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 The following is a journal-based CME activity presented by the American Academy of Date of release: July 2012 Dermatology and is made up of four phases: Expiration date: July 2015 1. Reading of the CME Information (delineated below) Ó 2012 by the American Academy of Dermatology, Inc.
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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 recommended—which have 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 predictive markers 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- Abbreviations used: 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 Molecular profiling 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 Senescence markers p16 mutations.Several studies have investigated Distinct gene expression BRAF mutation rate the presence of somatic p16 mutations in nevi, Mutation/deletion of 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 Increased microsatellite 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.
tumor suppressors 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 Proliferation markers 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 Apoptosis markers 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 Reexcision controversy 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 lanoma phenomenon 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 3. Annessi G, Cattaruzza MS, Abeni D, Baliva G, Laurenza M, Table III. Molecular features distinguishing Macchini V, et al. Correlation between clinical atypia and dysplastic nevi compared to common nevi and histologic dysplasia in acquired melanocytic nevi. J Am Acad 4. Tucker MA, Halpern A, Holly EA, Hartge P, Elder DE, Sagebiel RW, et al. Clinically recognized dysplastic nevi. A Proliferation index central risk factor for cutaneous melanoma. JAMA 1997;277: BRAF mutation rate Mutation/deletion of p16 gene 5. Kelly JW, Yeatman JM, Regalia C, Mason G, Henham AP. A Altered expression of p53 high incidence of melanoma found in patients with multiple Loss of PTEN expression dysplastic naevi by photographic surveillance. Med J Aust 6. NIH Consensus conference. Diagnosis and treatment of early CN, Common nevus; DN, dysplastic nevus; PTEN, phosphatase and melanoma. JAMA 1992;268:1314-9.
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