Chapter III.

Atypical (Dysplastic) Nevus

Rainer Hofmann-Wellenhof and H. Peter Soyer III.5

Contents portant marker for an increased risk of

melanoma. The maximum reported increased
III.5.1 Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
relative risk of sporadic melanoma varies from
III.5.2 Clinical Features . . . . . . . . . . . . . . . . . . . . . . . 88 2.4 for one or more atypical nevus to 32.0 for 10
III.5.3 Dermoscopic Criteria. . . . . . . . . . . . . . . . . . . 88
or more atypical nevi.
Clinical and dermoscopic follow-up docu-
III.5.4 Relevant Clinical Differential mentations and the histopathological recogni-
Diagnoses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 tion of dysplastic nevi in contiguity with a mela-
III.5.6 Histopathology. . . . . . . . . . . . . . . . . . . . . . . . . 91 noma prove the role of atypical nevi as a possible
precursor of melanoma. The importance of
III.5.7 Management. . . . . . . . . . . . . . . . . . . . . . . . . . . 92
atypical nevi as precursor lesions is tempered by
III.5.8 Case Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . 92 the fact that only a small percentage of melano-
III.5.8.1 Case 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92 mas develop in association with a nevus and es-
III.5.8.2 Case 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94 timates imply that only 1 in 10,000 atypical nevi
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
per year will progress to melanoma.
Multiple molecular biological studies have
tried to differentiate atypical nevi from com-
mon nevi and melanoma on genetic grounds,
but their results are conflicting. The germ-line
p16-gene, INK4a (CDKN2A) mutations on
III.5.1 Definition chromosome 9p21, which are frequently present
in familiar melanoma, have been found more
Atypical or dysplastic nevus is our preferred frequently in individuals with a high number of
term for a group of melanocytic skin tumors nevi, but there has been no significant correla-
which cause endless debate and controversy. tion with the number of atypical nevi. Investiga-
Synonyms include atypical mole, BK mole, tions of the development of atypical nevi and
Clark nevus, and nevus with architectural dis- the expression of 1p36 region with the PITSLRE
order. In 1978 Wallace H. Clark, Jr. first drew gene coding for a p58 protein kinase have re-
attention to this particular type of nevus by vealed controversial results.
studying numerous melanocytic nevi in patients Telomerase activity, another possible genetic
with concomitant melanomas. marker, was only increased in atypical nevi
In most common definitions of an atypical when tissue sections were histopathologically
nevus this nevus type is characterized by a di- selected. No differences were found between
ameter larger than 6 mm, color variegations, common nevi and atypical nevi when clinical
and irregularity of the border. As a rule, clinical criteria were used. Taken together, the molecu-
features of a congenital nevus are not present. lar studies demonstrate that some lesions among
The estimated prevalence of clinically atypi- the atypical nevi seem to be transitional be-
cal nevi ranges from 7 to 18% in population- tween common nevi and melanoma, but the
based samples. Atypical nevi represent an im- majority are not.
 88 R. Hofmann-Wellenhof, H.P. Soyer

III.5.2 Clinical Features

Atypical nevi are flat to elevated or even slightly
papillomatous pigmented lesions characterized
by various shades of brown coloration. They are
commonly situated on the trunk and extremi-
ties. Although atypical nevi are found mostly in
skin that has been exposed to sunlight, they also
may be seen on the buttocks, the volar surfaces,
and other covered parts such as genitalia and
soles.
Their number varies from one or two to sev-
eral hundred. Multiple atypical nevi in an indi-
vidual most often display a similar clinical sub-
type. The most common clinical types are: (a)
the “lentiginous type” with a flat surface and
homogenous dark brown or brown-black color;
(b) the “fried-egg” type with a raised central
portion and a flat peripheral annulus; (c) the
“targeted” type with concentric annular zones
that vary in degree of pigmentation; (d) the
“seborrheic keratosis-like” type with a verru-
cous surface and usually dark-brown color; and
(e) the “erythematous” type with a pink color
and only remnants of pigmentation.
Atypical nevi are larger than 6 mm and often
have a papule in the center surrounded by a Fig. III.5.1a.  Numerous atypical nevi on the back of a
macula. Different shades of brown are common, 32-year-old man. The nevi vary in diameter from a few
III.5 but shades of pink, red, and blue-gray may be millimeters to 1 cm and differ in shape and color
present as well (Fig. III.5.1). Following the
ABCD rule for detection of suspicious melano-
cytic lesions, atypical nevi often display all cri- plastic nevi without melanoma; type C, sporadic
teria of melanoma: asymmetry; irregular bor- dysplastic nevi with melanoma; type D-1, fa-
ders; multicolor pigmentation; and diameter milial dysplastic nevi with one person with mel-
larger than 6 mm. anoma in the family; and type D-2, familial
Many different terms are used for individu- dysplastic nevi with two or more family mem-
als with numerous atypical nevi: dysplastic ne- bers with melanoma. The relative risk of devel-
vus syndrome; atypical mole syndrome; familial oping a melanoma rises in the latter type up
atypical multiple mole melanoma syndrome 500–1000 times.
(FAMMM); and BK mole syndrome. The defi-
nition for this syndrome is equally controver-
sial. The common diagnostic criteria for this III.5.3 Dermoscopic Criteria
syndrome are: an individual with more than
100 melanocytic nevi with some nevi being In our estimation, the real challenge is to recog-
larger than 8 mm and also some atypical nevi. nize, within the many variations of atypical
The dysplastic nevus syndrome can be familiar nevi, those that are actually melanomas in situ
or sporadic. According to Kopf et al. five differ- or early invasive melanomas. Dermoscopy is es-
ent types of the dysplastic nevi syndrome can be sential to achieve this distinction.
distinguished: (a) type A, sporadic dysplastic Based on a morphological study of about 800
nevi without melanoma; type B, familial dys- atypical nevi in 23 patients, we classified atypi-
 Atypical (Dysplastic) Nevus Chapter III.5 89

Fig. III.5.2.  Different dermoscopic patterns of atypical nevi according to the main structural types. a Reticular;
b globular; c homogeneous; d reticular–globular; e reticular–homogeneous; f globular–homogeneous

cal nevi, according to the global dermoscopic The most common reticular type is charac-
patterns, into three types, namely, reticular, terized by a more or less prominent pigment
globular, and homogeneous. Frequently, combi- network with thin lines and regular meshes.
nations of these types are found, the combina- The pigment network is usually evenly distrib-
tion of reticular and globular types being most uted throughout the lesion and fades out at the
common (Fig. III.5.2). periphery.
 90 R. Hofmann-Wellenhof, H.P. Soyer

Fig. III.5.3.  Different dermoscopic patterns of atypical nevi according to the variation of pigmentation. a Hyper/
III.5 hypopigmented; b central hypopigmented; c central hyperpigmented; d eccentric hyperpigmented

The globular type is characterized by a dot- tion because this multicomponent pattern is
ted and/or globular pattern composed of nu- frequently found in early melanomas.
merous dots/globules of variable size and shape Besides the three structural dermoscopic ar-
(oval, round, or rectangular) more or less evenly chetypes of atypical nevi, a number of charac-
distributed throughout the lesion. A combina- teristic dermoscopic variants are caused by
tion of the globular and reticular type is com- variations in pigmentation (Fig. III.5.3). In this
mon. An interesting morphological presenta- context four very distinctive subtypes have been
tion of this combined pattern is an annular described:
arrangement of dots/globules at the periphery of
an otherwise typical reticulated atypical nevus 1. Atypical nevus with central hypopigmen-
indicating ongoing growth of the lesion. tation. This is usually a variant of the
The least frequent of the three major patterns reticular–homogeneous type with a
of atypical nevi is the homogeneous pattern, central hypopigmented area almost
characterized by a diffuse pigmentation of vari- devoid of other dermoscopic features
ous shades of brown coloration with only iso- accompanied by an annular reticulated
lated reticular and/or globular areas. An atypi- periphery. Frequently, the less-pigmented
cal nevus with all three patterns (reticular, center corresponds to a clinical papule
globular, homogeneous) requires special atten- (“fried-egg” type of atypical nevus).
 Atypical (Dysplastic) Nevus Chapter III.5 91

2. Atypical nevus with central hyperpig- III.5.4 Relevant Clinical Differential

mentation. This type, also called hyper- Diagnoses
melanotic nevus or black nevus, repre-
sents a distinctive variant composed of a Superficial spreading melanoma is the main
broad rim of prominent pigment network differential diagnosis. In most cases the atypical
lines at the periphery and a central, features of the ABCD rule are more prominent
diffuse, irregularly outlined black in melanomas with prominent color variegation
hyperpigmentation, also called black and striking asymmetry. Dermoscopy is helpful
lamella. for the differential diagnosis as the melanoma-
3. Atypical nevus with multifocal hypo/ specific dermoscopic criteria are much more
hyperpigmentation. This type is charac- frequent in melanomas than in atypical nevi.
terized by a multifocal hypo/hyperpig- Small congenital nevi are another important
mentation leading to patchy appearance differential diagnosis. Congenital nevi tend to
of the entire lesion. have a larger diameter than atypical nevi and
4. Atypical nevus with eccentric hyperpig- frequently show prominent hairs. Seborrheic
mentation. This type of atypical nevus is keratosis may cause in special cases some diffi-
of the utmost significance, because its culties in the differential diagnosis, but the dull
differential diagnosis includes melanoma surface and the hyperkeratosis leads to the cor-
in situ or even early invasive melanoma. rect diagnosis.
This type displays a hyperpigmented
eccentric area that reaches the border of
the lesion. Sometimes this area is a blotch, III.5.6 Histopathology
whereas in other instances the reticular
pattern is more pigmented. Architecturally dysplastic nevi are larger than
common nevi and contain, by definition, a junc-
tional component, which is commonly present
Most of the patients with multiple atypical nevi as “shoulder,” adjacent on both sites to a central
show one or two prominent dermoscopic types. compound part. Some lesions are entirely junc-
Nevi belonging not to the predominant types in tional. Nested melanocytes arranged predomi-
an individual should be investigated with addi- nantly at the tips and the sides of uniformly
tional alertness because they may be – similar elongated rete ridges form frequently a symmet-
to the clinical “ugly duckling” sign – a melano- ric silhouette (Fig. III.5.4). Sometimes the nests
ma. show a bridging between adjacent rete ridges.
Besides the three major patterns and the Concentric eosinophilic fibroplasia around the
above-mentioned distinctive subtypes based on rete ridges or lamellar fibroplasia is typically
the distribution of hypopigmented and hyper- found in the papillary dermis immediately be-
pigmented areas, additional dermoscopic crite- neath the dermo-epidermal junction. A patchy
ria may be occasionally found in atypical nevi, perivascular lymphocytic infiltrate is common.
such as streaks and blue-white structures. Very Cytomorphologically, some of the me-
rarely milia-like cysts and comedo-like open- lanocytes in dysplastic nevi show “random”
ings are observed in the compound and dermal cytological atypia, which presents as nuclear
types of atypical nevi. A delicate vascular pat- enlargement, slight irregularity, and hyper­
tern characterized by the presence of “comma- chromasia with clumping of the chromatin and
like” and dotted vessels is a common finding in occasionally prominent nucleoli.
atypical nevi. The great dilemma of the histopathological
diagnosis that has been discussed controversial-
ly for decades is the lack of clear morphological
parameters to discriminate dysplastic nevi from
melanoma, on the one hand, and from common
nevi, on the other hand. In few cases a diagnosis
 92 R. Hofmann-Wellenhof, H.P. Soyer

Fig. III.5.4.  Histopathology
of an atypical nevus. At scan-
ning magnification, the lesion
is confined to epidermis and
papillary dermis with nests
of melanocytes situated at
the dermo-epidermal junc-
tion of elongated rete ridges.
At closer magnification
bridging of nests and few
single cells in higher layers of
the epidermis are visible.

cannot be made with certainty. For such lesions III.5.8 Case Studies
the terms SAMPUS (superficial atypical mela-
nocytic proliferation of uncertain significance) III.5.8.1 Case 1
and MELTUMP (melanocytic tumor of uncer-
tain malignant potential) may be used.
Patient Comment

III.5.7 Management A 44-year-old woman visited the office of a der-

matologist for a routine check of her nevi. Her
The management depends on the appearance of mother had died of melanoma 3 years previ-
III.5 the atypical nevus and the overall number of ously.
atypical nevi in a given person. Atypical nevi
clinically and dermoscopically simulating mel-
anoma have to be excised. Also lesions with a Question Asked By the Physician
history of change in size, shape, or color should
be excised, or at least a short follow-up in 2 or Did you mention any change in one of your nevi
3 months, including clinical and dermoscopic or the development of new nevi?
documentation, is recommended. When a per-
son presents with only one atypical nevus, exci-
sion is justified, even if this nevus lacks suspi- Clinical Image Including Detailed
cious features; however, if an individual exhibits Description
numerous atypical nevi, documentation and
regular follow-up is recommended. The recom- Clinical examination revealed numerous mela-
mendation for follow-up periods varies from nocytic nevi on the whole body. The back had
3 months for individuals with familiar dysplas- more than 60 nevi varying in diameter.
tic nevus syndrome to once a year in persons
with only a few atypical nevi. Individuals should
also be instructed to do self-examination and Dermoscopic Image Including Detailed
subsequent sun protection. Description
Dermoscopy of one of the largest nevi on the
back showed a central hyperpigmented reticu-
 Atypical (Dysplastic) Nevus Chapter III.5 93

Case Study 1

lar–homogeneous type. No melanoma-specific Most of the atypical nevi belonged to the re-
criteria were detectable. Almost all other nevi ticular–homogeneous type with central hyper-
display variations of this dermoscopic type of pigmentation. No dermoscopic criteria suspi-
atypical nevi. cious for melanoma were detectable in any nevus;
thus, a follow-up in 3–6 months was recom-
mended.
Clinical Diagnosis Including Relevant
Differential Diagnosis
Comments
The familiar history of melanoma and the clini-
cal presentation with approximately 100 mela- Persons with numerous atypical nevi, especially
nocytic nevi, larger than 6 mm in diameter, led in the case of familiar dysplastic nevus syn-
to the correct diagnosis of a familiar dysplastic drome, bear a significantly higher melanoma
nevus syndrome. The dermoscopic image con- risk. Prophylactic excision of these atypical nevi
firmed this diagnosis. in such patients is not warranted, since the
probability that a single lesion will develop into
a melanoma is very low and the overall risk of
Performed Management melanoma cannot be reduced; therefore, regu-
lar skin examination with clinical and dermo-
An exact clinical and dermoscopic examination scopic photography is required to excise an
was performed. Subsequently, the nevi were eventually developing melanoma at a curable
clinical and dermoscopically monitored, and no stage. Affected individuals should be advised to
marked changes in comparison with the previ- perform self-examination and apply sun protec-
ous examination were noticed. tion.
 94 R. Hofmann-Wellenhof, H.P. Soyer

Case Study 2
III.5

III.5.8.2 Case 2 Clinical Image

Clinical examination revealed an asymmetric
Patient Comment brown to black macule with a diameter of 6 mm
and an irregular border. The other nevi were
The wife of a 66-year-old man noticed a change unsuspicious.
of color in a nevus on the shoulder. The patient
presented with eight atypical nevi on the trunk
and some dermal nevi. Dermoscopic Image
The dermoscopic image shows a reticular–ho-
Questions Asked By the Physician mogeneous pattern with eccentric hyperpig-
mentation. Atypical pigment network and ir-
Did you have a previous history of melanoma? regular streaks were present in the upper and
Did one of your first-degree relatives suffer from right part of the lesion.
melanoma?
 Atypical (Dysplastic) Nevus Chapter III.5 95

Clinical Diagnosis Including Relevant

Differential Diagnosis C Core Messages

Differential diagnosis included atypical nevus ■ Atypical nevi are defined as acquired
and melanoma. Non-melanocytic lesions were melanocytic nevi with a diameter larger
ruled out because of the prominent reticular than 6 mm, color variegations, and
pattern clearly visible in dermoscopy. The his- irregular border.
tory of change, the irregular streaks, and the ■ They simulate melanoma clinically,
atypical pigment network favored the diagnosis dermoscopically, and histopathologi-
of a melanoma. cally.
■ Atypical nevi are important markers
for melanoma, and to a lesser extent are
Histopathological Images also precursors of melanoma.
■ The dermoscopic classification accord-
Scanning magnification revealed the morpho- ing to the reticular, globular, homoge-
logical features of a melanoma in situ on the left neous type and combination of types
side and of a predominantly dermal atypical according to the distribution of
compound nevus on the right side. pigmentation is useful.
Higher magnification exhibited numerous ■ Regular total-body examinations with
atypical melanocytes at all levels of the epider- clinical and dermoscopic documenta-
mis featuring melanoma in situ. tion are recommended.
■ Suspicious and changing atypical nevi
have to be excised.
Performed Management   
Excision of the entire lesion in local anesthesia
was performed. Histopathological examination
revealed a melanoma in situ in association with References
a preexisting nevus.   1. Elder DE. Precursors to melanoma and their mim-
ics: nevi of special sites. Mod Pathol 2006;19 (Suppl
2):S4–S20
Comments   2. Roesch A, Burgdorf W, Stolz W, Landthaler M, Vogt
T. Dermatoscopy of “dysplastic nevi”: a beacon in
diagnostic darkness. Eur J Dermatol. 2006;16:479–
This rare example of a melanoma in situ in as- 493
sociation with a preexisting nevus underscores   3. Hussein MR. Melanocytic dysplastic nevi occupy
the importance of reported changes in a given the middle ground between benign melanocytic
atypical nevus and the usefulness of dermosco- naevi and cutaneous malignant melanomas: emerg-
py in detecting suspicious lesions among the ing clues. J Clin Pathol 2005;58:453–456
great variety of atypical nevi.   4. Gandini S, Sera F, Cattaruzza MS, Pasquini P, Abeni
D, Boyle P, Melchi CF. Meta-analysis of risk factors
for cutaneous melanoma: I. Common and atypical
nevi. Eur J Cancer 2005;41:28–44
  5. Celebi JT, Ward KM, Wanner M, Polsky D, Kopf
AW. Evaluation of germline CDKN2A, ARF, CDK4,
PTEN, and BRAF alterations in atypical mole syn-
drome. Clin Exp Dermatol 2005;30:68–70
  6. Culpepper KS, Granter SR, McKee PH. My ap-
proach to atypical melanocytic lesions. J Clin Pathol
2004;57:1121–1131
 96 R. Hofmann-Wellenhof, H.P. Soyer

  7. Shapiro M, Chren MM, Levy RM, Elder DE, LeBoit 18. Ackerman AB. Mythology and numerology in the
PE, Mihm MC Jr, Margolis DJ, Gimotty PA, Ming sphere of melanoma. Cancer 2000;88:491–496
ME. Variability in nomenclature used for nevi with 19. Greene MH. The genetics of hereditary melanoma
architectural disorder and cytologic atypia (micro- and nevi. 1998 update. Cancer 1999;86 (11 Suppl):
scopically dysplastic nevi) by dermatologists and 2464–2477
dermatopathologists. J Cutan Pathol 2004;31:523– 20. Murphy GF, Mihm MC Jr. Recognition and evalu-
530 ation of cytological dysplasia in acquired melano-
  8. Wang SQ, Kopf AW, Koenig K, Polsky D, Nudel K, cytic nevi. Hum Pathol 1999;30:506–512
Bart RS. Detection of melanomas in patients fol- 21. Cerroni L, Kerl H. Simulators of malignant mela-
lowed up with total cutaneous examinations, total noma of the skin. Eur J Dermatol 1998;8:388–396
cutaneous photography, and dermoscopy. J Am 22. Slade J, Marghoob AA, Salopek TG, Rigel DS, Kopf
Acad Dermatol 2004;50:15–20 AW, Bart RS. Atypical mole syndrome: risk fac-
  9. Naeyaert JM, Brochez L. Clinical practice. Dysplas- tor for cutaneous malignant melanoma and im-
tic nevi. N Engl J Med 2003;349:2233–2240 plications for management. J Am Acad Dermatol
10. Wetherington RW, Cockerell CJ. The “dysplastic” 1995;32:479–494
nevus: an update at 25 years. Adv Dermatol 2003; 23. Slade J, Salopek TG, Marghoob AA, Kopf AW, Ri-
19:237–248 gel DS. Risk of developing cutaneous malignant
11. Bauer J, Garbe C. Acquired melanocytic nevi as risk melanoma in atypical-mole syndrome: New York
factor for melanoma development. A comprehen- University experience and literature review. Recent
sive review of epidemiological data. Pigment Cell Results Cancer Res 1995;139:87–104
Res 2003;16:297–306 24. Bergman W, Gruis NA, Sandkuijl LA, Frants RR.
12. Kaddu S, Smolle J, Zenahlik P, Hofmann-Wellenhof Genetics of seven Dutch familial atypical multiple
R, Kerl H. Melanoma with benign melanocytic nae- mole-melanoma syndrome families: a review of
vus components: reappraisal of clinicopathological linkage results including chromosomes 1 and 9.
features and prognosis. Melanoma Res 2002;12:271– J Invest Dermatol 1994;103(5 Suppl):122S–125S
278 25. Marghoob AA, Kopf AW, Rigel DS, Bart RS, Fried-
13. Crowson AN, Magro CM, Sanchez-Carpintero I, man RJ, Yadav S, Abadir M, Sanfilippo L, Silverman
Mihm MC Jr. The precursors of malignant mela- MK, Vossaert KA. Risk of cutaneous malignant
noma. Recent Results Cancer Res 2002;160:75–84 melanoma in patients with “classic” atypical-mole
14. Hofmann-Wellenhof R, Blum A, Wolf IH, Zalaudek syndrome. A case-control study. Arch Dermatol
I, Piccolo D, Kerl H, Garbe C, Soyer HP. Dermo- 1994;130:993–998
scopic classification of Clark’s nevi (atypical mela- 26. Kopf AW, Friedman RJ, Rigel DS. Atypical mole
III.5 nocytic nevi). Clin Dermatol 2002;20:255–258 syndrome. J Am Acad Dermatol 1990;22:117–118
15. Hussein MR, Wood GS. Molecular aspects of mela- 27. Clark WH Jr, Reimer RR, Greene M, Ainsworth
nocytic dysplastic nevi. J Mol Diagn 2002;4:71–80 AM, Mastrangelo MJ. Origin of familial malig-
16. Tripp JM, Kopf AW, Marghoob AA, Bart RS. Man- nant melanomas from heritable melanocytic le-
agement of dysplastic nevi: a survey of fellows of the sions. “The B-K mole syndrome”. Arch Dermatol
American Academy of Dermatology. J Am Acad 1978;114:732–738
Dermatol 2002;46:674–682
17. Barnhill RL. Malignant melanoma, dysplastic
melano­cytic nevi, and Spitz tumors. Histologic
classification and characteristics. Clin Plast Surg
2000;27:331–360