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The dysplastic nevus: from historical perspective to management in the modern era
The dysplastic nevus: From historical perspective to
management in the modern era
Part II. Molecular aspects and clinical management
Keith Duffy, MD,a and Douglas Grossman, MD, PhDa,b
Salt Lake City, Utah
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potential molecular differences between dysplastic nevi, common nevi, and
melanoma and incorporate this knowledge into their practice of biopsying and
monitoring patients with nevi.
19.e2 Duffy and Grossman
J AM ACAD DERMATOL
The dysplastic nevus is a discreet histologic entity that exhibits some clinical and histologic featuresoverlapping with common nevi and melanoma. These overlapping features present a therapeuticchallenge, and with a lack of accepted guidelines, the management of dysplastic nevi remains acontroversial subject. Although some differences between dysplastic and common nevi can be detectedat the molecular level, there are currently no established markers to predict biologic behavior. In part II ofthis continuing medical education article, we will review the molecular aspects of dysplastic nevi and theirtherapeutic implications. Our goal is to provide the clinician with an up-to-date understanding of this entityto facilitate clinical management of patients with nevi that have histologic dysplasia. ( J Am Acad Dermatol2012;67:19.e1-12.)
Key words: common nevus; dysplasia; dysplastic nevus; melanoma; nevus.
LACK OF PREDICTIVE
not been widely adopted—
but guidelines for the clinical
Some dysplastic nevi exhibit molecular
management of DN lesions
characteristics distinct from ‘ common'
were never issued. The ‘‘con-
sensus conference'' yielded
These include distinct gene expression
no consensuA decade
with common nevi and
patterns, a higher proliferation index,
later, there remained a lack of
mutation or altered expression of p16
consensus among dermatol-
d There is a lack of con-
and p53, and increased microsatellite
ogists in the management of
sensus or guidelines for
patients with DN and the
Dysplastic nevi are similar to common
need for reexcision of DN
nevi with respect to clonality, markers of
after biopsy.With the pass-
The dysplastic nevus (DN)
senescence, rate of BRAF mutation, and
ing of yet another decade, it
is a distinct histologic entity
rate of recurrence after biopsy.
now seems timely to reassess
(see part I of this continuing
the collective clinical experi-
medical education article).
There are currently no markers that have
ence and incorporate new
been shown to predict biologic behavior
molecular insights concern-
some histologic features of
of dysplastic nevi.
ing DN. It is our hope that an
nondysplastic or ‘‘common''
Dysplastic nevi may be considered
informative review of all the
variants of melanocytic nevi that can be
evidence may lead the way
presence of neoplastic nests
managed like common nevi.
to a consensus regarding the
of melanocytes, and features
management of DN.
of melanoma such as cyto-logic atypia and dermal inflammatory response.The
The promise of molecular analyses
benign lesions (DN and CN) cannot be distinguished
from each other based on clinical examination
d There are currently no validated markers in
and DN often have some clinical features
nevi to predict biologic behavior
associated with melanoma, such as an irregular
d Molecular studies may identify differences
border and the asymmetric distribution of pigmen-
between dysplastic nevi, common nevi, and
Given these considerations, this review will
focus on studies based on lesions that have been
d Moleculareclinical correlations may identify
A conference among melanoma thought leaders,
convened at the National Institutes of Health in 1992,
As indicated above, there are limits to histologic
sought to define the histologic basis of ‘‘early''
analysis in distinguishing DN from CN and mela-
melanoma and DN.Changes in terminology were
noma. More importantly, histologic features are not
From the Department of Dermatologya and the Huntsman Cancer
Reprint requests: Doug Grossman, MD, PhD, Huntsman Cancer
Institute,b University of Utah Health Sciences Center.
Institute, Ste 5262, 2000 Circle of Hope, Salt Lake City, UT
Dr Grossman is supported by the Department of Dermatology and
84112. E-mail: .
the Huntsman Cancer Foundation.
Conflicts of interest: None declared.
J AM ACAD DERMATOL
Duffy and Grossman 19.e3
VOLUME 67, NUMBER 1
these included DN. Robinson et alreported evi-
dence for clonality in 81% of nevi, 25% of which were
DN. They found no correlation between the pres-
ence or absence of dysplasia and clonality. The
dysplastic nevus syndrome
demonstration of clonality, however, may not be
loss of heterozygosity
informative as to whether DN arise de novo or from a
mitogen-activated protein kinase
preexisting CN, because in both circumstances all of
phosphatase and tensin homolog
the cells would be expected to have arisen from asingle progenitor cell. Given the heterogeneity ofdysplasia observed within DN,it seems possiblethat some DN may arise within CN.
always a reliable predictor of the biologic behaviorof these lesions. The key questions in the clinician'smind relate to whether a given lesion is malignant or
benign, and its likelihood of recurrence, transforma-
tion to melanoma, and/or clinical progression and
many differences are apparent
metastasis. While various histologic features in mel-
from molecular profiling, their clinical sig-
anoma (ie, depth and ulceration) have been vali-
nificance is unknown
dated as predictors of recurrence and metastasis,
Scatolini et alisolated RNA from 18 CN, 11 DN,
no such histologic markers predictive of biologic
and 23 melanomas representing the radial and ver-
behavior have yet been validated for DN.
tical growth phases and examined global gene
It is possible that molecular analyses of these
melanocytic lesions will identify differences between
Expression patterns among DN were very similar
DN, CN, and melanoma that may prove useful in
with respect to genes involved in ectodermal devel-
predicting their biologic behavior. The first step is to
opment, while a greater heterogeneity of expression
characterize panels of lesions with defined histologic
was seen among genes involved in mitosis, apopto-
patterns at a molecular level to identify candidate
sis, and the regulation of transcription. Many simi-
markers. Second, candidate markers must be ana-
larities were seen between DN and CN, in particular
lyzed in panels of lesions with a known clinical
the expression of genes involved in mitosis, apopto-
outcome in order to develop hypotheses regarding
sis, and transcriptional regulation. Some prolifera-
the predictive value of particular markers. Finally, a
tion genes, however, were expressed at higher levels
blinded trial is necessary to validate such molecular-e
in DN than in CN. Expression patterns of a group of
clinical associations. The detection of specific
genes involved in cellular detoxification, RNA pro-
chromosomal gains/losses by fluorescence-based
cessing, and antigen presentation allowed separa-
in situ hybridization to differentiate and
tion of DN into two subclasses: one more similar to
mitotically active nevifrom melanoma is a para-
radial growth melanoma and with expression levels
digm for this approach.
higher than CN, and the other similar to vertical
MOLECULAR ASPECTS OF DYSPLATIC
growth melanoma and with expression levels lower
A number of studies have investigated DN at a
molecular level, and similarities and differences
Mutations in BRAF and Ras
between DN, CN, and melanoma are summarized
d Dysplastic nevi harbor mutations in BRAF
comparable to common nevi, but Ras muta-
Clonal origin of dysplastic nevi
The activation of the Ras/mitogen-activated pro-
d Studies of clonality in dysplastic nevi are
tein kinase (MAPK) pathway is predominant in
limited, but suggest that dysplastic nevi, like
melanoma, and approximately 60% of tumors ex-
most common nevi, are clonal
press a ‘‘driver mutation'' in the BRAF kinase (most
Although several studies have shown that most
commonly V600E) that may potentiate Ras signal-
nevi are clonal neoplasms (ie, arising from a single
ingand appears to be a useful therapeutic target in
melanocyte) based on pattern of X chromosome
metastatic melanoma.The BRAF mutation is also
inactivation in tissues from female patients, most
predominant in nevi,and several studies have
were limited to the study of CN, and only one of
examined its prevalence in DN. Wu et alexamined
19.e4 Duffy and Grossman
J AM ACAD DERMATOL
Table I. Differences and similarities between
regulator of the cell cycle, and its functional
dysplastic and common nevi
loss is common in tumors.A role for p16 inproliferative arrest of nevi is supported by the
Differences (DN versus CN)
common finding of large atypical nevi in patients
Distinct histologic features
with germline p16 mutations.No differences in
Marker of greater
Expression of apoptosis
clinical or histologic presentation of nevi, however,
were noted in comparing individuals with different
Higher proliferation index
p16 mutations.Several studies have investigated
Distinct gene expression
BRAF mutation rate
the presence of somatic p16 mutations in nevi,
Loss of PTEN expression
including DN. Wang et found no p16 mutations
in 20 nevi examined (six of which were DN).
Altered expression of p53*
Risk of transformation to
Similarly, Papp et alfound no p16 mutations
among 19 DN. By contrast, Lee et found four
Rate of recurrence after
p16 mutations (three missense and one intronic) in
3 of 12 DN. Interestingly, three of these mutationswere cytosine: thymine transitions at dipyrimidine
CN, Common nevus; DN, dysplastic nevus; PTEN, phosphatase andtensin homolog.
sequences, which is characteristic of mutations
*Reported in some but not all studies.
directly induced by ultraviolet lighTherefore,p16 mutations appear to be rare in nevi, but aninsufficient number of nevi have been examined to
a panel of 135 nevi and detected mutant BRAF in 81%
ascertain whether the incidence is increased in DN
of lesions representing a variety of nevus types:
compared to CN. On the other hand, p16 expres-
acquired, congenital, genital, CN, and DN. Similarly,
sion in some DN may be compromised by gene
Uribe et alreported comparable rates of BRAF
deletion (discussed below).
mutation in DN (13/21; 62%) and CN (16/24; 67%).
Mutations in p53, which is upregulated by DNA
Although these authors found that DN tended to
damage signaling and promotes apoptosis, are
exhibit stronger BRAF staining than CN (particularly
found in more than 50% of cancers and to a lesser
in the junctional component) and somewhat higher
extent in melanoma.Several studies have investi-
rates of phosphorylated Erk (downstream marker of
gated the presence of p53 mutations in DN. Lee
MAPK pathway activation; 10/21 DN versus 7/24
et found two p53 missense mutations in 12 DN
CN), there was not a general correlation between
examined. In another study, Levin et aldetected
BRAF mutation and MAPK activationThese stud-
p53 mutations in two of five DN and 2 of 11 CN. On
ies indicate that the presence of BRAF mutation does
the other hand, Papp et alfailed to identify p53
not appear to be a molecular factor distinguishing
mutations in 19 DN studied. Several groups have also
examined p53 expression in DN by immunohisto-
In contrast to congenital nevi, which commonly
chemistry, as a method to detect p53 mutations that
harbor Ras mutations,two studies performed by
increase protein stability. The p53 protein has gen-
Papp et alindicate that Ras mutations are rarely
erally not been observed in CN or although
present in DN. They found activating N-ras muta-
McGregor et found p53 to be present in a
tions in only 1 of 19and 1 of DN examined.
minority of DN but not in CN. Similarly, two subse-quent studies found that p53 protein expression wasincreased in DN compared to CN.These
Mutations and expression of tumor suppressor
immunohistochemical-based studies, however, are
problematic because of a variance in sensitivity of
detection and the lack of direct confirmation of p53
d Compared to common nevi, some dysplastic
nevi exhibit alterations in p16 or p53
The phosphatase and tensin homolog (PTEN)
phosphatase functions as a tumor suppressor
d Phosphatase and tensin homolog expression
through the inhibition of phosphatidylinositol kinase
is lost in a fraction of dysplastic and com-
signaling, resulting in diminished activation of the
survival kinase Akt, and is frequently lost in
As noted above, the p16 tumor suppressor is a
Several studies have evaluated the expression of
major melanoma predisposition gene that is com-
PTEN in panels of melanomas and nevi. Expression
monly mutated in families with inherited mela-
of PTEN appears to be retained in most (approxi-
noma. The p16 protein is a critical negative
mately 60-70%) nevi and absent in most melanomas;
J AM ACAD DERMATOL
Duffy and Grossman 19.e5
VOLUME 67, NUMBER 1
significant differences between DN and CN were not
50% (3/6) of CN. In this same study, a homozygous
deletion of 9p21 was found in 29% (4/14) of DN butin none of the CN. Similarly, Birindelli et iden-tified LOH at 9p21 in 15% (4/27) of melanomas and
Microsatellite instability and allelic loss of
9% (3/35) of DN examined, but in none of 26 CN.
Park et alhave also shown LOH for the p53-
containing locus in 43% (3/7) of DN; interestingly,
instability may be seen in
these three lesions also revealed LOH for 9p21.
some melanomas and dysplastic nevi, but
These early studies assessed the presence of the
p16-containing locus using various microsatellite
d Some dysplastic nevi may harbor deletions
markers as noted above, which may account for
in the p16-encoding chromosomal region
some of the variability and may overestimate loss of
the p16 gene. More recent studies have used fluo-
It is important to note that the lack of detection of
rescence in situ hybridization using sequence-
mutations in a gene is not synonymous with the
specific probes to directly detect loss of particular
presence of the gene and/or expression of wild-type
genes. Using this approach, Sini et found hem-
protein. This is because deletions may occur in one
izygous deletions within the 9p21 region in 10% (2/
allele (hemizygous deletion, referred to as loss of
20) of CN, 55% (12/22) of DN, and 59% (19/32) of
heterozygosity [LOH]) that will not be detected by
melanomas; specific probes for the p16 gene, how-
ever, identified deletions in none of the CN (0/20),
methods. In the context of LOH, mutation or loss
9% (2/22) of DN, and 19% (6/32) of melanomas.
of the remaining allele results in loss of function or
In summary, it appears that a subset of DN harbor
complete absence of the protein, which in the case of
genetic aberrations generally not seen in CN, which
a tumor suppressor may promote transformation.
include LOH of regions that may contain the gene
Historically, LOH of particular alleles was deter-
encoding p16. Whether hemizygous loss of p16 is
mined by assessing the presence or absence of
compensated by the remaining allele or results in
markers (microsatellites) associated with particular
decreased p16 protein levels in nevus cells remains an
genetic loci. Variation in microsatellites, referred to
open question. One study found lower levels of p16
as microsatellite instability, often occurs in chromo-
with nuclear localization by immunohistochemistry
somal regions containing tumor suppressor genes,
in DN compared to although an earlier study
and is a common feature of tumors (including
found comparable levels of p16 in DN and
melanoma). Hussein et alfound microsatelliteinstability at chromosomal regions 1p and 9p in DN
and melanomas, but not in CN; the overall preva-
lence of microsatellite instability was 31% (7/22) in
d Dysplastic nevi may exhibit higher prolifer-
melanomas, 28% (17/60) in DN, and 0% (0/30) in CN.
ative rates than common nevi but lower than
This result is consistent with a previous report by
Boni et alrevealing allelic losses at 1p in three ofnine DN and at 9q in one of nine DN. Bale et al
The observation of dark dots by dermoscopy at
mapped a ‘‘DN locus'' to a region on chromosome 1,
the periphery of some DN, as noted above, suggests
and this was confirmed in subsequent linkage stud-
that these nevi may be in the process of active
A more recent genome-wide association
proliferation.Several studies have investigated
study identified variants at 9p21 and 22q13 associ-
whether DN have higher rates of proliferation com-
ated with nevus developmentalthough it is not
pared to CN. Lebe et examined a panel of
clear if either set of variants favors development of
melanomas and nevi by immunohistochemistry us-
ing antibodies against cyclin D1 and Ki-67 to identify
Multiple additional studies have documented
proliferating cells. While melanomas had much
LOH in melanomas involving the region 9p21 that
higher rates of proliferation than nevi, an analysis
contains the p16 gene locus,and some studies
of 42 DN and 21 CN revealed comparable rates of
have shown increased LOH in DN compared to CN.
cyclin D1 expression but significantly higher rates of
Park et reported LOH in seven of nine DN at one
Ki-67 positivity in DN compared to CN. In a related
or more loci within 9p21, while LOH was not
study examining expression of cyclins D1 and D3,
detected in any of the 13 CN studied. Tran et al
Alekseenko et alfound significant differences be-
detected LOH in this region in approximately 40%
tween DN and CN. They reported mean rates of 8%
(17/44) of melanoma tumors, 64% (9/14) of DN, and
for melanoma (n = 14), 5% for DN (n = 24), and 0.3%
19.e6 Duffy and Grossman
J AM ACAD DERMATOL
for CN (n = 10) for cyclin D1, and rates of 18% for
development and potential progression of DN has
melanoma, 6% for DN, and 2% for CN for cyclin D3.
not been investigated.
These findings are consistent with the higher ex-pression of proliferative genes in DN compared to
Markers of senescence
CN, as reported by Scatolini et On the other
hand, Nasr et did not observe positive staining
d It is unknown if dysplastic nevi have in-
for Ki-67 or phosphorylated histone H3 in any
lesions among a panel of 20 DN and 20 CN. These
studies are limited by sensitivity of the staining and
d Most markers of senescence have not been
the markers examined, but taken together, it appears
examined in dysplastic nevi
that DN may be associated with higher rates ofproliferation than CN, although all nevi are generally
A current model to explain nevus development
less proliferative than melanomas.
and transformation to melanoma invokes the con-cept of senescence or terminal growth arrest.It isthought that nevi initially result from melanocyte
proliferation followed by a senescent state; failure of
some cells within a nevus to achieve (or escape of
d Lack of evidence that dysplastic nevi cells are
some cells from) senescence may lead to melanoma.
more resistant to apoptosis than those in
In this model, the initial hyperproliferation and
subsequent induction of senescence is mediated by
One explanation for the long-term persistence of
activation of an oncogene (such as mutant BRAF),
nevi is that nevomelanocytes are more resistant to
and the senescent state is maintained by expression
apoptosis than nonenevus-associated melanocytes,
of p16, which is sufficient to mediate senescence in
and this has been shown in vitro.There is no
some tumor cells in Consistent with this
evidence, however, that cells comprising DN are
model, expression of mutant (V600E) BRAF in hu-
more resistant to apoptosis than cells of CN based on
man melanocytes triggers cell growth followed by
the expression of apoptotic regulatory molecules.
growth arrest, and some nevi express markers of
Expression of the prototypic apoptosis inhibitor Bcl-
senescence, such as p16 and acidic beta-galactosid-
2 did not appear significantly different between DN
It has been debated, however, whether
and CN in two studiesalthough Tron et al
reported Bcl-2 expression in CN (5/7) but not DN (0/
marker of senescence and whether nevi are truly
6). The inhibitor of apoptosis protein Survivin is
senescent, given that nevus-derived cells can prolif-
broadly expressed in nevi, with no significant differ-
erate in vitro.There are obviously additional
ences noted between DN and Similarly, the
limitations to the senescence model, given that some
expression of various death receptors that trigger
nevi do not express mutant BRAF, and the majority of
extrinsic apoptotic pathways was comparable in DN
melanomas do not arise directly from nevi (see
and Finally, Zhang et alreported that the
below). Nevertheless, it would be interesting to
tumor suppressor RUNX3, a regulator of apoptosis
investigate the expression of senescence markers in
and proliferation, is expressed in equal proportions
DN compared to CN. Bennettinitially proposed
of DN (34/63; 54%) and CN (14/25; 56%).
that DN might represent escape from p16-dependentsenescence, and her group subsequently found thatp16 expression was reduced in Dbut studies
Increased reactive oxygen species in dysplastic
examining other senescence-associated markers in
nevi did not include DN.
Mutant active BRAF induces senescence by up-
d Dysplastic nevi may display higher levels of
regulating the tumor suppressor insulin-like growth
oxidative stress than common nevi
factorebinding protein 7 (IGFBP7), which acts
Pavel et alanalyzed melanocytes from DN and
through autocrine/paracrine pathways to inhibit
found elevated levels of reactive oxygen species
MAPK signaling, and IGFBP7 is frequently lost in
compared to CN. Similarly, Smit et isolated
melanomSeveral studies have examined the
melanocytes from DN lesions and adjacent skin,
link between mutant BRAF and IGFBP7 in DN.
and found that DN-associated melanocytes exhibited
Decarlo et analyzed a panel of DN and detected
higher levels of reactive oxygen species and oxida-
IGFBP7 expression in 48% (12/25) of DN expressing
tive DNA damage than normal melanocytes from the
wild-type BRAF and in 56% (5/9) of DN expressing
same patients. The role of oxidative stress in the
mutant BRAF. In another study of genital nevi,
J AM ACAD DERMATOL
Duffy and Grossman 19.e7
VOLUME 67, NUMBER 1
Nguyen et found IGFBP7 expression in 80% (8/
melanoma, but the patient was not a mutation
10) of DN with wild-type BRAF and 67% (2/3) DN with
carrier, suggesting a different etiology for the ocular
mutant BRAF; similarly, IGFBP7 was expressed in
and cutaneous melanomas in this family. In a more
100% (4/4) of CN with wild-type BRAF and 67% (2/3)
definitive study, Taylor et found no association
CN with mutant BRAF. While the absence of IGFBP7
among 44 patients between uveal melanoma and
in some mutant BRAF-expressing DN suggests that
cutaneous melanoma and/or DN. They found a 4.5%
this putative senescence pathway may not be intact in
prevalence of DN in patients with uveal melanoma
a subset of DN, a similar dissociation between mutant
compared to a 41% prevalence of DN in patients with
BRAF and IGFBP7 was observed in CN.
cutaneous melanomPatients with DN thereforedo not appear to have an increased risk for ocular
MANAGEMENT OF DYSPLASTIC NEVI
melanoma, and ophthalmologic screening in theabsence of ocular symptoms may not be indicated.
Variation in management of dysplastic nevi bydermatologistsKey points
d There is significant variation in practice in-
dicated by survey
d Multiple therapeutic modalities have been
d There is a lack of evidence supporting rou-
studied in dysplastic nevi, including imiqui-
tine ophthalmologic examinations for pa-
mod, 5-fluorouracil, tretinoin, isotretinoin,
tients with dysplastic nevi
and laser ablation
d No therapeutic treatment appears efficacious
As noted above, no guidelines regarding the man-
in eliminating dysplastic nevi
agement of DN emanated from the NIH conference in1992,and none have been forthcoming since. In a
Several pharmacologic agents have been used in
survey of fellows of the American Academy of
patients with DN. These include therapies that have
Dermatology regarding the management of patients
been efficacious for actinic keratoses, perhaps re-
with a history of histologically confirmed DN, Tripp
flecting a view that if DN are precursor lesions to
et alfound significant variation in physician prac-
melanoma they might respond like precursor lesions
tices. While 99% of the dermatologists recommended
to squamous cell carcinoma.
that these patients perform self-examinations of their
Dusza et altreated 14 DN in 10 patients with 5%
skin, 75% performed total body skin examinations on
imiquimod cream 3 times per week for 16 weeks.
follow-up visits, 60% recommended ophthalmologic
There were no obvious clinical changes in the size
examinations for some patients, 49% obtained base-
and morphology of the study nevi, but 4 of 14 treated
line total body skin photography for most patients,
nevi and none of 14 untreated nevi showed signif-
and 23% routinely used dermoscoRegarding
icant reduction of junctional and intraepidermal
follow-up visits for their patients with DN, 58%
nevomelanocytes and papillary dermal fibrosis with
recommended examinations every 12 months and
variable inflammation suggestive of partial regres-
33% recommended examinations every 6 months in
sion. Somani et alconducted a more limited trial of
most patients. Variation in surgical management of
5% imiquimod in which three patients applied
DN is discussed below.
imiquimod to a single clinically atypical nevus five
While there is clear evidence that the use of
nights per week for 12 weeks. Biopsy specimens of
photography and dermoscopy can enhance early
the nevi were obtained at the outset of the study, and
melanoma detection, their use is largely dependent
these nevi were excised after the treatment period.
on physician familiarity and training in these tech-
None of the lesions cleared; two proved to be DN
niques and economic feasibility of their incorpora-
and developed inflammatory reactions while the
tion into individual practiIs there evidence to
third lesion was a CN that demonstrated minimal
inform as to the indication for ophthalmologic
inflammation. The authors were concerned that the
examinations—notably, does a patient history of
two DN appeared to display more severe histologic
DN portend the future risk of developing ocular
atypia after imiquimod treatment.
melanoma? Vink et described five melanoma
Although systemic 5-fluorouracil (5-FU) has been
kindreds, each with a single member affected by
associated with eruptive DN (see above), topical
ocular melanoma, suggesting an association be-
application of 5-FU has been investigated as a
tween cutaneous and ocular melanoma. On the
potential therapeutic for DN. Bondi et altreated
other hand, Molven et described a family with
six DN in a 37-year-old woman with 5% 5-FU cream
inherited melanoma based on CDK4 (R24H) muta-
twice daily for 5 weeks; four CN from unrelated
tion and a single member who developed ocular
individuals were also treated. All six DN responded
19.e8 Duffy and Grossman
J AM ACAD DERMATOL
with inflammation, ulceration, and subsequent (clin-
In patients with numerous or clinically atypical
ical) disappearance of the lesion, while the four
nevi, there may be a tendency to remove lesions in a
control CN remained unchanged.Subsequent
‘‘prophylactic'' manner. Such practice of nevus re-
patch tests and intradermal skin testing in the patient
moval may be sought by the patient to reduce their
who responded had no evidence of contact sensitiv-
melanoma risk, or promulgated by the physician out
ity to 5-FU.The authors noted that an additional
of fear of missing a melanoma. It is clear that complete
four DN lesions in this patient responded to 5-FU,
removal of a patient's nevi will not prevent mela-
while those in additional patients did not. It does not
noma, which (as discussed above) is more likely to
appear that the response of DN to 5-FU has been
arise from isolated epidermal melanocytes in the skin
evaluated in any subsequent studies in the literature.
than from preexisting nevi. However, it is unclear to
The effect of topical tretinoin under occlusion
what extent ‘‘molectomy,'' however impractical this
with and without topical steroid was investigated by
might be, would reduce long-term melanoma risk in
Stam-Posthuma et in a prospective randomized,
high-risk patients. A report of one such case in a
double blind study. Three clinically atypical nevi in
patient with history of multiple melanomas described
30 patients were treated under Actiderm occlusion
the removal of 117 clinically atypical lesions over a
(Actiderm Cosmaceuticals, New York, NY, replaced
1-year period. The patient developed no subsequent
weekly for 4 months) either with placebo, 0.1%
melanombut to our knowledge this approach
tretinoin, or tretinoin in combination with 1% hy-
has not been formally studied.
drocortisone. Lesions were monitored by photogra-phy throughout the study period and histologically at
the end of the study, revealing that although about
40% of lesions treated with tretinoin or tretinoin plus
d The decision to reexcise relates to physician
hydrocortisone were reduced in size, they remained
perception of dysplastic nevi and their risk
clinically atypical and retained histologic
of transformation to melanoma
Edwards et altreated eight patients with DNS
d Some physicians reexcise dysplastic nevi to
with oral isotretinoin, 40 mg twice a day for 4
prevent recurrence and potential pseudome-
months. At the completion of therapy, at least three
previously identified and photographed clinically
with severe dysplasia should be
atypical lesions were rephotographed and removed
reexcised given the difficulty in distinguish-
for histologic evaluation. There were no clinical or
ing from melanoma
histologic changes observed in the lesions, which
d Dysplastic nevi that do not resemble mela-
were confirmed to be DN in these patients. Oral
noma, including dysplastic nevi with posi-
isotretinoin does not appear to have a significant
tive histologic margins, do not need to be
biologic effect on DN.
reexcised and may be observed like common
Finally, laser ablation has been attempted for the
removal of DN. Duke et treated 31 nevi (includ-ing DN) with a Q-switched ruby laser (694 nm, 40-60
Regarding surgical management, a survey by
nanoseconds, 7.5-8.0 J per cm2) and reported that
Tripp et found that 86% of dermatologists intend
although 16 (52%) of the nevi had a clinically visible
on biopsy to remove DN completely, 75% use
decrease in pigment at the 4-week follow-up visit, no
margins of $ 2 mm, and 67% would reexcise DN
lesion showed complete histologic removal of all
with positive histologic margins. Although the NIH
nevomelanocytes. A potential concern is that laser
Consensus Conferenceestablished margin guide-
treatment of nevi may increase the risk of malignancy
lines (2-5 mm) for the reexcision of DN, indications
by eliminating the protective pigment, thereby leav-
for reexcision were not specified. Because DN often
ing the remaining cells more vulnerable to ultraviolet
consist of melanocytes that extend beyond the clin-
light radiation and potentially obscuring the ability to
ical lesion, it is common for biopsy specimens (even
detect morphologic changes over time. However, to
when physician intent is to completely remove the
our knowledge, there have been no reports of
lesion) to have positive margins. The decision to
malignancies arising in laser-treated nevi.
reexcise versus observe likely relates to a variation inphysician perception of DN and the risk of transfor-
Prophylactic surgical removal
mation to melanoma.
A recent surveyed 101 dermatologists in
d There is a lack of evidence that prophylactic
the Chicago area regarding the role of histologic
removal of clinically atypical nevi reduces
grade and margin status documented in the pathol-
ogy report in their decision to reexcise or observe
J AM ACAD DERMATOL
Duffy and Grossman 19.e9
VOLUME 67, NUMBER 1
DN after biopsy. Positive margin status was corre-
Table II. Potential advantages/disadvantages of
lated with higher rates of decision to reexcise for all
reexcising dysplastic nevi
grades of nevi, but was most marked for lesions
diagnosed with ‘‘moderate'' dysplasia. While 81% of
Diagnostic confirmation (if partial
respondents indicated they would reexcise nevi with
moderate dysplasia and positive margins on biopsy,
Decrease risk of lesion recurrence
only 9% of respondents favored the reexcision of
May prevent ‘‘pseudomelanoma''
Risks of skin surgery
moderately dysplastic lesions with negative margins.
Medicolegal (defensive medicine)
There appear to be three primary reasons for
reexcising DN. First, there may be concern that aparticular lesion is melanoma, based on physician- or
primary melanoma with scar/fibrosis, the vast ma-
patient-related factors or the histologic results. As
jority of recurrent nevi were readily identifiable.
noted above, there is discordance among dermato-
Second, Goodson et studied the rate of clinical
pathologists as to identification of dysplasia and
recurrence and factors associated with recurrence of
cytologic atypiaand therefore lesions with se-
DN after biopsy. Of 195 DN with more than 2 years of
vere dysplasia could represent melanoma. It is there-
follow-up, seven (3.6%) demonstrated recurrence on
fore recommended that lesions with severe histologic
clinical examination. In all, 98 DN had a follow-up
atypia be reexcised. Lesions with only mild or mod-
period of at least 4 years with no clinical recurrence.
erate histologic atypia are a source of much greater
Of 61 CN biopsy sites examined, clinical recurrence
controversy. A second reason to reexcise DN is to
was observed in two (3.3%). For all nevi studied,
prevent their recurrence. This reason may in part be
recurrence was significantly associated with shave
seated in a fear that the lesion may recur as melanoma
biopsy technique but not with nevus dysplasia or
(thinking that if DN are precursors of melanoma then
subtype, or the presence of positive margin or con-
they should be completely removed). However,
genital features. This study suggests that the reexci-
given that the risk of melanoma arising in DN may
sion of nevi—including mildly to moderately DN with
be no greater than in CN (as discussed in part I of this
a positive histologic margin—may not be necessary.
review), following this course may lead one toreexcise all nevi with positive margins. In addition,
CONCLUSION AND RECOMMENDATIONS
one may want to avoid lesions recurring as ‘‘pseudo-
There is considerable variation among physicians
melanoma''—a benign histologic simulator of mela-
in their clinical approach to patients with DN, which
nomthat can be problematic for pathologists.
likely stems from different interpretations of the DN
Another potential concern is overdiagnosis of a
and its relative risk of transformation to melanoma.
recurrent DN as melanoma if the pathologist signing
Studies in recent years have identified some biologic
out the recurrent lesion has no knowledge of the
and molecular similarities between DN and CN, as
previous pathology. Reexcising DN for these reasons
well as differences (). Despite these distinc-
may represent a form of defensive medicine driven by
tions, including an increased proliferative rate, ge-
medicolegal concerns, but there also may be an
nomic instability, and the loss of p16 in some DN, in
implicit financial incentive to perform additional
general DN are far more similar to CN than to mela-
procedures. What may be perceived as an increasing
noma ). We look forward to future studies
tendency to over-biopsy and overtreat DN has been
that may identify subsets of DN, based on molecular
referred to in the lay press as the ‘‘nevomelanocytic
markers, that could be associated with higher risk. At
industrial complex.''The risks and benefits of
present, however, there is no clinical evidence that DN
reexcising DN are summarized in .
as a group behave more aggressively (ie, a tendency
Some of these concerns have been informed by
toward melanoma transformation) than CN, and no
two recent studies. First, King et analyzed clinical
markers have been validated to identify those lesions
findings and histologic changes in 357 cases (28%
(either DN or CN) that may be more predisposed to
were DN) of recurrent nevus phenomenon that were
melanoma transformation and/or metastasis.
compared with 34 cases of melanoma with regres-
If individual DN lesions can be distinguished from
sion. Most recurrences were in patients under 40
melanoma histologically, then such lesions appear to
years of age, and located on the back, with a median
represent a variant of melanocytic nevus, and given
recurrence time of 5 months. Many cases revealed
their prevalence could be considered a normal nevus
only pigment, and residual nevus was present in only
variant (such as blue nevus, Spitz nevus, etc). Just as
33% of cases, often associated with deeper adnexal
DN represent a particular nevus subtype to which
structures. While many recurrent nevi shared some
particular individuals are predisposed, similar find-
histologic similarities (ie, pseudomelanoma) with
ings have more recently been extended to patients
19.e10 Duffy and Grossman
J AM ACAD DERMATOL
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Altered expression of p53
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Welcome to the 2009 Survey Welcome to the National Hydrocephalus Foundations 2009 Survey. This is the fourth survey conducted by National Hydrocephalus Foundation in its 30 year history. Over the past 30 years, our knowledge of hydrocephalus diagnosis, treatment, population and living with the condition has advanced. Because of the advancements during the period, the focus and questions on each survey were slightly different which makes a direct correlation between surveys impossible.