CEBP FOCUS

Dysplastic Nevi and Melanoma

Alisa M. Goldstein and Margaret A. Tucker

Abstract
Dysplastic nevi are described as being on a continuum between common acquired nevi and melanoma
because they are morphologically and biologically intermediate between these 2 entities. Since initially being
reported as histologic lesions observed in melanoma-prone families, there has been considerable debate about
the definition of dysplastic nevi, the histologic and clinical criteria used to define them, and their biologic
importance. Their role as precursor lesions for melanoma is not their primary role in their relationship to
melanoma because of the rarity of transformation of any individual nevus to a melanoma. Although there is still
no single, universally agreed upon histologic or clinical definition or even name for these nevi, dysplastic nevi
should be considered important because of their association with an increased risk for melanoma. Cancer
Epidemiol Biomarkers Prev; 22(4); 528–32.
2013 AACR.

Introduction and B were subsequently excised and classified histolog-

Since dysplastic nevi were first reported in 1978 by ically as dysplastic nevi based on pathologic review.
Clark and colleagues (1) and shortly thereafter by Lynch However, even after multiple NIH consensus confer-
and colleagues (2, 3) as histologically defined lesions in ences and studies to examine reproducibility of dysplastic
melanoma-prone families, there has been acrimonious nevi by pathologists and/or clinicians studying these
debate about the definition, classification, and biologic lesions (4, 10–18), no single definition or name for these
importance of these lesions. The initial names used by melanocytic nevi has yet been accepted by all patholo-
Clark and colleagues were BK moles (and BK mole syn- gists, dermatopathologists, dermatologists, oncologists,
drome), named after 2 of the first melanoma-prone fam- other clinicians, epidemiologists, or geneticists (4, 7,
ilies seen with these lesions, and familial atypical multiple 8, 16). In addition, for some investigators, the use of the
moles and melanoma syndrome (FAMMM) by Lynch and term dysplastic requires histologic evaluation and atyp-
colleagues (1–4). Subsequently, the term "dysplastic ical is considered more appropriate for clinical classifica-
nevus" [and dysplastic nevus syndrome (DNS)] was pro- tion. Again, there is not universal agreement for this
posed as these benign melanocytic nevi are characterized differentiation in terminology. A problem with using
by architectural disorder and cytologic atypia, similar to "atypical" is that "atypical nevi" include a broad range of
dysplastic lesions in other organs, such as the cervix or different types of unusual morphology (19). As the criteria
esophagus (4–6). used to classify/define dysplastic nevi may vary (sub-
There have been numerous debates about the name of stantially), it is critical that all studies examining these
these lesions and both the histologic and clinical criteria lesions provide the clinical and/or histologic criteria used
used to define them [recently reviewed in refs. (4, 7, 8)]. In in the methods section. Even though no single definition is
1990, the International Agency for Research on Cancer accepted by all, the most commonly used term in the
proposed a detailed protocol to clinically identify and literature is dysplastic nevi (16, 19). For purposes of this
record these nevi for epidemiologic studies (9). The pro- review, we will use dysplastic nevi.
tocol proposed the following requirements: the presence of There has been extensive discussion about the histo-
a macular component of the lesion in at least one area plus logic criteria for dysplastic nevi in the pathologic and
the presence of at least three of the following features: (i) not dermatopathologic literature and this topic is not the
well-defined border, (ii) size 5 mm or more, (iii) variegated focus of the current review. However, the major histologic
color, (iv) uneven contour, (v) erythema (9). Figure 1 shows criteria involve architectural disorder and cytologic aty-
examples of clinically defined dysplastic nevi. Lesions A pia (4). The reader is referred to several recent reviews
detailing more information about the histologic criteria of
dysplastic nevi (4, 7, 8). The goals of this review are to
examine the relationship between dysplastic nevi and
Authors' Affiliation: Division of Cancer Epidemiology and Genetics,
National Cancer Institute, National Institutes of Health, Bethesda, Maryland
melanoma, and the implications for screening, detection,
and management.
Corresponding Author: Alisa M. Goldstein, Genetic Epidemiology Branch/
NCI, Executive Plaza South, Room 7004, 6120 Executive Blvd. MSC 7236,
Bethesda, MD 20892. Phone: 301-496-4375; Fax: 301-402-4489; E-mail: Dysplastic nevi as a risk factor for melanoma
goldstea@mail.nih.gov Melanoma results from the interplay of genetic, envi-
doi: 10.1158/1055-9965.EPI-12-1346 ronmental, and host factors. The major environmental risk

2013 American Association for Cancer Research. factor for melanoma is ultraviolet radiation. Increased

528 Cancer Epidemiol Biomarkers Prev; 22(4) April 2013

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 Dysplastic Nevi and Melanoma

A B
Figure 1. Examples of dysplastic
nevidefined based on clinical criteria.
A, the lesion is 8 mm in greatest
diameter. The lesion is partially flat
with an irregular and indistinct outline
and variable pigmentation. Because
of changes to the lesion, it was
excised and diagnosed as a
dysplastic nevus with severe
melanocytic dysplasia. B, the lesion
is 7 mm in diameter and is very
irregular with indistinct borders,
variable pigmentation, and an
asymmetric configuration. Excision C D
of the lesion resulted in a histologic
diagnosis of dysplastic nevus with
severe melanocytic dysplasia. C, the
lesion is 14 mm in greatest diameter.
It has an irregular, asymmetric
scalloped-shaped outline. The lesion
is partially flat with indistinct borders
and variably pigmented. D, the lesion
is 8  5 mm . It is partially flat with an
2

irregular outline and indistinct

borders.

number of nevi is one of the major host risk factors. 47 datasets that contained 10,499 cases and 14,256 con-
Other host factors include increased freckling, poor tan- trols. Of these, 27 datasets published risk estimates for
ning ability, fair complexion, light hair and eye color, and dysplastic nevi [denoted as atypical nevi by Gandini and
family history of melanoma (20–22). The major genetic colleagues; ref. (9)]. For all of the 27 datasets, the assess-
risk factors for melanoma include the high-risk suscepti- ment of the nevi was conducted by clinicians, although the
bility genes CDKN2A and CDK4 as well as numerous low- diagnostic criteria were not identical across all studies.
risk susceptibility loci identified primarily through can- Overall, dysplastic nevi were confirmed to be a highly
didate gene or genome-wide association studies of mel- significant risk factor for melanoma. Thirteen studies
anoma, pigmentation, or nevi (20, 23, 24). provided dichotomous data for dysplastic nevi. Among
Most epidemiologic studies that have evaluated dysplas- these 13 studies, the presence of dysplastic nevi conferred
tic nevi as a risk factor for melanoma have used clinical a 10-fold increased risk for melanoma [RR ¼ 10.1; 95%
criteria primarily or exclusively to classify these melano- confidence interval (CI), 5.0–20.3]. For the 15 studies with
cytic lesions (9). Overall, dysplastic nevi are relatively continuous data on number of dysplastic nevi, the relative
common with a frequency of about 10% (range, 7%– risks ranged from 1.6 (95% CI, 1.4–1.8) for subjects with
24%) in populations of northern European descent (21, one dysplastic nevus to 10.5 (95% CI, 5.1–21.8) for subjects
22). In contrast to common acquired nevi that occur pre- with 5 or more dysplastic nevi. There was, however,
dominantly in both sun-exposed and intermittently sun- significant heterogeneity between studies with hospital-
exposed areas of the body, dysplastic nevi not only occur in based controls showing lower risk estimates than other
sun-exposed and intermittently sun-exposed areas of the types of control subjects. Similarly, relative risks for one
body but also in areas with little or no sun exposure such as dysplastic nevus in case–control studies (n ¼ 20) were
the scalp, breast, and buttocks (22). Even though the criteria much lower and more precise than those in cohort studies
for dysplastic nevi sometimes differ between studies, there (n ¼ 8). In fact, the RR for having 5 dysplastic nevi was
is remarkable consistency in the risks identified in diverse reduced to 6.4 (95% CI, 3.8–10.3) when only case–control
high-risk and low-risk populations (21). However, as the studies were considered. Regardless, even with inconsis-
criteria used to classify dysplastic nevi vary across epide- tent definitions and different study designs, one fact is
miologic studies, it may be challenging to conduct joint clear; dysplastic nevi are one of the strongest and most
studies by directly combining data across studies. Even consistent risk factors for melanoma.
with these challenges, joint or meta-analyses have been
conducted and have shown dysplastic nevi to be a consis- Etiology of dysplastic nevi
tent risk factor for melanoma (for example, see (9, 25). The etiology of dysplastic nevi is not well characterized.
The largest meta-analysis to date was conducted by Similar to melanoma, dysplastic nevi seem to result from
Gandini and colleagues (9). This meta-analysis examined the interplay of genetic, host, and environmental factors.

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 CEBP FOCUS

There is evidence for a genetic component for nevi in cell, or cellular component from which another substance,
general with several loci including IRF4 (chromosome cell, or cellular component is formed especially by natural
6p25-p23), MTAP (9p21), and PLA2G6 (22q13) reported processes. Using these definitions, dysplastic nevi may be
from genome-wide association studies of melanocytic classified as a precursor of melanoma as dysplastic nevi
nevus count (26, 27), but there is less information for are potential and occasionally actual nonobligate precur-
dysplastic nevi. At present, molecular examination of sors of melanoma based on pathologic evaluation of
dysplastic nevi lesions is challenging because of the small melanoma tumors (4). Most studies have found that
nests of melanocytes in these lesions. As technology approximately 20% of melanomas arise out of a dysplastic
improves and the ability to examine single dysplastic nevi; the numbers arising out of other types of nevi have
nevus cells advances, the opportunities for further molec- not been well quantified and the majority of melanoma
ular exploration of dysplastic nevi lesions will increase. In tumors arise de novo (7).
anticipation of technologic advances, new studies should Although dysplastic nevi may be designated as pre-
collect tissue, if possible. cursors, the dysplastic nevus itself rarely progresses to
Although familial melanoma and dysplastic nevi (his- melanoma. Tucker and colleagues (37) prospectively fol-
torically called FAMMM or DNS) were originally thought lowed 33 melanoma-prone families for up to 25 years and
to be pleiotropic effects of a single gene, subsequent found that most dysplastic nevi remained stable over time
studies have shown that the genetics are more complex or regressed. During this follow-up study, few dysplastic
and that the genetic causes of familial melanoma and nevi progressed to become suspicious for melanoma.
dysplastic nevi are not the same (20, 28–31). In particular, Similar results have been observed for unselected indivi-
there is little evidence for dysplastic nevi being caused by duals with dysplastic nevi; the vast majority of dysplastic
mutations in the major melanoma susceptibility genes nevi remained stable or regressed (38). In addition, Tsao
CDKN2A or CDK4 (29–31). However, similar to dysplastic and colleagues (39) evaluated the risk of nevi transform-
nevi in unselected patients with melanoma, dysplastic ing into cutaneous melanoma. The authors estimated that
nevi are risk factors for melanoma in melanoma-prone the annual transformation rate of any single nevus into
families independent of CDKN2A mutations (32–34). The melanoma ranged from 1 or less in 200,000 for both men
discovery of additional high, intermediate, and low-risk and women younger than 40 years to about 1 in 33,000 for
susceptibility genes for both melanoma and dysplastic men older than 60 years. In addition, the lifetime risk of
nevi will lead to further deciphering of the genetic sim- any selected nevus transforming into melanoma by age 80
ilarities and differences between these entities. years (for a 20-year-old individual) was about 0.03% for
Multiple linkage studies have attempted to identify the men and 0.009% for women. Although Tsao and collea-
major genetic cause(s) for dysplastic nevi with limited gues (39) did not assess the lifetime risk for a dysplastic
success (29, 35). Zhu and colleagues (35) conducted a nevus transforming into melanoma, the authors estimated
genome-wide linkage scan for mole counts, including the annual dysplastic nevus transformation rate and
atypical subtypes using 796 microsatellite markers in showed that the rate was very low at about 1 in 30,089
424 families with 1,024 twins and siblings plus genotypes moles for males and 1 in 39,809 moles for females. Thus,
for 690 parents. The analysis showed suggestive but dysplastic nevi are important primarily as risk factors for
unconfirmed evidence of linkage to chromosomes 1, 6, melanoma; their role as precursors is less critical because
and X with lod (log of the odds) scores ranging from 2.0 to of the rarity of progression of any individual nevus to
2.2 across the 3 regions (35). de Snoo and colleagues (29) become a melanoma (4, 39).
conducted a linkage analysis of dysplastic nevi (denoted
atypical nevi in the study) in 4 Dutch p16-Leiden mela- Screening, Detection, and Management
noma-prone families including subjects as affected if they Because early diagnosis of thin melanoma tumors is
had 5 or more dysplastic nevi and were negative for the essential to survival after melanoma, it is important to
p16-Leiden CDKN2A founder mutation. The authors appropriately screen and manage individuals at increased
found suggestive but unconfirmed evidence for a dys- risk for melanoma. The presence of dysplastic nevi may be
plastic nevi susceptibility locus on chromosome 7q21.3 used to clinically identify individuals at increased risk for
(29). No replication of these preliminary findings has yet developing melanoma and to be part of the basis for
occurred and no susceptibility gene(s) for dysplastic nevi developing clinical guidelines. As previously mentioned,
have yet been identified. however, there are multiple host, environmental, and
genetic risk factors for melanoma and therefore screening
Dysplastic nevi as precursors of melanoma and management should incorporate all risk-related
Dysplastic nevi are clearly major risk factors for mela- information. However, for purposes of this review, we
noma, but are they precursors of melanoma? And what will focus on screening and management of dysplastic
does it mean to be a melanoma precursor? According to nevi.
the online Medical dictionary, MedlinePlus (Merriam Given the potential challenges in clinically diagnosing
Webster; ref. 36), a precursor is defined as: (i) one that dysplastic nevi for the general clinician, one question is
precedes and indicates the onset of another <angina may whether evaluation of nevus counts might be a useful
be the precursor of a second infarction> or (ii): a substance, alternative marker for risk. Few studies have had total

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 Dysplastic Nevi and Melanoma

body nevus counts of dysplastic and common acquired Although some patients may be tempted to have all of
nevi to directly examine this question. However, in 1997, their nevi removed, prophylactic removal of all nevi is not
Tucker and colleagues (40) reported that the risk of mel- appropriate as very few nevi progress to melanoma and
anoma associated with increased numbers of small (50) progression is unpredictable (19, 22, 39). Furthermore,
and large nevi (5) without any evidence of dysplastic even if all nevi were removed, risk for melanoma would
nevi was 4.6 (95% CI, 2.2–9.6) adjusted for age and freck- not be eliminated and the frequency of clinical follow-up
ling (18 cases and 17 controls). The risks associated with would not be altered because of the development of new
multiple dysplastic nevi ranged from 4.9 (95% CI, 2.5–9.8) nevi and de novo melanoma.
to 12 (95% CI, 4.4–31) mutually adjusted for other types of Dysplastic nevi are described as being on a continuum
nevi and adjusted for age, gender, number of sunburns, between common acquired nevi and melanoma because
freckles, solar damage, nevus excisions, number of scars, they are morphologically and biologically intermediate
and family history of melanoma (221 cases and 54 con- between these entities (4, 7). A subset of melanoma tumors
trols). Furthermore, increased numbers of small and large have been found to arise out of dysplastic nevi based on
nevi are correlated with the presence of dysplastic nevi; histologic evaluation of the tumors. Dysplastic nevi are,
approximately half of the controls with 50 or more small therefore, classified as potential and actual precursor
nevi had dysplastic nevi compared to approximately a lesions of melanoma, although they are nonobligate pre-
quarter of those with 25 or less small nevi. Therefore, cursors, as most melanomas do not develop from dys-
although increased numbers of small and large nevi are plastic nevi (4). Their role as precursors, however, is not
clearly risk markers for melanoma, identifying dysplastic their primary role in their relationship to melanoma
nevi adds additional information about level of risk. because of the rarity of transformation of any individual
Clinical guidelines for subjects with dysplastic nevi nevus to a melanoma. In conclusion, although no unified
include surveillance of the skin and particularly pigmen- definition or classification (or even name) for dysplastic
ted lesions, routine skilled clinical examinations, regular nevi exists and although dysplastic nevi are precursor
self-skin evaluation, and use of sun protective measures lesions for melanoma, dysplastic nevi should be consid-
(7, 8, 37). The frequency of the clinical examinations will ered important primarily because of their association with
vary depending on the age and sex of the individual and an increased risk for melanoma.
the activity of the pigmented lesions themselves. If nevi
are not changing, then less frequent clinical examinations Disclosure of Potential Conflicts of Interest
may be undertaken. A lesion that is changing in a manner No potential conflicts of interest were disclosed.
suspicious for melanoma should be removed by excision-
al biopsy. Adherence to these guidelines in melanoma- Authors' Contributions
prone families seems to decrease the risk of developing Conception and design: A.M. Goldstein
Acquisition of data (provided animals, acquired and managed patients,
new melanomas and changing nevi and aids in the detec- provided facilities, etc.): M.A. Tucker
tion of melanoma at an earlier stage (37, 41). Writing, review, and/or revision of the manuscript: A.M. Goldstein, M.A.
Once dysplastic nevi are identified, routine care should Tucker
Administrative, technical, or material support (i.e., reporting or orga-
include the use of total body photography to track changes nizing data, constructing databases): A.M. Goldstein, M.A. Tucker
of nevi over time. These lesions will change over time (37), Study supervision: A.M. Goldstein, M.A. Tucker
but most changes are not worrisome for melanoma. The
majority of dysplastic nevi undergo involution over years. Acknowledgments
As previously mentioned, lesions should only be biopsied The authors thank Mary Fraser and Geoff Tobias for their assistance.
when changing in a manner suspicious for melanoma.
Dermoscopy is an important adjunctive to the use of
photography (42). Use of either total body photography Grant Support
or dermoscopy or both may lead to a reduction in the This research was supported by the Intramural Research Program of the
NIH, NCI, DCEG.
number of benign nevi removed in proportion to mela-
nomas removed, but the skill of the examiner seems to be Received December 5, 2012; revised February 4, 2013; accepted February
an important component of dermoscopy success (43–45). 5, 2013; published online April 2, 2013.

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Dysplastic Nevi and Melanoma
Alisa M. Goldstein and Margaret A. Tucker

Cancer Epidemiol Biomarkers Prev 2013;22:528-532.

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