CME ARTICLE

Melanocytic Nevi of Special Sites

Christine S. Ahn, MD,* Analia Guerra, MD,† and Omar P. Sangüeza, MD‡

4. Identify unique features within subsets of benign atypical

Abstract: Melanocytic nevi located on specific regions of the body melanocytic nevi on the legs.
can demonstrate unusual histopathological features such as asym-
metry, irregular nesting patterns, pagetoid spread, cytologic atypia,
and rarely, mitotic activity. However, despite these features that may
raise concern for malignant melanoma, these lesions follow a benign INTRODUCTION
clinical course and do not require intervention. Also known as nevi In recent years, it has become increasingly clear that
of special sites or nevi with site-related atypia, these melanocytic benign melanocytic nevi on certain areas of the body tend to
nevi were initially described on acral sites and genitalia. Now, exhibit unusual histopathological features that mimic dysplastic
additional anatomical sites with known site-related atypia include the nevi and malignant melanoma. Features such as poor circum-
ear, conjunctivae, scalp, breast, flexural skin, legs, and back and scription, confluence of nests, pagetoid melanocytes, and single
shoulder. This continuing medical education article presents a review melanocytes in the upper levels of the epidermis with varying
of the histopathological characteristics of special site nevi based on degrees of cytologic atypia can lead to the misdiagnosis of
anatomic location. It is imperative for dermatologists, pathologists, otherwise clinically benign lesions. These nevi, designated as
and dermatopathologists to distinguish benign melanocytic nevi with “nevi of special sites” (NOSS), “nevi with site-related atypia”,
site-related atypia from malignant melanoma to avoid unnecessary or “special site nevi”, were initially described on acral skin and
surgical intervention or treatment. genitalia. However, additional anatomical sites have contrib-
uted to the growing list of body sites that can be associated
Key Words: atypical nevi, special site nevi, site-specific, Spitz with melanocytic lesions with atypical features.
nevus, epithelial blue nevus Different anatomic regions of the body have different
(Am J Dermatopathol 2016;38:867–881) skin microanatomy and features such as epidermal thickness,
appendage distribution, dermal-epidermal junction (DEJ) struc-
ture, dermal structure, and blood supply. In addition, there are
variations in histologic patterns seen in nevi among individuals
LEARNING OBJECTIVES within different physiologic stages, such as children, adoles-
At the completion of this CME, the reader will be cents, elderly, or in pregnancy.1 The cause of site-specific var-
able to: iation in the histologic features of melanocytic lesions is not
known, but it has been suggested that contributions of external
1. Identify the anatomic regions with known site-related factors, including trauma and ultraviolet exposure, and intrinsic
atypia factors such as age and hormonal influences may play a role in
2. Understand the commonly encountered unusual histopath- the development.2 It is important for dermatologists, patholo-
ological features of special site nevi based on anatomic gists, and dermatopathologists to be aware of and accurately
site, including the ear, scalp, flexures/milk line, breast, identify these nevi to avoid overtreatment or large and unnec-
genitalia, legs, acral skin, conjunctivae, and back essary excisions, as the unifying feature of nevi with site-related
3. Identify clinical settings in which nevi in the genitalia atypia is the exhibition of benign biologic behavior despite the
demonstrate special features such as melanocytic nevi presence of worrisome histologic features.
arising in a background of lichen sclerosus or epitheli- Anatomical sites associated with site-related atypia
oid blue nevi on genitalia discussed in this review include the ear, conjunctivae, scalp,
breast, flexural skin such as the axillae and inguinal folds, skin
From the *Resident, Department of Dermatology, Wake Forest School of of genitalia, including the vulva and penis, lower extremities,
Medicine, Winston-Salem, NC; †Dermatologist, International Dermatopa-
thology Fellow, Department of Pathology, Wake Forest School of Medi- acral skin, and the back and shoulder of elderly individuals.
cine, Winston-Salem, NC; and ‡Professor of Pathology and Dermatology,
Director of Dermatopathology, Department of Pathology, Wake Forest
School of Medicine, Winston-Salem, NC. MELANOCYTIC NEVI OF THE EAR
All authors and staff in a position to control the content of this CME activity
and their spouses/life partners (if any) have disclosed that they have no Melanocytic nevi of the ear can be challenging because
financial relationships with, or financial interests in, any commercial of the presence of features that overlap with malignant
organizations pertaining to this educational activity. melanoma. Although uncommon, melanoma of the external
Reprints: Omar P. Sangüeza, MD, Professor of Pathology and Dermatology, ear account for 3%–16% of melanomas in the head and neck
Director of Dermatopathology, Department of Pathology, Wake Forest
School of Medicine, Medical Center Boulevard, Winston-Salem, NC
region.3 In a retrospective review of 101 melanocytic nevi
27157 (e-mail: osanguez@[Link]). located on or around the ear, 30 compound nevi and 12 junc-
Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. tional nevi were noted to have atypical histologic features.

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Ahn et al Am J Dermatopathol  Volume 38, Number 12, December 2016

Among these nevi with atypical features, almost all lesions

demonstrated poor lateral circumscription (93%) and most
specimens demonstrated a stromal reaction comprising a lym-
phocytic infiltrate and focal dermal fibroplasia. One of the most
striking features of atypical melanocytic nevi on the ear is the
irregularity of the nesting pattern with respect to nesting shape,
size, and location, observed in 57% of cases. Large nests can
be seen at the rete tips, between the rete, and along the sides.
Cytologic atypia was observed in more than half of the speci-
mens, with 62% demonstrating uniformly large melanocytes
with a pale, finely granular cytoplasm. Melanocytes were not
seen above the DEJ in any lesions in this case series and
mitotic activity was notably absent.3 Other reassuring findings
include symmetry, a lack of nuclear pleomorphism, the
absence of pagetoid scatter of melanocytes, and maturation
of the dermal component in compound lesions.
In a study of 21 auricular melanocytic nevi, 67% of
lesions were poorly circumscribed, and 29% of lesions demon-
strated asymmetry. Irregular, oval melanocytic nests were often
seen forming contiguous groups of melanocytic nests, present at
the rete ridge tips alone (29%) or in both the rete ridge tips and
shoulders (71%). Pagetoid spread of melanocytes was seen in
57% of nevi, and in most cases, intraepidermal melanocytes
were confined to the lower third of the epidermis, although
infrequently they migrated to the upper third of the epidermis.
Cytologic atypia was frequently observed, with nearly 50% of
lesions demonstrating moderate-to-severe atypia with large
vesicular nuclei without prominent nucleoli and pale abundant
cytoplasm. In this case series, the lack of mitotic figures and
apoptotic melanocytes was reassuring in all cases.4,5
Like other special sites, nevi on the ear demonstrate
atypical and sometimes alarming histologic features, the most
notable of which are the irregular nesting pattern and the poor
circumscription and elongation of rete ridges with bridging
between them.5 Although the presence of irregular nests at the
DEJ, moderate-to-severe cytologic atypia, and occasional pa-
getoid spread of intraepidermal melanocytes can be concern-
ing for melanoma, mitotic figures and apoptotic melanocytes
are notably absent, and the pagetoid spread observed in ear
NOSS show spread of single cells rather than clusters of
intraepidermal melanocytes (Figs. 1A–C).4,5

MELANOCYTIC NEVI OF THE SCALP FIGURE 1. Melanocytic nevus of the ear. A, A dome-shaped,
The scalp is a site with predilection for benign but well-circumscribed, asymmetric melanocytic lesion. B, Nota-
histologically atypical nevi that demonstrate varying levels of ble variation in the size and shape of the melanocytic nests
architectural disorder.6 This has been observed more promi- throughout the dermis, as well as patchy inflammatory in-
filtrates, melanophages, and mild solar elastosis. C, Single
nently in children and adolescents. Compared with nevi on
melanocytes can be observed in the epidermis.
other anatomic sites, a higher proportion of nevi located on
the head and neck of children demonstrate atypical or dys-
plastic features.7 In a review of 229 nevi from the scalp of extending down the hair follicle infundibula.8 Other findings
adults, adolescents, and children, the nevi from the scalp of include pagetoid spread of cells above the junction with rare
adolescents (age 12–18 years) were notable for their asym- suprabasal melanocytes, and consistent but mild cytologic
metric silhouette and poor circumscription. The most striking atypia characterized by hyperchromatic large nuclei with
feature was the presence of large, confluent, bizarrely-shaped clumped chromatin (Figs. 2A–C). In the dermis, lamellar
nests varying in size and shape along the DEJ in an apparently and concentric fibroplasia can be seen with a mild and focal
random distribution. Nests can be located through the base dermal inflammatory infiltrate.5,6,8 The atypical features were
and tips of rete ridges, often demonstrating lentiginous pro- seen most distinctively in the scalp of adolescents, but not in
liferation along the basal layer, and can be observed adults or younger children.8

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FIGURE 2. Melanocytic nevus of the

scalp. A, An asymmetric lesion with
poor lateral circumscription. B,
Replacement of the entire basal layer
with atypical melanocytes and mostly
single melanocytes within the epi-
dermis. In the dermis, there is varia-
tion in the size and shape of nests
and surrounding dense inflammatory
infiltrate. C, Cleft formation where
atypical melanocytes have replaced
the basal layer.

In a review of 365 scalp nevi, 56 nevi demonstrating and are progenitors to the mammary glands and nipples that
histologic characteristics of special site nevi were identified. appear as mammary ridges extending from the axilla to the
In these lesions, melanocytes demonstrated nested rather than groin. Owing to this shared embryologic background, flexural
lengitinous growth patterns (98%), with large nests arranged nevi and breast nevi have many overlapping features, but are
at rete tips and ridges (86%). Similar to the nested and discussed separately in this review.
dyshesive pattern described by Fabrizi et al, melanocytes Flexural nevi commonly show asymmetry and a dyshe-
were often loosely adherent (82%) and individual melano- sive nest pattern characterized by enlarged junctional nests
cytes demonstrated cytologic atypia with large nuclei (93%) that arise at the edges and between rete regions. In addition,
and abundant pale cytoplasm with dusty melanin granules decreased cohesion of melanocytes can be seen, as well as
(96%). Pagetoid spread, asymmetry, and poor lateral circum- lentiginous and pagetoid melanocytic proliferation with
scription were less prominent in these scalp nevi, compared extension of the intraepidermal component along adnexae.1
with other studies. Furthermore, atypical nevi were not Lamellar and concentric fibroplasia can be seen in some le-
limited to adolescents in this review, but observed across sions and stromal response is variable. Cytologic atypia
a wider range of ages including prepubescent children and observed in flexural nevi is relatively mild and restricted to
adults up to 30 years.9 the junctional and papillary dermal portions. When present,
Nevi on the scalp of children, adolescents, and young atypia is uniform and usually lacks cellular pleomorphism or
adults may demonstrate asymmetry, poor circumscription, mitotic figures.6 A papillomatous pattern, characterized by
marked variation in the size and shape of nests, areas of variably sized nests along the tips and sides of rete ridges
confluence and scattered melanocytes above the DEJ. Fea- with an undulating or papillomatous epidermis, is seen more
tures that can mimic melanoma include pagetoid melanocytes often in the axillary and inguinal regions.6
and single melanocytes that can replace the basal layer In a review of 40 melanocytic nevi of flexural sites,
(Figs. 3A–C).5 including those from axillary creases, inguinal creases, perianal
areas, the umbilicus and pubis, 56% of nevi had a nested and
dyshesive pattern. Characteristic features observed in almost all
MELANOCYTIC NEVI OF FLEXURAL SITES cases were fibroplasia, maturation, and lentiginous melanocytic
Melanocytic nevi of the flexural regions, also known as proliferation. Extension of the intraepidermal component along
melanocytic nevi of the milk line, include the axillary, adnexae, lateral extension, and a lymphocytic infiltrate in the
umbilical, antecubital and popliteal fossae, and inguinal dermis were seen in approximately 50% of cases, and rarely,
region excluding the genitalia. The term “milk line” has also limited pagetoid spread was observed.10
been used to include nevi occurring on the breast based on In a review of atypical umbilical nevi, one of the key
embryonic development. The milk lines arise from ectoderm features observed in all lesions was confluent lamellar fibrosis

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FIGURE 3. Melanocytic nevus of the

scalp. A, An asymmetric melanocytic
lesion without melanocytes extend-
ing down the hair follicle, a reassur-
ing finding. B, Variation in the size
and shape of nests with surrounding
infiltrate composed of mostly lym-
phocytes. There is no evidence of
mitotic figures. C, Cytologic atypia
can be observed in the melanocytes.

that extended deeply into the dermis and entrapped dermal Ronglioletti et al performed a large study comparing the
melanocytes. In addition, shoulder architecture, bridging, histologic features of 101 breast nevi with 97 nevi of the torso
lentiginous growth, and high-grade junctional cytologic atypia and extremities to determine the prevalence of histologically
were observed. In less than half of the nevi studied, impaired atypical features in both groups. Specifically, they examined
maturation within areas of lamellar fibrosis were seen, along for the presence of asymmetry, lateral circumscription,
with abnormal configuration of entrapped dermal nests, lentiginous growth, suprabasal melanocytes, hair follicle
involvement of adnexae, suprapapillary plates, and large round involvement, pleomorphic and confluent nests, cytologic
junctional nests arranged in a nested and dyshesive pattern. atypia, stromal reaction and maturation. Using their scoring
Only 15% of lesions demonstrated pagetoid spread, which was method, atypical features were more commonly found in
usually focal and limited to the center of the nevi.11 breast nevi than in control locations (Figs. 4A–C, 5A–C).13

MELANOCYTIC NEVI OF THE BREAST MELANOCYTIC NEVI OF THE GENITALIA

Melanocytic nevi located on the breast, especially in Melanocytic nevi in the vulvar region, particularly in
young women, may exhibit significant atypia. Anatomically, young, premenopausal women, require special attention
they can occur anywhere on the breast, including on and because of their site-related atypia. Nevi of the vulvar
around the nipple, as well as the surrounding breast or chest region, which includes the areas of the labia minor, clitoris,
areas. On histology, melanocytic nevi of the breast tend to mons pubis, and perineum, demonstrate atypical histologic
show variation in the size and shape of nests and areas of features that are relatively common and consistent with
confluence. In a retrospective review of 39 melanocytic nevi each other, but distinct from nevi of other locations.
from the breast, a nested and dyshesive pattern with bridging of Although vulvar melanoma is uncommon, there is an
nests between rete ridges were observed in one-third of nevi. increased risk of over-diagnosing melanoma based on
Asymmetry was present in 13% and poor demarcation of these atypical features, which can lead to unnecessary
melanocytes at the lateral margins was seen in 8%. Intradermal radical or disfiguring surgeries.6
melanocytes and melanocytic atypia was present in 74%, and Three general architectural patterns have been
featured melanocytes with ample, clear-to-dusky cytoplasm described for genital NOSS. Across almost all lesions,
with small amounts of melanin while maintaining an accept- a prominent feature of nevi of genitalia is marked asymmetry,
able nuclear-to-cytoplasmic ratio. Melanocytic atypia could be junctional proliferation of round-to-oval nests with striking
observed in single melanocytes and in small aggregates within areas of confluence, as well as single melanocytes at different
the papillary dermis, but deep dermal melanocytes demon- levels of the epidermis including the stratum corneum. In
strated maturation. Other findings that can be observed are some cases, the entire basal layer can be replaced by single
stromal findings and the presence of dermal fibroplasia (Figs. melanocytes. In the nested pattern, oval nests are often
4A–C, 5A–C).1,12 oriented either perpendicularly or parallel to the DEJ. In the

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FIGURE 4. Melanocytic nevus of the breast. A, An asymmetric,

well-circumscribed melanocytic lesion. B, Confluence of mela-
nocytic nests, variation in the shape and size of nests, and evi-
dence of melanocyte maturation. C, Large melanocytes in the
epidermis and superficial dermis with ample cytoplasm, loaded FIGURE 5. Melanocytic nevus of the breast. A, A well-
with dusky melanin and surrounding dermal fibroplasia. circumscribed compound nevus with some elongation of rete
ridges and confluence of nests. B, Confluent nests at the DEJ,
with irregular and atypical-appearing nests based on size and
dyshesive nest pattern, nearly contiguous confluent dyshesive shape. C, Large melanocytes with dusky melanin and sur-
nests form a band that separates the epidermis from mature rounding dermal fibroplasia.
dermal melanocytes (Figs. 6A–C). In the crowded pattern, ill-
defined nests and single cells are closely arranged and can
obscure the DEJ.5 fusiform, some of which extended into the altered dermis.
In a review of 56 atypical genital nevi from the vulva, There was also a loss of cellular cohesion and separation of
mons pubis, and perineum, most lesions demonstrated nests nested melanocytes, creating a pseudovesicular appearance.
with variable size and shape, often large, irregular, and Cytologic atypia was severe in some lesions because of cellular

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FIGURE 6. Melanocytic nevus of the

vulva. A, A well-circumscribed com-
pound nevus with nests of variable
size and shape, some large and
irregular. B, Irregular nests extend-
ing into the dermis and single mel-
anocytes within the epidermis. C,
Melanocytes demonstrating cyto-
logic atypia and dense fibrosis in the
papillary dermis.

enlargement with prominent nuclei and nucleoli and chromatin nevi of genitalia (up to 7%) and thus cannot be relied on to
clumping, whereas maintaining appropriate nuclear-to- distinguish atypical nevi from melanoma.6
cytoplasmic ratio. Additionally, the cytoplasm often contained Genital melanocytic nevi arising in a background of
tan-gray dusty intracytoplasmic melanin pigment. All lesions lichen sclerosis pose additional diagnostic challenges. In
demonstrated dermal maturation, with focal upward migration a retrospective cohort study of 10 women with pigmented
of melanocytes observed in 18%.14 Lymphocytic infiltrate can lesions of the vulva or perineum with clinically suspicious
be seen, typically more often in young premenopausal women features, all cases but 1 demonstrated a clinically benign
or, to a lesser extent, in young men.1 Stromal reaction patterns melanocytic nevus superimposed on lichen sclerosis, and 1
in atypical melanocytic genital nevi can be present and show case of lichen sclerosis at the periphery of a vulvar melanoma.
broad areas of dense fibrosis in the papillary and reticular Clinically, worrisome signs included irregular borders, dark
dermis in either a lamellar or concentric pattern.5,15 In contrast pigmentation, growth, or symptoms such as pruritus. Histo-
to many other NOSS, dermal mitoses has been observed in logic analysis of lesions demonstrated a spectrum of lesions,

FIGURE 7. Melanocytic nevus aris-

ing within lichen sclerosis of the
vulva. A, A compound nevus within
dermal sclerosis characteristic of
lichen sclerosis, with some second-
ary background changes consistent
with trauma. B, Irregular melano-
cytic nests mimicking melanoma
with few single melanocytes along
the DEJ. Superficial and mid-dermal
nests seem entrapped in the sclero-
sis. C, Melanocytes are uniform,
with no mitotic figures.

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FIGURE 8. Epitheloid blue nevus of

the genitalia. A, Dense melanocytes
in the upper dermis extending to the
deep dermis. B and C, Polygonal
melanin-laden epithelioid melano-
cytes within the dermis.

including intradermal, junctional, and compound melanocytic melanoma because of the presence of irregular borders, black
nevi with varying degrees of atypia. Pathognomonic dermal pigmentation, and size .10 mm. Histologically, all but 1
sclerosis of lichen sclerosis was observed in all lesions, with lesion demonstrated characteristic features of lichen sclerosis.
extensive involvement of the surrounding skin. In nevi with In 2 of the 5 patients, lichen sclerosis preceded the develop-
a dermal melanocytic component, the superficial and mid- ment of the pigmented lesion, and 2 other patients later went
dermal melanocytic nests were seen entrapped in the on to develop lichen sclerosis in the area of the pigmented
sclerosis. The melanocytes were uniform, slightly large, with lesion. Overall, the lesions were symmetric and had well-
pagetoid features of abundant pale-gray cytoplasm with circumscribed lateral margins. Melanocytic nests demon-
a reactive nucleus and prominent nucleoli. All melanocytic strated variable size and shape with some degree of conflu-
nevi within lichen sclerosis were completely excised with no ence. Additionally, single melanocytes and small melanocytic
recurrence over a mean follow-up of 29 months.16 In a series nests were observed within the epidermis in all cases,
that also included men, clinically suspicious lesions located although dermal mitotic figures within melanocytes were
on the glans penis and vulva were biopsied to exclude notably absent.17 Thus, melanocytic nevi arising within lichen

FIGURE 9. Melanocytic nevus of the

knee. A, Hyperpigmented basal
melanocytes. B, Proliferation of sin-
gle melanocytes along the basal
layer that are hyperchromatic and
demonstrate prominent dendritic
processes.

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FIGURE 10. Melanocytic nevus of

the knee. A, A well-circumscribed,
asymmetric melanocytic lesion. B,
Fibrosis in the papillary dermis with
variation in the size and shape of the
nests. C, Single melanocytes in the
lower epidermis with abundant,
clear, and dusky cytoplasm with
a pseudo-pagetoid appearance.

sclerosis can demonstrate features that mimic melanoma such neoplastic cells of epithelioid blue nevi also do not exhibit
as irregular melanocytic nests and single pagetoid melano- maturation at the base of the lesion (Figs. 8A–C). Additional
cytes along the DEJ on a background of dermal sclerosis distinctive features of epithelioid blue nevi are the tendency
characteristic of lichen sclerosis (Figs. 7A–C). Although to be multiple, and to be seen in association with Carney
mitotic figures are rare, they can occur in these clinically complex, an autosomal dominant condition associated with
benign nevi, which can further pose diagnostic challenges. cutaneous and cardiac myxomas, spotty skin pigmentation,
Awareness and recognition of this group of melanocytic le- endocrine overactivity, and psammomatous melanotic
sions is important to avoid over diagnosis with subsequent schwannomas. However, numerous reports have described
wide excision and possible sentinel lymph node biopsy.14 epithelioid blue nevi on the back without evidence of Carney
In addition to nevi arising within lichen sclerosus in the complex.19
genitalia, epithelioid blue nevi are another type of nevi with
unique histological characteristics that can be encountered on
the genitalia. Epithelioid blue nevi are a cytologic variant of MELANOCYTIC NEVI OF THE LEGS
common blue nevi with distinct histologic findings, initially It is widely recognized that nevi from the leg often
described in patients with Carney complex, and reported most exhibit unusual features. On the knee, characteristic features
often in the literature on the genitalia, although they can also of melanocytic proliferations are the presence of prominent
occur on nonmucosal skin. Epithelioid blue nevi are fibrosis and marked variation in the size and shape of the
characterized by melanin-laden polygonal epithelioid mela- nests. Some of these features are attributed to trauma, because
nocytes within the dermis. In contrast to the usual stromal the knee is an area exposed to constant trauma. Nevi on the
changes that are typically seen in blue nevi, epithelioid blue knee and shin also demonstrate proliferation of single
nevi demonstrate minimal or no dermal fibrosis.18 The melanocytes along the basal layer of the epidermis, some of

FIGURE 11. Melanocytic nevus of

the thigh. A, An intraepidermal Spitz
nevus. B, Pagetoid spread of single
epithelioid melanocytes, demon-
strating prominent dendritic
processes.

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FIGURE 12. Melanocytic nevus

from the thigh. A, epidermal hyper-
plasia, often seen in Spitz nevi. B,
Areas of focal sclerotic collagen in
the dermis. C, Pagetoid spread of
single epithelioid melanocytes and
mitotic figures in the epidermis.

which can be hyperchromatic and demonstrate prominent demonstrated severe architectural disorder, with prominent
dendritic processes (Figs. 9A–B, 10A–C). Site-specific histo- single-cell proliferation and circumscription, asymmetry and
pathologic features have been identified in melanocytic nevi mild cytologic atypia.20 In a comparative study, dysplastic
located on the lower legs, especially in women. In a review of nevi from the lower legs of women were compared with
nevi of the ankle, 11 melanocytic lesions with atypical fea- control groups of dysplastic nevi from the lower legs of
tures were identified. The lesions were typically small (rang- men, the backs of women, and common nevi on the lower
ing between 2 to 4 mm) and lacked lamellar or concentric legs of women. Compared with nevi located on the back,
fibrosis of the papillary dermis. However, more than half lower leg nevi in women were typically smaller in size and

FIGURE 13. Melanocytic nevus of

the sole. A, A well-circumscribed
compound nevus with columns of
pigment in the stratum corneum. B,
Variation in nest size and shape with
some single melanocytes replacing
the basal layer of the epidermis and
fibroplasia in the papillary dermis.
Clefting of intraepidermal nests and
upward migration of melanocytes
can also be seen. C, Dendritic mel-
anocytes at the basal layer of the
epidermis.

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FIGURE 14. Melanocytic nevus of

the sole. A, A well-circumscribed,
symmetric melanocytic lesion. B and
C, Columns of melanocytes in the
stratum corneum, dendritic mela-
nocytes at the basal layer of the
epidermis, and fibroplasia can be
seen in the papillary dermis.

had significantly more pagetoid spread. Other notable differ- mitotic figures could be seen limited to the DEJ, with no
ences were cytologic atypia with the presence of large mela- dermal mitotic figures (Figs. 12A–C).21,22
nocytes, and band-like pigmentation in the dermis underlying
the nevus.2
In a review of 27 patients with a small melanocytic MELANOCYTIC NEVI OF ACRAL SKIN
lesion of the leg, all lesions demonstrated relatively small Acral nevi tend to be more cellular than common nevi,
intraepidermal proliferation of melanocytes with abun- and nevus cells can be arranged in a lentiginous pattern rather
dant, clear cytoplasm, and an epithelioid or pseudo- than in a nested pattern in the epidermis. Nests are often
pagetoid appearance. Melanocytes were arranged as single symmetrical and surrounded by a cleft so they appear well
cells in the lower portion of the epidermis, or less often, as demarcated from adjacent keratinocytes. Up to 85% of benign
small nests located at the DEJ. Apoptotic cells in the acral nevi show bridging between rete.5 Palmo-plantar nevi
epidermis were observed in 44% of cases, and characteristically show upward migration of melanocytes,
superficial perivascular lymphocytic infiltrate was present which in some cases can be very prominent. An acronym that
in 22%.20 has been used to describe palmar and plantar nevi is Melano-
On the thigh, a subset of benign atypical melanocytic cytic Acral Nevus with Intraepithelial Ascent of Cells
nevi demonstrating spitzoid and dysplastic features has been (MANIAC). Pigment in the stratum corneum, or the presence
identified (Figs. 11A–B). In a review of 29 such lesions that of columns of melanin in the stratum corneum is a very help-
were excised, most individuals were women younger than ful clue for the diagnosis of nevi in acral skin. This retention
40 years. All lesions were either compound or junctional of pigment in the stratum corneum may be physiologically
nevi, and 69% were re-excised with no residual tumor iden- related to the upwardly migrating cells because of constant
tified. In all lesions, spitzoid cells and dysplastic changes trauma to acral sites. If present, nevus cells in the dermis
were observed, along with pagetoid spread in 20 of the 29 demonstrate maturation, bland cytology, and lack mitotic
lesions. In rare cases, ganglion-like cells and sclerotic col- activity (Figs. 13A–C, 14A–C).1,6 A band-like inflammatory
lagen could be seen in the dermis. In the compound nevi, infiltrate is occasionally seen in association with fibroplasia or
a superficial compound melanocytic proliferation was focal disappearance of intraepidermal melanocytes.5
observed, and the dermal component did not typically In a review of 158 acral lesions, pagetoid spread was
extend beyond the papillary dermis. In more than half of observed in only 36% of nevi. More than half of lesions
cases, suprabasilar spread was observed, with a predomi- demonstrated bridging retia, 40% had significant inflam-
nantly epithelioid cell population. In the remaining cases, matory infiltrate, and 39% showed fibroplasia.23 In another
there was a predominance of spindle cells or a relatively review of 26 acral nevi, inflammatory infiltrates were
equal proportion of epithelioid and spindled cells. Rare seen even less commonly, and the authors suggested that

FIGURE 15. Melanocytic nevus of

the conjunctivae. A, A symmetric
and well-circumscribed melanocytic
lesion, well demarcated from sur-
rounding stroma. Goblet cells can
be seen in the epidermis. B, Epithe-
lioid melanocytes throughout the
nevus.

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Am J Dermatopathol  Volume 38, Number 12, December 2016 Special Site Nevi

FIGURE 16. Melanocytic nevus of

the back. A, A mostly symmetric but
poorly circumscribed compound
nevus. B, Variation in the size and
shape of nests in the dermis with
a surrounding inflammatory infil-
trate. C, Lamellar fibroplasia in the
superficial dermis.

the presence of a lymphocytic infiltrate should signal for

careful search for other features worrisome for
malignancy.24

MELANOCYTIC NEVI OF THE CONJUNCTIVAE

The most common pigmented lesions of the conjunc-
tivae are melanoses, keratoses, and nevocellular nevi. In rare
cases, blue nevi, spindle cell epithelioid cell nevi, and
melanoma can occur on conjunctiva. Among conjunctival
nevi, the most common pattern is compound, comprising up
to 25% of conjunctival nevi.25 The mucosal epithelium con-
tains goblet cells, which are not seen in the epidermis and can
be mistaken for pagetoid growth. Reassuring findings in con-
junctival pigmented lesions are symmetry, demarcation from
surrounding stroma, and pigment stratification. Mitotic activ-
ity is very rarely seen. In a review of 410 consecutive con-
junctival nevi, blue nevi made up approximately 2.4% of
lesions studied (Figs. 15A–B). Overall, histologic features
of conjunctival nevi are typically considered unusual rather
than atypical because of site-related distinct histologic
features.6

MELANOCYTIC NEVI ON THE BACK IN

ELDERLY PATIENTS
On the back, and particularly in older individuals,
lentigines or architecturally disordered nevi can demonstrate
FIGURE 17. Melanocytic nevus of the back. A, An asymmetric
single-cell junctional melanocytic proliferations that can melanocytic lesion with confluent nests, with single melano-
resemble lentiginous melanoma in situ. Designated as “len- cytes. Elongation of the rete ridges and variation in the size
tiginous dysplastic nevi of elderly,” these lesions occur spo- and shape of melanocytic nests, especially at the DEJ. B, Single
radically and are seen most often in sun-damaged skin on the melanocytes with hyperchromatic nuclei along the basal layer
back or posterior shoulders of elderly men.26 These melano- of the epidermis, resembling lentiginous melanoma in situ.
cytic lesions are broad and asymmetric with areas of Presence of fibroplasia in the papillary dermis.

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Ahn et al Am J Dermatopathol  Volume 38, Number 12, December 2016

confluence mainly in the suprapapillary plates. Hyperchro- 6. Hosler GA, Moresi JM, Barrett TL. Nevi with site-related atypia: a review
matic melanocytic nuclei can be seen, which are also seen in of melanocytic nevi with atypical histologic features based on anatomic
site. J Cutan Pathol. 2008;35:889–898.
lentiginous melanoma in situ. Elongation of the rete ridges is 7. Fernandez M, Raimer SS, Sánchez RL. Dysplastic nevi of the scalp and
a common feature as is the presence of perilesional inflam- forehead in children. Pediatr Dermatol. 2001;18:5–8.
matory infiltrates and pigment incontinence. In addition, 8. Fabrizi G, Pagliarello C, Parente P, et al. Atypical nevi of the scalp in
there is variation in the size and shape of the nests and single adolescents. J Cutan Pathol. 2007;34:365–369.
9. Fisher KR, Maize JC Jr, Maize JC Sr. Histologic features of scalp mel-
melanocytes, especially those localized at the DEJ. Lamellar anocytic nevi. J Am Acad Dermatol. 2013;68:466–472.
fibroplasia and melanophages in the papillary dermis are 10. Rongioletti F, Ball RA, Marcus R, et al. Histopathological features of flexural
other features commonly seen in these lesions (Figs. 16A–C, melanocytic nevi: a study of 40 cases. J Cutan Pathol. 2000;27:215–217.
17A–B).26 11. Arps DP, Fullen DR, Chan MP. Atypical umbilical naevi: histopatholog-
In 1 study, 77 nevi of patients above 60 years were ical analysis of 20 cases. Histopathology. 2015;66:363–369.
12. Nicolau AA, Aşchie M. Morphologic and immunohistochemical features
reviewed; 42 of these nevi (37 men and 5 women) were of breast nevi. Rom J Morphol Embryol. 2013;54:371–375.
located on the back. The histological pattern in 73 of the 77 13. Rongioletti F, Urso C, Batolo D, et al. Melanocytic nevi of the breast:
specimens had features of a Clark’s nevus. The bulk of these a histologic case-control study. J Cutan Pathol. 2004;31:137–140.
lesions represented de novo junctional lentiginous dysplastic 14. Gleason BC, Hirsch MS, Nucci MR, et al. Atypical genital nevi.
A clinicopathologic analysis of 56 cases. Am J Surg Pathol. 2008;32:51–57.
nevi because only 3 of the 73 specimens had nests of mela- 15. Clark WH Jr, Hood AF, Tucker MA, et al. Atypical melanocytic nevi of
nocytes in the dermis.27 the genital type with a discussion of reciprocal parenchymal-stromal
interactions in the biology of neoplasia. Hum Pathol. 1998;29(1 suppl
1):S1–S24.
DISCUSSION 16. Carlson JA, Mu XC, Slominski A, et al. Melanocytic proliferations asso-
ciated with lichen sclerosus. Arch Dermatol. 2002;138:77–87.
Site-specific features are important components to the 17. El Shabrawi-Caelen L, Soyer HP, Schaeppi H, et al. Genital lentigines
histopathologic evaluation of melanocytic lesions. In addition and melanocytic nevi with superimposed lichen sclerosus: a diagnostic
to site-specific regions, some age-specific and sex-specific challenge. J Am Acad Dermatol. 2004;50:690–694.
features are recognized, such as scalp lesions on younger 18. Izquierdo MJ, Pastor MA, Carrasco L, et al. Epithelioid blue naevus
individuals (including children to young adults), or lesions on of the genital mucosa: report of four cases. Br J Dermatol. 2001;145:
496–501.
the back of elderly individuals. Distinguishing between 19. Moreno C, Requena L, Kutzner H, et al. Epithelioid blue nevus: a rare
acceptable atypical features, ie, lesions that will clinically variant of blue nevus not always associated with the Carney complex.
act benign, and lesions that must be removed is critical for the J Cutan Pathol. 2000;27:218–223.
appropriate management of these lesions. Evaluation of 20. Khalifeh I, Taraif S, Reed JA, et al. A subgroup of melanocytic nevi on
the distal lower extremity (ankle) shares features of acral nevi, dysplastic
histopathologic findings together with the clinical history is nevi, and melanoma in situ: a potential misdiagnosis of melanoma in situ.
a key component for the complete evaluation of melanocytic Am J Surg Pathol. 2007;31:1130–1136.
lesions from sites known to produce melanocytic lesions with 21. Donati P, Muscardin L, Cota C, et al. The melanocytic epithelioid cell
atypical features, or special site nevi. nevus of the thigh of woman: a simulator of melanoma. Am J Dermato-
pathol. 2012;34:853–855.
22. Buonaccorsi JN, Lynott J, Plaza JA. Atypical melanocytic lesions of the
thigh with spitzoid and dysplastic features: a clinicopathologic study of
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1. Elder DE. Precursors to melanoma and their mimics: nevi of special sites. 23. Boyd AS, Rapini RP. Acral melanocytic neoplasms: a histologic analysis
Mod Pathol. 2006;19(suppl 2):S4–S20. of 158 lesions. J Am Acad Dermatol. 1994;31(5 pt 1):740–745.
2. Coras B, Landthaler M, Stolz W, et al. Dysplastic melanocytic nevi of the 24. Fallowfield ME, Collina G, Cook MG. Melanocytic lesions of the palm
lower leg: sex- and site-specific histopathology. Am J Dermatopathol. and sole. Histopathology. 1994;24:463–467.
2010;32:599–602. 25. Shields CL, Fasiuddin AF, Mashayekhi A, et al. Conjunctival nevi:
3. Lazova R, Lester B, Glusac EJ, et al. The characteristic histopathologic clinical features and natural course in 410 consecutive patients. Arch
features of nevi on and around the ear. J Cutan Pathol. 2005;32:40–44. Ophthalmol. 2004;122:167–175.
4. Saad AG, Patel S, Mutasim DF. Melanocytic nevi of the auricular region: 26. Wick MR, Patterson JW. Cutaneous melanocytic lesions: selected
histologic characteristics and diagnostic difficulties. Am J Dermatopa- problem areas. Am J Clin Pathol. 2005;124 Suppl:S52–S83.
thol. 2005;27:111–115. 27. Kossard S, Commens C, Symons M, et al. Lentinginous dysplastic naevi
5. Mason AR, Mohr MR, Koch LH, et al. Nevi of special sites. Clin Lab in the elderly: a potential precursor for malignant melanoma. Australas J
Med. 2011;31:229–242. Dermatol. 1991;32:27–37.

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Am J Dermatopathol  Volume 38, Number 12, December 2016 Special Site Nevi

CME EXAM
INSTRUCTIONS FOR OBTAINING AMA PRA CATEGORY 1 CREDITSTM

The American Journal of Dermatopathology includes CME-certified content that is designed to meet the educational
needs of its readers.
An annual total of 12 AMA PRA Category 1 Credits™ is available through the twelve 2016 issues of The American
Journal of Dermatopathology. This activity is available for credit through November 21, 2017.

Accreditation Statement
Lippincott Continuing Medical Education Institute, Inc., is accredited by the Accreditation Council for Continuing
Medical Education to provide continuing medical education for physicians.

Credit Designation Statement

Lippincott Continuing Medical Education Institute, Inc., designates this journal-based CME activity for a maximum of one (1)
AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

To earn CME credit, you must read the article in The American Journal of Dermatopathology and complete the quiz,
answering at least 80 percent of the questions correctly. Mail the Answer Sheet along with a check or money order for the $15
processing fee, to Lippincott CME Institute, Inc., Wolters Kluwer Health, Two Commerce Square, 2001 Market Street, 3rd
Floor, Philadelphia, PA 19103. Only the first entry will be considered for credit, and must be postmarked by the expiration date.
Answer sheets will be graded and certificates will be mailed to each participant within 6 to 8 weeks of participation.

CME EXAMINATION
December 2016
Please mark your answers on the ANSWER SHEET.

At the completion of this CME, the reader will be able to identify the anatomic regions with known site-related atypia,
understand the commonly encountered unusual histopathological features of special site nevi based on anatomic site, including
the ear, scalp, flexures/milk line, breast, genitalia, legs, acral skin, conjunctivae, and back, identify clinical settings in which nevi
in the genitalia demonstrate special features such as melanocytic nevi arising in a background of lichen sclerosus or epithelioid
blue nevi on genitalia and identify unique features within subsets of benign atypical melanocytic nevi on the legs.

1. The most important feature in the differential diagnosis between melanocytic nevi and melanomas from the genital area is:
A. Asymmetry
B. Presence of prominent dendritic melanocytes in the epidermis
C. Fibrosis
D. Melanocytes in the upper levels of the epidermis
E. Inflammatory infiltrates.

2. A 12-year-old boy is referred to dermatology for evaluation of an irregularly shaped melanocytic nevus on the scalp. On
histopathological examination, the most expected feature is:
A. Patchy inflammatory infiltrates
B. Asymmetry
C. Numerous mitotic figures
D. Irregular or dyshesive nesting pattern
E. Lentiginous proliferation.

3. Which of the following can be a prominent feature in melanocytic nevi located on acral skin?
A. Poor lateral circumscription
B. Cytologic atypia
C. Dyshesive nesting pattern
D. Spitzoid cells with dysplastic features
E. Upward migration of melanocytes.

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Ahn et al Am J Dermatopathol  Volume 38, Number 12, December 2016

4. Which of the following is true regarding genital melanocytic nevi arising in lichen sclerosis?
A. They are often asymmetric with poorly circumscribed lateral margins
B. Dermal mitotic figures are present and numerous
C. Pathognomonic dermal sclerosis is usually absent or subtle
D. Melanocytic nests can be seen entrapped in dermal sclerosis
E. Melanocytes demonstrate marked cytologic atypia with abnormal nuclear-to-cytoplasmic ratio.

5. Which of the following is a common feature on melanocytic nevi on the thigh?

A. Dermal fibroplasia
B. Dendritic melanocytes
C. Inflammatory infiltrates
D. Large size
E. Epithelioid (spitzoid) melanocytes in the epidermis.

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