellulite
cline. Acta Derm Venereol 1998;78:157. batterica acuta veniva prescritto un farmaco antibiotico
4. Yagi H, Tokura Y, Matsushita K, Hanaoka K, Furukawa F, Takigawa (amoxicillina/acido clavulanico 1 g, 2 compresse/die) per
M. Wells’ syndrome: a pathogenic role for circulating CD4+ CD7- cells 10 giorni. Il quadro sintomatologico e obiettivo, tuttavia,
expressing interleukin-5 mRNA. Br J Dermatol 1997;136:918-23.
5. Espana A, Sanz ML, Sola J, Gil P. Well’s sindrome (eosinophilic cel- non traeva beneficio dalla terapia e la paziente mostrava una
lulitis): correlation between clinical activity, eosinophil levels, lieve progressione delle manifestazioni. Venivano, pertan-
eosinophil cation protein and interleukin-5. Br J Dermatol to, programmati specifici esami di laboratorio e una biopsia
1999;140:127-30. incisionale bilaterale per la diagnosi istologica delle lesioni.
6. Moosavi M, Mehregan DR. Wells’ syndrome: a clinical and histopatho- Le indagini di laboratorio mostravano: emocromo con formula
logic review of seven cases. Int J Dermatol 2003;42:62-7.
leucocitaria nella norma e assenza di eosinofilia periferica.
Address reprint requests to: Dr. M. L. Bernardini, Via V. Veneto 24,
Gli indici di flogosi erano positivi: VES=40 mm 1° ora. Nel-
60122 Ancona. E-mail: mbernardini@email.it la norma risultavano anche le analisi urinarie, il dosaggio
delle immunoglobuline, incluse le IgE, la sierologia immu-
nologica (complemento, anticorpi anti-nucleo); l’esame col-
turale per batteri e funghi era negativo; gli esami delle feci
risultavano negativi per uova e parassiti. All’esame ecogra-
Un caso di cellulite eosinofilica fico risultava assente il coinvolgimento delle articolazioni
del ginocchio sottostanti. La sezione istologica, colorata in
(Sindrome di Wells) non recidivante ematossilina-eosina, mostrava una discreta dissociazione
edematosa delle fibre collagene del derma e un moderato
con quadro istologico atipico infiltrato linfoplasmacellulare perivascolare, associato alla pre-
senza di granulociti eosinofili (E). Questi ultimi apparivano
Egregio Direttore, sia dispersi tra le fibre che in piccoli aggregati. Non vi era
alcuna evidenza di vasculite. Era, inoltre, presente un depo-
sito focale di materiale eosinofilico con detriti nucleari, cir-
L a cellulite eosinofilica (CE) è stata descritta per la prima
volta da Wells nel 1971 come un’entità patologica distin-
ta a eziologia sconosciuta 1. Viene, comunque, segnalata in
condato da alcuni istiociti (Figure 3-5). Tale reperto era inter-
pretabile come una classica «figura a fiamma» (FF), carat-
letteratura una concomitanza della malattia con infezioni teristica, sia pure non patognomonica, delle CE. L’insieme dei
cutanee batteriche o virali, morsi di artropodi, infestazioni reperti unitamente ai dati clinico-anamnestici orientavano
(oncocerchiasi, ascariasi e toxocariasi), sindromi ipereosi- verso una diagnosi di SW. Veniva prescritto, pertanto, corti-
nofile, disordini mieloproliferativi, leucemie, carcinoma sone per via generale (betametasone per os, 2 mg/die a sca-
anale, assunzione di farmaci o interventi chirurgici; più rara- lare) per un totale di 10 giorni di terapia e, in associazione,
mente è stata descritta un’anamnesi positiva per il fenome- un anti-istaminico per os (cetirizina compresse 10 mg/die) per
no di Reynaud, orticaria ed ereditarietà genetica 2. I pazien- 15 giorni. Il quadro clinico tendeva a mostrare netti segni di
ti con sindrome di Wells (SW) in genere presentano una o miglioramento già dopo la prima settimana di terapia e si
poche placche cutanee che ricordano una cellulite acuta, tut- aveva una completa risoluzione entro 2 settimane. La pazien-
tavia l’esame colturale per batteri non risulta mai positivo e te non ha mostrato a tutt’oggi recidive, a un follow-up di cir-
gli antimicrobici somministrati per via sistemica non sem- ca 2 anni. Nella SW i reperti istologici sono generalmente
brano migliorare il quadro clinico o istologico delle lesioni, caratterizzati da un iniziale infiltrato di E nel derma super-
a eccezione di un singolo caso di risposta alla minociclina ficiale e profondo. Le FF si formano durante la fase subacu-
riportato in letteratura 3. Le lesioni iniziali evolvono velo- ta quando gli E, degranulanti, rivestono i fasci di fibre col-
Bibliografia
1. Dumont FJ. FK 506, an immunosuppressant targeting calcineurin
function. Curr Med Chem 2000;7:731-48.
2. Gupta AK, Adamiak A, Chow M. Tacrolimus: a review of its use for
the management of dermatoses. J Eur Acad Dermatol Venereol
Figura 2. — At the two-week control examination: re-epithelialisation of 2002;16:100-14.
the previous bulla and the absence of new lesions. 3. Büdinger L, Borradori L, Yee C, Eming R, Ferencik S, Grosse-Wil-
de H et al. Identification and characterization of autoreactive T cell
responses to bullous pemphigoid antigen 2 in patients and healthy
controls. J Clin Invest 1998;102:2082-9.
4. Ko M-J, Chu C-Y. Topical tacrolimus therapy for localized bullous
remission of the dermatosis, and so maintenance treatment pemphigoid. Br J Dermatol 2003;149:1079-80.
with a single daily administration of 0.1% tacrolimus oint- 5. Chu J, Bradley M, Marinkovich MP. Topical tacrolimus is a useful
adjunctive therapy for bullous pemphigoid. Arch Dermatol
ment was recommended. No relapse occurred after 2 months. 2003;139:813-5.
In the localized bullous pemphigoid the same desmosomal
antigens as those of generalized bullous pemphigoid have Address reprint requests to: Prof. G. Altomare, Via Riccardo Galeazzi
been recognized, and T lymphocytes play a determining role 4, 20161 Milano. E-mail: gianfranco.altomare@unimi.it
in the pathogenesis of the lesions.
It has been demonstrated that T lymphocytes are impor-
tant for the induction and regulation of both cell- and anti-
body-mediated immune responses in various autoimmune
diseases.
It has been found that the serum of patients with bullous Tacrolimus topico nella terapia
pemphigoid contains self-reactive T lymphocytes that pro-
duce both Th2 (IL4 and IL13) and Th1 cytokines (gamma- del pemfigoide bolloso localizzato
IFN), which respectively regulate the secretion of IgG4 and
IgG1 by B lymphocytes. In particular, self-reactive T cells that Egregio Direttore,
recognized the bullous pemphigoid antigen (BP 180) and
give rise to a Th2-mediated response have only been found
in the serum of bullous pemphigoid patients.3
Given the limited extension of the lesions, the majority of
I l tacrolimus è un nuovo immunomodulatore che inibendo
in modo specifico l’attività della calcineurina blocca le
fasi precoci di attivazione delle cellule T e la produzione di
cases of localized bullous pemphigoid do not require sytemic svariate citochine (IL2, IL3, IL4, G-CSF, TNF …)1.
immunosuppressive treatment, and the therapy of choice is A tutt’oggi sono stati effettuati vari studi clinici riguardanti
based on the use of highly potent topical corticosteroids. l’utilizzo del tacrolimus topico nella terapia della dermatite
The authors of 2 case reports published in 2003 (1 of atopica dove si è rivelato efficace nel ridurre i sintomi e la gra-
dyshidrosis-form localized bullous pemphigoid and 1 of vità della malattia sia nell’adulto che in età pediatrica.
generalized bullous pemphigoid) described the good results Sono, comunque, in continuo aumento le segnalazioni,
obtained using this new topical immunomodulator inhibiting seppur spesso limitate a singoli casi, della sua efficacia tera-
T lymphocytes.4, 5 peutica anche in altre dermatosi immunomediate, tra cui,
In our case, we preferred using this new immunomodulator per citarne alcune, il lichen ruber planus, il lichen sclero-
rather than conventional topical corticosteroid therapy in atrofico, il pioderma gangrenoso e l’alopecia areata 2.
order to avoid worsening the already considerably atrophied Riportiamo il caso di una paziente affetta da pemfigoide
cicatricial tissue at the site of the bullous lesions because, bolloso localizzato in cui il trattamento topico con tacrolimus
unlike corticosteroids, tacrolimus does not give rise to local 0,1% unguento ha determinato la rapida risoluzione della
side effects even after long term treatment; in particular, it dermatosi.
La paziente, di 45 anni, in buone condizioni generali, si è importante atrofia del tessuto cicatriziale sede delle lesioni
presentata presso il nostro ambulatorio per la comparsa da cir- bollose.
ca 1 mese al III inferiore della gamba sinistra di alcuni ele- Il tacrolimus, infatti, a differenza dei corticosteroidi non
menti eritemato-vescico-bollosi associati a intenso prurito determina effetti collaterali locali anche nell’utilizzo per
(Figura 1). lunghi periodi, in particolare non presenta quell’effetto atrofo-
Tali lesioni insorgevano nel contesto di un’ampia cicatri- genico proprio dei corticosteroidi topici. L’unico effetto col-
ce esito di 2 pregressi interventi chirurgici per la rottura del laterale consiste nell’insorgenza di bruciore e prurito tran-
tendine d’Achille (il primo nel 1997 e il secondo nel 1999). sitorio nella sede di applicazione, effetto tra l’altro non veri-
Non si evidenziavano lesioni in altre zone cutanee né inte- ficatosi nella nostra paziente nonostante il ricorso alla tera-
ressamento delle mucose. pia in occlusiva.
L’esame istologico e l’immunofluorescenza diretta effet- Sulla base della nostra esperienza, in attesa di studi su
tuati su cute perilesionale confermavano la diagnosi clinica ampie casistiche che permettano di dimostrare l’effettiva
di pemfigoide bolloso localizzato. Gli esami ematochimici efficacia di questo nuovo immunomodulatore, riteniamo il
di routine risultavano nella norma e l’immunofluorescenza tacrolimus una possibile alternativa ai corticosteroidi topici
indiretta era negativa. anche nelle dermatosi bollose autoimmuni.
Considerata la spiccata atrofia del tessuto cicatriziale,
abbiamo ritenuto opportuno evitare l’utilizzo di topici ste-
roidei a elevata potenza e abbiamo deciso di impostare una
terapia locale con tacrolimus 0,1% unguento 2 volte/die con
bendaggio occlusivo e anti-istaminici sistemici per control-
lare la sintomatologia pruriginosa (levocetirizina 5 mg/die).
Al controllo dopo 2 settimane la manifestazione era miglio-
rata con riepitelizzazione della pregressa bolla e assenza di The safety profile of topical pimecrolimus
nuove lesioni (Figura 2), permaneva modesto prurito. A 1
mese dall’inizio della terapia la dermatosi andava in completa
in the treatment of atopic dermatitis
remissione per cui, come mantenimento, veniva consigliata G. GIROLOMONI 1, C. GELMETTI 2, A. VIERUCCI 3
un’unica applicazione quotidiana di tacrolimus 0,1% unguen- 1Department
to. Non si sono evidenziate recidive a distanza di 2 mesi. of Biomedical and Surgical Sciences
Nel pemfigoide bolloso localizzato, vengono riconosciu- Section of Dermatology, University of Verona, Verona, Italy
2Institute of Dermatological Sciences
ti gli stessi antigeni desmosomiali del pemfigoide bolloso
generalizzato e nella patogenesi delle lesioni rivestono un ruo- IRCCS Ospedale Maggiore, University of Milan, Milan, Italy
3Department of Pediatrics, University of Florence
lo determinante i linfociti T.
A. Meyer Pediatric Hospital, Florence, Italy
È stato dimostrato che i linfociti T sono importanti sia
nell’induzione sia nella regolazione di entrambe le risposte
immuni, cellulo-mediate e anticorpo-mediate, in diverse
patologie autoimmuni.
Nel siero di pazienti affetti da pemfigoide bolloso sono sta- Dear Editor
ti riscontrati linfociti T autoreattivi producenti sia citochine
Th2 (IL4 e IL13) che Th1 (IFN gamma) le quali regolano
rispettivamente la secrezione di IgG4 e IgG1 da parte dei T he United States Food & Drug Administration (FDA)
has recently issued a Public Health Advisory about the
safety profile of topical calcineurin inhibitors (better
linfociti B. In particolare, solo nel siero di questi pazienti
sono state ritrovate cellule T autoreattive che riconoscono known as topical immunomodulators or TIMs: pime-
l’antigene del pemfigoide bolloso (BP180) dando origine a crolimus and tacrolimus). The FDA also announced of its
una risposta autoimmune Th2 mediata 3. intention to add a “black-box” warning (a special warning
Il pemfigoide bolloso localizzato, nella maggior parte dei on the drug package) to the labeling for the 2 drugs, and
casi, data la limitata estensione delle lesioni, non necessita that current indications for which these drugs have been
del ricorso a un trattamento immunosoppressivo sistemico, granted approval might be subject to change. This action
infatti la terapia d’elezione si basa sull’utilizzo di cortico- was based on a recommendation from the FDA Pediatric
steroidi topici a elevata potenza. Advisory Committee because of concerns of potential
Nel 2003 sono stati riportati 2 casi, un pemfigoide bollo- safety risks (especially skin cancer and lymphoma) in
so localizzato disidrosiforme e un pemfigoide bolloso gene- pediatric patients affected with atopic dermatitis (AD)
ralizzato, in cui gli Autori si sono avvalsi, con buoni risultati, and receiving therapy with a TIM. We feel deeply troubled
di questo nuovo immunomodulatore topico che inibisce i by the FDA’s actions, because there is no evidence that top-
linfociti T 4, 5. ical use of pimecroliums and tacrolimus is harmful. The
Nel nostro caso abbiamo preferito ricorrere a tacrolimus American Academy of Dermatology, the American Acad-
unguento piuttosto che alla terapia convenzionale con cor- emy of Allergy, Asthma and Immunology, the Society for
ticosteroidi topici per evitare il peggioramento della già Pediatric Dermatology, The British Association of Der-
matologists, the European Society for Pediatric Derma- is a process consisting of a review of the full body of the
tology, the German Society of Dermatology, the Austrian clinical data that will allow a full evidence-based evaluation
Society of Dermatology, the European Dermatology of the risk /benefit profile of these drugs.8 The EMEA feels
Forum, the European Academy of Dermatology and that such a comprehensive review of the clinical data is the
Venereology, and other scientific societies as well as most effective way to achieve an objective assessment and
patient associations (National Society for Atopic Eczema) provide guidance for patients and physicians regarding the
have unanimously expressed similar concern for the FDA’s use of TIMs. In the meantime, drug labels remain unchanged.
actions. AD is a chronic, recurring and frustrating condition.
Over the last decade, both agents have been extensive- Many patients suffer from AD on the face and sensitive skin
ly studied in clinical trials and their efficacy and safety in sites where long-term application of topical corticosteroids
the treatment of AD have been demonstrated.1-5 In partic- is not indicated. Patients need alternatives to topical steroids
ular, pimecrolimus has been investigated in more than due to side effects. The health and safety of our patients are
19 000 patients (of which 2 600 were infants and 7 300 of paramount importance to physicians. We are concerned
were children). In addition, more than 5 million patients, that the aforementioned warnings confuse and unneces-
over half of them children, have been treated with pime- sarily worry our patients and their families as well as health
crolimus since its approval, and post marketing surveil- care providers. It is the responsibility of health authorities
lance studies (PMS) show that there is no clinical evi- to present a balanced and fair review of the evidence. Cur-
dence suggesting an increased risk of malignancies in rent labeling sufficiently describes the appropriate use and
patients treated with pimecrolimus. In particular: a) the safety of these medications. We strongly believe that the
incidence of malignancies in patients treated with pime- recent recommendations of the Pediatric Advisory Com-
crolimus in the course of clinical studies was lower than that mittee and the FDA Health Alert are not justified on the
in patients in the control group treated with placebo or basis of scientific evidence and should be revised. In order
topical corticosteroids (2 cases out of 19 000 versus 5 cas- to provide further evidence confirming the safety of pime-
es out of 4 000); b) PMS data from clinical use in over 5 crolimus, long-term clinical studies have been started,
million patients treated with pimecrolimus, as of March with a registry including 4 000 pediatric patients who will
2005, show very few cases of malignancies. The number be followed for a period of 10 years.
is well below the expected background incidence in the
population treated and, in addition, is lower than the rate
expected in the general population. Moreover, no causal References
relationship with pimecrolimus was established for any
of the cases reported; c) those lymphomas identified by 1. Ashcroft DM, Dimmock P, Garside R, Stein K, Williams HC. Efficacy
spontaneous adverse event reporting systems do not have and tolerability of topical pimecrolimus and tacrolimus in the treatment
the clinical presentation and histology that characterize of atopic dermatitis: meta-analysis of randomised controlled trials. Br
lymphomas occurring in the setting of immunosuppres- Med J 2005;330:516-24.
sive therapy. 2. Meurer M, Fartasch M, Albrecht G, Vogt T, Worm M, Ruzicka T et al.
Systemic absorption of both drugs is very limited,6 and Long-term efficacy and safety of pimecrolimus cream 1% in adults with
moderate atopic dermatitis. Dermatology 2004;208:365-72.
even though in some patients blood concentrations have 3. Kempers S, Boguniewicz M, Carter E, Jarratt M, Parisier D, Stewart
been detected, the values are usually very low and insufficient D et al. A randomized investigator-blinded study comparing pime-
to cause the sustained systemic immunosuppression that crolimus cream 1% with tacrolimus ointment 0.03% in the treatment
would be responsible for lymphomas. This is true even in of pediatric patients with moderate atopic dermatitis. J Am Acad Der-
young children with moderate-to-severe dermatitis affect- matol 2004;51:515-25.
ing a large body surface area. 4. Papp KA, Werfel T, Folster-Holst R, Ortonne JP, Potter PC, de Prost
Y et al. Long-term control of atopic dermatitis with pimecrolimus
There is no evidence of photocarcinogenic or mutagenic cream 1% in infants and young children: a two-year study. J Am Acad
potential in animals treated with pimecrolimus. Lymphomas Dermatol 2005;52:240-6.
that have the characteristics of diseases related to systemic 5. Luger TA, Lahfa M, Folster-Holst R, Gulliver WP, Allen R, Molloy S
immunosuppression have only been observed in animals et al. Long-term safety and tolerability of pimecrolimus cream 1% and
exposed to high systemic levels of calcineurin inhibitors. topical corticosteroids in adults with moderate to severe atopic der-
These animals experienced prolonged systemic exposure matitis. J Dermatol Treat 2004;15:169-78.
6. Billich A, Aschauer H, Aszòdi A, Stuetz A. Percutaneous absorption
that is much greater than that achieved with topical applica- of drugs used in atopic eczema: pimecrolimus permeates less through
tion in humans. skin than corticosteroids and tacrolimus. Int J Pharmacol 2004;269:
There is no increased incidence of systemic or cutaneous 29-35.
infections in patients treated with topical pimecrolimus. 7. Papp KA, Breuer K, Meurer M, Ortonne JP, Potter PC, de Prost Y
There is no evidence of systemic immunosuppression due et al. Long-term treatment of atopic dermatitis with pimecrolimus
to topical pimecrolimus as showed by antibody response to cream 1% in infants does not interfere with the development of
protective antibodies after vaccination. J Am Acad Dermatol
vaccination and by tests on delayed-type hypersensitivity.7 2005;52:247-53.
The European Medicines Agency (EMEA) did not take any 8. European Medicines Agency: Committee for Medical Products for
immediate action but decided to start a referral process. This Human Use. Press release. April 18-21, 2005.
Il profilo di sicurezza del è stata stabilita una relazione causale con pimecrolimus; c)
i rari casi di linfoma osservati presentano un pattern istolo-
pimecrolimus topico gico differente da quello che tipicamente caratterizza i linfo-
mi insorgenti nei pazienti sottoposti a terapie immunosop-
nella terapia della dermatite atopica pressive.
L’assorbimento sistemico di entrambi i farmaci è assai
limitato 6, e anche in quei rari casi in cui le concentrazioni
ematiche dei farmaci siano rilevabili, sono molto basse e
Egregio Direttore, assolutamente insufficienti a causare un’immunosoppres-
sione protratta. Questo si verifica anche nei bambini con
L a Food & Drug Administration (FDA) americana ha
recentemente richiamato l’attenzione sul profilo di sicu-
rezza degli inibitori della calcineurina a uso topico, meglio
dermatite moderata/severa estesa a vaste aree corporee.
Non esiste alcuna evidenza di un potenziale fotocarcino-
genico o mutagenico del pimecrolimus negli animali. I linfo-
noti come immunomodulatori topici (o topical immunomo- mi che tipicamente si associano alla immunosoppressione
dulators, TIM): pimecrolimus e tacrolimus. In questo avvi- sono stati descritti solo in animali esposti per tempi prolun-
so, inoltre, la FDA informa la classe medica e il pubblico del- gati a elevati livelli sistemici di inibitori della calcineurina,
la propria intenzione di apporre una speciale avvertenza livelli decine di volte più alti di quelli che sono mai stati
(«black-box» warning) sulla confezione dei farmaci riguar- misurati nell’uomo dopo applicazione topica.
do il potenziale rischio di sviluppo di neoplasie (special- Non esiste alcuna evidenza che i pazienti trattati con pime-
mente linfomi e tumori cutanei) nei pazienti pediatrici affet- crolimus abbiano un’incidenza più alta di infezioni sistemi-
ti da dermatite atopica (DA) sottoposti a terapia con TIM, e che o cutanee, e non c’è alcuna evidenza che terapie anche
l’eventualità di apportare una modifica alle attuali indica- prolungate con pimecrolimus causino immunosoppressione
zioni per cui tali farmaci sono registrati. Questa eventuale sistemica, come dimostrato dalle risposte anticorpali alle
azione dell’FDA ci preoccupa, in quanto non esiste alcuna vaccinazioni anti-infettive o dalle riposte ai test che misurano
evidenza che l’uso topico di questi farmaci sia pericoloso. l’ipersensibilità ritardata 7.
Preoccupazione riguardo a quest’azione dell’FDA è stata L’agenzia europea per i farmaci (European Medicines
manifestata dalla American Academy of Dermatology, Ame- Agency, EMEA) non ha preso alcun provvedimento imme-
rican Academy of Allergy, Asthma and Immunology, Society diato, ma ha deciso di aprire una procedura di «referral» che
for Pediatric Dermatology, British Association of Derma- consiste in una revisione dettagliata dei dati clinici che con-
tologists, European Society for Pediatric Dermatology, Ger- sentirà una valutazione accurata, basata su prove scientifiche
man Society of Dermatology, Austrian Society of Dermato- convincenti, del rapporto rischio/beneficio di questi farma-
logy, European Dermatology Forum, European Academy ci 8. L’EMEA ritiene che tale procedura rappresenti il mez-
of Dermatology and Venereology, e altre società scientifiche, zo migliore e più efficace per consentire una valutazione
nonché da associazioni di pazienti (National Society for Ato- obiettiva in grado di fornire a medici e pazienti le regole per
pic Eczema). un corretto utilizzo di questi farmaci. Nel frattempo le indi-
Durante gli ultimi 10 anni, entrambi i farmaci sono stati cazioni resteranno invariate.
studiati in maniera approfondita in numerosi trials clinici, e La DA è una patologia cronica, ricorrente e a suo modo fru-
la loro efficacia e sicurezza nella terapia della DA è stata strante. In molti pazienti la malattia colpisce il volto, il col-
ampiamente dimostrata 1-5. In particolare, gli studi clinici lo e altre sedi «sensibili» dove l’applicazione prolungata di
con pimecrolimus hanno coinvolto più di 19 000 pazienti corticosteroidi non è appropriata. Questi pazienti necessi-
(di cui 7 600 bambini e 2 600 con meno di 2 anni di età). Inol- tano, quindi, di alternative agli steroidi topici. Noi siamo
tre, più di 5 milioni di pazienti, più della metà dei quali bam- preoccupati che l’allarme menzionato sia causa di confu-
bini, sono stati trattati con pimecrolimus dopo la sua appro- sione e di preoccupazione impropria nei pazienti, nelle loro
vazione, e studi di farmacovigilanza postmarketing hanno famiglie e nel personale sanitario. Dal momento che è respon-
dimostrato che non esiste alcuna evidenza clinica che sug- sabilità delle autorità sanitarie presentare le evidenze in
gerisca un rischio aumentato di tumori nei pazienti trattati con maniera giusta e corretta, riteniamo che le informazioni
pimecrolimus. In particolare si è evidenziato che: a) l’inci- attualmente presenti nei farmaci descrivono in maniera appro-
denza di neoplasie nei pazienti trattati con pimecrolimus nel priata le loro modalità d’impiego e il profilo di sicurezza. Per-
corso degli studi clinici è inferiore a quella dei pazienti del tanto, reputiamo che le recenti raccomandazioni dell’FDA
gruppo di controllo trattati con placebo o corticosteroidi ( 2 non siano giustificate dall’evidenza scientifica e dovrebbe-
casi su 19 000 contro 5 casi su 4 000); b) i dati di sorve- ro essere riconsiderate. Al fine di fornire ulteriore conferma
glianza postmarketing, aggiornati a Marzo 2005, riportano della sicurezza di pimecrolimus, sono stati iniziati studi a
un numero esiguo di neoplasie, inferiore a quello atteso nel- lungo termine e un registro che include 4 000 pazienti pedia-
la popolazione generale. Inoltre, in nessuno dei casi riportati trici che saranno seguiti per un periodo di 10 anni.